U.S. patent application number 15/017802 was filed with the patent office on 2016-08-04 for novel tricyclic compounds.
This patent application is currently assigned to AbbVie Inc.. The applicant listed for this patent is AbbVie Inc.. Invention is credited to Maria A. Argiriadi, David J. Calderwood, Anna M. Ericsson, Bryan A. Fiamengo, Kristine E. Frank, Michael M. Friedman, Dawn M. George, Eric R. Goedken, Nathan S. Josephsohn, Biqin C. Li, Michael J. Morytko, Kent D. Stewart, Jeffrey W. Voss, Grier A. Wallace, Lu Wang, Neil Wishart, Kevin R. Woller.
Application Number | 20160222020 15/017802 |
Document ID | / |
Family ID | 44070404 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160222020 |
Kind Code |
A1 |
Wishart; Neil ; et
al. |
August 4, 2016 |
NOVEL TRICYCLIC COMPOUNDS
Abstract
The invention provides compounds of Formula (I) and Formula (II)
##STR00001## pharmaceutically acceptable salts, pro-drugs,
biologically active metabolites, stereoisomers and isomers thereof
wherein the variable are defined herein. The compounds of the
invention are useful for treating immunological and oncological
conditions.
Inventors: |
Wishart; Neil; (Jefferson,
MA) ; Argiriadi; Maria A.; (Wayland, MA) ;
Calderwood; David J.; (Framingham, MA) ; Ericsson;
Anna M.; (Shrewsbury, MA) ; Fiamengo; Bryan A.;
(Worcester, MA) ; Frank; Kristine E.; (Grayslake,
IL) ; Friedman; Michael M.; (Brookline, MA) ;
George; Dawn M.; (Charlton, MA) ; Goedken; Eric
R.; (Worcester, MA) ; Josephsohn; Nathan S.;
(Cambridge, MA) ; Li; Biqin C.; (Southborough,
MA) ; Morytko; Michael J.; (Framingham, MA) ;
Stewart; Kent D.; (Gurnee, IL) ; Voss; Jeffrey
W.; (Holden, MA) ; Wallace; Grier A.;
(Sterling, MA) ; Wang; Lu; (Northborough, MA)
; Woller; Kevin R.; (Antioch, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
AbbVie Inc.
North Chicago
IL
|
Family ID: |
44070404 |
Appl. No.: |
15/017802 |
Filed: |
February 8, 2016 |
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13761501 |
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15017802 |
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12958115 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/08 20180101; A61P
11/00 20180101; A61P 19/02 20180101; A61P 25/00 20180101; A61P
39/00 20180101; A61P 1/04 20180101; A61P 5/02 20180101; A61P 9/10
20180101; A61P 25/16 20180101; A61P 37/00 20180101; A61P 39/04
20180101; A61P 31/12 20180101; A61P 11/06 20180101; A61P 17/14
20180101; A61P 7/06 20180101; A61P 31/16 20180101; A61P 37/02
20180101; A61P 7/04 20180101; A61P 31/20 20180101; A61P 7/00
20180101; A61P 15/08 20180101; A61P 5/10 20180101; A61P 31/10
20180101; A61P 17/02 20180101; A61P 21/04 20180101; A61P 31/14
20180101; A61P 33/02 20180101; A61P 7/10 20180101; A61P 27/02
20180101; A61P 3/10 20180101; A61P 13/12 20180101; C07D 513/14
20130101; A61P 35/02 20180101; A61P 9/00 20180101; C07D 487/14
20130101; A61P 5/38 20180101; A61P 29/00 20180101; A61P 1/16
20180101; C07D 498/14 20130101; A61K 31/437 20130101; A61K 45/06
20130101; A61P 27/06 20180101; A61P 11/16 20180101; A61P 43/00
20180101; A61P 7/08 20180101; A61P 17/00 20180101; A61P 31/18
20180101; A61P 9/04 20180101; A61K 31/4985 20130101; A61P 13/02
20180101; A61P 19/00 20180101; A61P 37/08 20180101; C07D 471/14
20130101; A61P 7/02 20180101; A61P 17/06 20180101; A61P 25/22
20180101; A61P 5/14 20180101; A61P 5/06 20180101; A61P 9/12
20180101; A61P 25/28 20180101; A61P 35/00 20180101; A61P 35/04
20180101; A61P 25/14 20180101; A61P 33/14 20180101; A61P 31/04
20180101; A61P 37/06 20180101 |
International
Class: |
C07D 487/14 20060101
C07D487/14; A61K 31/437 20060101 A61K031/437; C07D 471/14 20060101
C07D471/14; A61K 31/4985 20060101 A61K031/4985; A61K 45/06 20060101
A61K045/06 |
Claims
1. A compound of Formula (Ib) ##STR01376## pharmaceutically
acceptable salts, pro-drugs, biologically active metabolites,
stereoisomers and isomers thereof wherein R.sup.1, R.sup.2 and
R.sup.5 are each independently hydrogen, deuterium,
--N(R.sup.a)(R.sup.b), halogen, --OR.sup.a, --SR.sup.a,
--S(O)R.sup.a, --S(O).sub.2R.sup.a, --NO.sub.2, --C(O)OR.sup.a,
--CN, --C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)(R.sup.b),
--C(O)R.sup.a, --C(OH)R.sup.aR.sup.b,
--N(R.sup.a)S(O).sub.2--R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--CF.sub.3, --OCF.sub.3, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, or optionally substituted
(C.sub.6-C.sub.10)aryl; wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or optionally
substituted (C.sub.1-C.sub.10)heteroaryl linked through a nitrogen;
R.sup.3 is hydrogen, an optionally substituted bridged
(C.sub.5-C.sub.12)cycloalkyl, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclyl, optionally substituted
(C.sub.1-C.sub.8)alkyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.3-C.sub.8)cycloalkenyl, optionally substituted
(C.sub.6-C.sub.10)aryl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.2-C.sub.10)heterocyclyl; or R.sup.3 is -A-D-E-G, wherein: A
is a bond, --C(O)--, optionally substituted
(C.sub.1-C.sub.6)alkylene, optionally substituted
(C.sub.2-C.sub.6)alkenylene, optionally substituted
(C.sub.2-C.sub.6)alkynylene, optionally substituted
(C.sub.3-C.sub.12)cycloalkylene, optionally substituted
(C.sub.2-C.sub.6)heterocyclylene, --C(O)N(R.sup.a)--R.sup.e--,
--N(R.sup.a)C(O)--R.sup.e--, --O--R.sup.e--,
--N(R.sup.a)--R.sup.e--, --S--R.sup.e--, --S(O).sub.2--R.sup.e--,
--S(O)R.sup.e--, --C(O--R.sup.a)(R.sup.b)--R.sup.e--,
--S(O).sub.2N(R.sup.a)--R.sup.e--,
--N(R.sup.a)S(O).sub.2--R.sup.e-- or
--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--; D is an optionally
substituted (C.sub.1-C.sub.8)alkylene, optionally substituted
bridged (C.sub.5-C.sub.12)cycloalkylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkylene, optionally substituted bridged
(C.sub.5-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.6-C.sub.10)arylene, optionally substituted
(C.sub.1-C.sub.10)heteroarylene, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclylene or an optionally substituted
(C.sub.2-C.sub.10)heterocyclylene; E is a bond, --R.sup.e--,
--R.sup.e--C(.dbd.NCN)--R.sup.e--, --R.sup.e--C(O)--R.sup.e--,
--R.sup.e--C(O)C(O)--R.sup.e--, --R.sup.e--C(O)O--R.sup.e--,
--R.sup.e--C(O)C(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)--C(O)C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--, .dbd.N--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.eC(O)N(R.sup.a)R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)OR.sup.e--, --R.sup.e--OC(O)--R.sup.e,
--R.sup.e--OC(O)--O--R.sup.e,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--,
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--, or
--R.sup.e--N(R.sup.a)S(O).sub.2N(R.sup.a)--R.sup.e--; or E is
##STR01377## where in all cases, E is linked to either a carbon or
a nitrogen atom in D; G is hydrogen, deuterium,
--N(R.sup.a)(R.sup.b), halogen, --OR.sup.a, --SR.sup.a,
--S(O)R.sup.a, --S(O).sub.2R.sup.a, --NO.sub.2, --C(O)OR.sup.a,
--CN, --C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)OR.sup.b, --OC(O)N(R.sup.a),
--N(R.sup.a)C(O)N(R.sup.b).sub.2, --C(O--R.sup.a)(R.sup.b).sub.2,
--C(O)R.sup.a, --CF.sub.3, --OCF.sub.3,
--N(R.sup.a)S(O).sub.2R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--S(O).sub.2N(R.sup.a)C(O)R.sup.b, an optionally substituted
--(C.sub.1-C.sub.6)alkyl, an optionally substituted
--(C.sub.2-C.sub.6)alkenyl, an optionally substituted
--(C.sub.2-C.sub.6)alkynyl, an optionally substituted
--(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
--(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
--(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
--(C.sub.6-C.sub.10)aryl; wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; R.sup.6 is a hydrogen, halogen, deuterium, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, C(O)OH, C(O)OCH.sub.3, CN,
an optionally substituted bridged (C.sub.5-C.sub.12)cycloalkyl
group, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclyl group, optionally substituted
(C.sub.1-C.sub.8)alkyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.3-C.sub.8)cycloalkenyl, optionally substituted
(C.sub.6-C.sub.10)aryl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.2-C.sub.10)heterocyclyl or -J-L-M-Q; wherein: J is a bond,
--C(O)--, optionally substituted (C.sub.1-C.sub.6)alkylene,
optionally substituted (C.sub.2-C.sub.6)alkenylene, optionally
substituted (C.sub.2-C.sub.6)alkynylene, optionally substituted
(C.sub.3-C.sub.12)cycloalkylene, optionally substituted
(C.sub.2-C.sub.6)heterocyclylene, --C(O)N(R.sup.a)--R.sup.e--,
--N(R.sup.a)C(O)--R.sup.e--, --O--R.sup.e--,
--N(R.sup.a)--R.sup.e--, --S--R.sup.e--, --S(O).sub.2--R.sup.e--,
--S(O)R.sup.e--, --C(O--R.sup.a)(R.sup.b)--R.sup.e--,
--S(O).sub.2N(R.sup.a)--R.sup.e--,
--N(R.sup.a)S(O).sub.2--R.sup.e-- or
--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--; L is a bond, an optionally
substituted (C.sub.1-C.sub.8)alkylene, optionally substituted
bridged (C.sub.5-C.sub.12)cycloalkylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkylene, optionally substituted bridged
(C.sub.5-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.6-C.sub.10)arylene, optionally substituted
(C.sub.1-C.sub.10)heteroarylene, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclylene or an optionally substituted
(C.sub.2-C.sub.10)heterocyclylene; M is a bond, --R.sup.e--,
--R.sup.e--C(O)--R.sup.e--, --R.sup.e--C(O)C(O)--R.sup.e--,
--R.sup.e--C(O)O--R.sup.e--, --R.sup.e--OC(O)--R.sup.e,
--R.sup.e--C(O)C(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)--C(O)C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--C(O)N(R.sup.a)R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)OR.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--, or
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--; or M is ##STR01378##
where in all cases, M is linked to either a carbon or a nitrogen
atom in L; Q is hydrogen, deuterium, --N(R.sup.a)(R.sup.b),
halogen, --OR.sup.a, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a, --NO.sub.2, --C(O)OR.sup.a, --CN,
--C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)R.sup.b,
--N(R.sup.a)C(O)OR.sup.b, --N(R.sup.a)C(O)N(R.sup.b).sub.2,
--C(O--R.sup.a)(R.sup.b).sub.2, --C(O)R.sup.a, --CF.sub.3,
--OCF.sub.3, --N(R.sup.a)S(O).sub.2R.sup.b,
--S(O).sub.2N(R.sup.a)(R.sup.b), --S(O).sub.2N(R.sup.a)C(O)R.sup.b,
an optionally substituted (C.sub.1-C.sub.6)alkyl, an optionally
substituted (C.sub.2-C.sub.6)alkenyl, an optionally substituted
(C.sub.2-C.sub.6)alkynyl, an optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; R.sup.a and R.sup.b are each independently hydrogen,
deuterium, CN, an optionally substituted (C.sub.1-C.sub.10)alkyl,
an optionally substituted (C.sub.2-C.sub.10)alkenyl, an optionally
substituted (C.sub.2-C.sub.10)alkynyl, an optionally substituted
(C.sub.1-C.sub.10)alkyl-O--(C.sub.1-C.sub.10)alkyl, an optionally
substituted (C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10)heterocyclyl, an optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.10)cycloalkyl, an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.6-C.sub.10)aryl, an optionally
substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heteroaryl, or an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heterocyclyl; and
R.sup.e for each occurrence is independently a bond, an optionally
substituted (C.sub.1-C.sub.10)alkylene, an optionally substituted
(C.sub.2-C.sub.10)alkenylene, an optionally substituted
(C.sub.2-C.sub.10)alkynylene, an optionally substituted
--(C.sub.1-C.sub.10)alkylene-O--(C.sub.1-C.sub.10)alkylene group,
an optionally substituted (C.sub.3-C.sub.10)cycloalkylene, an
optionally substituted (C.sub.6-C.sub.10)arylene, an optionally
substituted (C.sub.1-C.sub.10)heteroarylene, or an optionally
substituted (C.sub.1-C.sub.10)heterocyclylene.
2. The compound of claim 1 wherein R.sup.3 is -A-D-E-G and A is a
bond, optionally substituted (C.sub.1-C.sub.6)alkylene, optionally
substituted (C.sub.3-C.sub.12)cycloalkylene or optionally
substituted (C.sub.2-C.sub.6)heterocyclylene.
3. The compound of claim 1 wherein R.sup.3 is -A-D-E-G and D is an
optionally substituted (C.sub.1-C.sub.8)alkylene, optionally
substituted (C.sub.3-C.sub.10)cycloalkylene, optionally substituted
bridged (C.sub.5-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.3-C.sub.10)bridged heterocyclylene or optionally substituted
(C.sub.2-C.sub.10)heterocyclylene.
4. The compound of claim 3 wherein D is optionally substituted
(C.sub.1-C.sub.6)alkylene, optionally substituted
(C.sub.3-C.sub.6)cycloalkylene, optionally substituted
bicyclo[2.2.2]octany-1-yl, optionally substituted
2,5-diazabicyclo[2.2.1]heptane, optionally substituted
2,6-diazabicyclo[3.2.1]octane, optionally substituted
octahydropyrrolo[3,4-c]pyrrole, optionally substituted
octahydropyrrolo[3,2-b]pyridine, optionally substituted
1,4-diazepane, optionally substituted cubane, optionally
substituted 1,4-dioxane-spiro[4.4]nonane, optionally substituted
2,5-diazaspiro[3.5]nonane, optionally substituted piperidine,
optionally substituted piperazine, optionally substituted
pyrrolidine, optionally substituted tetrahydrofuran or optionally
substituted tetrahydropyran.
5. The compound of claim 1 wherein R.sup.3 is -A-D-E-G and E is a
bond, --R.sup.e--, --R.sup.e--C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--, .dbd.N--R.sup.e--.
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)O--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.eC(O)N(R.sup.a)R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--,
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2N(R.sup.a)--R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e, --R.sup.e--C(O)O--R.sup.e,
--R.sup.e--OC(O)--R.sup.e; or ##STR01379## wherein R.sup.a for each
occurrence is independently hydrogen, CN, an optionally substituted
(C.sub.1-C.sub.10)alkyl or an optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.10)cycloalkyl; and
R.sup.e for each occurrence is independently a bond, an optionally
substituted (C.sub.1-C.sub.10)alkylene, an optionally substituted
(C.sub.3-C.sub.10)cycloalkylene, an optionally substituted
(C.sub.6-C.sub.10)arylene, an optionally substituted
(C.sub.1-C.sub.10)heteroarylene, or an optionally substituted
(C.sub.1-C.sub.10)heterocyclylene.
6. The compound of claim 1 wherein R.sup.3 is -A-D-E-G and G is
hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen, --OR.sup.a,
--S(O).sub.2R.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --CF.sub.3,
--S(O).sub.2N(R.sup.a)(R.sup.b), an optionally substituted
--(C.sub.1-C.sub.6)alkyl, an optionally substituted
--(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
--(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
--(C.sub.1-C.sub.10) heterocyclyl, or an optionally substituted
--(C.sub.6-C.sub.10)aryl; wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; R.sup.a is independently hydrogen, CN, an optionally
substituted (C.sub.1-C.sub.10)alkyl, an optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, or an optionally substituted
(C.sub.6-C.sub.10)aryl.
7. The compound of claim 6 wherein G is hydrogen, deuterium,
--N(R.sup.a)(R.sup.b), halogen, --OR.sup.a, --S(O).sub.2R.sup.a,
--CN, --C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)R.sup.b,
--CF.sub.3, --S(O).sub.2N(R.sup.a)(R.sup.b), an optionally
substituted --(C.sub.1-C.sub.4)alkyl, an optionally substituted
--(C.sub.3-C.sub.6)cycloalkyl, optionally substituted azepanyl,
optionally substituted azetidinyl, optionally substituted
benzo[d]isoxazolyl, optionally substituted 4,5-dihydroisoxazolyl,
optionally substituted isothiazolidinyl, optionally substituted
isothiazolyl, optionally substituted isoxazolyl, optionally
substituted morpholinyl, optionally substituted oxadiazolyl,
optionally substituted oxazolyl, optionally substituted oxetanyl,
optionally substitute phenyl, optionally substituted piperazinyl,
optionally substituted piperidinyl, optionally substituted
pyrazinyl, optionally substituted pyrazolyl, optionally substituted
pyridazinyl, optionally substituted pyridinyl, optionally
substituted pyrimidinyl, optionally substituted pyrrolidinyl,
optionally substituted pyrrolyl, optionally substituted
tetrahydrofuranyl, optionally substituted tetrahydropyranyl,
optionally substituted tetrahydrothiopyranyl, optionally
substituted thienyl, optionally substituted thiomorpholinyl,
optionally substituted 1,1-dioxo-thiomorpholinyl, optionally
substituted thiazolyl or optionally substituted triazolyl.
8. The compound of claim 1 wherein R.sup.3 is hydrogen, optionally
substituted (C.sub.1-C.sub.8)alkyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, or optionally substituted
(C.sub.2-C.sub.10)heterocyclyl.
9. The compound of claim 1 wherein R.sup.6 is -J-L-M-Q and J is a
bond, optionally substituted (C.sub.1-C.sub.6)alkylene, or an
optionally substituted (C.sub.2-C.sub.6)alkenylene.
10. The compound of claim 1 wherein R.sup.6 is -J-L-M-Q and L is a
bond, or an optionally substituted (C.sub.1-C.sub.8)alkylene.
11. The compound of claim 1 wherein R.sup.6 is -J-L-M-Q and M is a
bond, --R.sup.e--, --R.sup.e--C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--C(O)N(R.sup.a)R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--, or
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--; where in all cases, M
is linked to either a carbon or a nitrogen atom in L.
12. The compound of claim 1 wherein R.sup.6 is J-L-M-Q and Q is
hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen, --OR.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a, --NO.sub.2,
--C(O)OR.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)C(O)OR.sup.b,
--N(R.sup.a)C(O)N(R.sup.b).sub.2, --C(O--R.sup.a)(R.sup.b).sub.2,
--C(O)R.sup.a, --CF.sub.3, --OCF.sub.3,
--N(R.sup.a)S(O).sub.2R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--S(O).sub.2N(R.sup.a)C(O)R.sup.b, an optionally substituted
(C.sub.1-C.sub.6)alkyl, an optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
(C.sub.6-C.sub.10)aryl; wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; R.sup.a and R.sup.b are each independently hydrogen,
deuterium, an optionally substituted (C.sub.1-C.sub.6)alkyl, an
optionally substituted (C.sub.2-C.sub.10)alkenyl, an optionally
substituted (C.sub.3-C.sub.6)cycloalkyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, or an optionally substituted
(C.sub.1-C.sub.10)heterocyclyl.
13. The compound of claim 1 wherein the compound is
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(2,4-difluorophenyl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(4-(trifluoromethyl)phenyl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyridin-3-yl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(3-(trifluoromethyl)phenyl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrazin-2-yl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrimidin-5-yl)methanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-cyclopropylethanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(phenyl)methanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-cyclobutylethanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-3-cyclobutylpropan-1-one;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1H-pyrazol-4-yl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1H-pyrazol-3-yl)methanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)propan-1-one;
N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-
-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
ne-1-carbonyl)cyclopropanecarbonitrile;
3-43S,4S)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidi-
n-1-yl)-3-oxopropanenitrile;
3-((3R,4R)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperid-
in-1-yl)-3-oxopropanenitrile;
N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;
N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1-methyl-1H-pyrazol-4-yl)methanone;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyridin-4-yl)methanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-(3-methylisoxazol-5-yl)ethanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-(2,4-difluorophenyl)ethanone;
6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)pyridazine-3-carbonitrile;
5-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)pyrazine-2-carbonitrile;
2-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)thiazole-5-carbonitrile;
6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)nicotinonitrile;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrrolidin-1-yl)methanone;
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
ne-1-carbonyl)azetidine-3-carbonitrile;
(cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-N,N,4-trimethylpipe-
ridine-1-carboxamide;
1-((cis)-1-(cyclopropylsulfonyl)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a-
]pyrrolo[2,3-e]pyrazine;
(cis)-N-(cyanomethyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-m-
ethylpiperidine-1-carboxamide;
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(isoxazol-5-yl)methanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3,3,3-trifluoropropan-1-one;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-hydroxy-3-methylbutan-1-one;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-methoxyethanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-methoxypropan-1-one;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)pent-4-yn-1-one;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(4-chlorophenyl)ethanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(3-chlorophenyl)ethanone;
4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
dine-1-carbonyl)benzonitrile;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-(3-chloroisoxazol-5-yl)propan-1-one;
3-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-2-oxoethyl)benzonitrile;
4-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-2-oxoethyl)benzonitrile;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(1H-pyrrol-2-yl)ethanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(pyrazin-2-yl)ethanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(pyrimidin-2-yl)ethanone;
5-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile;
N-(4-(3-allyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)cyclopropanesulfonamide;
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopr-
opanesulfonamide;
N-(4-(3-propyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]-
octan-1-yl)cyclopropanesulfonamide;
2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)thiazole-5-carbonitrile;
N-(4-(3-(2,3-dihydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
dine-1-carbonyl)pyrrolidine-3-carbonitrile;
(3R,4R)--N-(4-(cyanomethyl)phenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyra-
zin-1-yl)-4-methylpiperidine-1-carboxamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(morpholino)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(4-methylpiperazin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(piperidin-1-yl)methanone;
(3R,4R)--N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
-1-yl)-4-methylpiperidine-1-carboxamide;
(3R,4R)--N-(3-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)-4-methylpiperidine-1-carboxamide;
(R)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpi-
peridine-1-carbonyl)pyrrolidine-2-carbonitrile;
(S)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpi-
peridine-1-carbonyl)pyrrolidine-2-carbonitrile;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluoroazetidin-1-yl)methanone;
2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)benzo[d]oxazole;
N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyr-
rolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(azetidin-1-yl)methanone;
(3R,4R)--N-(4-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)-4-methylpiperidine-1-carboxamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-3-fluoropyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluoropyrrolidin-1-yl)methanone;
1-((3R,4R)-4-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo-
[1,5-a]pyrrolo[2,3-e]pyrazine;
(R)--N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cy-
clopropanesulfonamide;
(S)--N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cy-
clopropanesulfonamide;
3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluorome-
thyl)piperidin-1-yl)-3-oxopropanenitrile;
3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluorome-
thyl)piperidin-1-yl)-3-oxopropanenitrile;
N-(3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-3-oxopropyl)acetamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrofuran-2-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrofuran-3-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-methoxycyclohexyl)methanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-hydroxypropan-1-one;
1-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazine;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-4,4,4-trifluorobutan-1-one;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-3-yl)methanone;
4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-4-oxobutanenitrile;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-2-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-methylpyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-fluoroazetidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((S)-3-fluoropyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-methylpyrrolidin-1-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-morpholin-3-yl)methanone;
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-(methylsulfonyl)propan-1-one;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1,4-dioxan-2-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrothiophen-3-yl-1,1-dioxide)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluorocyclobutyl)methanone;
N-((1S,3R,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)aniline;
N-((1R,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)aniline;
3-bromo-1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoroazetidin-1-yl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoropyrrolidin-1-yl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-d-
ifluoropiperidin-1-yl)methanone;
(R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)azetidine-3-carbonitrile;
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrim-
idin-2-yl)piperidine-1-carboxamide;
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrid-
in-2-yl)piperidine-1-carboxamide;
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrim-
idin-4-yl)piperidine-1-carboxamide;
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyraz-
in-2-yl)piperidine-1-carboxamide;
1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
N-((3S,5R)-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-5-methylpyrrol-
idin-3-yl)cyclopropanesulfonamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1-methylpyrrolidin-3-yl)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1-methylpiperidin-4-yl)methanone; (3R,4R)-phenyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate;
((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-y-
l)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone;
(R)-1-(1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo[1,5-a]pyrrol-
o[2,3-e]pyrazine;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(pyrro-
lidin-1-yl)methanone;
3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic
acid;
(S)-1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carbonyl)pyrrolidine-3-carbonitrile; (R)-cyclopentyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate;
(E)-N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylp-
iperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide;
4-((1R,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylamin-
o)benzonitrile;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluorocyclobutyl)methanone;
5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cycl-
opentylamino)pyrazine-2-carbonitrile;
N-((1S,3S,4R)-3-(3-bromo-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-e-
thylcyclopentyl)cyclopropane sulfonamide;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(4,4-difluorocyclohexyl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-1-yl)(3,3--
dimethylpyrrolidin-1-yl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoropiperidin-1-yl)methanone;
(R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)piperidine-4-carbonitrile;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(thiom-
orpholino-1, 1-dioxide)methanone;
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(azepan-1-yl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-d-
imethylpiperidin-1-yl)methanone;
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4-chl-
oropiperidin-1-yl)methanone;
5-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thylamino)pyrazine-2-carbonitrile;
5-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thylamino)pyrazine-2-carbonitrile;
1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)piperidine-3-carbonitrile;
N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-yl)cyclopropanesulfonamide;
1-(3,3-difluorocyclobutyl)-6H-imidazo-[1,5-a]pyrrolo[2,3-e]pyrazine;
N-(1-(6H-imidazol[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclop-
ropanesulfonamide;
(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic
acid;
N-((1S,3S,4R)-3-(3-chloro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1--
yl)-4-ethylcyclopentyl)cyclopropanesulfonamide;
4-(((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclobutoxy)meth-
yl)benzonitrile;
5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-ylamino)pyrazine-2-carbonitrile;
N-((3S,5R)-5-ethyl-1-(6H-imidazol[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrol-
idin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide;
4-((1R,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cycl-
opentyloxy)benzonitrile;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-1-methylcyclopropane-1-sulfonamide;
1-((1S,4S)-5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazabicyclo[2.2.1]hepta-
n-2-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3-difluoroazetidine-1-sulfonamide;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3-difluoropyrrolidine-1-sulfonamide;
(S)--N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-meth-
ylcyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide;
N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)cyclopropanesulfonamide;
N-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)-3,3,3-trifluoropropane-1-sulfonamide;
N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)-3,3,3-trifluoropropane-1-sulfonamide;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-1-ethylcyclopropane-1-sulfonamide;
1-((3aR,6aS)-5-(3,3,3-trifluoropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrr-
ol-2(1H)-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
1-(6-fluoro-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imida-
zo[1,5-a]pyrrolo[2,3-e]pyrazine;
4-([4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cubanyl]methoxy)benzon-
itrile;
N-((3R,4S)-4-methyl-1-(3,3,3-trifluoropropylsulfonyl)piperidin-3-y-
l)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-amine;
1-(2-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-5-yl)-6H-im-
idazo[1,5-a]pyrrolo[2,3-e]pyrazine;
1-((3aS,7aR)-4-(3,3,3-trifluoropropylsulfonyl)octahydro-1H-pyrrolo[3,2-b]-
pyridin-1-yl)-6H-imidazo[1, 5-a]pyrrolo[2,3-e]pyrazine;
1-(7-methyl-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imida-
zo[1,5-a]pyrrolo[2,3-e]pyrazine;
1-(5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-2-yl)-6H-im-
idazo[1,5-a]pyrrolo[2,3-e]pyrazine;
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-3-yl)-3,3,3-t-
rifluoropropane-1-sulfonamide;
1-((1R,5S)-2-(3,3,3-trifluoropropylsulfonyl)-2,6-diazabicyclo[3.2.1]octan-
-6-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]-
pyrazine;
N-(4-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)p-
henyl)methanesulfonamide;
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3-chlorobenzenesulfonamide; Cyclopropanesulfonic acid
[(1S,3R,4R)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-amide; Cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-amide;
1-((1S,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8-
b-tetraaza-as-indacene-3-carboxylic acid;
1-((1R,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8-
b-tetraaza-as-indacene-3-carboxylic acid; Cyclopropanesulfonic acid
[(1S,3R,4S)-3-methyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-
-1-yl)-cyclopentyl]-amide;
1-[(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indace-
n-1-yl)-cyclopentyl]-2-methyl-propan-2-ol; Cyclopropanesulfonic
acid
[(1S,3R,4S)-3-ethyl-4-[3-(2,2,2-trifluoro-ethyl)-6H-2,5,6,8b-tetraaza-as--
indacen-1-yl]-cyclopentyl]-amide;
[(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-acetic acid ethyl ester or
1-[(1S,2R,4R)-2-Ethyl-4-(3-methoxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-cyc-
lopentyl]-3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacene.
14-24. (canceled)
25. A pharmaceutical composition comprising a compound of Formula
(Ib) as defined in claim 1 ##STR01380## a pharmaceutically
acceptable carrier and excipient and a second therapeutic agent
selected from the group consisting of cytokine suppressive
anti-inflammatory drugs, antibodies to or antagonists of other
human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5,
IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons,
EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154,
HUMIRA.TM., REMICADE.TM., SIMPONI.TM. (golimumab), CIMZIA.TM.,
ACTEMRA.TM., CDP 571, soluble p55 or p75 TNF receptors, ENBREL.TM.,
Lenercept, TNF.alpha. converting enzyme inhibitors, IL-1
inhibitors, Interleukin 11, IL-18 antagonists, IL-12 antagonists,
IL-12 antibodies, soluble IL-12 receptors, IL-12 binding proteins,
non-depleting anti-CD4 inhibitors FK506, rapamycin, mycophenolate
mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids,
phosphodiesterase inhibitors, adensosine agonists, antithrombotic
agents, complement inhibitors, adrenergic agents, IL-1.beta.
converting enzyme inhibitors, T-cell signalling kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines,
derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib,
hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen,
valdecoxib, sulfasalazine, meloxicam, acetate, gold sodium
thiomalate, aspirin, triamcinolone acetonide, propoxyphene
napsylate/apap, folate, nabumetone, diclofenac, piroxicam,
etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone
bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,
tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,
acetaminophen, alendronate sodium, morphine sulfate, lidocaine
hydrochloride, indomethacin, glucosamine sulf/chondroitin,
amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen,
olopatadine HCl misoprostol, naproxen sodium, omeprazole,
cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP,
anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, S1P1
agonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071,
Mesopram, methotrexate, leflunomide, corticosteroids, budenoside,
dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine,
IL-1.beta. converting enzyme inhibitors, IL-1ra, T cell signaling
inhibitors, tyrosine kinase inhibitors, 6-mercaptopurines, IL-11,
mesalamine, prednisone, azathioprine, mercaptopurine, infliximab,
methylprednisolone sodium succinate, diphenoxylate/atrop sulfate,
loperamide hydrochloride, omeprazole, folate,
ciprofloxacin/dextrose-water, hydrocodone, bitartrate/apap,
tetracycline hydrochloride, fluocinonide, metronidazole,
thimerosal/boric acid, cholestyramine/sucrose, ciprofloxacin
hydrochloride, hyoscyamine sulfate, meperidine hydrochloride,
midazolam hydrochloride, oxycodone HCl/acetaminophen, promethazine
hydrochloride, sodium phosphate, sulfamethoxazole/trimethoprim,
polycarbophil, propoxyphene napsylate, hydrocortisone,
multivitamins, balsalazide disodium, codeine phosphate/apap,
colesevelam HCl, cyanocobalamin, folic acid, levofloxacin,
natalizumab, interferon-gamma, methylprednisolone, azathioprine,
cyclophosphamide, cyclosporine, methotrexate, 4-aminopyridine,
tizanidine, interferon-.beta.1a, AVONEX.RTM., interferon-.beta.1b,
BETASERON.RTM., interferon .alpha.-n3, interferon-.alpha.,
interferon .beta.1A-IF, Peginterferon .alpha. 2b, Copolymer 1,
COPAXONE.RTM., hyperbaric oxygen, intravenous immunoglobulin,
cladribine, cyclosporine, FK506, mycophenolate mofetil,
leflunomide, NSAIDs, corticosteroids, prednisolone,
phosphodiesterase inhibitors, adensosine agonists, antithrombotic
agents, complement inhibitors, adrenergic agents, antiinflammatory
cytokines, interferon-.beta., IFN.beta.1a, IFN.beta.1b, copaxone,
corticosteroids, caspase inhibitors, inhibitors of caspase-1,
antibodies to CD40 ligand and CD80, alemtuzumab, dronabinol,
daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine,
glatiramer acetate, natalizumab, sinnabidol, .alpha.-immunokine
NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists,
BBR-2778, calagualine, CPI-1189, liposome encapsulated
mitoxantrone, THC.CBD, cannabinoid agonists, MBP-8298, mesopram,
MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone
allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide,
TGF-beta2, tiplimotide, VLA-4 antagonists, interferon gamma
antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen,
meloxicam, indomethacin, diclofenac, methotrexate, azathioprine,
minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine,
naproxen, leflunomide, methylprednisolone acetate, indomethacin,
hydroxychloroquine sulfate, prednisone, sulindac, betamethasone
diprop augmented, infliximab, methotrexate, folate, triamcinolone
acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac
sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone,
tolmetin sodium, calcipotriene, cyclosporine, diclofenac
sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium
thiomalate, hydrocodone bitartrate/apap, risedronate sodium,
sulfadiazine, thioguanine, valdecoxib, alefacept, and efalizumab,
diclofenac, naproxen, ibuprofen, piroxicam, indomethacin, COX2
inhibitors, rofecoxib, valdecoxib, hydroxychloroquine, steroids,
prednisolone, budenoside, dexamethasone, cytotoxics, azathioprine,
cyclophosphamide, mycophenolate mofetil, inhibitors of PDE4, purine
synthesis inhibitor, sulfasalazine, 5-aminosalicylic acid,
olsalazine, Imuran.RTM., CTLA-4-IgG, anti-B7 family antibodies,
anti-PD-1 family antibodies, anti-cytokine antibodies,
fonotolizumab, anti-IFNg antibody, anti-receptor receptor
antibodies, anti-IL-6 receptor antibody, antibodies to B-cell
surface molecules, LJP 394, Rituximab, anti-CD20 antibody and
lymphostat-B.
26. A method of treating, ameliorating, or preventing a disease or
disorder associated with abnormal or deregulated kinase activity in
an individual in need thereof, comprising administering a
therapeutically effective amount of a compound of claim 1, wherein
the disease or disorder is rheumatoid arthritis (RA), juvenile
rheumatoid arthritis (JRA), Crohn's disease, psoriasis, psoriatic
arthritis, ankylosing spondylitis associated lung disease, or
ulcerative colitis.
27. The method of claim 26, wherein the disease or disorder is
rheumatoid arthritis (RA).
28. The method of claim 26, wherein the disease or disorder is
juvenile rheumatoid arthritis (JRA).
29. The method of claim 26, wherein the disease or disorder is
Crohn's disease.
30. The method of claim 26, wherein the disease or disorder is
psoriasis.
31. The method of claim 26, wherein the disease or disorder is
psoriatic arthritis.
32. method use of claim 26, wherein the disease or disorder is
ankylosing spondylitis associated lung disease.
33. The method of claim 26, wherein the disease or disorder is
ulcerative colitis.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. Utility
application Ser. No. 12/481,028 filed on Jun. 9, 2009, which claims
priority to U.S. Provisional application Ser. No. 61/131,599 filed
on Jun. 10, 2008, U.S. Provisional application Ser. No. 61/131,602
filed on Jun. 10, 2008, U.S. Provisional Application Ser. No.
61/190,159 filed on Aug. 26, 2008 and U.S. Provisional application
Ser. No. 61/201,064 filed Dec. 5, 2008, the contents of which are
incorporated herein. This application also claims priority to U.S.
Provisional Application Ser. No. 61/265,363 filed on Dec. 1, 2009,
and U.S. Provisional application Ser. No. 61/364,116 filed Jul. 14,
2010, the content of which are incorporated herein.
BACKGROUND OF THE INVENTION
[0002] The invention provides a novel class of compounds,
pharmaceutical compositions comprising such compounds and methods
of using such compounds to treat or prevent diseases or disorders
associated with abnormal or deregulated kinase activity,
particularly diseases or disorders that involve abnormal activation
of the Jak1, Jak2, Jak3, Tyk2, KDR, Flt-3, CDK2, CDK4, TANK, Trk,
FAK, Abl, Bcr-Abl, cMet, b-RAF, FGFR3, c-kit, PDGR-R, Syk, BTK,
CSF1R, PKC kinases or Aurora kinases.
[0003] The protein kinases represent a large family of proteins
that play a central role in the regulation of a wide variety of
cellular processes and maintenance of cellular function. A partial,
non-limiting, list of these kinases include: non-receptor tyrosine
kinases such as the Janus kinase family (Jak1, Jsk2, Jak3 and
Tyk2): the fusion kinases, such as BCR-Abl, focal adhesion kinase
(FAK), Fes, Lck and Syk; receptor tyrosine kinases such as
platelet-derived growth factor receptor kinase (PDGF-R), the
receptor kinase for stem cell factor, c-kit, the hepatocyte growth
factor receptor, c-Met, and the fibroblast growth factor receptor.
FGFR3, and serine/threonine kinases such as b-RAF,
mitogen-activated protein kinases (e.g., MKJ6) and SAPK2.beta..
Aberrant kinase activity has been observed in many disease states
including benign and malignant proliferative disorders as well as
diseases resulting from inappropriate activation of the immune and
nervous systems. The novel compounds of this invention inhibit the
activity of one or more protein kinases and are, therefore,
expected to be useful in the treatment of kinase-mediated
diseases.
SUMMARY OF THE INVENTION
[0004] In a first embodiment the invention provides a compound of
Formula (I)
##STR00002##
pharmaceutically acceptable salts, pro-drugs, biologically active
metabolites, stereoisomers and isomers thereof wherein
[0005] T is N, U is N, X is CR.sup.3 and Y is N; or
[0006] T is CR.sup.6, U is N, X is CR.sup.3 and Y is N; or
[0007] T is N, U is CR.sup.4, X is CR.sup.3 and Y is N; or
[0008] T is CR.sup.6, U is CR.sup.4, X is CR.sup.3 and Y is N;
or
[0009] T is CR.sup.6, U is N, X is NR.sup.3 and Y is C; or
[0010] T is O, U is N, X is CR.sup.3 and Y is C; or
[0011] T is NR.sup.6, U is N, X is CR.sup.3 and Y is C; or
[0012] T is CR.sup.6, U is CR.sup.4, X is NR.sup.3 and Y is C;
or
[0013] T is S, U is N, X is CR.sup.3 and Y is C; or
[0014] T is N, U is CR.sup.4, X is NR.sup.3 and Y is C; or
[0015] T is N, U is N, X is NR.sup.3 and Y is C;
[0016] R.sup.1, R.sup.2 and R.sup.5 are each independently
hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen, --OR.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a, --NO.sub.2,
--C(O)OR.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)(R.sup.b), --C(O)R.sup.a, --C(OH)R.sup.aR.sup.b,
--N(R.sup.a)S(O).sub.2--R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--CF.sub.3, --OCF.sub.3, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, or optionally substituted
(C.sub.6-C.sub.10)aryl; [0017] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may fond a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or optionally
substituted (C.sub.1-C.sub.10)heteroaryl linked through a
nitrogen;
[0018] R.sup.3 is hydrogen, an optionally substituted bridged
(C.sub.5-C.sub.12)cycloalkyl, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclyl, optionally substituted
(C.sub.1-C.sub.8)alkyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.3-C.sub.8)cycloalkenyl, optionally substituted
(C.sub.6-C.sub.10)aryl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.2-C.sub.10)heterocyclyl; or
[0019] R.sup.3 is -A-D-E-G, wherein:
[0020] A is a bond, --C(O)--, optionally substituted
(C.sub.1-C.sub.6)alkylene, optionally substituted
(C.sub.2-C.sub.6)alkenylene, optionally substituted
(C.sub.2-C.sub.6)alkynylene, optionally substituted
(C.sub.3-C.sub.12)cycloalkylene, optionally substituted
(C.sub.2-C.sub.6)heterocyclylene, --C(O)N(R.sup.a)--R.sup.e--,
--N(R.sup.a)C(O)--R.sup.e--, --O--R.sup.e--,
--N(R.sup.a)--R.sup.e--, --S--R.sup.e--, --S(O).sub.2--R.sup.e--,
--S(O)R.sup.e--, --C(O--R.sup.a)(R.sup.b)--R.sup.e--,
--S(O).sub.2N(R.sup.a)--R.sup.e--,
--N(R.sup.a)S(O).sub.2--R.sup.e-- or
--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--;
[0021] D is an optionally substituted (C.sub.1-C.sub.8)alkylene,
optionally substituted bridged (C.sub.5-C.sub.12)cycloalkylene,
optionally substituted (C.sub.3-C.sub.10)cycloalkylene, optionally
substituted bridged (C.sub.5-C.sub.10)cycloalkenylene, optionally
substituted (C.sub.3-C.sub.10)cycloalkenylene, optionally
substituted (C.sub.6-C.sub.10)arylene, optionally substituted
(C.sub.1-C.sub.10)heteroarylene, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclylene or an optionally substituted
(C.sub.2-C.sub.10)heterocyclylene;
[0022] E is a bond, --R.sup.e--, --R.sup.e--C(.dbd.NCN)--R.sup.e--,
--R.sup.e--C(O)--R.sup.e--, --R.sup.e--C(O)C(O)--R.sup.e--,
--R.sup.e--C(O)O--R.sup.e--,
--R.sup.e--C(O)C(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)--C(O)C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--, .dbd.N--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.eC(O)N(R.sup.a)R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)OR.sup.e--, --R.sup.e--OC(O)--R.sup.e,
--R.sup.e--OC(O)--O--R.sup.e,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--,
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--, or
--R.sup.e--N(R.sup.a)S(O).sub.2N(R.sup.a)--R.sup.e--; or
[0023] E is
##STR00003##
[0024] where in all cases, E is linked to either a carbon or a
nitrogen atom in D;
[0025] G is hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen,
--OR.sup.a, --SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--NO.sub.2, --C(O)OR.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)C(O)OR.sup.b,
--OC(O)N(R.sup.a), --N(R.sup.a)C(O)N(R.sup.b).sub.2,
--C(O--R.sup.a)(R.sup.b).sub.2, --C(O)R.sup.a, --CF.sub.3,
--OCF.sub.3, --N(R.sup.a)S(O).sub.2R.sup.b,
--S(O).sub.2N(R.sup.a)(R.sup.b), --S(O).sub.2N(R.sup.a)C(O)R.sup.b,
an optionally substituted --(C.sub.1-C.sub.6)alkyl, an optionally
substituted --(C.sub.2-C.sub.6)alkenyl, an optionally substituted
--(C.sub.2-C.sub.6)alkynyl, an optionally substituted
--(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
--(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
--(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
--(C.sub.6-C.sub.10)aryl; [0026] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen;
[0027] R.sup.4 and R.sup.6 are each independently a hydrogen,
halogen, deuterium, CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, C(O)OH, C(O)OCH.sub.3, CN, an optionally
substituted bridged (C.sub.5-C.sub.12)cycloalkyl group, optionally
substituted bridged (C.sub.2-C.sub.10)heterocyclyl group,
optionally substituted (C.sub.1-C.sub.8)alkyl, optionally
substituted (C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.3-C.sub.8)cycloalkenyl, optionally substituted
(C.sub.6-C.sub.10)aryl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.2-C.sub.10)heterocyclyl or -J-L-M-Q;
[0028] wherein:
[0029] J is a bond, --C(O)--, optionally substituted
(C.sub.1-C.sub.6)alkylene, optionally substituted
(C.sub.2-C.sub.6)alkenylene, optionally substituted
(C.sub.2-C.sub.6)alkynylene, optionally substituted
(C.sub.3-C.sub.12)cycloalkylene, optionally substituted
(C.sub.2-C.sub.6)heterocyclylene, --C(O)N(R.sup.a)--R.sup.e--,
--N(R.sup.a)C(O)--R.sup.e--, --O--R.sup.e--,
--N(R.sup.a)--R.sup.e--, --S--R.sup.e--, --S(O).sub.2--R.sup.e--,
--S(O)R.sup.e--, --C(O--R.sup.a)(R.sup.b)--R.sup.e--,
--S(O).sub.2N(R.sup.a)--R.sup.e--,
--N(R.sup.a)S(O).sub.2--R.sup.e-- or
--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--;
[0030] L is a bond, an optionally substituted
(C.sub.1-C.sub.8)alkylene, optionally substituted bridged
(C.sub.5-C.sub.12)cycloalkylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkylene, optionally substituted bridged
(C.sub.5-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.6-C.sub.10)arylene, optionally substituted
(C.sub.1-C.sub.10)heteroarylene, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclylene or an optionally substituted
(C.sub.2-C.sub.10)heterocyclylene;
[0031] M is a bond, --R.sup.e--, --R.sup.e--C(O)--R.sup.e--,
--R.sup.e--C(O)C(O)--R.sup.e--, --R.sup.e--C(O)O--R.sup.e--,
--R.sup.e--OC(O)--R.sup.e,
--R.sup.e--C(O)C(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)--C(O)C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--C(O)N(R.sup.a)R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)OR.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--, or
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--; or
[0032] M is
##STR00004##
where in all cases, M is linked to either a carbon or a nitrogen
atom in L;
[0033] Q is hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen,
--OR.sup.a, --SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--NO.sub.2, --C(O)OR.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)C(O)OR.sup.b,
--N(R.sup.a)C(O)N(R.sup.b).sub.2, --C(O--R.sup.a)(R.sup.b).sub.2,
--C(O)R.sup.a, --CF.sub.3, --OCF.sub.3,
--N(R.sup.a)S(O).sub.2R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--S(O).sub.2N(R.sup.a)C(O)R.sup.b, an optionally substituted
(C.sub.1-C.sub.6)alkyl, an optionally substituted
(C.sub.2-C.sub.6)alkenyl, an optionally substituted
(C.sub.2-C.sub.6)alkynyl, an optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
(C.sub.6-C.sub.10)aryl; [0034] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; [0035] R.sup.a and R.sup.b are each independently
hydrogen, deuterium, CN, an optionally substituted
(C.sub.1-C.sub.10)alkyl, an optionally substituted
(C.sub.2-C.sub.10)alkenyl, an optionally substituted
(C.sub.2-C.sub.10)alkynyl, an optionally substituted
(C.sub.1-C.sub.10)alkyl-O--(C.sub.1-C.sub.10)alkyl, an optionally
substituted (C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10)heterocyclyl, an optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.10)cycloalkyl, an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.6-C.sub.10)aryl, an optionally
substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heteroaryl, or an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heterocyclyl; and
[0036] R.sup.e for each occurrence is independently a bond, an
optionally substituted (C.sub.1-C.sub.10)alkylene, an optionally
substituted (C.sub.2-C.sub.10)alkenylene, an optionally substituted
(C.sub.2-C.sub.10)alkynylene, an optionally substituted
--(C.sub.1-C.sub.10)alkylene-O--(C.sub.1-C.sub.10)alkylene group,
an optionally substituted (C.sub.3-C.sub.10)cycloalkylene, an
optionally substituted (C.sub.6-C.sub.10)arylene, an optionally
substituted (C.sub.1-C.sub.10)heteroarylene, or an optionally
substituted (C.sub.1-C.sub.10)heterocyclylene;
[0037] provided that when T is N, U is CR.sup.4, X is NR.sup.3 and
Y is C, R.sup.4 is not OH;
[0038] provided that when T is N, U is CR.sup.4, X is NR.sup.3 and
Y is C, R.sup.1 is H;
[0039] provided that when the compound is
##STR00005##
[0040] R.sup.3 is defined as above and R.sup.6 is not linked to the
pyrazole ring by a nitrogen or oxygen atom; and
[0041] provided that when the compound is
##STR00006##
[0042] when R.sup.3 is H, CH.sub.3 or C(O)OH then R.sup.4 is not H,
--C(O)OCH.sub.2CH.sub.3, --C(O)NH-optionally substituted phenyl,
--NHC(O)-optionally substituted phenyl or --S(O).sub.2-phenyl.
[0043] In a second embodiment the invention provides a compound
according to the first embodiment wherein R.sup.3 is -A-D-E-G and A
is a bond, optionally substituted (C.sub.1-C.sub.6)alkylene,
optionally substituted (C.sub.3-C.sub.12)cycloalkylene or
optionally substituted (C.sub.2-C.sub.6)heterocyclylene.
[0044] In a third embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.3
is -A-D-E-G and D is an optionally substituted
(C.sub.1-C.sub.8)alkylene, optionally substituted
(C.sub.3-C.sub.10)cycloalkylene, optionally substituted bridged
(C.sub.5-C.sub.10)cycloalkenylene, optionally substituted
(C.sub.3-C.sub.10)bridged heterocyclylene or optionally substituted
(C.sub.2-C.sub.10)heterocyclylene.
[0045] In a fourth embodiment the invention provides a compound
according to the any of the foregoing embodiments 3 wherein D is
optionally substituted (C.sub.1-C.sub.6)alkylene, optionally
substituted (C.sub.3-C.sub.6)cycloalkylene, optionally substituted
bicyclo[2.2.2]octany-1-yl, optionally substituted
2,5-diazabicyclo[2.2.1]heptane, optionally substituted
2,6-diazabicyclo[3.2.1]octane, optionally substituted
octahydropyrrolo[3,4-c]pyrrole, optionally substituted
octahydropyrrolo[3,2-b]pyridine, optionally substituted
1,4-diazepane, optionally substituted cubane, optionally
substituted 1,4-dioxane-spiro[4.4]nonane, optionally substituted
2,5-diazaspiro[3.5]nonane, optionally substituted piperidine,
optionally substituted piperazine, optionally substituted
pyrrolidine, optionally substituted tetrahydrofuran or optionally
substituted tetrahydropyran.
[0046] In a fifth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.3
is -A-D-E-G and E is a bond, --R.sup.e--,
--R.sup.e--C(O)--R.sup.e--, --R.sup.e--O--R.sup.e--,
--R.sup.e--S(O).sub.2--R.sup.e--, --R.sup.e--N(R.sup.a)--R.sup.e--,
.dbd.N--R.sup.e--. --R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)O--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.eC(O)N(R.sup.a)R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--,
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2N(R.sup.a)--R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e, --R.sup.e--C(O)O--R.sup.e,
--R.sup.e--OC(O)--R.sup.e; or
##STR00007##
wherein
[0047] R.sup.a for each occurrence is independently hydrogen, CN,
an optionally substituted (C.sub.1-C.sub.10)alkyl or an optionally
substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.10)cycloalkyl; and
[0048] R.sup.e for each occurrence is independently a bond, an
optionally substituted (C.sub.1-C.sub.10)alkylene, an optionally
substituted (C.sub.3-C.sub.10)cycloalkylene, an optionally
substituted (C.sub.6-C.sub.10)arylene, an optionally substituted
(C.sub.1-C.sub.10)heteroarylene, or an optionally substituted
(C.sub.1-C.sub.10)heterocyclylene.
[0049] In a sixth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.3
is -A-D-E-G and G is hydrogen, deuterium, --N(R.sup.a)(R.sup.b),
halogen, --OR.sup.a, --S(O).sub.2R.sup.a, --CN,
--C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)R.sup.b, --CF.sub.3,
--S(O).sub.2N(R.sup.a)(R.sup.b), an optionally substituted
--(C.sub.1-C.sub.6)alkyl, an optionally substituted
--(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
--(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
--(C.sub.1-C.sub.10) heterocyclyl, or an optionally substituted
--(C.sub.6-C.sub.10)aryl; [0050] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen; [0051] R.sup.a is independently hydrogen, CN, an
optionally substituted (C.sub.1-C.sub.10)alkyl, an optionally
substituted (C.sub.3-C.sub.10)cycloalkyl, or an optionally
substituted (C.sub.6-C.sub.10)aryl.
[0052] In a seventh embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein G is
hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen, --OR.sup.a,
--S(O).sub.2R.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --CF.sub.3,
--S(O).sub.2N(R.sup.a)(R.sup.b), an optionally substituted
--(C.sub.1-C.sub.4)alkyl, an optionally substituted
--(C.sub.3-C.sub.6)cycloalkyl, optionally substituted azepanyl,
optionally substituted azetidinyl, optionally substituted
benzo[d]isoxazolyl, optionally substituted 4,5-dihydroisoxazolyl,
optionally substituted isothiazolidinyl, optionally substituted
isothiazolyl, optionally substituted isoxazolyl, optionally
substituted morpholinyl, optionally substituted oxadiazolyl,
optionally substituted oxazolyl, optionally substituted oxetanyl,
optionally substitute phenyl, optionally substituted piperazinyl,
optionally substituted piperidinyl, optionally substituted
pyrazinyl, optionally substituted pyrazolyl, optionally substituted
pyridazinyl, optionally substituted pyridinyl, optionally
substituted pyrimidinyl, optionally substituted pyrrolidinyl,
optionally substituted pyrrolyl, optionally substituted
tetrahydrofuranyl, optionally substituted tetrahydropyranyl,
optionally substituted tetrahydrothiopyranyl, optionally
substituted thienyl, optionally substituted thiomorpholinyl,
optionally substituted 1,1-dioxo-thiomorpholinyl, optionally
substituted thiazolyl or optionally substituted triazolyl.
[0053] In eighth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.3
is hydrogen, optionally substituted (C.sub.1-C.sub.8)alkyl,
optionally substituted (C.sub.3-C.sub.10)cycloalkyl, or optionally
substituted (C.sub.2-C.sub.10)heterocyclyl.
[0054] In a ninth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.6
is J-L-M-Q and J is a bond, optionally substituted
(C.sub.1-C.sub.6)alkylene, or an optionally substituted
(C.sub.2-C.sub.6)alkenylene.
[0055] In a tenth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.6
is J-L-M-Q and L is a bond, or an optionally substituted
(C.sub.1-C.sub.8)alkylene.
[0056] In an eleventh embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.6
is J-L-M-Q and M is a bond, --R.sup.e--,
--R.sup.e--C(O)--R.sup.e--, --R.sup.e--O--R.sup.e--,
--R.sup.e--S(O).sub.2--R.sup.e--, --R.sup.e--S(O)--R.sup.e--,
--R.sup.e--S--R.sup.e--, --R.sup.e--N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.e--C(O)N(R.sup.a)R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--, or
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--; where in all cases, M
is linked to either a carbon or a nitrogen atom in L.
[0057] In a twelfth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein R.sup.6
is J-L-M-Q and Q is hydrogen, deuterium, --N(R.sup.a)(R.sup.b),
halogen, --OR.sup.a, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a, --NO.sub.2, --C(O)OR.sup.a, --CN,
--C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)
C(O)OR.sup.b, --N(R.sup.a)C(O)N(R.sup.b).sub.2,
--C(O--R.sup.a)(R.sup.b).sub.2, --C(O)R.sup.a, --CF.sub.3,
--OCF.sub.3, --N(R.sup.a)S(O).sub.2R.sup.b,
--S(O).sub.2N(R.sup.a)(R.sup.b), --S(O).sub.2N(R.sup.a)
C(O)R.sup.b, an optionally substituted (C.sub.1-C.sub.6)alkyl, an
optionally substituted (C.sub.3-C.sub.10)cycloalkyl, an optionally
substituted (C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
(C.sub.6-C.sub.10)aryl; [0058] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen;
[0059] R.sup.a and R.sup.b are each independently hydrogen,
deuterium, an optionally substituted (C.sub.1-C.sub.6)alkyl, an
optionally substituted (C.sub.2-C.sub.10)alkenyl, an optionally
substituted (C.sub.3-C.sub.6)cycloalkyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, or an optionally substituted
(C.sub.1-C.sub.10)heterocyclyl.
[0060] In a thirteenth embodiment the invention provides a compound
according to the any of the foregoing embodiments wherein T is N, U
is N, X is CR.sup.3 and Y is N and forms a compound of Formula
(Ia)
##STR00008##
[0061] In a fourteenth embodiment the invention provides a compound
according to the thirteenth embodiment wherein in the compound is
[0062]
N-(1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobu-
tyl)cyclopropanesulfonamide; [0063]
N-(1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobu-
tyl)-2-cyanoacetamide; [0064]
(S)-1-((1-(cyclopropylsulfonyl)pyrrolidin-3-yl)methyl)-6H-pyrrolo[2,3-e][-
1,2,4]triazolo[4,3-a]pyrazine; [0065]
N-((1S,3R,4R)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0066]
N-((1R,3S,4S)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0067]
N-((1R,3R,4S)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0068]
N-((1S,3S,4R)-4-ethyl-3-fluoro-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0069]
(1S,3R)-1-[3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-isothi-
azolidin-2-yl-1,1-dioxide]cyclopentane; [0070]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-N-methylcyclopropanesulfonamide; [0071]
1-((1S,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine; [0072]
(S)-5-(3-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyr-
rolidin-1-yl)pyrazine-2-carbonitrile; [0073]
N-(cyclopropylmethyl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]tr-
iazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;
[0074]
N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-2-(4-cyanophenyl)acetamide; [0075]
N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)cyclopropanecarboxamide; [0076]
N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-2-cyclopropylacetamide; [0077]
N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-cyanobenzamide; [0078]
N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methanesulfonamide; [0079]
1-((1S,2S,4R)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-py-
rrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0080]
1-((1R,2R,4S)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-py-
rrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0081]
1-((1R,2S,4R)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-py-
rrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0082]
1-((1S,2R,4S)-4-((azetidin-1-ylsulfonyl)methyl)-2-ethylcyclopentyl)-6H-py-
rrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0083]
N-((1S,3R,4S)-3-ethyl-4-(7-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0084]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-N-(2-hydroxyethyl)cyclopropanesulfonamide; [0085]
5-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntylamino)pyrazine-2-carbonitrile [0086]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-methylaniline; [0087]
1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazol-
o[4,3-a]pyrazine; [0088]
1-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-1H-pyrrole-3-carbonitrile; [0089]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)aniline; [0090]
N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclob-
utyl)methyl)-2-cyanoacetamide; [0091]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-fluoroaniline; [0092]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-chloroaniline; [0093]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-3,4-dichloroaniline; [0094]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-methoxyaniline; [0095]
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)-4-methoxy-N-(4-methoxyphenyl)aniline; [0096]
3-((3R,4R)-4-methyl-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)piperidin-1-yl)-3-oxopropanenitrile; [0097]
1-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)-1H-pyrazole-4-sulfonamide; [0098]
3-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntylamino)benzonitrile; [0099]
N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)aniline; [0100]
4-((1S,2R,4S)-4-(benzyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazine; [0101]
4-((1R,2S,4R)-4-(benzyloxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazine; [0102]
5-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)isoxazole-4-sulfonamide; [0103]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)cyclobutanesulfonamide; [0104]
6-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)nicotinonitrile; [0105]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)pyrrolidine-1-carboxamide; [0106]
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)benzonitrile; [0107]
4-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)benzonitrile; [0108]
4-methyl-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)aniline; [0109]
4-chloro-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)aniline; [0110]
3-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentylamino)benzonitrile; [0111]
4-fluoro-N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)aniline; [0112]
N-((1S,3S,4R)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)aniline; [0113]
N-((1R,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)aniline; [0114]
5-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentylamino)pyrazine-2-carbonitrile; [0115]
6-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentylamino)nicotinonitrile; [0116]
6-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)nicotinonitrile; [0117]
6-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)nicotinonitrile; [0118]
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine; [0119]
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine; [0120]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0121]
5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentylamino)pyrazine-2-carbonitrile; [0122]
6-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentylamino)nicotinonitrile; [0123]
2-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentylamino)thiazole-5-carbonitrile; [0124]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)azetidine-1-sulfonamide; [0125]
N-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)cyclopropanesulfonamide; [0126]
N-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)cyclopropanesulfonamide; [0127]
3-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)azetidine-1-sulfonamide; [0128]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-3,3-difluoroazetidine-1-sulfonamide; [0129]
5-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0130]
5-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0131]
6-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)nicotinonitrile; [0132]
6-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)nicotinonitrile; [0133]
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentylamino)thiazole-5-carbonitrile; [0134]
5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0135]
5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0136]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)pyrrolidine-1-sulfonamide; [0137]
5-(((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entyl)methylamino)pyrazine-2-carbonitrile; [0138]
(S)--N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide;
[0139]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-3,3-difluoropyrrolidine-1-sulfonamide; [0140]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-4,4-difluoropiperidine-1-sulfonamide; [0141]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-1-methylcyclopropane-1-sulfonamide; [0142]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)-1-methylcyclopropane-1-sulfonamide; [0143]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)azetidine-1-sulfonamide; [0144]
6-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentylamino)nicotinonitrile; [0145]
N-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)cyclopentanesulfonamide; [0146]
5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methoxy)pyrazine-2-carboxamide; [0147]
((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)cyclopentyl)methanol; [0148]
((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)cyclopentyl)methanol; [0149]
5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile; [0150]
5-(((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile; [0151]
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)-3,3-difluoroazetidine-1-sulfonamide; [0152]
N-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)aniline; [0153]
1-((1S,2R,4R)-2-ethyl-4-(5-(trifluoromethyl)pyridin-2-yloxy)cyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0154]
1-((1R,2S,4S)-2-ethyl-4-(5-(trifluoromethyl)pyridin-2-yloxy)cyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0155]
5-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0156]
5-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)pyrazine-2-carbonitrile; [0157]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2,2,2-trifluoroethanesulfonamide; [0158]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-4-methylpiperazine-1-sulfonamide; [0159]
4-((1S,3S,4R)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)benzonitrile; [0160]
4-((1R,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)benzonitrile; [0161]
3-(((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)methyl)benzonitrile; [0162]
3-(((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)methyl)benzonitrile; [0163]
4-(((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)methyl)benzonitrile; [0164]
4-(((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyloxy)methyl)benzonitrile; [0165]
1-ethyl-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)cyclopropane-1-sulfonamide; [0166]
N-(((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methyl)cyclopropanesulfonamide; [0167]
N-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methyl)cyclopropanesulfonamide; [0168]
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)-2-fluorobenzonitrile; [0169]
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)-3-fluorobenzonitrile; [0170]
3-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)benzonitrile; [0171]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-morpholinoethanesulfonamide; [0172]
1-butyl-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)cyclopropane-1-sulfonamide; [0173]
2-(3,3-difluoropyrrolidin-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;
[0174]
2-(((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entyl)methylamino)isonicotinonitrile; [0175]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-methylpropane-2-sulfonamide; [0176]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-(1H-1,2,4-triazol-1-yl)ethanesulfonamide; [0177]
2-(4,4-difluoropiperidin-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e]-
[1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;
[0178]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)ethanesulfonamide; [0179]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-(1H-1,2,3-triazol-1-yl)ethanesulfonamide; [0180]
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentanol; [0181]
1-((1S,2R,4R)-2-ethyl-4-(3,3,3-trifluoropropoxy)cyclopentyl)-6H-pyrrolo[2-
,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0182]
N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0183]
(1S,3R,4S)--N-(2-(3,3-difluoropyrrolidin-1-ylsulfonyl)ethyl)-3-ethyl-4-(6-
H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine;
[0184]
N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0185]
N-((1S,3R,4S)-3-ethyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lopentyl)cyclopropanesulfonamide;
[0186]
N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazin-1-yl)cyclopentyl)-N-(hydroxymethyl)cyclopropanesulfonamide;
[0187]
N-((1S,3S,4R)-3-(8-cyano-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide; [0188]
1-((1S,2R,4S)-4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine; [0189]
1-((1S,2R,4S)-4-(cyclopropylmethoxy)-2-methylcyclopentyl)-6H-pyrrolo[2,3--
e][1,2,4]triazolo[4,3-a]pyrazine; [0190]
1-((1S,2R,4S)-2-ethyl-4-(2,2,2-trifluoro
ethylsulfonyl)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
e; [0191]
1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl-
)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0192]
1-((1S,2R,4S)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6-
H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0193]
1-((1R,2R,4S)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6-
H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0194]
1-((1S,2R,4R)-4-(cyclopropylmethoxy)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine; [0195]
1-((1S,2R,4R)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0196]
2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide;
[0197]
1-((1S,2R,4S)-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0198]
1-((1R,2R,4S)-2-ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)cyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0199]
1-((1S,2R,4R)-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)cyclopentyl)-6-
H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0200]
1-((1S,2R,4S)-2-ethyl-4-(2-methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazine; [0201]
1-((1R,2R,4S)-2-ethyl-4-(2-methoxyethoxy)cyclopentyl)-6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazine; [0202]
1-((1S,2R,4R)-2-ethyl-4-isopropoxycyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]tr-
iazolo[4,3-a]pyrazine; [0203]
N-((3R,5R)-1-ethyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)pyrrolidin-3-yl)cyclopropanesulfonamide; [0204]
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone; [0205]
1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine; [0206]
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-N-(2,2,2-trifluoroethyl)cyclopentanamine; [0207]
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone O-cyclopropylmethyl oxime; [0208]
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone O-2-(methylsulfonyl)ethyl oxime; [0209]
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone O-cyclobutylmethyl oxime; [0210]
1-((1S,2R,4R)-4-(4,4-dimethylcyclohexyloxy)-2-ethylcyclopentyl)-6H-pyrrol-
o[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0211]
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-methoxyethanesulfonamide; [0212]
N-((3R,5R)-1-acetyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)pyrrolidin-3-yl)cyclopropanesulfonamide; [0213]
1-((3S,4R)-1-(cyclopropylmethylsulfonyl)-4-ethylpyrrolidin-3-yl)-6H-pyrro-
lo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0214]
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetic acid; [0215]
N-cyclopropyl-2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4-
,3-a]pyrazin-1-yl)cyclopentyl)acetamide; [0216]
3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyc-
lopentanone 0-tetrahydro-2H-pyran-4-yl oxime; [0217]
1-((1S,2R,4S)-4-(3,3-difluoroazetidin-1-yl)-2-ethylcyclopentyl)-6H-pyrrol-
o[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0218]
1-((1S,2R,4S)-4-(3,3-difluoropyrrolidin-1-yl)-2-ethylcyclopentyl)-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine; [0219] Dimethyl-carbamic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0220]
{3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)-cyclopentylamino]-oxetan-3-yl}-acetonitrile; [0221]
Cyclopropanesulfonic acid
cyanomethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)-cyclopentyl]-amide; [0222]
1-[(3R,4S)-4-Ethyl-1-(2-morpholin-4-yl-ethyl)-pyrrolidin-3-yl]-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0223]
Cyclopropanesulfonic acid
[(3R,5R)-1-(2,2-difluoro-ethyl)-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide; [0224]
1-[(3R,4S)-4-Ethyl-1-(3,3,3-trifluoro-propane-1-sulfonyl)-pyrrolidin-3-yl-
]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0225]
3-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-propionitrile; [0226]
1-[(3R,4S)-4-Ethyl-1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl]-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0227]
2-Cyclopropyl-1-[(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3--
a]pyrazin-1-yl)-pyrrolidin-1-yl]-ethanone; [0228]
1-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-pyrrolidin-1-yl]-2-(tetrahydro-pyran-4-yl)-ethanone; [0229]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid cyclopropylmethyl-amide; [0230]
Cyclopropanesulfonic acid
[(3R,5R)-1-ethyl-5-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)--
pyrrolidin-3-yl]-methyl-amide; [0231]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide;
[0232] 3,3-Difluoro-cyclobutanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0233] Cyclopropanesulfonic acid
[(1S,4S)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-amide; [0234] Cyclopropanesulfonic acid
[(1R,4R)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-amide; [0235]
1-[(1S,2R,4R)-4-(4,4-Difluoro-cyclohexyloxy)-2-ethyl-cyclopentyl]-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0236]
1-[(1R,2R,4R)-4-(4,4-Difluoro-cyclohexyloxy)-2-ethyl-cyclopentyl]-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0237]
6-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-pyrrolidin-1-yl]-nicotinonitrile; [0238]
1-[(3R,4S)-1-(3,3-Difluoro-cyclobutanesulfonyl)-4-ethyl-pyrrolidin-3-yl]--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0239]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-bis-(4,4,4-trifluoro-butyl)-amine; [0240]
1-[(1S,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0241]
4-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-pyrrolidin-1-ylmethyl]-benzonitrile; [0242]
3-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-pyrrolidin-1-yl]-3-oxo-propionitrile; [0243]
1-[(1S,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0244]
1-[(1R,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0245]
1-[(1R,2R,4R)-2-Ethyl-4-(4-trifluoromethyl-cyclohexyloxy)-cyclopentyl]-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0246]
{3-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-pyrrolidin-1-yl]-oxetan-3-yl}-acetonitrile; [0247]
3-[(1S,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-propionitrile; [0248]
3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-propionitrile; [0249] Cyclopropanesulfonic
acid
(2-cyano-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4-
,3-a]pyrazin-1-yl)-cyclopentyl]-amide; [0250]
4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-cyclohexanecarbonitrile; [0251]
4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-cyclohexanecarbonitrile; [0252]
1-((3R,4S)-1-Cyclopropanesulfonyl-4-ethyl-pyrrolidin-3-yl)-6H-pyrrolo[2,3-
-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0253]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-N-(4,4,4-trifluoro-butyl)-acetamide; [0254]
Cyclopropyl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0255] 3,3-Difluoro-azetidine-1-carboxylic
acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0256] Cyanomethyl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0257]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-N-(tetrahydro-pyran-4-ylmethyl)-acetamide; [0258]
3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-1,1-dimethyl-urea; [0259] Dimethyl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0260]
(1S,3R,4S)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol; [0261]
(1R,3R,4R)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol; [0262]
(1S,3R,4R)-3-Ethyl-1-(morpholine-4-sulfonylmethyl)-4-(6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentanol; [0263]
N-Cyclopropylmethyl-N-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]tria-
zolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-acetamide; [0264]
1-[(1S,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-2-methyl-propan-2-ol; [0265]
1-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-2-methyl-propan-2-ol; [0266]
1-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-2-methyl-propan-2-ol; [0267]
1-[(1R,2R,4S)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclo-
pentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0268]
1-[(1S,2R,4S)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclo-
pentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0269]
1-[(1S,2R,4R)-4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-ethyl-cyclo-
pentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0270]
1-[(1S,2R,4R)-2-Ethyl-4-(5-methyl-isoxazol-3-ylmethoxy)-cyclopentyl]-6H-p-
yrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0271]
Oxetan-3-yl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0272] Cyclobutyl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0273] Cyclopropanesulfonic acid
[(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0274]
{3-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)-cyclopentylamino]-oxetan-3-yl}-acetonitrile; [0275]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-carbamic acid isopropyl ester; [0276]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-oxetan-3-yl-amine; [0277]
1-((3R,4S)-1-Benzyl-4-isopropyl-pyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]-
triazolo[4,3-a]pyrazin-1-yl; [0278] 3-Fluoro-propane-1-sulfonic
acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0279]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-(3-methyl-oxetan-3-yl)-amine; [0280]
1-[(1S,2R,4R)-2-Ethyl-4-(2-morpholin-4-yl-ethoxy)-cyclopentyl]-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0281]
Carbamoylmethyl-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)-cyclopentyl ester; [0282] 4-Hydroxy-piperidine-1-carboxylic
acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0283] (2,2,2-Trifluoro-ethyl)-carbamic acid
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0284]
Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-amine; [0285]
Pentane-2-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0286] 3-Phenyl-propane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0287] 4,4,4-Trifluoro-butane-1-sulfonic
acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0288] 2-Ethyl-cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0289] 2-Methyl-propane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0290] 2-Phenyl-ethanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0291]
C-Cyclohexyl-N-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,-
3-a]pyrazin-1-yl)-cyclopentyl]-methanesulfonamide; [0292]
Butane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0293] Propane-2-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0294]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-C-phenyl-methanesulfonamide; [0295]
Propane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazi-
n-1-yl)-cyclopentyl]-amide; [0296] 3-Methyl-butane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0297]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-C,C-difluoro-methanesulfonamide; [0298]
4-Cyano-butane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0299] 2-Ethoxy-ethanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0300]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-C-(tetrahydro-furan-2-yl)-methanesulfonamide;
[0301] Tetrahydro-pyran-4-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0302] 3-Cyano-propane-1-sulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0303]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-C-(5-methyl-isoxazol-3-yl)-methanesulfonamide;
[0304]
N-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)-cyclopentyl]-C-(tetrahydro-pyran-2-yl)-methanesulfonamide;
[0305] 2-Pyridin-2-yl-ethanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-amide; [0306]
C-(2,2-Dichloro-cyclopropyl)-N-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1-
,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-methanesulfonamide;
[0307]
(3S,4R)-3-Isopropyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-pyrrolidine-1-carboxylic acid cyclobutylamide; [0308]
(1S,3R,4S)-3-Ethyl-1-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)-cyclopentanol; [0309] Carbonic acid
(1S,3R,4S)-3-ethyl-4-[6-(toluene-4-sulfonyl)-6H-pyrrolo[2,3-e][1,2,4]tria-
zolo[4,3-a]pyrazin-1-yl]-cyclopentyl ester 4-nitro-phenyl ester;
[0310] Cyclobutyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0311] 4-Hydroxy-piperidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0312]
3-(Cyclopropylmethyl-amino)-4-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-cyclobut-3-ene-1,2-dion-
e; [0313]
3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)-cyclopentylamino]-4-(oxetan-3-ylamino)-cyclobut-3-ene-1,2-di-
one; [0314]
3-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentylamino]-4-(3,3,3-trifluoro-propylamino)-cyclobut-3-ene-1,2--
dione; [0315]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-methyl-oxetan-3-yl-amine; [0316]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-(3-methyl-oxetan-3-ylmethyl)-amine; [0317]
3-Cyclopropylamino-4-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triaz-
olo[4,3-a]pyrazin-1-yl)-cyclopentylamino]-cyclobut-3-ene-1,2-dione;
[0318] Cyanomethyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0319] Cyclopropyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0320] (2,2,2-Trifluoro-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0321] 3,3-Difluoro-azetidine-1-carboxylic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0322] 4-Cyano-piperidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0323]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (1-cyano-cyclopropyl)-amide; [0324]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (1-cyano-cyclopropyl)-amide; [0325]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid cyclobutylamide; [0326]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid cyclobutylamide; [0327]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide;
[0328]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide;
[0329]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid cyanomethyl-amide; [0330]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid cyanomethyl-amide; [0331]
(2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]tria-
zolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-oxetan-3-yl-amine; [0332]
Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-yl)-amine;
[0333]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (oxazol-4-ylmethyl)-amide; [0334]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (oxazol-4-ylmethyl)-amide; [0335]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; [0336]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; [0337]
(2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]tria-
zolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(3-methyl-oxetan-3-O-amine;
[0338] 3-Cyano-azetidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0339] Benzyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0340] Oxetan-3-yl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0341] (1-Cyano-cyclopropyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0342] (3-Methyl-oxetan-3-yl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0343] (R)-3-Hydroxy-pyrrolidine-1-carboxylic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0344] (S)-3-Hydroxy-pyrrolidine-1-carboxylic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0345] 4-Fluoro-piperidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0346] (2,2-Difluoro-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0347]
(3,3-Difluoro-azetidin-1-yl)-[(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]-
triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-methanone; [0348]
1-[(1S,2R,4R)-2-Ethyl-4-(pyrazol-1-yloxy)-cyclopentyl]-6H-pyrrolo[2,3-e][-
1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0349]
(3,3-Difluoro-azetidin-1-yl)-[(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]-
triazolo[4,3-a]pyrazin-1-yl)-pyrrolidin-1-yl]-methanone; [0350]
{2-[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-pyrrolidin-1-yl]-4,5-dihydro-oxazol-4-yl}-methanol; [0351]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid oxetan-3-ylamide; [0352]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid oxetan-3-ylamide; [0353]
3-Fluoro-azetidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0354] (1-Methyl-cyclobutyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0355] (1-Hydroxy-cyclopropylmethyl)-carbamic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0356] Methyl-oxetan-3-yl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0357] (3-Methyl-oxetan-3-ylmethyl)-carbamic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0358] Phenyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0359]
[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)--
pyrrolidin-1-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone; [0360]
[(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)--
pyrrolidin-1-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone; [0361]
(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentanecarbonitrile; [0362]
[(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)--
pyrrolidin-1-yl]-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone; [0363]
[(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)--
pyrrolidin-1-yl]-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone; [0364]
tert-Butyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0365] (2,2-Dimethyl-propyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0366] (2-Methoxy-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0367]
(3,5-Bis-trifluoromethyl-benzyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0368] (2-Dimethylamino-ethyl)-methyl-carbamic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0369]
(3-Dimethylamino-propyl)-methyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0370]
Benzyl-isopropyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0371] (R)-3-Hydroxy-piperidine-1-carboxylic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0372] 4-Methyl-piperazine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0373]
4-Acetyl-piperazine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0374]
4-(2-Fluoro-phenyl)-piperazine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)-cyclopentyl ester; compound with trifluoro-acetic acid;
[0375] Pyridin-2-ylmethyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0376]
Pyridin-3-ylmethyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0377]
Pyridin-4-ylmethyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0378]
Isobutyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0379]
[(S)-1-(Tetrahydro-furan-2-yl)methyl]-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)-cyclopentyl ester; [0380]
[(R)-1-(Tetrahydro-furan-2-yl)methyl]-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0381] (2-Cyano-ethyl)-cyclopropyl-carbamic
acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0382] Diisobutyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0383] Azetidine-1-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0384] (2-Methoxy-ethyl)-methyl-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0385] Morpholine-4-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0386] Thiomorpholine-4-carboxylic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0387] (2-Dimethylamino-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0388]
(3-Dimethylamino-propyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0389]
(2-Pyrrolidin-1-yl-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0390]
(3-Pyrrolidin-1-yl-propyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0391]
(2-Piperidin-1-yl-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0392]
(3-Piperidin-1-yl-propyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0393]
(2-Morpholin-4-yl-ethyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0394]
(3-Morpholin-4-yl-propyl)-carbamic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; compound with trifluoro-acetic acid; [0395]
1-[(1S,2R,4S)-4-(2,2-Difluoro-ethoxy)-2-ethyl-cyclopentyl]-6H-pyrrolo[2,3-
-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0396]
1-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyloxy]-2-methyl-propan-2-ol; [0397]
(2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]tria-
zolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;
[0398]
Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;
[0399]
Cyclopropylmethyl-[(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)-cyclopentyl]-(2,2,2-trifluoro-ethyl)-amine;
[0400]
1-((7S,8R)-8-Ethyl-1,4-dioxa-spiro[4.4]non-7-yl)-6-(toluene-4-sulf-
onyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0401]
1-[(1R,3R,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-2-methyl-propan-2-ol; [0402] Acetic acid
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-cyclopentyl ester; [0403]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid cyclopropylmethyl-amide; [0404]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid cyclopropylmethyl-amide; [0405]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (2-cyclopropyl-ethyl)-amide; [0406]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-carboxylic acid (2-cyclopropyl-ethyl)-amide; [0407]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid oxetan-3-ylamide; [0408]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid oxetan-3-ylamide; [0409]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-oxetan-3-yl-(4,4,4-trifluoro-butyl)-amine;
[0410]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)-cyclopentanesulfonic acid cyclopropylamide; [0411]
2-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-ethanol; [0412]
2-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-ethanol; [0413]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid cyclobutylamide; [0414]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid cyclobutylamide; [0415]
1-[(1S,2R,4S)-2-Ethyl-4-(3-methoxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-cyc-
lopentyl]-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl;
[0416]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid amide; [0417]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid amide; [0418]
4-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-butyronitrile; [0419]
4-[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-cyclopentyl]-butyronitrile; [0420]
[(1R,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-acetonitrile; [0421]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-acetonitrile; [0422]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-(5-methyl-isoxazol-3-ylmethyl)-oxetan-3-yl-amine;
[0423]
{5-[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)-cyclopentylmethyl]-[1,2,4]oxadiazol-3-yl}-methanol; [0424]
1-[(1S,2R,4S)-4-(3-Cyclopropyl-pyrazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0425]
1-[(1S,2R,4S)-4-(5-Cyclopropyl-pyrazol-1-yl)-2-ethyl-cyclopentyl]-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0426]
(3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid (2,2,2-trifluoro-ethyl)-amide; [0427]
(3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-p-
yrrolidine-1-sulfonic acid (2,2,2-trifluoro-ethyl)-amide; [0428]
1-[(1S,2R,4S)-4-(3-Cyclopropyl-[1,2,4]triazol-1-yl)-2-ethyl-cyclopentyl]--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; [0429]
1-[(1S,2R,4S)-4-(5-Cyclopropyl-[1,2,4]triazol-1-yl)-2-ethyl-cyclopentyl]--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl; or [0430]
[(1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)-cyclopentyl]-oxetan-3-yl-(3,3,3-trifluoro-propyl)-amine.
[0431] In a fifteenth embodiment the invention provides a compound
according to the first through twelfth embodiments wherein T is
CR.sup.6, U is N, X is CR.sup.3 and Y is N and forms a compound of
Formula (Ib)
##STR00009##
[0432] In a sixteenth embodiment the invention provides a compound
according to the fifteenth embodiment wherein the compound is
[0433]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(2,4-difluorophenyl)methanone; [0434]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(4-(trifluoromethyl)phenyl)methanone; [0435]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyridin-3-yl)methanone; [0436]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(3-(trifluoromethyl)phenyl)methanone; [0437]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrazin-2-yl)methanone; [0438]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrimidin-5-yl)methanone; [0439]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-cyclopropylethanone; [0440]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(phenyl)methanone; [0441]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-cyclobutylethanone; [0442]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-3-cyclobutylpropan-1-one; [0443]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1H-pyrazol-4-yl)methanone; [0444]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1H-pyrazol-3-yl)methanone; [0445]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)propan-1-one; [0446]
N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-
-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0447]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
ne-1-carbonyl)cyclopropanecarbonitrile; [0448]
3-43S,4S)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidi-
n-1-yl)-3-oxopropanenitrile; [0449]
3-((3R,4R)-4-ethyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperid-
in-1-yl)-3-oxopropanenitrile; [0450]
N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0451]
N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0452]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(1-methyl-1H-pyrazol-4-yl)methanone; [0453]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyridin-4-yl)methanone; [0454]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-(3-methylisoxazol-5-yl)ethanone; [0455]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)-2-(2,4-difluorophenyl)ethanone; [0456]
6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)pyridazine-3-carbonitrile; [0457]
5-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)pyrazine-2-carbonitrile; [0458]
2-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)thiazole-5-carbonitrile; [0459]
6-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)nicotinonitrile; [0460]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(pyrrolidin-1-yl)methanone; [0461]
1-((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
ne-1-carbonyl)azetidine-3-carbonitrile; [0462]
(cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-N,N,4-trimethylpipe-
ridine-1-carboxamide; [0463]
1-((cis)-1-(cyclopropylsulfonyl)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a-
]pyrrolo[2,3-e]pyrazine; [0464]
(cis)-N-(cyanomethyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-m-
ethylpiperidine-1-carboxamide; [0465]
((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin--
1-yl)(isoxazol-5-yl)methanone; [0466]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3,3,3-trifluoropropan-1-one; [0467]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-hydroxy-3-methylbutan-1-one; [0468]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-methoxyethanone; [0469]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-methoxypropan-1-one; [0470]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)pent-4-yn-1-one; [0471]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(4-chlorophenyl)ethanone; [0472]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(3-chlorophenyl)ethanone; [0473]
4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
dine-1-carbonyl)benzonitrile; [0474]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-(3-chloroisoxazol-5-yl)propan-1-one; [0475]
3-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-2-oxoethyl)benzonitrile; [0476]
4-(2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-2-oxoethyl)benzonitrile; [0477]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(1H-pyrrol-2-yl)ethanone; [0478]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(pyrazin-2-yl)ethanone; [0479]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone; [0480]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-2-(pyrimidin-2-yl)ethanone; [0481]
5-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile; [0482]
N-(4-(3-allyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)cyclopropanesulfonamide; [0483]
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopr-
opanesulfonamide; [0484]
N-(4-(3-propyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]-
octan-1-yl)cyclopropanesulfonamide; [0485]
2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)thiazole-5-carbonitrile; [0486]
N-(4-(3-(2,3-dihydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide; [0487]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
dine-1-carbonyl)pyrrolidine-3-carbonitrile; [0488]
(3R,4R)--N-(4-(cyanomethyl)phenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyra-
zin-1-yl)-4-methylpiperidine-1-carboxamide; [0489]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(morpholino)methanone; [0490]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(4-methylpiperazin-1-yl)methanone; [0491]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(piperidin-1-yl)methanone; [0492]
(3R,4R)--N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
-1-yl)-4-methylpiperidine-1-carboxamide; [0493]
(3R,4R)--N-(3-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)-4-methylpiperidine-1-carboxamide; [0494]
(R)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpi-
peridine-1-carbonyl)pyrrolidine-2-carbonitrile; [0495]
(S)-1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpi-
peridine-1-carbonyl)pyrrolidine-2-carbonitrile; [0496]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone; [0497]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methanone; [0498]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluoroazetidin-1-yl)methanone; [0499]
2-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)benzo[d]oxazole; [0500]
N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyr-
rolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide; [0501]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(azetidin-1-yl)methanone; [0502]
(3R,4R)--N-(4-cyanophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl-
)-4-methylpiperidine-1-carboxamide; [0503]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-3-fluoropyrrolidin-1-yl)methanone; [0504]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluoropyrrolidin-1-yl)methanone; [0505]
1-((3R,4R)-4-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo-
[1,5-a]pyrrolo[2,3-e]pyrazine; [0506]
(R)--N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cy-
clopropanesulfonamide; [0507]
(S)--N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cy-
clopropanesulfonamide; [0508]
3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluorome-
thyl)piperidin-1-yl)-3-oxopropanenitrile; [0509]
3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluorome-
thyl)piperidin-1-yl)-3-oxopropanenitrile; [0510]
N-(3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpip-
eridin-1-yl)-3-oxopropyl)acetamide; [0511]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrofuran-2-yl)methanone; [0512]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrofuran-3-yl)methanone; [0513]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-methoxycyclohexyl)methanone; [0514]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-hydroxypropan-1-one; [0515]
1-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazine; [0516]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-4,4,4-trifluorobutan-1-one; [0517]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-4-yl)methanone; [0518]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-3-yl)methanone; [0519]
4-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-4-oxobutanenitrile; [0520]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydro-2H-pyran-2-yl)methanone; [0521]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone; [0522]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-methylpyrrolidin-1-yl)methanone; [0523]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3-fluoroazetidin-1-yl)methanone; [0524]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((S)-3-fluoropyrrolidin-1-yl)methanone; [0525]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-2-methylpyrrolidin-1-yl)methanone; [0526]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)((R)-morpholin-3-yl)methanone; [0527]
1-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)-3-(methylsulfonyl)propan-1-one; [0528]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1,4-dioxan-2-yl)methanone; [0529]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(tetrahydrothiophen-3-yl-1,1-dioxide)methanone; [0530]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(3,3-difluorocyclobutyl)methanone; [0531]
N-((1S,3R,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)aniline; [0532]
N-((1R,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)aniline; [0533]
3-bromo-1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
[0534]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoroazetidin-1-yl)methanone; [0535]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoropyrrolidin-1-yl)methanone; [0536]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-d-
ifluoropiperidin-1-yl)methanone; [0537]
(R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)azetidine-3-carbonitrile; [0538]
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrim-
idin-2-yl)piperidine-1-carboxamide; [0539]
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrid-
in-2-yl)piperidine-1-carboxamide; [0540]
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrim-
idin-4-yl)piperidine-1-carboxamide; [0541]
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyraz-
in-2-yl)piperidine-1-carboxamide; [0542]
1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
[0543]
N-((3S,5R)-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-5-methylpyrrol-
idin-3-yl)cyclopropanesulfonamide; [0544]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1-methylpyrrolidin-3-yl)methanone; [0545]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(1-methylpiperidin-4-yl)methanone; [0546] (3R,4R)-phenyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate; [0547]
((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)((R)-2-
-(trifluoromethyl)pyrrolidin-1-yl)methanone; [0548]
(R)-1-(1-(pyrrolidin-1-ylsulfonyl)piperidin-3-yl)-6H-imidazo[1,5-a]pyrrol-
o[2,3-e]pyrazine; [0549]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(pyrro-
lidin-1-yl)methanone; [0550]
3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic
acid; [0551]
(S)-1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-ca-
rbonyl)pyrrolidine-3-carbonitrile; [0552] (R)-cyclopentyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate;
[0553]
(E)-N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4--
methylpiperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide; [0554]
4-((1R,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylamin-
o)benzonitrile; [0555]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluorocyclobutyl)methanone; [0556]
5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cycl-
opentylamino)pyrazine-2-carbonitrile; [0557]
N-((1S,3S,4R)-3-(3-bromo-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-e-
thylcyclopentyl)cyclopropanesulfonamide; [0558]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(4,4-difluorocyclohexyl)methanone; [0559]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-1-yl)(3,3--
dimethylpyrrolidin-1-yl)methanone; [0560]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(3,3-d-
ifluoropiperidin-1-yl)methanone; [0561]
(R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)piperidine-4-carbonitrile;
[0562]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl-
)(thiomorpholino-1,1-dioxide)methanone; [0563]
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(azepan-1-yl)methanone; [0564]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-d-
imethylpiperidin-1-yl)methanone; [0565]
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4-chl-
oropiperidin-1-yl)methanone; [0566]
5-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thylamino)pyrazine-2-carbonitrile; [0567]
5-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thylamino)pyrazine-2-carbonitrile; [0568]
1-((R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbon-
yl)piperidine-3-carbonitrile; [0569]
N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-yl)cyclopropanesulfonamide; [0570]
1-(3,3-difluorocyclobutyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;
[0571]
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-
cyclopropanesulfonamide; [0572]
(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic
acid; [0573]
N-((1S,3S,4R)-3-(3-chloro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4--
ethylcyclopentyl)cyclopropanesulfonamide; [0574]
4-(((cis)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclobutoxy)meth-
yl)benzonitrile; [0575]
5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-ylamino)pyrazine-2-carbonitrile; [0576]
N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-yl)-3,3,3-trifluoropropane-1-sulfonamide; [0577]
4-((1R,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cycl-
opentyloxy)benzonitrile; [0578]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-1-methylcyclopropane-1-sulfonamide; [0579]
1-((1S,4S)-5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazabicyclo[2.2.1]hepta-
n-2-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0580]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3-difluoroazetidine-1-sulfonamide; [0581]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0582]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3,3-difluoropyrrolidine-1-sulfonamide; [0583]
(S)--N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-meth-
ylcyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide; [0584]
N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)cyclopropanesulfonamide; [0585]
N-(((1S,3R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)-3,3,3-trifluoropropane-1-sulfonamide; [0586]
N-(((1S,3S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)me-
thyl)-3,3,3-trifluoropropane-1-sulfonamide; [0587]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-1-ethylcyclopropane-1-sulfonamide; [0588]
1-((3aR,6aS)-5-(3,3,3-trifluoropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrr-
ol-2(1H)-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0589]
1-(6-fluoro-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imida-
zo[1,5-a]pyrrolo[2,3-e]pyrazine; [0590]
4-([4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cubanyl]methoxy)benzon-
itrile; [0591]
N-((3R,4S)-4-methyl-1-(3,3,3-trifluoropropylsulfonyl)piperidin-3-yl)-6H-i-
midazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-amine; [0592]
1-(2-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-5-yl)-6H-im-
idazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0593]
1-((3aS,7aR)-4-(3,3,3-trifluoropropylsulfonyl)octahydro-1H-pyrrolo[3,2-b]-
pyridin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0594]
1-(7-methyl-4-(3,3,3-trifluoropropylsulfonyl)-1,4-diazepan-1-yl)-6H-imida-
zo[1,5-a]pyrrolo[2,3-e]pyrazine; [0595]
1-(5-(3,3,3-trifluoropropylsulfonyl)-2,5-diazaspiro[3.5]nonan-2-yl)-6H-im-
idazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0596]
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-3-yl)-3,3,3-t-
rifluoropropane-1-sulfonamide; [0597]
1-((1R,5S)-2-(3,3,3-trifluoropropylsulfonyl)-2,6-diazabicyclo[3.2.1]octan-
-6-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine; [0598]
1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]-
pyrazine; [0599]
N-(4-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)met-
hanesulfonamide; [0600]
N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyc-
lopentyl)-3-chlorobenzenesulfonamide; [0601] Cyclopropanesulfonic
acid
[(1S,3R,4R)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-amide; [0602] Cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-amide; [0603]
1-((1S,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8-
b-tetraaza-as-indacene-3-carboxylic acid; [0604]
1-((1R,2R,4S)-4-Cyclopropanesulfonylamino-2-ethyl-cyclopentyl)-6H-2,5,6,8-
b-tetraaza-as-indacene-3-carboxylic acid; [0605]
Cyclopropanesulfonic acid
[(1S,3R,4S)-3-methyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen-
-1-yl)-cyclopentyl]-amide; [0606]
1-[(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indace-
n-1-yl)-cyclopentyl]-2-methyl-propan-2-ol; [0607]
Cyclopropanesulfonic acid
{(1S,3R,4S)-3-ethyl-4-[3-(2,2,2-trifluoro-ethyl)-6H-2,5,6,8b-tetraaz-
a-as-indacen-1-yl]-cyclopentyl}-amide; [0608]
[(1R,3R,4S)-3-Ethyl-4-(3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacen--
1-yl)-cyclopentyl]-acetic acid ethyl ester or [0609]
1-[(1S,2R,4R)-2-Ethyl-4-(3-methoxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-cyc-
lopentyl]-3-trifluoromethyl-6H-2,5,6,8b-tetraaza-as-indacene.
[0610] In a seventeenth embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is N, U is CR.sup.4, X is CR.sup.3 and Y is N and forms a
compound of Formula (Ic)
##STR00010##
[0611] In an eighteenth embodiment the invention provides a
compound according to the seventeenth embodiment wherein the
compound is [0612]
3-((3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperi-
din-1-yl)-3-oxopropanenitrile; [0613]
5-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)pyrazine-
-2-carbonitrile; [0614]
(S)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbon-
yl)cyclopropanecarbonitrile; [0615]
N-((1S,3R,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)cyclopropanesulfonamide; [0616]
N-((1R,3S,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)cyclopropanesulfonamide; [0617]
(S)-6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)nico-
tinonitrile; [0618]
(R)-6-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)nico-
tinonitrile; [0619]
(S)-2-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)thia-
zole-5-carbonitrile; [0620]
(R)-2-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)thia-
zole-5-carbonitrile; [0621]
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-d-
ifluoroazetidin-1-yl)methanone; [0622]
(S)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-d-
ifluoroazetidin-1-yl)methanone; [0623]
5-((1R,3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile; [0624]
5-((1S,3R,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile; [0625]
5-((1R,3R,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile; [0626]
5-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentylamino)pyrazine-2-carbonitrile; [0627]
N-(4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-y-
l)cyclopropanesulfonamide; [0628]
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-d-
ifluorocyclobutyl)methanone; [0629]
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-d-
ifluoropyrrolidin-1-yl)methanone; [0630]
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(4,4-d-
ifluoropiperidin-1-yl)methanone; [0631]
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0632]
N-((1R,3R,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0633]
N-((1R,3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0634]
N-((1S,3R,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0635]
((R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)((R)-2-
-(trifluoromethyl)pyrrolidin-1-yl)methanone; [0636]
N-((3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrroli-
din-3-yl)cyclopropanesulfonamide; [0637]
1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;
[0638]
N-((3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrroli-
din-3-yl)-3,3,3-trifluoropropane-1-sulfonamide; [0639]
3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine;
[0640]
N-((1R,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8--
yl)cyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0641]
N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)-3,3,3-trifluoropropane-1-sulfonamide; [0642]
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)cyclopropanesulfonamide; [0643]
N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)cyclopropanesulfonamide; [0644]
N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)-3,3-difluoroazetidine-1-sulfonamide; [0645]
3-chloro-N-((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin--
8-yl)cyclopentyl)-4-fluorobenzenesulfonamide; [0646]
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3-difluoroazetidine-1-sulfonamide; [0647]
N-(((1S,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyc-
lopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide; [0648]
N-((1R,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide; [0649]
N-(((1S,3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyc-
lopentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide; [0650]
N-((1R,3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cycl-
opentyl)methyl)-3,3,3-trifluoropropane-1-sulfonamide; [0651]
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)morpholine-4-sulfonamide; [0652]
3,3,3-Trifluoro-propane-1-sulfonic acid
[(2S,4S,5R)-4-methyl-5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-tetr-
ahydro-furan-2-ylmethyl]-amide; [0653]
3,3,3-Trifluoro-propane-1-sulfonic acid
[(2R,4R,5S)-4-methyl-5-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-
-tetrahydro-furan-2-ylmethyl]-amide; [0654]
3,3,3-Trifluoro-propane-1-sulfonic acid
methyl-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-y-
l)-cyclopentyl]-amide; [0655] Azetidine-1-sulfonic acid
[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cycl-
opentyl]-amide; [0656]
{3-[(1S,3R,4S)-3-Methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-c-
yclopentylamino]-oxetan-3-yl}-acetonitrile; [0657]
3,3-Difluoro-cyclobutanesulfonic acid
[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cycl-
opentyl]-amide; [0658]
8-[(1S,2R,4S)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6-
,8a-tetraaza-as-indacene; [0659]
8-[(1R,2R)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6,8a-
-tetraaza-as-indacene; [0660] 3-Fluoro-azetidine-1-sulfonic acid
[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cycl-
opentyl]-amide; [0661] 3-Fluoro-propane-1-sulfonic acid
[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-cycl-
opentyl]-amide; [0662] Cyclopropanesulfonic acid
[(1S,3R,4S)-3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)-cyclopentyl]-amide; [0663] Cyclopropanesulfonic acid
[(1R,3S,4R)-3-methyl-4-(7-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)-cyclopentyl]-amide; [0664]
2-Cyano-N-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin--
8-yl)-cyclopentyl]-acetamide; [0665]
8-[(1S,2R,4R)-2-Methyl-4-(tetrahydro-pyran-4-yloxy)-cyclopentyl]-3H-3,4,6-
,8a-tetraaza-as-indacene; [0666]
(2-Cyclopropyl-ethyl)-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,-
3-e]pyrazin-8-yl)-cyclopentyl]-oxetan-3-yl-amine; [0667]
Cyclopropylmethyl-[(1S,3R,4S)-3-methyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-
pyrazin-8-yl)-cyclopentyl]-oxetan-3-yl-amine; [0668]
(3R,4S)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-pyrrolidi-
ne-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; or [0669]
(3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-pyrrolidi-
ne-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide. [0670] In a
nineteenth embodiment the invention provides a compound according
to the first through twelfth embodiments wherein T is CR.sup.6, U
is CR.sup.4, X is CR.sup.3 and Y is N and forms a compound of
Formula (Id)
##STR00011##
[0671] In a twentieth embodiment the invention provides a compound
according to the nineteenth embodiment wherein the compound is
[0672]
N-(4-(3H-dipyrrolo[1,2-a:2',3'-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-yl)cy-
clopropanesulfonamide.
[0673] In a twenty-first embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is CR.sup.6, U is N, X is NR.sup.3 and Y is C and forms a
compound of Formula (Ie)
##STR00012##
[0674] In a twenty-second embodiment the invention provides a
compound according to the twenty-first embodiment wherein the
compound is [0675]
(R)-1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1-carb-
onyl)cyclopropanecarbonitrile; or [0676]
(S)-1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-1-carb-
onyl)cyclopropanecarbonitrile.
[0677] In a twenty-third embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is O, U is N, X is CR.sup.3 and Y is C and forms a compound of
Formula (If)
##STR00013##
[0678] In a twenty-fourth embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is NR.sup.6, U is N, X is CR.sup.3 and Y is C and forms a
compound of Formula (Ig)
##STR00014##
[0679] In a twenty-fifth embodiment the invention provides a
compound according to the twenty-fourth embodiment wherein the
compound is [0680]
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine; [0681]
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine; or [0682]
N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]-
octan-1-yl)cyclopropanesulfonamide.
[0683] In a twenty-sixth embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is CR.sup.6, U is CR.sup.4, X is NR.sup.3 and Y is C and forms a
compound of Formula (Ih)
##STR00015##
[0684] In a twenty-seventh embodiment the invention provides a
compound according to the twenty-sixth embodiment wherein the
compound is [0685]
1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;
[0686]
1-cyclohexyl-2-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine;
or [0687]
1-cyclohexyl-2-(trifluoromethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[-
2,3-b]pyridine.
[0688] In a twenty-eighth embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is S, U is N, X is CR.sup.3 and Y is C and forms a compound of
Formula (Ii)
##STR00016##
[0689] In a twenty-ninth embodiment the invention provides a
compound according to the first through twelfth embodiments wherein
T is N, U is CR.sup.4, X is NR.sup.3 and Y is C and forms a
compound of formula (Ij)
##STR00017##
[0690] In a thirtieth embodiment the invention provides a compound
according to the twenty-ninth embodiment wherein the compound is
[0691]
N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyc-
lopentyl)cyclopropanesulfonamide; [0692]
N-((1S,3S,4R)-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylcy-
clopentyl)cyclopropanesulfonamide; [0693]
N-((1S,3S,4R)-3-(2-cyclopropylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-y-
l)-4-methylcyclopentyl)cyclopropanesulfonamide; [0694]
N-((1S,3R,4S)-3-methyl-4-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6-
H)-yl)cyclopentyl)cyclopropanesulfonamide; [0695]
Cyclopropanesulfonic acid
[(1S,3R,4S)-3-methyl-4-(2-trifluoromethyl-imidazo[4,5-d]pyrrolo[2,3--
b]pyridin-1(6H)-yl)-cyclopentyl]-amide; [0696] Cyclopropanesulfonic
acid
[(1S,3R,4S)-3-ethyl-4-(2-trifluoromethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyri-
din-1(6H)-yl)-cyclopentyl]-amide; [0697] Cyclopropanesulfonic acid
[(1S,3S,4R)-3-(2-difluoromethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)-4-ethyl-cyclopentyl]-amide; [0698] Cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(2-methyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)-cyclopentyl]-amide; [0699] Cyclopropanesulfonic acid
[(1S,3S,4R)-3-(2-amino-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1
(6H)-yl)-4-ethyl-cyclopentyl]-amide.
[0700] according to the first through twelfth embodiments wherein
is N, U is N, X is NR.sup.3 and Y is C and forms a compound of
Formula (Ik)
##STR00018##
[0701] In a thirty-second embodiment the invention provides a
compound according to the thirty-first embodiment wherein the
compound is [0702] Cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(6H-[1,2,3]triazolo[4,5-d]pyrrolo[2,3-b]pyridin-1-y-
l)-cyclopentyl]-amide.
[0703] In a thirty-third embodiment the invention provides a
compound of Formula (II) wherein the compound is
##STR00019##
pharmaceutically acceptable salts, pro-drugs, biologically active
metabolites, stereoisomers and isomers thereof wherein
[0704] R.sup.1, and R.sup.2 are independently hydrogen, deuterium,
--N(R.sup.a)(R.sup.b), halogen, --OR.sup.a, --SR.sup.a,
--S(O)R.sup.a, --S(O).sub.2R.sup.a, --NO.sub.2, --C(O)OR.sup.a,
--CN, --C(O)N(R.sup.a)(R.sup.b), --N(R.sup.a)C(O)(R.sup.b),
--C(O)R.sup.a, --C(OH)R.sup.aR.sup.b,
--N(R.sup.a)S(O).sub.2--R.sup.b, --S(O).sub.2N(R.sup.a)(R.sup.b),
--CF.sub.3, --OCF.sub.3, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.1-C.sub.10) heterocyclyl, or optionally substituted
(C.sub.6-C.sub.10)aryl; [0705] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or optionally
substituted (C.sub.1-C.sub.10)heteroaryl linked through a
nitrogen;
[0706] R.sup.3 is hydrogen, an optionally substituted bridged
(C.sub.5-C.sub.12)cycloalkyl, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclyl, optionally substituted
(C.sub.1-C.sub.8)alkyl, optionally substituted
(C.sub.3-C.sub.10)cycloalkyl, optionally substituted
(C.sub.3-C.sub.8)cycloalkenyl, optionally substituted
(C.sub.6-C.sub.10)aryl, optionally substituted
(C.sub.1-C.sub.10)heteroaryl, optionally substituted
(C.sub.2-C.sub.10)heterocyclyl; or
[0707] R.sup.3 is -A-D-E-G, wherein:
[0708] A is a bond, --C(O)--, optionally substituted
(C.sub.1-C.sub.6)alkylene, optionally substituted
(C.sub.2-C.sub.6)alkenylene, optionally substituted
(C.sub.2-C.sub.6)alkynylene, optionally substituted
(C.sub.3-C.sub.12)cycloalkylene, optionally substituted
(C.sub.2-C.sub.6)heterocyclylene, --C(O)N(R.sup.a)--R.sup.e--,
--N(R.sup.a)C(O)--R.sup.e--, --O--R.sup.e--,
--N(R.sup.a)--R.sup.e--, --S--R.sup.e--, --S(O).sub.2--R.sup.e--,
--S(O)R.sup.e--, --C(O--R.sup.a)(R.sup.b)--R.sup.e--,
--S(O).sub.2N(R.sup.a)--R.sup.e--,
--N(R.sup.a)S(O).sub.2--R.sup.e-- or
--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--;
[0709] D is an optionally substituted (C.sub.1-C.sub.8)alkylene,
optionally substituted bridged (C.sub.5-C.sub.12)cycloalkylene,
optionally substituted (C.sub.3-C.sub.10)cycloalkylene, optionally
substituted bridged (C.sub.5-C.sub.10)cycloalkenylene, optionally
substituted (C.sub.3-C.sub.10)cycloalkenylene, optionally
substituted (C.sub.6-C.sub.10)arylene, optionally substituted
(C.sub.1-C.sub.10)heteroarylene, optionally substituted bridged
(C.sub.2-C.sub.10)heterocyclylene or an optionally substituted
(C.sub.2-C.sub.10)heterocyclylene;
[0710] E is a bond, --R.sup.e--, --R.sup.e--C(.dbd.NCN)--R.sup.e--,
--R.sup.e--C(O)--R.sup.e--, --R.sup.e--C(O)C(O)--R.sup.e--,
--R.sup.e--C(O)O--R.sup.e--,
--R.sup.e--C(O)C(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)--C(O)C(O)--R.sup.e--,
--R.sup.e--O--R.sup.e--, --R.sup.e--S(O).sub.2--R.sup.e--,
--R.sup.e--S(O)--R.sup.e--, --R.sup.e--S--R.sup.e--,
--R.sup.e--N(R.sup.a)--R.sup.e--, .dbd.N--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)--R.sup.e--,
--R.sup.eC(O)N(R.sup.a)R.sup.e--,
--R.sup.e--OC(O)N(R.sup.a)--R.sup.e--,
--R.sup.e--N(R.sup.a)C(O)OR.sup.e--, --R.sup.e--OC(O)--R.sup.e,
--R.sup.e--OC(O)--O--R.sup.e,
--R.sup.e--N(R.sup.a)C(O)N(R.sup.b)--R.sup.e--,
--R.sup.e--N(R.sup.a)S(O).sub.2--R.sup.e--,
--R.sup.e--S(O).sub.2N(R.sup.a)--R.sup.e--, or
--R.sup.e--N(R.sup.a)S(O).sub.2N(R.sup.a)--R.sup.e--; or
[0711] E is
##STR00020##
[0712] where in all cases, E is linked to either a carbon or a
nitrogen atom in D;
[0713] G is hydrogen, deuterium, --N(R.sup.a)(R.sup.b), halogen,
--OR.sup.a, --SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--NO.sub.2, --C(O)OR.sup.a, --CN, --C(O)N(R.sup.a)(R.sup.b),
--N(R.sup.a)C(O)R.sup.b, --N(R.sup.a)C(O)OR.sup.b,
--OC(O)N(R.sup.a), --N(R.sup.a)C(O)N(R.sup.b).sub.2,
--C(O--R.sup.a)(R.sup.b).sub.2, --C(O)R.sup.a, --CF.sub.3,
--OCF.sub.3, --N(R.sup.a)S(O).sub.2R.sup.b,
--S(O).sub.2N(R.sup.a)(R.sup.b), --S(O).sub.2N(R.sup.a)C(O)R.sup.b,
an optionally substituted --(C.sub.1-C.sub.6)alkyl, an optionally
substituted --(C.sub.2-C.sub.6)alkenyl, an optionally substituted
--(C.sub.2-C.sub.6)alkynyl, an optionally substituted
--(C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
--(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
--(C.sub.1-C.sub.10) heterocyclyl, an optionally substituted
--(C.sub.6-C.sub.10)aryl; [0714] wherein in a moiety containing
--N(R.sup.a)(R.sup.b), the nitrogen, R.sup.a and R.sup.b may form a
ring such that --N(R.sup.a)(R.sup.b) represents an optionally
substituted (C.sub.2-C.sub.10)heterocyclyl or an optionally
substituted (C.sub.1-C.sub.10) heteroaryl linked through a
nitrogen;
[0715] R.sup.a and R.sup.b are each independently hydrogen,
deuterium, CN, an optionally substituted (C.sub.1-C.sub.10)alkyl,
an optionally substituted (C.sub.2-C.sub.10)alkenyl, an optionally
substituted (C.sub.2-C.sub.10)alkynyl, an optionally substituted
(C.sub.1-C.sub.10)alkyl-O--(C.sub.1-C.sub.10)alkyl, an optionally
substituted (C.sub.3-C.sub.10)cycloalkyl, an optionally substituted
(C.sub.6-C.sub.10)aryl, an optionally substituted
(C.sub.1-C.sub.10)heteroaryl, an optionally substituted
(C.sub.1-C.sub.10)heterocyclyl, an optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.3-C.sub.10)cycloalkyl, an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.6-C.sub.10)aryl, an optionally
substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heteroaryl, or an
optionally substituted
--(C.sub.1-C.sub.6)alkylene-(C.sub.1-C.sub.10)heterocyclyl; and
[0716] R.sup.e for each occurrence is independently a bond, an
optionally substituted (C.sub.1-C.sub.10)alkylene, an optionally
substituted (C.sub.2-C.sub.10)alkenylene, an optionally substituted
(C.sub.2-C.sub.10)alkynylene, an optionally substituted
--(C.sub.1-C.sub.10)alkylene-O--(C.sub.1-C.sub.10)alkylene group,
an optionally substituted (C.sub.3-C.sub.10)cycloalkylene, an
optionally substituted (C.sub.6-C.sub.10)arylene, an optionally
substituted (C.sub.1-C.sub.10)heteroarylene, or an optionally
substituted (C.sub.1-C.sub.10)heterocyclylene.
[0717] In a thirty-fourth embodiment the invention provides a
compound according to the thirty-third embodiment wherein the
compound is [0718]
1-Cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine;
[0719] Cyclopropanesulfonic acid
[(1S,3R,4S)-3-ethyl-4-(3,6,7,8-tetrahydro-3,4,9-triaza-cyclopenta[a]napht-
halen-9-yl)-cyclopentyl]-amide; or [0720] Cyclopropanesulfonic acid
[(1S,3S,4R)-3-(3,6-dihydro-2H-dipyrrolo[2,3-b;2',3'-d]pyridin-1-yl)-4-eth-
yl-cyclopentyl]-amide.
[0721] In a thirty-fifth embodiment the invention provides a
pharmaceutical composition comprising a compound of Formula (I) or
Formula (II) as defined in any of the foregoing embodiments
##STR00021##
a pharmaceutically acceptable carrier and excipient and a second
therapeutic agent selected from the group consisting of cytokine
suppressive anti-inflammatory drugs, antibodies to or antagonists
of other human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4,
IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23,
interferons, EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands
including CD154, HUMIRA.TM., REMICADE.TM., SIMPONI.TM. (golimumab),
CIMZIA.TM., ACTEMRA.TM., CDP 571, soluble p55 or p75 TNF receptors,
ENBREL.TM., Lenercept, TNF.alpha. converting enzyme inhibitors,
IL-1 inhibitors, Interleukin 11, IL-18 antagonists, IL-12
antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12
binding proteins, non-depleting anti-CD4 inhibitors FK506,
rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen,
corticosteroids, phosphodiesterase inhibitors, adensosine agonists,
antithrombotic agents, complement inhibitors, adrenergic agents,
IL-1.beta. converting enzyme inhibitors, T-cell signalling kinase
inhibitors, metalloproteinase inhibitors, sulfasalazine,
6-mercaptopurines, derivatives p75TNFRIgG, sIL-1RI, sIL-1RII,
sIL-6R, celecoxib, hydroxychloroquine sulfate, rofecoxib,
infliximab, naproxen, valdecoxib, sulfasalazine, meloxicam,
acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,
propoxyphene napsylate/apap, folate, nabumetone, diclofenac,
piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl,
hydrocodone bitartrate/apap, diclofenac sodium/misoprostol,
fentanyl, anakinra, tramadol HCl, salsalate, sulindac,
cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium,
morphine sulfate, lidocaine hydrochloride, indomethacin,
glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine,
oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen
sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA,
CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, VX-740, Roflumilast,
IC-485, CDC-801, S1P1 agonists, FTY720, PKC family inhibitors,
Ruboxistaurin, AEB-071, Mesopram, methotrexate, leflunomide,
corticosteroids, budenoside, dexamethasone, sulfasalazine,
5-aminosalicylic acid, olsalazine, IL-1.beta. converting enzyme
inhibitors, IL-1ra, T cell signaling inhibitors, tyrosine kinase
inhibitors, 6-mercaptopurines, IL-11, mesalamine, prednisone,
azathioprine, mercaptopurine, infliximab, methylprednisolone sodium
succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride,
omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone,
bitartrate/apap, tetracycline hydrochloride, fluocinonide,
metronidazole, thimerosal/boric acid, cholestyramine/sucrose,
ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidine
hydrochloride, midazolam hydrochloride, oxycodone
HCl/acetaminophen, promethazine hydrochloride, sodium phosphate,
sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene
napsylate, hydrocortisone, multivitamins, balsalazide disodium,
codeine phosphate/apap, colesevelam HCl, cyanocobalamin, folic
acid, levofloxacin, natalizumab, interferon-gamma,
methylprednisolone, azathioprine, cyclophosphamide, cyclosporine,
methotrexate, 4-aminopyridine, tizanidine, interferon-.beta.1a,
AVONEX.RTM., interferon-.beta.1b, BETASERON.RTM., interferon
.alpha.-n3, interferon-.alpha., interferon .beta.1A-IF,
Peginterferon .alpha. 2b, Copolymer 1, COPAXONE.RTM., hyperbaric
oxygen, intravenous immunoglobulin, cladribine, cyclosporine,
FK506, mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids,
prednisolone, phosphodiesterase inhibitors, adensosine agonists,
antithrombotic agents, complement inhibitors, adrenergic agents,
antiinflammatory cytokines, interferon-.beta., IFN.beta.1a,
IFN.beta.1b, copaxone, corticosteroids, caspase inhibitors,
inhibitors of caspase-1, antibodies to CD40 ligand and CD80,
alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden
hydrochloride, fampridine, glatiramer acetate, natalizumab,
sinnabidol, .alpha.-immunokine NNSO3, ABR-215062, AnergiX.MS,
chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189,
liposome encapsulated mitoxantrone, THC.CBD, cannabinoid agonists,
MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax,
pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel,
teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists,
interferon gamma antagonists, IL-4 agonists, diclofenac,
misoprostol, naproxen, meloxicam, indomethacin, diclofenac,
methotrexate, azathioprine, minocyclin, prednisone, etanercept,
rofecoxib, sulfasalazine, naproxen, leflunomide, methylprednisolone
acetate, indomethacin, hydroxychloroquine sulfate, prednisone,
sulindac, betamethasone diprop augmented, infliximab, methotrexate,
folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide,
piroxicam, diclofenac sodium, ketoprofen, meloxicam,
methylprednisolone, nabumetone, tolmetin sodium, calcipotriene,
cyclosporine, diclofenac sodium/misoprostol, fluocinonide,
glucosamine sulfate, gold sodium thiomalate, hydrocodone
bitartrate/apap, risedronate sodium, sulfadiazine, thioguanine,
valdecoxib, alefacept, and efalizumab, diclofenac, naproxen,
ibuprofen, piroxicam, indomethacin, COX2 inhibitors, rofecoxib,
valdecoxib, hydroxychloroquine, steroids, prednisolone, budenoside,
dexamethasone, cytotoxics, azathioprine, cyclophosphamide,
mycophenolate mofetil, inhibitors of PDE4, purine synthesis
inhibitor, sulfasalazine, 5-aminosalicylic acid, olsalazine,
Imuran.RTM., CTLA-4-IgG, anti-B7 family antibodies, anti-PD-1
family antibodies, anti-cytokine antibodies, fonotolizumab,
anti-IFNg antibody, anti-receptor receptor antibodies, anti-IL-6
receptor antibody, antibodies to B-cell surface molecules, LJP 394,
Rituximab, anti-CD20 antibody and lymphostat-B.
DETAILED DESCRIPTION OF THE INVENTION
[0722] Protein kinases are a broad and diverse class, of over 500
enzymes, that include oncogenes, growth factors receptors, signal
transduction intermediates, apoptosis related kinases and cyclin
dependent kinases. They are responsible for the transfer of a
phosphate group to specific tyrosine, serine or threonine amino
acid residues, and are broadly classified as tyrosine and
serine/threonine kinases as a result of their substrate
specificity.
[0723] The Jak family kinases (Jak1, Jak2, Jak3 and Tyk2) are
cytoplasmic tyrosine kinases that associate with membrane bound
cytokine receptors. Cytokine binding to their receptor initiates
Jak kinase activation via trans and autophosphorylation processes.
The activated Jak kinases phosphorylate residues on the cytokine
receptors creating phosphotyrosine binding sites for SH2 domain
containing proteins such as Signal Transduction Activators of
Transcript (STAT) factors and other signal regulators transduction
such as suppressor of cytokine signaling (SOCS) proteins and SH2
domain-containing inositol 5'-phosphatases (SHIP). Activation of
STAT factors via this process leads to their dimerization, nuclear
translocation and new mRNA transcription resulting in expression of
immunocyte proliferation and survival factors as well as additional
cytokines, chemokines and molecules that facilitate cellular
trafficking (see Journal of Immunology, 2007, 178, p. 2623). Jak
kinases transduce signals for many different cytokine families and
hence potentially play roles in diseases with widely different
pathologies including but not limited to the following examples.
Both Jak1 and Jak3 control signaling of the so-called common gamma
chain cytokines (IL2, IL4, IL7, IL9, IL15 and IL21), hence
simultaneous inhibition of either Jak1 or Jak3 could be predicted
to impact Th1 mediated diseases such as rheumatoid arthritis via
blockade of IL2, IL7 and IL15 signaling. On the other hand, IL2
signaling has recently been shown to be essential for development
and homeostasis of T-regulatory cells (Malek T R et al., Immunity,
2002, 17(2), p. 167-78). Thus, based on genetic data, blockade of
IL2 signaling alone is predicted to result in autoimmunity
(Yamanouchi J et al., Nat Genet., 2007, 39(3), p. 329-37, and
Willerford D M et al., Immunity, 1995, 3(4), p. 521-30). Th2
mediated diseases such as asthma or atopic dermatitis via IL4 and
IL9 signaling blockade. Jak1 and Tyk2 mediate signaling of IL13
(see Int. Immunity, 2000, 12, p. 1499). Hence, blockade of these
may also be predicted to have a therapeutic effect in asthma. These
two kinases are also thought to mediate Type I interferon
signaling; their blockade could therefore be predicted to reduce
the severity of systemic lupus erythematosus (SLE). Tyk2 and Jak2
mediate signaling of IL12 and IL23. In fact, blockade of these
cytokines using monoclonal antibodies has been effective in
treating psoriasis. Therefore blockade of this pathway using
inhibitors of these kinases could be predicted to be effective in
psoriasis as well. In summary, this invention describes
small-molecule compounds that inhibit, regulate and/or modulate Jak
family kinase activity that is pivotal to several mechanisms
thought critical to the progression of autoimmune diseases
including, but not limited to, rheumatoid arthritis (RA), systemic
lupus erythematosus (SLE), multiple sclerosis (MS), Crohn's
disease, psoriasis and asthma.
[0724] Several pathologically significant cytokines signal via Jak1
alone (Guschin D, et al., EMBO J. 1995 Apr. 3; 14(7):1421-9;
Parganas E, et al., Cell. 1998 May 1; 93(3):385-95; Rodig S. J., et
al., Cell. 1998 May 1; 93(3):373-83). Blockade of one of these,
IL6, using an IL6R neutralizing antibody, has been shown to
significantly improve disease scores in human rheumatoid arthritis
patients (Nishimoto N. et al., Ann Rheum Dis., 2007, 66(9), p.
1162-7). Similarly, blockaded of GCSF signaling, which is also
mediated by Jak1 alone, using neutralizing monoclonal antibodies or
target gene deletion protects mice from experimental arthritis
(Lawlor K. E. et al., Proc Natl Acad Sci U.S.A., 2004, 101(31), p.
11398-403). Accordingly, the identification of small-molecule
compounds that inhibit, regulate and/or modulate the signal
transduction of kinases, such as Jak1, is a desirable means to
prevent or treat autoimmune diseases or other diseases related to
abberant Jak1 function.
[0725] Jak2 is also activated in a wide variety of human cancers
such as prostate, colon, ovarian and breast cancers, melanoma,
leukemia and other haematopoietic malignancies. In addition,
somatic point mutation of the Jak2 gene has been identified to be
highly associated with classic myeloproliferative disorders (MPD)
and infrequently in other myeloid disorders. Constitutive
activation of Jak2 activity is also caused by chromosomal
translocation in hematopoeitic malignancies. It has also been shown
that inhibition of the Jak/STAT pathway, and in particular
inhibition of Jak2 activity, results in anti-proliferative and
pro-apoptotic effects largely due to inhibition of phosphorylation
of STAT. Furthermore, pharmacological modulation or inhibition of
Jak2 activity could effectively block tumor growth and induce
apoptosis by reducing the STAT phosphorylation in cell culture and
human tumor xenografts in vivo. Accordingly, the identification of
small-molecule compounds that inhibit, regulate and/or modulate the
signal transduction of kinases, particularly Jak2, is desirable as
a means to treat or prevent diseases and conditions associated with
cancers.
[0726] Jak kinases also transmit signals regulating essential
physiological processes whose inhibition could be undesirable. For
example Jak2 mediates the signaling of Erythropoetin (Epo) and
Granulocyte/Monocyte-Colony Stimulating Factor (GM-CSF).
Individuals with genetic, congenital or acquired defects in these
signaling pathways can develop potentially life-threatening
complications such as anemia and neutrophil dysfunction.
Accordingly, one non-limiting aspect of this invention also relates
to a method to identify compounds that may have a favorable safety
profile as a result of them selectively avoiding inhibition of
Jak2.
[0727] The protein kinase C family is a group of serine/threonine
kinases that comprises twelve related isoenzymes. Its members are
encoded by different genes and are sub-classified according to
their requirements for activation. The classical enzymes (cPKC)
require diacylglycerol (DAG), phosphatidylserine (PS) and calcium
for activation. The novel PKC's (nPKC) require DAG and PS but are
calcium independent. The atypical PKC's (aPKC) do not require
calcium or DAG.
[0728] PKCtheta is a member of the nPKC sub-family (Baier, G., et
al., J. Biol. Chem., 1993, 268, 4997). It has a restricted
expression pattern, found predominantly in T cells and skeletal
muscle (Mischak, H. et al., FEBS Lett., 1993, 326, p. 51), with
some expression reported in mast cells (Liu, Y. et al., J. Leukoc.
Biol., 2001, 69, p. 831) and endothelial cells (Mattila, P. et al.,
Life Sci., 1994, 55, p. 1253).
[0729] Upon T cell activation, a supramolecular activation complex
(SMAC) forms at the site of contact between the T cell and the
antigen presenting cell (APC). PKCtheta is the only PKC isoform
found to localize at the SMAC (Monks, C. et al., Nature, 1997, 385,
83), placing it in proximity with other signaling enzymes that
mediate T cell activation processes.
[0730] In another study (Baier-Bitterlich, G. et al., Mol. Cell.
Biol., 1996, 16, 842) the role of PKCtheta in the activation of
AP-1, a transcription factor important in the activation of the
IL-2 gene, was confirmed. In unstimulated T cells, constitutively
active PKCtheta stimulated AP-1 activity while in cells with
dominant negative PKCtheta, AP-1 activity was not induced upon
activation by PMA.
[0731] Other studies showed that PKCtheta, via activation of
I.kappa.B kinase beta, mediates activation of NF-.kappa.B induced
by T cell receptor/CD28 co-stimulation (N. Coudronniere et al.,
Proc. Nat. Acad. Sci. U.S.A., 2000, 97, p. 3394; and Lin, X. et
al., Mol. Cell. Biol., 2000, 20, p. 2933).
[0732] Proliferation of peripheral T cells from PKCtheta knockout
mice, in response to T cell receptor (TCR)/CD28 stimulation was
greatly diminished compared to T cells from wild type mice. In
addition, the amount of IL-2 released from the T cells was also
greatly reduced (Sun, Z. et al., Nature, 2000, 404, p. 402). It has
also been shown that PKCtheta-deficient mice show impaired
pulmonary inflammation and airway hyperresponsiveness (AHR) in a
Th2-dependent murine asthma model, with no defects in viral
clearance and Th1-dependent cytotoxic T cell function (Berg-Brown,
N. N. et al., J. Exp. Med., 2004, 199, p. 743; Marsland, B. J. et
al., J. Exp. Med., 2004, 200, p. 181). The impaired Th2 cell
response results in reduced levels of IL-4 and immunoglobulin E
(IgE), contributing to the AHR and inflammatory pathophysiology.
Otherwise, the PKCtheta knockout mice seemed normal and
fertile.
[0733] Evidence also exists that PKCtheta participates in the IgE
receptor (Fc.epsilon.RI)-mediated response of mast cells (Liu, Y.
et al., J. Leukoc. Biol., 2001, 69, p. 831). In human-cultured mast
cells (HCMC), it has been demonstrated that PKC kinase activity
rapidly localizes to the membrane following Fc.epsilon.RI
cross-linking (Kimata, M. et al., Biochem. Biophys. Res. Commun.,
1999, 257(3), p. 895). A recent study examining in vitro activity
of bone marrow mast cells (BMMC) derived from wild-type and
PKCtheta-deficient mice shows that upon FceRI cross linking, BMMCs
from PKCtheta-deficient mice reduced levels of IL-6, tumor necrosis
factor-alpha (TNF.alpha.) and IL-13 in comparison with BMMCs from
wild-type mice, suggesting a potential role for PKCtheta in mast
cell cytokine production in addition to T cell activation
(Ciarletta, A. B. et al., poster presentation at the 2005 American
Thoracic Society International Conference).
[0734] The studies cited above and others studies confirm the
critical role of PKCtheta in T cells activation and in mast cell
(MC) signaling. Thus an inhibitor of PKCtheta would be of
therapeutic benefit in treating immunological disorders and other
diseases mediated by the inappropriate activation of T cells and MC
signaling.
[0735] Many of the kinases, whether a receptor or non-receptor
tyrosine kinase or a S/T kinase have been found to be involved in
cellular signaling pathways involved in numerous pathogenic
conditions, including immunomodulation, inflammation, or
proliferative disorders such as cancer.
[0736] Many autoimmune diseases and disease associated with chronic
inflammation, as well as acute responses, have been linked to
excessive or unregulated production or activity of one or more
cytokines.
[0737] The compounds of the invention are also useful in the
treatment of cardiovascular disorders, such as acute myocardial
infarction, acute coronary syndrome, chronic heart failure,
myocardial infarction, atherosclerosis, viral myocarditis, cardiac
allograft rejection, and sepsis-associated cardiac dysfunction.
Furthermore, the compounds of the present invention are also useful
for the treatment of central nervous system disorders such as
meningococcal meningitis, Alzheimer's disease and Parkinson's
disease.
[0738] The compounds of the invention are also useful in the
treatment of an ocular condition, a cancer, a solid tumor, a
sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a
rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma,
hypersensitivity reactions, hyperkinetic movement disorders,
hypersensitivity pneumonitis, hypertension, hypokinetic movement
disorders, aordic and peripheral aneuryisms,
hypothalamic-pituitary-adrenal axis evaluation, aortic dissection,
arterial hypertension, arteriosclerosis, arteriovenous fistula,
ataxia, spinocerebellar degenerations, streptococcal myositis,
structural lesions of the cerebellum, Subacute sclerosing
panencephalitis, Syncope, syphilis of the cardiovascular system,
systemic anaphalaxis, systemic inflammatory response syndrome,
systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL,
Telangiectasia, thromboangitis obliterans, transplants,
trauma/hemorrhage, type III hypersensitivity reactions, type IV
hypersensitivity, unstable angina, uremia, urosepsis, urticaria,
valvular heart diseases, varicose veins, vasculitis, venous
diseases, venous thrombosis, ventricular fibrillation, viral and
fungal infections, vital encephalitis/aseptic meningitis,
vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff
syndrome, Wilson's disease, xenograft rejection of any organ or
tissue, heart transplant rejection, hemachromatosis, hemodialysis,
hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura,
hemorrhage, idiopathic pulmonary fibrosis, antibody mediated
cytotoxicity, Asthenia, infantile spinal muscular atrophy,
inflammation of the aorta, influenza A, ionizing radiation
exposure, iridocyclitis/uveitis/optic neuritis, juvenile spinal
muscular atrophy, lymphoma, myeloma, leukaemia, malignant ascites,
hematopoietic cancers, a diabetic condition such as
insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy
or microangiopathy, sickle cell anaemia, chronic inflammation,
glomerulonephritis, graft rejection, Lyme disease, von Hippel
Lindau disease, pemphigoid, Paget's disease, fibrosis, sarcoidosis,
cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu
disease, chronic occlusive pulmonary disease, asthma or edema
following burns, trauma, radiation, stroke, hypoxia, ischemia,
ovarian hyperstimulation syndrome, post perfusion syndrome, post
pump syndrome, post-MI cardiotomy syndrome, preeclampsia,
menometrorrhagia, endometriosis, pulmonary hypertension, infantile
hemangioma, or infection by Herpes simplex, Herpes Zoster, human
immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis,
progressive supranucleo palsy, primary pulmonary hypertension,
radiation therapy, Raynaud's phenomenon, Raynaud's disease,
Refsum's disease, regular narrow QRS tachycardia, renovascular
hypertension, restrictive cardiomyopathy, sarcoma, senile chorea,
senile dementia of Lewy body type, shock, skin allograft, skin
changes syndrome, ocular or macular edema, ocular neovascular
disease, scleritis, radial keratotomy, uveitis, vitritis, myopia,
optic pits, chronic retinal detachment, post-laser treatment
complications, conjunctivitis, Stargardt's disease, Eales disease,
retinopathy, macular degeneration, restenosis, ischemia/reperfusion
injury, ischemic stroke, vascular occlusion, carotid obstructive
disease, ulcerative colitis, inflammatory bowel disease, diabetes,
diabetes mellitus, insulin dependent diabetes mellitus, allergic
diseases, dermatitis scleroderma, graft versus host disease, organ
transplant rejection (including but not limited to bone marrow and
solid organ rejection), acute or chronic immune disease associated
with organ transplantation, sarcoidosis, disseminated intravascular
coagulation, Kawasaki's disease, nephrotic syndrome, chronic
fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein
purpurea, microscopic vasculitis of the kidneys, chronic active
hepatitis, septic shock, toxic shock syndrome, sepsis syndrome,
cachexia, infectious diseases, parasitic diseases, acquired
immunodeficiency syndrome, acute transverse myelitis, Huntington's
chorea, stroke, primary biliary cirrhosis, hemolytic anemia,
malignancies, Addison's disease, idiopathic Addison's disease,
sporadic, polyglandular deficiency type I and polyglandular
deficiency type II, Schmidt's syndrome, adult (acute) respiratory
distress syndrome, alopecia, alopecia areata, seronegative
arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy,
ulcerative colitic arthropathy, enteropathic synovitis, chlamydia,
yersinia and salmonella associated arthropathy, atheromatous
disease/arteriosclerosis, atopic allergy, autoimmune bullous
disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid,
linear IgA disease, autoimmune haemolytic anaemia, Coombs positive
haemolytic anaemia, acquired pernicious anaemia, juvenile
pernicious anaemia, peripheral vascular disorders, peritonitis,
pernicious anemia, myalgic encephalitis/Royal Free Disease, chronic
mucocutaneous candidiasis, giant cell arteritis, primary sclerosing
hepatitis, cryptogenic autoimmune hepatitis, Acquired
Immunodeficiency Disease Syndrome, Acquired Immunodeficiency
Related Diseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle
arrythmias, HIV infection/HIV neuropathy, common varied
immunodeficiency (common variable hypogammaglobulinaemia), dilated
cardiomyopathy, female infertility, ovarian failure, premature
ovarian failure, fibrotic lung disease, chronic wound healing,
cryptogenic fibrosing alveolitis, post-inflammatory interstitial
lung disease, interstitial pneumonitis, pneumocystis carinii
pneumonia, pneumonia, connective tissue disease associated
interstitial lung disease, mixed connective tissue disease,
associated lung disease, systemic sclerosis associated interstitial
lung disease, rheumatoid arthritis associated interstitial lung
disease, systemic lupus erythematosus associated lung disease,
dermatomyositis/polymyositis associated lung disease, Sjogren's
disease associated lung disease, ankylosing spondylitis associated
lung disease, vasculitic diffuse lung disease, haemosiderosis
associated lung disease, drug-induced interstitial lung disease,
radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic
pneumonia, lymphocytic infiltrative lung disease, postinfectious
interstitial lung disease, gouty arthritis, autoimmune hepatitis,
type-1 autoimmune hepatitis (classical autoimmune or lupoid
hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody
hepatitis), autoimmune mediated hypoglycaemia, type B insulin
resistance with acanthosis nigricans, hypoparathyroidism, acute
immune disease associated with organ transplantation, chronic
immune disease associated with organ transplantation,
osteoarthritis, primary sclerosing cholangitis, psoriasis type 1,
psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia,
renal disease NOS, glomerulonephritides, microscopic vasulitis of
the kidneys, Lyme disease, discoid lupus erythematosus, male
infertility idiopathic or NOS, sperm autoimmunity, multiple
sclerosis (all subtypes), sympathetic ophthalmia, pulmonary
hypertension secondary to connective tissue disease, acute and
chronic pain (different forms of pain), Goodpasture's syndrome,
pulmonary manifestation of polyarteritis nodosa, acute rheumatic
fever, rheumatoid spondylitis, Still's disease, systemic sclerosis,
Sjogren's syndrome, Takayasu's disease/arteritis, autoimmune
thrombocytopaenia, toxicity, transplants, and diseases involving
inappropriate vascularization for example diabetic retinopathy,
retinopathy of prematurity, choroidal neovascularization due to
age-related macular degeneration, and infantile hemangiomas in
human beings. In addition, such compounds may be useful in the
treatment of disorders such as ascites, effusions, and exudates,
including for example macular edema, cerebral edema, acute lung
injury, adult respiratory distress syndrome (ARDS), proliferative
disorders such as restenosis, fibrotic disorders such as hepatic
cirrhosis and atherosclerosis, mesangial cell proliferative
disorders such as diabetic nephropathy, malignant nephrosclerosis,
thrombotic microangiopathy syndromes, and glomerulopathies,
myocardial angiogenesis, coronary and cerebral collaterals,
ischemic limb angiogenesis, ischemia/reperfusion injury, peptic
ulcer Helicobacter related diseases, virally-induced angiogenic
disorders, preeclampsia, menometrorrhagia, cat scratch fever,
rubeosis, neovascular glaucoma and retinopathies such as those
associated with diabetic retinopathy, retinopathy of prematurity,
or age-related macular degeneration. In addition, these compounds
can be used as active agents against hyperproliferative disorders
such as thyroid hyperplasia (especially Grave's disease), and cysts
(such as hypervascularity of ovarian stroma characteristic of
polycystic ovarian syndrome (Stein-Leventhal syndrome) and
polycystic kidney disease since such diseases require a
proliferation of blood vessel cells for growth and/or
metastasis.
[0739] Compounds of Formula (I) or Formula (II) of the invention
can be used alone or in combination with an additional agent, e.g.,
a therapeutic agent, said additional agent being selected by the
skilled artisan for its intended purpose. For example, the
additional agent can be a therapeutic agent art-recognized as being
useful to treat the disease or condition being treated by the
compound of the present invention. The additional agent also can be
an agent that imparts a beneficial attribute to the therapeutic
composition e.g., an agent that affects the viscosity of the
composition.
[0740] It should further be understood that the combinations which
are to be included within this invention are those combinations
useful for their intended purpose. The agents set forth below are
illustrative for purposes and not intended to be limited. The
combinations, which are part of this invention, can be the
compounds of the present invention and at least one additional
agent selected from the lists below. The combination can also
include more than one additional agent, e.g., two or three
additional agents if the combination is such that the formed
composition can perform its intended function.
[0741] Preferred combinations are non-steroidal anti-inflammatory
drug(s) also referred to as NSAIDS which include drugs like
ibuprofen. Other preferred combinations are corticosteroids
including prednisolone; the well known side-effects of steroid use
can be reduced or even eliminated by tapering the steroid dose
required when treating patients in combination with the compounds
of this invention. Non-limiting examples of therapeutic agents for
rheumatoid arthritis with which a compound of Formula (I) or
Formula (II) of the invention can be combined include the
following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);
antibodies to or antagonists of other human cytokines or growth
factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6,
IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons,
EMAP-II, GM-CSF, FGF, and PDGF. Compounds of the invention can be
combined with antibodies to cell surface molecules such as CD2,
CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1),
CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or
CD40L).
[0742] Preferred combinations of therapeutic agents may interfere
at different points in the autoimmune and subsequent inflammatory
cascade; preferred examples include TNF antagonists like chimeric,
humanized or human TNF antibodies, D2E7 (U.S. Pat. No. 6,090,382,
HUMIRA.TM.), CA2 (REMICADE.TM.), SIMPONI.TM. (golimumab),
CIMZIA.TM., ACTEMRA.TM., CDP 571, and soluble p55 or p75 TNF
receptors, derivatives, thereof, (p75TNFR1gG (ENBREL.TM.) or
p55TNFR1gG (Lenercept), and also TNF.alpha. converting enzyme
(TACE) inhibitors; similarly IL-1 inhibitors
(Interleukin-1-converting enzyme inhibitors, IL-1RA etc.) may be
effective for the same reason. Other preferred combinations include
Interleukin 11. Yet other preferred combinations are the other key
players of the autoimmune response which may act parallel to,
dependent on or in concert with IL-18 function; especially
preferred are IL-12 antagonists including IL-12 antibodies or
soluble IL-12 receptors, or IL-12 binding proteins. It has been
shown that IL-12 and IL-18 have overlapping but distinct functions
and a combination of antagonists to both may be most effective. Yet
another preferred combination is non-depleting anti-CD4 inhibitors.
Yet other preferred combinations include antagonists of the
co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including
antibodies, soluble receptors or antagonistic ligands.
[0743] A compound of Formula (I) or Formula (II) of the invention
may also be combined with agents, such as methotrexate,
6-mercaptopurine, azathioprine sulphasalazine, mesalazine,
olsalazine chloroquinine/hydroxychloroquine, pencillamine,
aurothiomalate (intramuscular and oral), azathioprine, cochicine,
corticosteroids (oral, inhaled and local injection), beta-2
adrenoreceptor agonists (salbutamol, terbutaline, salmeteral),
xanthines (theophylline, aminophylline), cromoglycate, nedocromil,
ketotifen, ipratropium and oxitropium, cyclosporin, FK506,
rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example,
ibuprofen, corticosteroids such as prednisolone, phosphodiesterase
inhibitors, adensosine agonists, antithrombotic agents, complement
inhibitors, adrenergic agents, agents which interfere with
signalling by proinflammatory cytokines such as TNF.alpha., or IL-1
(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta.
converting enzyme inhibitors, T-cell signalling inhibitors such as
kinase inhibitors, metalloproteinase inhibitors, sulfasalazine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors and the derivatives p75TNFRIgG
(Enbrel.TM.) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII,
sIL-6R), antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13
and TGF.beta.), celecoxib, folic acid, hydroxychloroquine sulfate,
rofecoxib, etanercept, infliximab, naproxen, valdecoxib,
sulfasalazine, methylprednisolone, meloxicam, methylprednisolone
acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide,
propoxyphene napsylate/apap, folate, nabumetone, diclofenac,
piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl,
hydrocodone bitartrate/apap, diclofenac sodium/misoprostol,
fentanyl, anakinra, tramadol HCl, salsalate, sulindac,
cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium,
prednisolone, morphine sulfate, lidocaine hydrochloride,
indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,
sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl
misoprostol, naproxen sodium, omeprazole, cyclophosphamide,
rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12,
Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,
Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC
family inhibitors (such as Ruboxistaurin or AEB-071) and Mesopram.
Preferred combinations include methotrexate or leflunomide and in
moderate or severe rheumatoid arthritis cases, cyclosporine and
anti-TNF antibodies as noted above.
[0744] Non-limiting examples of therapeutic agents for inflammatory
bowel disease with which a compound of Formula (I) or Formula (II)
of the invention can be combined include the following: budenoside;
epidermal growth factor; corticosteroids; cyclosporin,
sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine;
metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine;
balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor
antagonists; anti-IL-1.beta. monoclonal antibodies; anti-IL-6
monoclonal antibodies; growth factors; elastase inhibitors;
pyridinyl-imidazole compounds; antibodies to or antagonists of
other human cytokines or growth factors, for example, TNF, LT,
IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II,
GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3,
CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their
ligands; methotrexate; cyclosporine; FK506; rapamycin;
mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen;
corticosteroids such as prednisolone; phosphodiesterase inhibitors;
adenosine agonists; antithrombotic agents; complement inhibitors;
adrenergic agents; agents which interfere with signalling by
proinflammatory cytokines such as TNR.alpha. or IL-1 (e.g. NIK,
IKK, or MAP kinase inhibitors); IL-1.beta. converting enzyme
inhibitors; TNR.alpha. converting enzyme inhibitors; T-cell
signalling inhibitors such as kinase inhibitors; metalloproteinase
inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines;
angiotensin converting enzyme inhibitors; soluble cytokine
receptors and derivatives thereof (e.g. soluble p55 or p75 TNF
receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory
cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF.beta.). Preferred
examples of therapeutic agents for Crohn's disease with which a
compound of Formula (I) or Formula (II) can be combined include the
following: TNF antagonists, for example, anti-TNF antibodies, D2E7
(U.S. Pat. No. 6,090,382, HUMIRA.TM.), CA2 (REMICADE.TM.), CDP 571,
TNFR-Ig constructs, (p75TNFRIgG (ENBREL.TM.) and p55TNFRIgG
(LENERCEPT.TM.) inhibitors and PDE4 inhibitors. A compound of
Formula (I) or Formula (II) can be combined with corticosteroids,
for example, budenoside and dexamethasone; sulfasalazine,
5-aminosalicylic acid; olsalazine; and agents which interfere with
synthesis or action of proinflammatory cytokines such as IL-1, for
example, IL-1.beta. converting enzyme inhibitors and IL-1ra; T cell
signaling inhibitors, for example, tyrosine kinase inhibitors;
6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine;
mercaptopurine; infliximab; methylprednisolone sodium succinate;
diphenoxylate/atrop sulfate; loperamide hydrochloride;
methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;
hydrocodone bitartrate/apap; tetracycline hydrochloride;
fluocinonide; metronidazole; thimerosal/boric acid;
cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine
sulfate; meperidine hydrochloride; midazolam hydrochloride;
oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium
phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil;
propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide
disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin;
folic acid; levofloxacin; methylprednisolone; natalizumab and
interferon-gamma.
[0745] Non-limiting examples of therapeutic agents for multiple
sclerosis with which a compound of Formula (I) or Formula (II) can
be combined include the following: corticosteroids; prednisolone;
methylprednisolone; azathioprine; cyclophosphamide; cyclosporine;
methotrexate; 4-aminopyridine; tizanidine; interferon-.beta.1a
(AVONEX.RTM.; Biogen); interferon-.beta.1b (BETASERON.RTM.;
Chiron/Berlex); interferon .alpha.-n3) (Interferon
Sciences/Fujimoto), interferon-.alpha. (Alfa Wassermann/J&J),
interferon .beta.1A-IF (Serono/Inhale Therapeutics), Peginterferon
.alpha. 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;
COPAXONE.RTM.; Teva Pharmaceutical Industries, Inc.); hyperbaric
oxygen; intravenous immunoglobulin; cladribine; antibodies to or
antagonists of other human cytokines or growth factors and their
receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8,
IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A
compound of Formula (I) or Formula (II) can be combined with
antibodies to cell surface molecules such as CD2, CD3, CD4, CD8,
CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or
their ligands. A compound of Formula (I) or Formula (II) may also
be combined with agents such as methotrexate, cyclosporine, FK506,
rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist,
NSAIDs, for example, ibuprofen, corticosteroids such as
prednisolone, phosphodiesterase inhibitors, adensosine agonists,
antithrombotic agents, complement inhibitors, adrenergic agents,
agents which interfere with signalling by proinflammatory cytokines
such as TNF, or IL-1 (e.g., NIK, IKK, p38 or MAP kinase
inhibitors), IL-1.beta. converting enzyme inhibitors, TACE
inhibitors, T-cell signaling inhibitors such as kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, azathioprine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and
TGF.beta.).
[0746] Preferred examples of therapeutic agents for multiple
sclerosis in which a compound of Formula (I) or Formula (II) can be
combined to include interferon-.beta., for example, IFN.beta.1a and
IFN.beta.1b; copaxone, corticosteroids, caspase inhibitors, for
example inhibitors of caspase-1, IL-1 inhibitors, TNF inhibitors,
and antibodies to CD40 ligand and CD80.
[0747] A compound of Formula (I) or Formula (II) may also be
combined with agents, such as alemtuzumab, dronabinol, daclizumab,
mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer
acetate, natalizumab, sinnabidol, .alpha.-immunokine NNSO3,
ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778,
calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone),
THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor),
MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone
allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide,
TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-14035,
VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma
antagonists and IL-4 agonists.
[0748] Non-limiting examples of therapeutic agents for ankylosing
spondylitis with which a compound of Formula (I) or Formula (II)
can be combined include the following: ibuprofen, diclofenac,
misoprostol, naproxen, meloxicam, indomethacin, diclofenac,
celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine,
minocyclin, prednisone, and anti-TNF antibodies, D2E7 (U.S. Pat.
No. 6,090,382; HUMIRA.TM.), CA2 (REMICADE.TM.), CDP 571, TNFR-Ig
constructs, (p75TNFRIgG (ENBREL.TM.) and p55TNFRIgG
(LENERCEPT.TM.)
[0749] Non-limiting examples of therapeutic agents for asthma with
which a compound of Formula (I) or Formula (II) can be combined
include the following: albuterol, salmeterol/fluticasone,
montelukast sodium, fluticasone propionate, budesonide, prednisone,
salmeterol xinafoate, levalbuterol HCl, albuterol
sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone
acetonide, beclomethasone dipropionate, ipratropium bromide,
azithromycin, pirbuterol acetate, prednisolone, theophylline
anhydrous, methylprednisolone sodium succinate, clarithromycin,
zafirlukast, folmoterol fumarate, influenza virus vaccine,
amoxicillin trihydrate, flunisolide, allergy injection, cromolyn
sodium, fexofenadine hydrochloride, flunisolide/menthol,
amoxicillin/clavulanate, levofloxacin, inhaler assist device,
guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,
doxycycline hyclate, guaifenesin/d-methorphan,
p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine
hydrochloride, mometasone furoate, salmeterol xinafoate,
benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine
HCl/pseudoephed, phenylephrine/cod/promethazine,
codeine/promethazine, cefprozil, dexamethasone,
guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone,
nedocromil sodium, terbutaline sulfate, epinephrine,
methylprednisolone, anti-IL-13 antibody, and metaproterenol
sulfate.
[0750] Non-limiting examples of therapeutic agents for COPD with
which a compound of Formula (I) or Formula (II) can be combined
include the following: albuterol sulfate/ipratropium, ipratropium
bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate,
fluticasone propionate, prednisone, theophylline anhydrous,
methylprednisolone sodium succinate, montelukast sodium,
budesonide, formoterol fumarate, triamcinolone acetonide,
levofloxacin, guaifenesin, azithromycin, beclomethasone
dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium,
amoxicillin trihydrate, gatifloxacin, zafirlukast,
amoxicillin/clavulanate, flunisolide/menthol,
chlorpheniramine/hydrocodone, metaproterenol sulfate,
methylprednisolone, mometasone furoate,
p-ephedrine/cod/chlorphenir, pirbuterol acetate,
p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide,
(R,R)-formoterol, TgAAT, cilomilast and roflumilast.
[0751] Non-limiting examples of therapeutic agents for HCV with
which a compound of Formula (I) or Formula (II) can be combined
include the following: Interferon-alpha-2.alpha.,
Interferon-alpha-2.beta., Interferon-alpha con1,
Interferon-alpha-n1, pegylated interferon-alpha-2.alpha., pegylated
interferon-alpha-2.beta., ribavirin, peginterferon
alfa-2b+ribavirin, ursodeoxycholic acid, glycyrrhizic acid,
thymalfasin, Maxamine, VX-497 and any compounds that are used to
treat HCV through intervention with the following targets: HCV
polymerase, HCV protease, HCV helicase, and HCV IRES (internal
ribosome entry site).
[0752] Non-limiting examples of therapeutic agents for Idiopathic
Pulmonary Fibrosis with which a compound of Formula (I) or Formula
(II) can be combined include the following: prednisone,
azathioprine, albuterol, colchicine, albuterol sulfate, digoxin,
gamma interferon, methylprednisolone sodium succinate, lorazepam,
furosemide, lisinopril, nitroglycerin, spironolactone,
cyclophosphamide, ipratropium bromide, actinomycin d, alteplase,
fluticasone propionate, levofloxacin, metaproterenol sulfate,
morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone
acetonide, tacrolimus anhydrous, calcium, interferon-alpha,
methotrexate, mycophenolate mofetil and
interferon-gamma-1.beta..
[0753] Non-limiting examples of therapeutic agents for myocardial
infarction with which a compound of Formula (I) or Formula (II) can
be combined include the following: aspirin, nitroglycerin,
metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel
bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol
succinate, warfarin sodium, lisinopril, isosorbide mononitrate,
digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril
maleate, torsemide, retavase, losartan potassium, quinapril
hydrochloride/magnesium carbonate, bumetanide, alteplase,
enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate,
diltiazem hydrochloride, captopril, irbesartan, valsartan,
propranolol hydrochloride, fosinopril sodium, lidocaine
hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate,
aminocaproic acid, spironolactone, interferon, sotalol
hydrochloride, potassium chloride, docusate sodium, dobutamine HCl,
alprazolam, pravastatin sodium, atorvastatin calcium, midazolam
hydrochloride, meperidine hydrochloride, isosorbide dinitrate,
epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin,
ezetimibe/simvastatin, avasimibe, and cariporide.
[0754] Non-limiting examples of therapeutic agents for psoriasis
with which a compound of Formula (I) or Formula (II) can be
combined include the following: calcipotriene, clobetasol
propionate, triamcinolone acetonide, halobetasol propionate,
tazarotene, methotrexate, fluocinonide, betamethasone diprop
augmented, fluocinolone acetonide, acitretin, tar shampoo,
betamethasone valerate, mometasone furoate, ketoconazole,
pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide,
urea, betamethasone, clobetasol propionate/emoll, fluticasone
propionate, azithromycin, hydrocortisone, moisturizing formula,
folic acid, desonide, pimecrolimus, coal tar, diflorasone
diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth
subgal/znox/resor, methylprednisolone acetate, prednisone,
sunscreen, halcinonide, salicylic acid, anthralin, clocortolone
pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic
acid/sulfur, desoximetasone, diazepam, emollient,
fluocinonide/emollient, mineral oil/castor oil/na lact, mineral
oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic
acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,
infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,
pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and
ustekinamab.
[0755] Non-limiting examples of therapeutic agents for psoriatic
arthritis with which a compound of Formula (I) or Formula (II) can
be combined include the following: methotrexate, etanercept,
rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen,
leflunomide, methylprednisolone acetate, indomethacin,
hydroxychloroquine sulfate, prednisone, sulindac, betamethasone
diprop augmented, infliximab, methotrexate, folate, triamcinolone
acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac
sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone,
tolmetin sodium, calcipotriene, cyclosporine, diclofenac
sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium
thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate
sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7
(U.S. Pat. No. 6,090,382, HUMIRA.TM.), and efalizumab.
[0756] Non-limiting examples of therapeutic agents for restenosis
with which a compound of Formula (I) or Formula (II) can be
combined include the following: sirolimus, paclitaxel, everolimus,
tacrolimus, ABT-578, and acetaminophen.
[0757] Non-limiting examples of therapeutic agents for sciatica
with which a compound of Formula (I) or Formula (II) can be
combined include the following: hydrocodone bitartrate/apap,
rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen,
ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib,
methylprednisolone acetate, prednisone, codeine phosphate/apap,
tramadol hcl/acetaminophen, metaxalone, meloxicam, methocarbamol,
lidocaine hydrochloride, diclofenac sodium, gabapentin,
dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin,
acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl,
diclofenac sodium/misoprostol, propoxyphene n-pap,
asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, tramadol HCl,
etodolac, propoxyphene HCl, amitriptyline HCl, carisoprodol/codeine
phos/asa, morphine sulfate, multivitamins, naproxen sodium,
orphenadrine citrate, and temazepam.
[0758] Preferred examples of therapeutic agents for SLE (Lupus)
with which a compound of Formula (I) or Formula (II) can be
combined include the following: NSAIDS, for example, diclofenac,
naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for
example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for
example, hydroxychloroquine; steroids, for example, prednisone,
prednisolone, budenoside, dexamethasone; cytotoxics, for example,
azathioprine, cyclophosphamide, mycophenolate mofetil,
methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for
example Cellcept.RTM.. A compound of Formula (I) or Formula (II)
may also be combined with agents such as sulfasalazine,
5-aminosalicylic acid, olsalazine, Imuran.RTM. and agents which
interfere with synthesis, production or action of proinflammatory
cytokines such as IL-1, for example, caspase inhibitors like
IL-1.beta. converting enzyme inhibitors and IL-1ra. A compound of
Formula (I) or Formula (II) may also be used with T cell signaling
inhibitors, for example, tyrosine kinase inhibitors; or molecules
that target T cell activation molecules, for example, CTLA-4-IgG or
anti-B7 family antibodies, anti-PD-1 family antibodies. A compound
of Formula (I) or Formula (II) can be combined with IL-11 or
anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg
antibody), or anti-receptor receptor antibodies, for example,
anti-IL-6 receptor antibody and antibodies to B-cell surface
molecules. A compound of Formula (I) or Formula (II) may also be
used with UP 394 (abetimus), agents that deplete or inactivate
B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B
(anti-BlyS antibody), TNF antagonists, for example, anti-TNF
antibodies, D2E7 (U.S. Pat. No. 6,090,382; HUMIRA.TM.), CA2
(REMICADE.TM.), CDP 571, TNFR-Ig constructs, (p75TNFRIgG
(ENBREL.TM.) and p55TNFRIgG (LENERCEPT.TM.).
[0759] In this invention, the following definitions are
applicable:
[0760] A "therapeutically effective amount" is an amount of a
compound of Formula (I) or Formula (II) or a combination of two or
more such compounds, which inhibits, totally or partially, the
progression of the condition or alleviates, at least partially, one
or more symptoms of the condition. A therapeutically effective
amount can also be an amount which is prophylactically effective.
The amount which is therapeutically effective will depend upon the
patient's size and gender, the condition to be treated, the
severity of the condition and the result sought. For a given
patient, a therapeutically effective amount can be determined by
methods known to those of skill in the art.
[0761] "Pharmaceutically acceptable salts" refers to those salts
which retain the biological effectiveness and properties of the
free bases and which are obtained by reaction with inorganic acids,
for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, and phosphoric acid or organic acids such as sulfonic
acid, carboxylic acid, organic phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid,
fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic
acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or
mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or
mixtures thereof), and the like. These salts can be prepared by
methods known to those skilled in the art.
[0762] Certain compounds of Formula (I) or Formula (II) which have
acidic substituents may exist as salts with pharmaceutically
acceptable bases. The present invention includes such salts.
Examples of such salts include sodium salts, potassium salts,
lysine salts and arginine salts. These salts may be prepared by
methods known to those skilled in the art.
[0763] Certain compounds of Formula (I) or Formula (II) and their
salts may exist in more than one crystal form and the present
invention includes each crystal form and mixtures thereof.
[0764] Certain compounds of Formula (I) or Formula (II) and their
salts may also exist in the form of solvates, for example hydrates,
and the present invention includes each solvate and mixtures
thereof.
[0765] Certain compounds of Formula (I) or Formula (II) may contain
one or more chiral centers, and exist in different optically active
forms. When compounds of Formula (I) or Formula (II) contain one
chiral center, the compounds exist in two enantiomeric forms and
the present invention includes both enantiomers and mixtures of
enantiomers, such as racemic mixtures. The enantiomers may be
resolved by methods known to those skilled in the art, for example
by formation of diastereoisomeric salts which may be separated, for
example, by crystallization; formation of diastereoisomeric
derivatives or complexes which may be separated, for example, by
crystallization, gas-liquid or liquid chromatography; selective
reaction of one enantiomer with an enantiomer-specific reagent, for
example enzymatic esterification; or gas-liquid or liquid
chromatography in a chiral environment, for example on a chiral
support for example silica with a bound chiral ligand or in the
presence of a chiral solvent. It will be appreciated that where the
desired enantiomer is converted into another chemical entity by one
of the separation procedures described above, a further step is
required to liberate the desired enantiomeric form. Alternatively,
specific enantiomers may be synthesized by asymmetric synthesis
using optically active reagents, substrates, catalysts or solvents,
or by converting one enantiomer into the other by asymmetric
transformation.
[0766] When a compound of Formula (I) or Formula (II) contains more
than one chiral center, it may exist in diastereoisomeric forms.
The diastereoisomeric compounds may be separated by methods known
to those skilled in the art, for example chromatography or
crystallization and the individual enantiomers may be separated as
described above. The present invention includes each
diastereoisomer of compounds of Formula (I) or Formula (II), and
mixtures thereof.
[0767] Certain compounds of Formula (I) or Formula (II) may exist
in different tautomeric forms or as different geometric isomers,
and the present invention includes each tautomer and/or geometric
isomer of compounds of Formula (I) or Formula (II) and mixtures
thereof.
[0768] Certain compounds of Formula (I) or Formula (II) may exist
in different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of compounds of
Formula (I) or Formula (II) and mixtures thereof.
[0769] Certain compounds of Formula (I) or Formula (II) may exist
in zwitterionic form and the present invention includes each
zwitterionic form of compounds of Formula (I) or Formula (II) and
mixtures thereof.
[0770] As used herein the tem "pro-drug" refers to an agent which
is converted into the parent drug in vivo by some physiological
chemical process (e.g., a prodrug on being brought to the
physiological pH is converted to the desired drug form). Pro-drugs
are often useful because, in some situations, they may be easier to
administer than the parent drug. They may, for instance, be
bioavailable by oral administration whereas the parent drug is not.
The pro-drug may also have improved solubility in pharmacological
compositions over the parent drug. An example, without limitation,
of a pro-drug would be a compound of the present invention wherein
it is administered as an ester (the "pro-drug") to facilitate
transmittal across a cell membrane where water solubility is not
beneficial, but then it is metabolically hydrolyzed to the
carboxylic acid once inside the cell where water solubility is
beneficial.
[0771] Pro-drugs have many useful properties. For example, a
pro-drug may be more water soluble than the ultimate drug, thereby
facilitating intravenous administration of the drug. A pro-drug may
also have a higher level of oral bioavailability than the ultimate
drug. After administration, the prodrug is enzymatically or
chemically cleaved to deliver the ultimate drug in the blood or
tissue.
[0772] Exemplary pro-drugs upon cleavage release the corresponding
free acid, and such hydrolyzable ester-forming residues of the
compounds of this invention include but are not limited to
carboxylic acid substituents wherein the free hydrogen is replaced
by (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.12)alkanoyloxymethyl,
(C.sub.4-C.sub.9)1-(alkanoyloxy)ethyl,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylamino ethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)-alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0773] Other exemplary pro-drugs release an alcohol of Formula (I)
or Formula (II) wherein the free hydrogen of the hydroxyl
substituent (e.g., R group contains hydroxyl) is replaced by
(C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-(C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.12)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylamino-methyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylactyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl wherein said .alpha.-aminoacyl
moieties are independently any of the naturally occurring L-amino
acids found in proteins, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from detachment of the hydroxyl of the hemiacetal of a
carbohydrate).
[0774] As used herein, the term "bridged (C.sub.5-C.sub.12)
cycloalkyl group" means a saturated or unsaturated, bicyclic or
polycyclic bridged hydrocarbon group having two or three
C.sub.3-C.sub.10 cycloalkyl rings. Non bridged cycloalkyls are
excluded. Bridged cyclic hydrocarbon may include, such as
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl,
bornyl, bornenyl, norbornyl, norbornenyl,
6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, and adamantyl.
[0775] As used herein the term "bridged (C.sub.2-C.sub.10)
heterocyclyl" means bicyclic or polycyclic aza-bridged hydrocarbon
groups and may include azanorbornyl, quinuclidinyl,
isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl,
azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl,
azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl,
azabicyclo[3.3.0]nonanyl, and azabicyclo[3.3.1]nonanyl.
[0776] The term "heterocyclic", "heterocyclyl" or
"heterocyclylene", as used herein, include non-aromatic, ring
systems, including, but not limited to, monocyclic, bicyclic,
tricyclic and spirocyclic rings, which can be completely saturated
or which can contain one or more units of unsaturation, for the
avoidance of doubt, the degree of unsaturation does not result in
an aromatic ring system) and have 5 to 12 atoms including at least
one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes
of exemplification, which should not be construed as limiting the
scope of this invention, the following are examples of heterocyclic
rings: azepinyl, azetidinyl, indolinyl, isoindolinyl, morpholinyl,
piperazinyl, piperidinyl, pyrrolidinyl, quinucludinyl,
thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,
tetrahydroindolyl, thiomorpholinyl and tropanyl.
[0777] The term "heteroaryl" or "heteroarylene" as used herein,
include aromatic ring systems, including, but not limited to,
monocyclic, bicyclic and tricyclic rings, and have 5 to 12 atoms
including at least one heteroatom, such as nitrogen, oxygen, or
sulfur. For purposes of exemplification, which should not be
construed as limiting the scope of this invention: azaindolyl,
benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,
benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl,
imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl,
pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl,
quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl,
thiadiazolyl, or thienyl.
[0778] An "heterocycloalkyl" group, as used herein, is a
heterocyclic group that is linked to a compound by an aliphatic
group having from one to about eight carbon atoms. For example, a
heterocycloalkyl group is a morpholinomethyl group.
[0779] As used herein, "alkyl", "alkylene" or notations such as
"(C.sub.1-C.sub.8)" include straight chained or branched
hydrocarbons which are completely saturated. Examples of alkyls are
methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and isomers
thereof. As used herein, "alkenyl", "alkenylene", "alkynylene" and
"alkynyl" means C.sub.2-C.sub.8 and includes straight chained or
branched hydrocarbons which contain one or more units of
unsaturation, one or more double bonds for alkenyl and one or more
triple bonds for alkynyl.
[0780] As used herein, "aromatic" groups (or "aryl" or "arylene"
groups) include aromatic carbocyclic ring systems (e.g. phenyl) and
fused polycyclic aromatic ring systems (e.g. naphthyl, biphenyl and
1,2,3,4-tetrahydronaphthyl).
[0781] As used herein, "cycloalkyl" or "cycloalkylene" means
C.sub.3-C.sub.12 monocyclic or multicyclic (e.g., bicyclic,
tricyclic, spirocyclic, etc.) hydrocarbons that is completely
saturated or has one or more unsaturated bonds but does not amount
to an aromatic group. Examples of a cycloalkyl group are
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and
cyclohexenyl.
[0782] As used herein, many moieties or substituents are termed as
being either "substituted" or "optionally substituted". When a
moiety is modified by one of these terms, unless otherwise noted,
it denotes that any portion of the moiety that is known to one
skilled in the art as being available for substitution can be
substituted, which includes one or more substituents, where if more
than one substituent then each substituent is independently
selected. Such means for substitution are well-known in the art
and/or taught by the instant disclosure. For purposes of
exemplification, which should not be construed as limiting the
scope of this invention, some examples of groups that are
substituents are: (C.sub.1-C.sub.8)alkyl groups,
(C.sub.2-C.sub.8)alkenyl groups, (C.sub.2-C.sub.8)alkynyl groups,
(C.sub.3-C.sub.10)cycloalkyl groups, halogen (F, Cl, Br or I),
halogenated (C.sub.1-C.sub.8)alkyl groups (for example but not
limited to CF.sub.3), --O--(C.sub.1-C.sub.8)alkyl groups, --OH,
--S--(C.sub.1-C.sub.8)alkyl groups, --SH,
--NH(C.sub.1-C.sub.8)alkyl groups,
--N((C.sub.1-C.sub.8)alkyl).sub.2 groups, --NH.sub.2,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.8)alkyl groups,
--C(O)N((C.sub.1-C.sub.8)alkyl).sub.2, --NHC(O)H, --NHC(O)
(C.sub.1-C.sub.8)alkyl groups, --NHC(O) (C.sub.3-C.sub.8)cycloalkyl
groups, --N((C.sub.1-C.sub.8)alkyl)C(O)H,
--N((C.sub.1-C.sub.8)alkyl)C(O)(C.sub.1-C.sub.8)alkyl groups,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.8)alkyl groups,
--N((C.sub.1-C.sub.8)alkyl)C(O)NH.sub.2 groups,
--NHC(O)N((C.sub.1-C.sub.8)alkyl).sub.2 groups,
--N((C.sub.1-C.sub.8)alkyl)C(O)N((C.sub.1-C.sub.8)alkyl).sub.2
groups, --N((C.sub.1-C.sub.8)alkyl)C(O)NH((C.sub.1-C.sub.8)alkyl),
--C(O)H, --C(O)(C.sub.1-C.sub.8)alkyl groups, --CN, --NO.sub.2,
--S(O)(C.sub.1-C.sub.8)alkyl groups,
--S(O).sub.2(C.sub.1-C.sub.8)alkyl groups,
--S(O).sub.2N((C.sub.1-C.sub.8)alkyl).sub.2 groups,
--S(O).sub.2NH(C.sub.1-C.sub.8)alkyl groups,
--S(O).sub.2NH(C.sub.3-C.sub.8)cycloalkyl groups,
--S(O).sub.2NH.sub.2 groups, --NHS(O).sub.2(C.sub.1-C.sub.8)alkyl
groups, --N((C.sub.1-C.sub.8)alkyl)S(O).sub.2(C.sub.1-C.sub.8)alkyl
groups, --(C.sub.1-C.sub.8)alkyl-O--(C.sub.1-C.sub.8)alkyl groups,
--O--(C.sub.1-C.sub.8)alkyl-O--(C.sub.1-C.sub.8)alkyl groups,
--C(O)OH, --C(O)O(C.sub.1-C.sub.8)alkyl groups, NHOH,
NHO(C.sub.1-C.sub.8)alkyl groups, --O-halogenated
(C.sub.1-C.sub.8)alkyl groups (for example but not limited to
--OCF.sub.3), --S(O).sub.2-halogenated (C.sub.1-C.sub.8)alkyl
groups (for example but not limited to S(O).sub.2CF.sub.3),
--S-halogenated (C.sub.1-C.sub.8)alkyl groups (for example but not
limited to --SCF.sub.3), --(C.sub.1-C.sub.6) heterocycle (for
example but not limited to pyrrolidine, tetrahydrofuran, pyran or
morpholine), --(C.sub.1-C.sub.6) heteroaryl (for example but not
limited to tetrazole, imidazole, furan, pyrazine or pyrazole),
-phenyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl groups,
--N((C.sub.1-C.sub.6)alkyl)C(O)O--(C.sub.1-C.sub.6)alkyl groups,
--C(.dbd.NH)--(C.sub.1-C.sub.6)alkyl groups,
--C(.dbd.NOH)--(C.sub.1-C.sub.6)alkyl groups, or
--C(.dbd.N--O--(C.sub.1-C.sub.6)alkyl)-(C.sub.1-C.sub.6)alkyl
groups.
[0783] ".largecircle." in Formula (I) represents an aromatic
ring.
[0784] One or more compounds of this invention can be administered
to a human patient by themselves or in pharmaceutical compositions
where they are mixed with biologically suitable carriers or
excipient(s) at doses to treat or ameliorate a disease or condition
as described herein. Mixtures of these compounds can also be
administered to the patient as a simple mixture or in suitable
formulated pharmaceutical compositions. A therapeutically effective
dose refers to that amount of the compound or compounds sufficient
to result in the prevention or attenuation of a disease or
condition as described herein. Techniques for formulation and
administration of the compounds of the instant application may be
found in references well known to one of ordinary skill in the art,
such as "Remington's Pharmaceutical Sciences," Mack Publishing Co.,
Easton, Pa., latest edition.
[0785] Suitable routes of administration may, for example, include
oral, eyedrop, rectal, transmucosal, topical, or intestinal
administration; parenteral delivery, including intramuscular,
subcutaneous, intramedullary injections, as well as intrathecal,
direct intraventricular, intravenous, intraperitoneal, intranasal,
or intraocular injections.
[0786] Alternatively, one may administer the compound in a local
rather than a systemic manner, for example, via injection of the
compound directly into an edematous site, often in a depot or
sustained release formulation.
[0787] Furthermore, one may administer the drug in a targeted drug
delivery system, for example, in a liposome coated with endothelial
cell-specific antibody.
[0788] The pharmaceutical compositions of the present invention may
be manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0789] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in a conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0790] For injection, the agents of the invention may be formulated
in aqueous solutions, preferably in physiologically compatible
buffers such as Hanks' solution, Ringer's solution, or
physiological saline buffer. For transmucosal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the
art.
[0791] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by
combining the active compound with a solid excipient, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate.
[0792] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0793] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0794] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0795] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g. gelatin for use in an inhaler or insufflator may
be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0796] The compounds can be formulated for parenteral
administration by injection, e.g. bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g. in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0797] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions.
[0798] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use.
[0799] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0800] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly or by intramuscular
injection). Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0801] An example of a pharmaceutical carrier for the hydrophobic
compounds of the invention is a cosolvent system comprising benzyl
alcohol, a nonpolar surfactant, a water-miscible organic polymer,
and an aqueous phase. The cosolvent system may be the VPD
co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8%
w/v of the nonpolar surfactant polysorbate 80, and 65% w/v
polyethylene glycol 300, made up to volume in absolute ethanol. The
VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a
5% dextrose in water solution. This co-solvent system dissolves
hydrophobic compounds well, and itself produces low toxicity upon
systemic administration. Naturally, the proportions of a co-solvent
system may be varied considerably without destroying its solubility
and toxicity characteristics. Furthermore, the identity of the
co-solvent components may be varied: for example, other
low-toxicity nonpolar surfactants may be used instead of
polysorbate 80; the fraction size of polyethylene glycol may be
varied; other biocompatible polymers may replace polyethylene
glycol, e.g. polyvinyl pyrrolidone; and other sugars or
polysaccharides may substitute for dextrose.
[0802] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are well known examples of delivery vehicles or carriers for
hydrophobic drugs. Certain organic solvents such as
dimethysulfoxide also may be employed, although usually at the cost
of greater toxicity. Additionally, the compounds may be delivered
using a sustained-release system, such as semipermeable matrices of
solid hydrophobic polymers containing the therapeutic agent.
Various sustained-release materials have been established and are
well known by those skilled in the art. Sustained-release capsules
may, depending on their chemical nature, release the compounds for
a few hours up to over several days. Depending on the chemical
nature and the biological stability of the therapeutic reagent,
additional strategies for protein stabilization may be
employed.
[0803] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0804] Many of the compounds of the invention may be provided as
salts with pharmaceutically compatible counterions.
Pharmaceutically compatible salts may be formed with many acids,
including but not limited to hydrochloric, sulfuric, acetic,
lactic, tartaric, malic, succinic, etc. Salts tend to be more
soluble in aqueous or other protonic solvents than are the
corresponding free base forms.
[0805] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredients are
contained in an effective amount to achieve its intended purpose.
More specifically, a therapeutically effective amount means an
amount effective to prevent development of or to alleviate the
existing symptoms of the subject being treated. Determination of
the effective amounts is well within the capability of those
skilled in the art.
[0806] For any compound used in a method of the present invention,
the therapeutically effective dose can be estimated initially from
cellular assays. For example, a dose can be formulated in cellular
and animal models to achieve a circulating concentration range that
includes the IC.sub.50 as determined in cellular assays (i.e., the
concentration of the test compound which achieves a half-maximal
inhibition of a given protein kinase activity). In some cases it is
appropriate to determine the IC.sub.50 in the presence of 3 to 5%
serum albumin since such a determination approximates the binding
effects of plasma protein on the compound. Such information can be
used to more accurately determine useful doses in humans. Further,
the most preferred compounds for systemic administration
effectively inhibit protein kinase signaling in intact cells at
levels that are safely achievable in plasma.
[0807] A therapeutically effective dose refers to that amount of
the compound that results in amelioration of symptoms in a patient.
Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the maximum
tolerated dose (MTD) and the ED.sub.50 (effective dose for 50%
maximal response). The dose ratio between toxic and therapeutic
effects is the therapeutic index and it can be expressed as the
ratio between MTD and ED.sub.50. Compounds which exhibit high
therapeutic indices are preferred. The data obtained from these
cell culture assays and animal studies can be used in formulating a
range of dosage for use in humans. The dosage of such compounds
lies preferably within a range of circulating concentrations that
include the ED.sub.50 with little or no toxicity. The dosage may
vary within this range depending upon the dosage form employed and
the route of administration utilized. The exact formulation, route
of administration and dosage can be chosen by the individual
physician in view of the patient's condition (see e.g. Fingl et
al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.
1). In the treatment of crises, the administration of an acute
bolus or an infusion approaching the MTD may be required to obtain
a rapid response.
[0808] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the kinase modulating effects, or minimal effective
concentration (MEC). The MEC will vary for each compound but can be
estimated from in vitro data; e.g. the concentration necessary to
achieve 50-90% inhibition of protein kinase using the assays
described herein. Dosages necessary to achieve the MEC will depend
on individual characteristics and route of administration. However,
HPLC assays or bioassays can be used to determine plasma
concentrations.
[0809] Dosage intervals can also be determined using the MEC value.
Compounds should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably
between 30-90% and most preferably between 50-90% until the desired
amelioration of symptoms is achieved. In cases of local
administration or selective uptake, the effective local
concentration of the drug may not be related to plasma
concentration.
[0810] The amount of composition administered will, of course, be
dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0811] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. Compositions comprising a compound of the invention
formulated in a compatible pharmaceutical carrier may also be
prepared, placed in an appropriate container, and labelled for
treatment of an indicated condition.
[0812] In some formulations it may be beneficial to use the
compounds of the present invention in the form of particles of very
small size, for example as obtained by fluid energy milling.
[0813] The use of compounds of the present invention in the
manufacture of pharmaceutical compositions is illustrated by the
following description. In this description the term "active
compound" denotes any compound of the invention but particularly
any compound which is the final product of one of the following
Examples.
a) Capsules
[0814] In the preparation of capsules, 10 parts by weight of active
compound and 240 parts by weight of lactose can be de-aggregated
and blended. The mixture can be filled into hard gelatin capsules,
each capsule containing a unit dose or part of a unit dose of
active compound.
b) Tablets
[0815] Tablets can be prepared, for example, from the following
ingredients.
TABLE-US-00001 Parts by weight Active compound 10 Lactose 190 Maize
starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3
[0816] The active compound, the lactose and some of the starch can
be de-aggregated, blended and the resulting mixture can be
granulated with a solution of the polyvinylpyrrolidone in ethanol.
The dry granulate can be blended with the magnesium stearate and
the rest of the starch. The mixture is then compressed in a
tabletting machine to give tablets each containing a unit dose or a
part of a unit dose of active compound.
c) Enteric Coated Tablets
[0817] Tablets can be prepared by the method described in (b)
above. The tablets can be enteric coated in a conventional manner
using a solution of 20% cellulose acetate phthalate and 3% diethyl
phthalate in ethanol:dichloromethane (1:1).
d) Suppositories
[0818] In the preparation of suppositories, for example, 100 parts
by weight of active compound can be incorporated in 1300 parts by
weight of triglyceride suppository base and the mixture formed into
suppositories each containing a therapeutically effective amount of
active ingredient.
[0819] In the compositions of the present invention the active
compound may, if desired, be associated with other compatible
pharmacologically active ingredients. For example, the compounds of
this invention can be administered in combination with another
therapeutic agent that is known to treat a disease or condition
described herein. For example, with one or more additional
pharmaceutical agents that inhibit or prevent the production of
VEGF or angiopoietins, attenuate intracellular responses to VEGF or
angiopoietins, block intracellular signal transduction, inhibit
vascular hyperpermeability, reduce inflammation, or inhibit or
prevent the formation of edema or neovascularization. The compounds
of the invention can be administered prior to, subsequent to or
simultaneously with the additional pharmaceutical agent, whichever
course of administration is appropriate. The additional
pharmaceutical agents include, but are not limited to, anti-edemic
steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL1 agents,
antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2
inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-1R
inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin
inhibitors and immunosuppressants. The compounds of the invention
and the additional pharmaceutical agents act either additively or
synergistically. Thus, the administration of such a combination of
substances that inhibit angiogenesis, vascular hyperpermeability
and/or inhibit the formation of edema can provide greater relief
from the deleterious effects of a hyperproliferative disorder,
angiogenesis, vascular hyperpermeability or edema than the
administration of either substance alone. In the treatment of
malignant disorders combinations with antiproliferative or
cytotoxic chemotherapies or radiation are included in the scope of
the present invention.
[0820] The present invention also comprises the use of a compound
of Formula (I) or Formula (II) as a medicament.
[0821] A further aspect of the present invention provides the use
of a compound of Formula (I) or Formula (II) or a salt thereof in
the manufacture of a medicament for treating vascular
hyperpermeability, angiogenesis-dependent disorders, proliferative
diseases and/or disorders of the immune system in mammals,
particularly human beings.
[0822] The present invention also provides a method of treating
vascular hyperpermeability, inappropriate neovascularization,
proliferative diseases and/or disorders of the immune system which
comprises the administration of a therapeutically effective amount
of a compound of Formula (I) or Formula (II) to a mammal,
particularly a human being, in need thereof.
ABBREVIATIONS
[0823] aa Amino acids [0824] Ac.sub.2O Acetic anhydride [0825] AcOH
Glacial acetic acid [0826] ATP Adenosine triphosphate [0827] b.p.
Boiling point [0828] BArF
tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate [0829] Bn Benzyl
[0830] Boc t-Butoxycarbonyl [0831] BOP-Cl
Bis(2-oxo-3-oxazolidinyl)phosphonic chloride [0832] BSA Bovine
serum albumin [0833] BuOH Butanol [0834] CAN Ceric ammonium nitrate
[0835] Cbz Carboxybenzyl [0836] CDI 1,1'-Carbonyldiimidazole [0837]
COD 1,5-Cyclooctadiene [0838] concd Concentrated [0839] CT Computed
tomography [0840] cym p-cymene (4-isopropyltoluene) [0841] CyPFt-Bu
1-Dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene
[0842] d Doublet [0843] DAST Diethylaminosulfur trifluoride [0844]
dba Dibenzylideneacetone [0845] DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene [0846] DCC
Dicyclohexylcarbodiimide [0847] DCE Dichloroethane [0848] DCM
Dichloromethane (methylene chloride) [0849] dd Doublet of doublets
[0850] DEAD Diethyl azodicarboxylate [0851] DIBAL-H
Diisobutylaluminium hydride [0852] DIAD Diisopropyl
azodicarboxylate [0853] DIEA N,N-Diisopropylethylamine [0854] DMA
Dimethylacetamide [0855] DMAP N,N-Dimethylaminopyridine [0856] DME
1,2-Dimethoxyethane [0857] DMEM Dulbecco's Modified Eagle Medium
[0858] DMF N,N-Dimethylfoimamide [0859] DMS Dimethylsulfide [0860]
DMSO Dimethyl sulfoxide [0861] DNP-HSA Dinitrophenyl-human serum
albumin [0862] DPPA Diphenyl phosphorazidate [0863] dppf
1,1'-Bis(diphenylphosphino)ferrocene [0864] dr Diastereomeric ratio
[0865] DTT Dithiothreitol [0866] EDC.HCl
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0867]
EDTA Ethylene diamine tetraacetic acid [0868] EGTA Ethylene glycol
tetraacetic acid [0869] equiv Equivalent(s) [0870] er Enantiomeric
ratio [0871] Et.sub.2NH Diethylamine [0872] EtOAc Ethyl acetate
[0873] Et.sub.2O Diethyl ether [0874] EtOH Ethanol [0875] FBS Fetal
bovine serum [0876] FLAG DYKDDDDK peptide sequence [0877] g Gram(s)
[0878] GST Glutathione S-transferase [0879] h Hour(s) [0880]
H.sub.2SO.sub.4 Sulfuric acid [0881] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0882] HEPES
N-2-Hydroxyethylpiperazine-N-2-ethanesulfonic acid [0883] HOBt
Hydroxybenzotriazole [0884] HPLC High-pressure liquid
chromatography [0885] Hz Hertz [0886] IBCF Isobutylchlorofoi late
[0887] i.d. Intradermal [0888] IFA Incomplete Freunds Adjuvant
[0889] IPA Isopropyl alcohol [0890] KHMDS Potassium
hexamethyldisilazane [0891] LAH Lithium aluminum hydride [0892] LC
Liquid chromatography [0893] LDA Lithium diisopropylamide [0894]
LHMDS Lithium bis(trimethylsilyl)amide [0895] LiBH.sub.4 Lithium
borohydride [0896] LiOH Lithium hydroxide [0897] m Multiplet [0898]
M Molar [0899] m-CPBA meta-Chloroperbenzoic acid [0900] MeCN
Acetonitrile [0901] MeOH Methyl alcohol [0902] min Minute(s) [0903]
mL Milliliter(s) [0904] mmHg Millimeters of mercury [0905] mmol
Millimole [0906] MOPS 3-(N-morpholino)-propanesulfonic acid [0907]
MOPSO 3-(N-morpholino)-2-hydroxypropanesulfonic acid [0908] MS Mass
spectrometry [0909] MTBE Methyl tert-butyl ether [0910] n- Normal
(nonbranched) [0911] n-BuLi n-Butyl lithium [0912] N Normal [0913]
NaHMDS Sodium bis(trimethylsilyl)amide [0914] NaOAc Sodium acetate
[0915] Na(OAc).sub.3BH Sodium triacetoxyborohydride [0916] NaOt-Bu
Sodium tert-butoxide [0917] NBS N-Bromosuccinimide [0918] NCS
N-Chlorosuccinimide [0919] ND Not determined [0920] NH.sub.4OAc
Ammonium acetate [0921] NIS N-Iodosuccinimide [0922] NMM
N-Methylmorpholine [0923] NMP N-Methylpyrrolidinone [0924] NMR
Nuclear magnetic resonance [0925] OD Optical density [0926] or
Optical rotation [0927] OVA Ovalbumin [0928] p- Para [0929] PBS
Phosphate buffered saline [0930] PFPAA
2,2,3,3,3-Pentafluoropropanoic Anhydride [0931] pH -log [H.sup.+]
[0932] PMB p-Methoxybenzyl [0933] pNAG
Nitrophenyl-N-acetyl-.beta.-D-glucosaminide [0934] P(n-Bu).sub.3
tri-n-Butyl phosphine [0935] POCl.sub.3 Phosphorus oxychloride
[0936] PPh.sub.3 Triphenylphosphine [0937] ppm Parts per million
[0938] PrOH Propanol [0939] psi Pounds per square inch [0940] rcf
Relative centrifugal force [0941] RP-HPLC Reverse-phase
high-pressure liquid chromatography [0942] R.sub.t Retention time
[0943] rt Room temperature [0944] s Singlet [0945] SEM
2-(Trimethylsilyl)ethoxymethyl [0946] SEM-Cl
2-(Trimethylsilyl)ethoxymethyl chloride [0947] SFC Supercritical
Fluid Chromatography [0948] SLM Standard liters per minute [0949] t
Triplet [0950] t- Tertiary [0951] TBDMS tert-Butyldimethylsilyl
[0952] TBDMSCl tert-Butyldimethylsilyl chloride [0953] TBAB
Tetra-n-butylammonium bromide [0954] TBAF Tetra-n-butylammonium
fluoride [0955] TBAI Tetra-n-butylammonium iodide [0956] TEA
Triethylamine [0957] tert- Tertiary [0958] TFA Trifluoroacetic acid
[0959] TFAA Trifluoracetic anhydride [0960] THF Tetrahydrofuran
[0961] TIPS Triisopropylsilyl [0962] TLC Thin layer chromatography
[0963] TMA Trimethyl aluminium [0964] TMAD
N,N,N',N'-Tetramethylazodicarbonamide or
1,1'-azobis(N,N-dimethylformamide) or diamide [Sigma.RTM.] [0965]
TMOF Trimethyl orthoformate [0966] TMS Trimethylsilyl [0967] TPP
2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide
[0968] TsCl para-Toluenesulfonyl chloride [0969] TsOH
para-Toluenesulfonic acid [0970] USP United States Pharmacopeia
[0971] UV Ultraviolet [0972] wt % Weight percent [0973] w/v
Weight/volume
ASSAYS
[0974] In Vitro Jak1 Kinase Activity Measured by Time-Resolved
Fluorescence Resonance Energy Transfer (trFRET)
[0975] Varying concentrations of inhibitor were added to an assay
well containing: Jak1 enzyme (aa 845-1142; expressed in SF9 cells
as a GST fusion and purified by glutathione affinity
chromatography; 4 nM), peptide substrate (biotin-TYR2, Sequence:
Biotin-(Ahx)-AEEEYFFLFA-amide; 2 .mu.M), MOPSO pH 6.5 (50 mM),
MgCl.sub.2 (10 mM), MnCl.sub.2 (2 mM), DTT (2.5 mM), BSA (0.01%
w/v), Na.sub.3VO.sub.4 (0.1 mM) and ATP (0.001 mM). After about 60
min incubation at rt, the reaction was quenched by addition of EDTA
(final concentration: 100 mM) and developed by addition of
revelation reagents (final approximate concentrations: 30 mM HEPES
pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 80 ng/mL PT66K
(europium labeled anti-phosphotyrosine antibody cat #61T66KLB
Cisbio, Bedford, Mass.) and 3.12 .mu.g/mL SAXL (Phycolink
streptavidin-allophycocyanin acceptor, cat #PJ52S, Prozyme, San
Leandro, Calif.). The developed reaction was incubated in the dark
either at about 4.degree. C. for about 14 h or for about 60 min at
rt, then read via a time-resolved fluorescence detector (Rubystar,
BMG) using a 337 nm laser for excitation and emission wavelength of
665 nm. Within the linear range of the assay, the observed signal
at 665 nm is directly related to phosphorylated product and used to
calculate the IC.sub.50 values.
In Vitro Jak3 Kinase Activity Measured by Time-Resolved
Fluorescence Resonance Energy Transfer (trFRET)
[0976] Varying concentrations of inhibitor were added to an assay
well containing: Jak3 enzyme (aa 811-1103; expressed in SF9 cells
as a GST fusion and purified by glutathione affinity
chromatography; 3 nM), peptide substrate (biotin-TYR2, Sequence:
Biotin-(Ahx)-AEEEYFFLFA-amide; 2 .mu.M), MOPSO pH 6.5 (50 mM),
MgCl.sub.2 (10 mM), MnCl.sub.2 (2 mM), DTT (2.5 mM), BSA (0.01%
w/v), Na.sub.3VO.sub.4 (0.1 mM) and ATP (0.001 mM). After about 60
min incubation at rt, the reaction was quenched by addition of EDTA
(final concentration: 100 mM) and developed by addition of
revelation reagents (final approximate concentrations: 30 mM HEPES
pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 80 ng/mL PT66K
(europium labeled anti-phosphotyrosine antibody cat #61T66KLB
Cisbio, Bedford, Mass.) and 0.8 .mu.g/mL SAXL (Phycolink
streptavidin-allophycocyanin acceptor, cat #PJ52S, Prozyme, San
Leandro, Calif.). The developed reaction was incubated in the dark
either at about 4.degree. C. for about 14 h or for about 60 min at
rt, then read via a time-resolved fluorescence detector (Rubystar,
BMG) using a 337 nm laser for excitation and emission wavelength of
665 nm. Within the linear range of the assay, the observed signal
at 665 nm is directly related to phosphorylated product and used to
calculate the IC.sub.50 values.
In Vitro Syk Kinase Activity Measured by Time-Resolved Fluorescence
Resonance Energy Transfer (trFRET)
[0977] 0.3 nM Syk catalytic domain (aa356-635, purified in-house at
the Abbott Bioreseach Center) was mixed with 0.1 .mu.M peptide
substrate (biotin-TYR1, Sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH)
at varying concentrations of inhibitor in reaction buffer: 50 mM
MOPSO pH 6.5, 10 mM MgCl.sub.2, 2 mM MnCl.sub.2, 2.5 mM DTT, 0.01%
BSA, 0.1 mM Na.sub.3VO.sub.4 and 0.001 mM ATP. After about 60 mM
incubation at rt, the reaction was quenched by addition of EDTA
(final concentration: 100 mM) and developed by addition of
revelation reagents (final approximate concentrations: 30 mM HEPES
pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 90 ng/mL PT66K
(europium labeled anti-phosphotyrosine antibody cat #61T66KLB
Cisbio, Bedford, Mass.) and 0.6 .mu.g/mL SAXL (Phycolink
streptavidin-allophycocyanin acceptor, cat #PJ52S, Prozyme, San
Leandro, Calif.). The developed reaction was incubated in the dark
either at about 4.degree. C. for about 14 h or for about 60 min at
rt, then read via a time-resolved fluorescence detector (Rubystar,
BMG) using a 337 nm laser for excitation and emission wavelength of
665 nm. Within the linear range of the assay, the observed signal
at 665 nm is directly related to phosphorylated product and used to
calculate the IC.sub.50 values.
Other In Vitro Kinase Assays Measured by Time-Resolved Fluorescence
Resonance Energy Transfer (trFRET)
[0978] Other kinase assays were performed using a similar protocol.
Additional purified enzymes Tyk2 (aa 880-1185 with an N-terminal
histidine-tag and C-terminal FLAG tag; purified in-house by
immobilized metal ion affinity chromatography), RET (aa 711-1072
with an N-terminal histidine-tag; purified by immobilized metal ion
affinity chromatography), Syk (aa356-635 with a C-terminal
histidine tag; purified by immobilized metal ion affinity
chromatography), and KDR (aa 792-1354 with an N-terminal
histidine-tag; purified in-house by immobilized metal ion affinity
and ion-exchange chromatography) were expressed in SF9 cells and
Aurora 1/B (aa1-344 with a N-terminal histidine-tag and purified by
immobilized metal ion affinity chromatography) was expressed in E.
coli. Other enzymes used are available from commercial sources.
Enzymes were mixed with biotinylated substrates at varying
concentrations of inhibitor in different reaction buffers (see
Table A). After about 60 min incubation at rt, the reaction was
quenched by addition of EDTA and developed by addition of
revelation reagents (final approximate concentrations: 30 mM HEPES
pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, varying amounts of
donor europium labeled antibodies and acceptor streptavidin labeled
allophycocyanin (SAXL)). The developed reactions were incubated in
the dark either at about 4.degree. C. for about 14 h or for about
60 min at rt, then read in a time-resolved fluorescence detector
(Rubystar, BMG Labtech) as described above.
TABLE-US-00002 TABLE A Specific conditions (per 40 .mu.L enzyme
reaction) for the various enzymes are detailed below: Enzyme ATP
DMSO Reaction Assay Conc. Substrate Conc. Conc. Time Detection
Enzyme Construct Substrate Buffer (ng/well) Conc. (mM) (%) (mM)
condition Jak1 aa 845-1142 Biotin- MOPSO 5 2 .mu.M 0.001 5 60 8
ng/well TYR2 PT66K, 0.39 .mu.g/ well SAXL Jak2 Millipore Biotin-
MOPSO 2.5 2 .mu.M 0.001 5 60 8 ng/well cat# 14-640 TYR1 PT66K,
0.078 .mu.g/ well SAXL Jak3 aa 811-1103 Biotin- MOPSO 4.5 2 .mu.M
0.001 5 60 8 ng/well TYR2 PT66K, 0.078 .mu.g/ well SAXL Tyk2
aa880-1185 Biotin- MOPSO 9 2 .mu.M 0.001 5 60 8 ng/well TYR1 PT66K,
0.078 .mu.g/ well SAXL Aurora aa1-344 KinEASE MOPS 20 0.5 .mu.M 0.1
5 60 15 ng/ 1/B S2 well Eu-STK- Ab, 0.34 .mu.g/ wel SAXL KDR
aa789-1354 Biotin- HEPES 10 2 .mu.M 0.1 5 60 8 ng/well TYR2 PT66K,
0.078 .mu.g/ well SAXL JNK1 Millipore Biotin- MOPS 10 1 .mu.M 0.01
5 60 2.58 ng/ cat# 14-327 ATF2- well pep Anti- pATF2- Eu, 0.6
.mu.g/ well SAXL JNK2 Millipore Biotin- MOPS 5 0.5 .mu.M 0.01 5 60
2.58 ng/ cat# 14-329 ATF2- well pep Anti- pATF2- Eu, 0.6 .mu.g/
well SAXL RET aa711-1072 Biotin- HEPES 4 10 ng/well 0.01 5 60 8
ng/well poly PT66K, GluTyr 0.078 .mu.g/ well SAXL P70 S6 Millipore
KinEASE MOPS 0.5 0.25 .mu.M 0.01 5 60 15 ng/ Kinase cat # 14-486 S3
well Eu-STK- Ab, 0.34 .mu.g/ well SAXL PKN2 Invitrogen KinEASE MOPS
0.7 0.5 .mu.M 0.001 5 60 15 ng/ cat # S3 well PV3879 Eu-STK- Ab,
0.34 .mu.g/ well SAXL Syk aa356-635 Biotin- MOPSO 0.4 0.1 .mu.M
0.001 5 60 6.8 ng/ TYR1 well PT66K, 0.045 .mu.g/ well SAXL CDK2/
Millipore Biotin- MOPS 50 2 .mu.M 0.1 5 60 15 ng/ Cyclin A cat #
14-448 MBP well Anti- pMBP- Eu; 0.34 .mu.g/ well SAXL
Reaction Buffers:
[0979] MOPSO buffer contains: 50 mM MOPSO pH 6.5, 10 mM MgCl.sub.2,
2 mM MnCl.sub.2, 2.5 mM DTT, 0.01% BSA, and 0.1 mM
Na.sub.3VO.sub.4
[0980] HEPES buffer contains: 50 mM HEPES pH 7.1, 2.5 mM DTT, 10 mM
MgCl.sub.2, 2 mM MnCl.sub.2, 0.01% BSA, and 0.1 mM
Na.sub.3VO.sub.4
[0981] MOPS buffer contains: 20 mM MOPS pH 7.2, 10 mM MgCl.sub.2, 5
mM EGTA, 5 mM Beta-phosphoglycerol, 1 mM Na.sub.3VO.sub.4, 0.01%
Triton-X-100 and 1 mM DTT
Substrates:
[0982] Biotin-ATF2-peptide sequence:
Biotin-(Ahx)-AGAGDQTPTPTRFLKRPR-amide Biotin-TYR1-peptide sequence:
Biotin-(Ahx)-GAEEEIYAAFFA-COOH Biotin-TYR2-peptide sequence:
Biotin-(Ahx)-AEEEYFFLFA-amide Biotin-MBP-peptide sequence:
Biotin-(Ahx)-VHFFKNIVTPRTPPPSQGKGAEGQR-amide Biotin-polyGluTyr
peptide was purchased from Cisbio (cat #61GT0BLA, Bedford, Mass.)
KinEASE S2 and S3 peptides were purchased from Cisbio (cat
#62ST0PEB, Bedford, Mass.)
Detection Reagents:
[0983] Anti-pATF2-Eu was custom-labeled by Cisbio (Bedford, Mass.)
Anti-pMBP-Eu was custom-labeled by Cisbio (Bedford, Mass.) PT66K
was purchased from Cisbio (cat #61T66KLB, Bedford, Mass.) SAXL was
purchased from Prozyme (cat #PJ25S, San Leandro, Calif.) Human
T-Blasts IL-2 pSTAT5 Cellular Assay
Materials:
[0984] Phytohemaglutinin T-blasts were prepared from Leukopacks
purchased from Biological Specialty Corporation, Colmar, Pa. 18915,
and cryopreserved in 5% DMSO/media prior to assay. For this assay
the cells were thawed in assay medium with the following
composition: RPMI 1640 medium (Gibco 11875093) with 2 mM
L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco 15630-080), 100
.mu.g/mL Pen/Strep (Gibco 15140-122), and 10% heat inactivated FBS
(Gibco 10438026). Other materials used in the assay: DMSO (Sigma
D2650), 96-well dilution plates (polypropylene) (Corning 3365),
96-well assay plates (white, 1/2 area, 96 well) (Corning 3642),
D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 .mu.g)),
Alphascreen pSTAT5 kit (Perkin Elmer TGRS5S10K) and Alphascreen
protein A kit (Perkin Elmer 6760617M)
Methods:
[0985] T-Blasts were thawed and cultured for about 24 h without
IL-2 prior to assay. Test compounds or controls are dissolved and
serially diluted in 100% DMSO. DMSO stocks are subsequently diluted
1:50 in cell culture media to create the 4.times. compound stocks
(containing 2% DMSO). Using a Corning white 96 well, 1/2 area
plate, cells are plated at 2.times.10.sup.5/10 .mu.l/well in 10
.mu.L media followed by addition of 5 .mu.L of 4.times. test
compound in duplicate. Cells are incubated with compound for about
0.5 h at about 37.degree. C. Next, 5 .mu.L of IL-2 stock is added
at 20 ng/mL final concentration. IL-2 is stored as a 4 .mu.g/mL
stock solution, as specified by the manufacturer, at about
-20.degree. C. in aliquots and diluted 1:50 with assay media (to 80
ng/mL) just prior to use. The contents of the wells are mixed by
carefully tapping sides of plate(s) several times followed by
incubation at about 37.degree. C. for about 15 min. The assay is
terminated by adding 5 .mu.L of 5.times. AlphaScreen lysis buffer
and shaking on an orbital shaker for about 10 min at rt.
Alphascreen acceptor bead mix is reconstituted following Perkin
Elmer's protocol. 30 .mu.L/well of reconstituted Alphascreen
acceptor bead mix was added, covered with foil then shaken on
orbital shaker for about 2 min on high then about 2 h on low. Donor
bead mix is reconstituted following Perkin Elmer's AlphaScreen
protocol; 12 .mu.L/well are added, covered with foil then shaken
for about 2 min on high, and about 2 h on low. Plates are read on
an EnVision reader following Perkin Elmer's AlphaScreen protocol
instructions. TF-1 IL-6 pSTAT3 Cellular Assay
Materials:
[0986] TF-1 cells (ATCC #CRL-2003). Culture medium: DMEM medium
(Gibco 11960-044) with 2 mM L-glutamine (Gibco 25030-081), 10 mM
HEPES (Gibco 15630-080), 100 .mu.g/mL Pen/Strep (Gibco 15140-122),
1.5 g/L sodium bicarbonate (Gibco 25080-094), 1 mM sodium pyruvate
(Gibco 11360-070), 10% heat inactivated FBS (Gibco 10437-028), and
2 ng/mL GM-CSF (R&D 215-GM-010). Other materials used in this
assay: DMSO (Sigma D2650), 96-well dilution plates (polypropylene)
(Corning 3365), 96-well assay plates (white, 1/2 area, 96 well)
(Corning 3642), D-PBS (Gibco 14040133), IL-6 (R&D 206-IL/CF-050
(50 .mu.g)), Alphascreen pSTAT3 kit (Perkin Elmer TGRS3S10K) and
Alphascreen protein A kit (Perkin Elmer 6760617M).
Methods:
[0987] Prior to the assay, cells are cultured for about 18 h in the
culture medium without GM-CSF. Test compounds or controls are
dissolved and serially diluted in 100% DMSO. DMSO stocks are
subsequently diluted 1:50 in cell culture media to create the
4.times. compound stocks (containing 2% DMSO). Using a Corning
white 96 well, 1/2 area plate, cells are plated at
2.times.10.sup.7/10 .mu.L/well in 10 .mu.L media followed by
addition of 5 .mu.L of the 4.times. test compound stock in
duplicate. Cells are incubated with compound for about 0.5 h at
about 37.degree. C. followed by addition of 5 .mu.L of 400 ng/mL
IL-6. IL-6 is stored in 10 .mu.g/mL aliquots using endotoxin free
D-PBS (0.1% BSA) at about -20.degree. C. Prior to assay IL-6 is
diluted to 400 ng/mL in culture media and applied (5 .mu.L/well) to
all wells, except to negative control wells where 5 .mu.L/well of
media is added. The contents of the wells are mixed carefully by
tapping the side of the plate several times. Plates are incubated
at about 37.degree. C. for about 30 min. Cells are lysed by adding
5 .mu.L of 5.times. AlphaScreen cell lysis buffer to all wells,
shaken for about 10 min at rt then assayed. Alternatively, assay
plates may be frozen at about 80.degree. C. and thawed later at rt.
Using the pSTAT3 SureFire Assay kit (Perkin Elmer #TGRS3S10K)
acceptor bead mix is reconstituted following Perkin Elmer's
AlphaScreen protocol instructions. 30 .mu.L are added per well then
the plate is covered with foil and shaken on an orbital shaker for
about 2 min on high, then about 2 h on low at rt. Donor bead mix is
reconstituted following Perkin Elmer's AlphaScreen protocol
instructions. 12 .mu.L are added per well, then covered with foil
and shaken on orbital shaker for about 2 min on high, then about 2
h on low at about 37.degree. C. Plates are read on an EnVision
reader following Perkin Elmer's AlphaScreen protocol instructions
at rt.
UT7/EPO pSTAT5 Cellular Assay
Materials:
[0988] UT7/EPO cells are passaged with erythropoietin (EPO), split
twice per week and fresh culture medium is thawed and added at time
of split. Culture Medium: DMEM medium (Gibco 11960-044) with 2 mM
L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco 15630-080), 100
U/mL Pen/Strep (Gibco 15140-122), 10% heat inactivated FBS (Gibco
10437-028), EPO (5 .mu.L/mL=7.1 .mu.L of a 7 .mu.g/mL stock per mL
of medium). Assay media: DMEM, 2 mM L-glutamine, 5% FBS, 10 mM
HEPES. Other materials used in the assay: DMSO (Sigma D2650),
96-well dilution plates (polypropylene) (Corning 3365), 96-well
assay plates (white, 1/2 area, 96 well) (Corning 3642), D-PBS
(Gibco 14040133), IL-2 (R&D 202-IL-10 (10 .mu.g), Alphascreen
pSTAT5 kit (Perkin Elmer TGRS5S10K) and Alphascreen protein A kit
(Perkin Elmer 6760617M).
Methods:
[0989] Culture cells for about 16 h without EPO prior to running
assay. Test compounds or controls are dissolved and serially
diluted in 100% DMSO. DMSO stocks are subsequently diluted 1:50 in
cell culture media to create the 4.times. compound stocks
(containing 2% DMSO). Using a Corning white 96 well, 1/2 area
plate, cells are plated at 2.times.10.sup.5/10 .mu.L/well in 10
.mu.L media followed by addition of 5 .mu.L of 4.times. test
compound stock in duplicate. Cells are incubated with compound for
about 0.5 h at about 37.degree. C. After incubation, 5 .mu.L of EPO
is added to afford a final concentration of 1 nM EPO. The contents
of the wells are mixed by carefully tapping sides of the plate
several times followed by incubation at about 37.degree. C. for
about 20 min. 5 .mu.L of 5.times. AlphaScreen lysis buffer are
added followed by shaking on an orbital shaker for about 10 min at
rt. 30 .mu.L/well of acceptor beads are added after reconstitution
following Perkin Elmer's AlphaScreen protocol, covered with foil
and shaken on orbital shaker for about 2 min on high, then about 2
h on low. Donor beads are reconstituted following Perkin Elmer's
AlphaScreen protocol instructions followed by addition of 12
.mu.L/well, covered with foil and shaken on an orbital shaker for
about 2 min on high, about 2 h on low. Plates are read on an
EnVision reader following Perkin Elmer's AlphaScreen protocol
instructions.
Antigen-Induced Degranulation of RBL-2H3 Cells:
[0990] RBL-2H3 cells are maintained in T75 flasks at about
37.degree. C. and 5% CO.sub.2, and passaged every 3-4 days. To
harvest cells, 20 mL of PBS is used to rinse the flask once, and
then 3 mL of Trypsin-EDTA is added and incubated at about
37.degree. C. for about 2 min. Cells are transferred to a tube with
20 mL medium, spun down at 1000 RPM at rt for about 5 min and
resuspended at 1.times.10.sup.6 cells/mL. Cells are sensitized by
adding DNP-specific mouse IgE to a final concentration of 0.1
.mu.g/mL. 50 .mu.L of cells are added to each well of a 96 well
flat bottom plate (50.times.10.sup.3 cells/well) and incubated
overnight at about 37.degree. C. in 5% CO.sub.2. The next day,
compounds are prepared in 100% DMSO at 10 mM. Each compound is then
serially diluted 1:4 six times in 100% DMSO. Each compound dilution
is then diluted 1:20 and then 1:25, both dilutions in Tyrode's
buffer. Media is aspirated from the cell plates and the cells are
rinsed twice with 100 .mu.L of Tyrode's buffer (prewarmed to about
37.degree. C.). 50 .mu.L of compounds diluted in Tyrode's buffer
are added to each well and the plates are incubated for about 15
min at about 37.degree. C. in 5% CO.sub.2. 50 .mu.L of 0.2 .mu.g/mL
DNP-HSA in Tyrode's buffer is then added to each well and the
plates are incubated for about 30 min at about 37.degree. C. in 5%
CO.sub.2. The final concentration of the various components in the
incubation mix are 0.002-10 .mu.M compounds, 0.1% DMSO, and 0.1
.mu.g/mL DNP-HSA. As one control, 0.2% DMSO (no compound) in
Tyrode's buffer is added to a set of wells to determine maximum
stimulated release. As a second control, Tyrode's buffer without
DNP-HSA is added to a set of wells with containing 0.2% DMSO
without compounds to determine unstimulated release. Each condition
(compounds and controls) is set up in triplicate wells. At the end
of the 30 min incubation, 50 .mu.L of supernate is transferred to a
new 96 well plate. The remaining supernate in the cell plates is
aspirated and replaced with 50 .mu.L of 0.1% Triton X-100 in
Tyrode's buffer to lyse the cells. 50 .mu.L of freshly prepared 1.8
mM 4-Nitrophenyl N-acetyl-.beta.-D-glucosaminide (pNAG) is then
added to each well of supernate and cell lysate and the plates are
incubated for about 60 min at about 37.degree. C. in 5% CO.sub.2.
100 .mu.L of 7.5 mg/mL sodium bicarbonate is added to each well to
stop the reaction. The plates are then read at 405 nm on a
Molecular Devices SpectraMax 250 plate reader.
Calculation of Results
[0991] 1) The plate background OD.sub.405 obtained from wells
containing Tyrode's buffer and pNAG (no supernate or lysate) is
subtracted from the OD.sub.405 reading for each well containing
supernate or lysate. 2) The release for each well is expressed as
the percentage of the total release for that well, where the total
release is twice the release in the supernate plus the release in
the cell lysate. This calculation corrects for variable cell number
in each well. 3) The maximum response is the mean response of wells
containing DNP-HSA but no compound. 4) The minimum response is the
mean response of wells containing no DNP-HSA and no compound. 5)
The response in each compound well is calculated as a percentage of
the maximum response (expressed as % control) where the maximum
response is 100% and the minimum response is 0%. 6) A dose response
curve is generated for each compound and the IC.sub.50 of the curve
is calculated using Prism GraphPad software and nonlinear least
squares regression analysis.
[0992] Acute in vivo measurement of JAK inhibition by compounds is
measured using the:
Concanavalin A (Con A)-Induced Cytokine Production in Lewis
Rats
[0993] The test compound is formulated in an inert vehicle (for
example but not limited to 0.5% hydroxypropylmethyl cellulose
(Sigma, cat # H3785)/0.02% Tween 80 (Sigma, cat #4780) in water) at
the desired concentration to achieve doses in the range of 0.01-100
mg/kg. Six-week-old male Lewis rats (125 g-150 g) (Charles River
Laboratories) are dosed with the compound orally, at time zero (0
min). After about 30 min the rats are injected intravenously (i.v.)
with 10 mg/kg Concanavalin A (Con A, AmershamBioscience, cat
#17-0450-01) dissolved in PBS (Invitrogen, cat #14190). About 4 h
later, the rats are cardiac bled and their plasma is analyzed for
levels of IL-2 (ELISA kit: R&D Systems cat #R2000) and
IFN-.gamma. (ELISA kit: R&D Systems cat #RIF00).
[0994] Acute in vivo measurement of Fc.gamma. receptor signaling
inhibition of the compounds is measured using the:
Reverse Passive Arthus Model
[0995] On day 0, OVA was made up at a concentration of 17.5 mg/mL,
in PBS by rocking gently until a solution was formed. 2% Evans Blue
solution (Sigma Aldrich, cat # E2129) was then added to double the
volume for a final concentration of 8.75 mg/mL of OVA and 1% Evans
Blue dye. Anti-OVA antibody (Abazyme), stock concentration 10
mg/mL, was thawed and a 400 .mu.g/100 .mu.L solution was made with
PBS. Compounds were made up by adding the vehicle, 0.5% HPMC with
0.02% Tween80, and vortexing for about 15 seconds followed by
homogenizing for a minimum of about 2 min at 28,000 rpm until there
was a fine particulate suspension with no clumps of compound. Rats
were weighed and dosed with compound at a pre-determined t-max
based on pharmacokinetic studies. Animals were then placed under
general anesthesia with a 5% isoflourane and oxygen mixture and
shaved. Using a 1/2 mL insulin syringe two sites were injected
i.d., 1 site with 100 .mu.L of 400 .mu.g/100 .mu.L of anti-OVA
antibody, and 1 site with 100 .mu.L of sterile PBS. Each site was
then circled with permanent marker for explant later. Right after
i.d. injections animals were injected with 200 .mu.L of the OVA (10
mg/kg)/Evans Blue mixture i.v., using a 1/2 mL insulin syringe.
About four hours post injection animals were euthanized, bled via
cardiac puncture and blood was collected using a plasma separating
tube. Blood samples were stored on ice until centrifugation (within
about 2 h of collection). Each injection site was removed with a
disposable biopsy punch (Acuderm Acu-Punch Disposable 12 mm), cut
into four pieces and placed in a pre-labeled 2 mL eppendorf tube.
One mL of DMF was added to each biopsy tube and placed in a heat
block for about 24 h at about 50.degree. C. About 24 h after
incubation 100 .mu.L of each sample was added to a 96 well flat
bottom plate. The samples were read at 620 nm on a plate reader
using the Softmax software in order to measure the levels of Evan's
Blue dye. Background was removed by subtracting the OD from the PBS
injected site from the OD of the anti-OVA injected site for each
individual animal. Plasma samples were spun down in a
microcentrifuge for about 5 min at 16.1 rcf. 200 .mu.L of plasma
was placed in a 1.7 mL eppendorf tube for drug level measurement
and tubes were stored at -80.degree. C. until evaluation.
[0996] Chronic in vivo effects of the compounds on anc arthritis
disease model is measured using the:
Adjuvant Induced Arthritis (AIA) in a Lewis Rat
[0997] Female Lewis rats, (6 weeks of age, 125 g-150 g in weight
from Charles River Laboratories) are immunized intradermally (i.d.)
in the right hind-footpad with 100 .mu.L of a suspension of mineral
oil (Sigma, cat # M5905) and containing 200 .mu.g M. tuberculosis,
H37RA (Difco, Cat.TM.231141). The inflammation appears in the
contra-lateral (left) hind paw seven days after the initial
immunization. Seven days post immunization, the compound is
formulated in an inert vehicle (for example but not limited to 0.5%
hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02% Tween 80
(Sigma, cat #4780) in water) and dosed orally once or twice a day
for at least 10 days. Baseline paw volume is taken on day 0 using a
water displacement pleythsmograph (Vgo Basile North America Inc. PA
19473, Model #7140). Rats are lightly anesthetized with an inhalant
anesthetic (isoflurane) and the contra-lateral (left) hind paw is
dipped into the plethysmograph and the paw volume is recorded. The
rats are scored every other day up to day 17 after immunization. On
day 17 after immunization, all rats are exsanguinated by cardiac
puncture under isoflurane anesthesia, and the left hind paw is
collected to assess the impact on bone erosion using micro-CT scans
(SCANCO Medical, Southeastern, Pa., Model.TM. .mu.CT 40) at a voxel
size of 18 .mu.m, a threshold of 400, sigma-gauss 0.8,
support-gauss 1.0. Bone volume and density is determined for a 360
.mu.m (200 slice) vertical section encompassing the tarsal section
of the paw. The 360 .mu.m section is analyzed from the base of the
metatarsals to the top of the tibia, with the lower reference point
fixed at the tibiotalar junction. Drug exposure is determined in
the plasma using LC/MS. or the:
Collagen Induced Arthritis (CIA) in a Lewis Rat
[0998] On day -1 Collagen Type II (CII), soluble from bovine nasal
septum (Elastin Products, Cat #CN276) was weighed out for a dose of
600 .mu.g/rat, 0.01M acetic acid (150 .mu.L HOAc USP grade. J. T.
Baker, order#9522-03, and 250 mL Milli Q Water) was added for a
concentration of 4 mg/mL. The vial was covered with aluminum foil
and placed on a rocker at about 4.degree. C. overnight. On day 0
collagen stock solution was diluted 1:1 with Incomplete Freunds
adjuvant (IFA) (Difco labs, cat #263910) using a glass Hamilton
luer lock syringe (SGE Syringe Perfection VWR cat #007230), final
concentration 2 mg/mL. Female Lewis rats (Charles River
Laboratories) acclimated for 7 days at the time of immunization
weighing approximately 150 g were anesthetized in an anesthesia
chamber using isoflurane (5%) and oxygen. Once the rats were
completely anesthetized, they were transferred to a nose cone to
maintain anesthesia during the injections. Rats were shaved at the
base of the tail, 300 .mu.L of collagen was injected i.d. on the
rump of the rat, n=9 per group. 100 .mu.L at three sites with a 500
.mu.L leur lock syringe and a 27 g needle. IFA control rats are
injected in the same manner (n=6). The IFA is a 1:1 emulsion with
the 0.01M acetic acid. Boost was done on day 6 of the study.
Shaving was not done on this day and injections were done in the
same manner as the immunization. The inflammation appears in both
hind paws 10 days after the initial immunization. 10 days post
immunization, the compound was formulated in an inert vehicle (for
example but not limited to 0.5% hydroxypropylmethyl cellulose
(Sigma, cat # H3785)/0.02% Tween 80 (Sigma, cat #4780) in water)
and dosed orally once or twice a day for at least 9 days. Baseline
paw volume was taken on day 7 using a water displacement
pleythsmograph (Vgo Basile North America Inc. PA 19473, Model
#7140). Rats were lightly anesthetized with an inhalant anesthetic
(isoflurane) and both hind paws were dipped into the plethysmograph
and the paw volume was recorded. The rats were scored 2 to 3 times
a week up to day 18 after immunization. On day 18 after
immunization, all rats were exsanguinated by cardiac puncture under
isoflurane anesthesia, and the hind paws were collected to assess
the impact on bone erosion using micro-CT scans (SCANCO Medical,
Southeastern, Pa., Model # .mu.CT 40) at a voxel size of 18 .mu.m,
a threshold of 400, sigma-gauss 0.8, support-gauss 1.0. Bone volume
and density was determined for a 360 .mu.m (200 slice) vertical
section encompassing the tarsal section of the paw. The 360 .mu.m
section was analyzed from the base of the metatarsals to the top of
the tibia, with the lower reference point fixed at the tibiotalar
junction. Drug exposure was determined from plasma using LC/MS.
[0999] Chronic in vivo effects of the compounds on an asthma
disease model is measured using the:
OVA Induced Rat Asthma Model
[1000] Female Brown Norway rats (7-9 weeks of age) were sensitized
on day 0 and 7 with 40 .mu.g ovalbumin (OVA) (Sigma-Aldrich, St.
Louis, Mo.) in a 20 mg/ml solution of Alum Imject (Pierce,
Rockford, Ill.). The rats were subsequently challenged
intratracheally on day 19 and 20 with 1.5 .mu.g OVA in 50 .mu.L
PBS. Dosing of inhibitor began on day 18 and continues through day
22. On day 22, 48 h after the second challenge, rats were subjected
to an anesthetized and restrained pulmonary function test. Airway
hyperresponsiveness (AHR) was assessed using whole body
plethysmography. Briefly, a surgical plane of anesthesia was
induced with an intraperitoneal injection of 60 mg/kg ketamine and
5 mg/kg xylazine (Henry Schein, Inc., Melville, N.Y.). A tracheal
cannula was surgically inserted between the 3rd and 4th tracheal
rings. Spontaneous breathing was prevented by jugular vein
injection of 0.12 mg/kg pancuronium bromide (Sigma-Aldrich, St
Louis, Mo.). Animals were placed in a whole body plethysmograph
(Buxco Electronics, Inc., Wilmington, N.C.) and mechanically
ventilated with 0.2 mL room air at 150 breaths per minute with a
volume controlled ventilator (Harvard Apparatus, Framingham,
Mass.). Pressure in the lung and flow within the plethysmograph
were measured using transducers and lung resistance was calculated
as pressure/flow using Biosystem Xa software (Buxco Electronics).
Airway resistance was measured at baseline and following challenge
with 3, 10, and 30 mg/mL methacholine (Sigma Aldrich, St. Louis,
Mo.) delivered with an inline ultrasonic nebulizer. Upon completion
of pulmonary function testing, the lungs were lavaged 3 times with
1 mL sterile PBS. The volume from the first wash was centrifuged at
2000 rpm for 5 min, and the supernatant is stored for subsequent
analysis. The volume of washes 2 through 3 are added to the pellet
derived from the first wash and subsequently processed for
evaluation of cellular infiltrate by flow cytometry. Plasma was
collected from blood drawn from the vena cava and was used for
evaluation of drug concentrations.
[1001] The teachings of all references, including journal articles,
patents and published patent applications, are incorporated herein
by reference in their entirety.
[1002] The following examples are for illustrative purposes and are
not to be construed as limiting the scope of the present
invention.
General Synthetic Schemes
[1003] Compounds of the invention may be prepared using the
synthetic transformations illustrated in Schemes I-XXVIII. Starting
materials are commercially available, may be prepared by the
procedures described herein, by literature procedures, or by
procedures that would be well known to one skilled in the art of
organic chemistry. Methods for preparing
pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compounds of the
invention are illustrated in Scheme I. In Scheme I, step a,
commercially available 3,5-dibromopyrazin-2-amine 1 is reacted with
a (trimethylsilyl)acetylene via a Sonogashira cross coupling using
methods known to one skilled in the art (for example Example #1 or
WO2006058120A1) to give alkyne 2. Alkyne 2 can be cyclized (Scheme
I, step b) to provide protected pyrrolo[2,3-b]pyrazine 3 using
methods known to one skilled in the art (for example Example #1 or
WO2006058120A1). In Scheme I, step c, a substituted hydrazine is
introduced by reaction with pyrrolopyrazines 3 under
Buchwald-Hartwig amination conditions (for example Example #1 or
Advanced Synthesis & Catalysis 2004, 346, 1599-1626) to give
pyrrolopyrazines 4. If R'' is such that pyrrolopyrazines 4 contain
a hydrazide (R''.dbd.--C(O)R'''), the material may be directly
cyclized to pyrrolotriazolopyrazines 7 (Scheme I, step h) using
conditions such as those described in General Procedures B or ZZZZ
or by methods known to one skilled in the art (for example
Bioorganic & Medicinal Chemistry Letters 2007, 17(12),
3373-3377 or Journal of Medicinal Chemistry 1990, 33(9),
2326-2334). If R'' is a protecting group, deprotection of compounds
4 (Scheme I, step d) to yield hydrazinylpyrrolopyrazines 5 can be
performed using conditions such as those described in General
Procedures E, E.1, F, F.1, Y or BB; or Greene, T. W. and Wuts, P.
G. M. "Protective Groups in Organic Synthesis, 3.sup.rd Edition",
1999, Wiley-Interscience. For example, a protecting group such as a
t-butoxycarbonyl (Boc) group can be removed with acid using
conditions such as those described in Example #1, General
Procedures E and E.1, or by methods known to one skilled in the art
(for example, the books from Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2.sup.nd
edition", 1999, Wiley-VCH or Greene, T. W. and Wuts, P. G. M.
referenced above). The formation of hydrazides 6 from
hydrazinylpyrrolopyrazines 5 (Scheme I, step e) may be accomplished
by a variety of methods known to one skilled in the art including
in situ conditions such as those described in Example #1, General
Procedure A, or standard peptide coupling methods such as those
found in Larock, R. C. referenced above. The hydrazides 6 may be
cyclized to pyrrolotriazolopyrazines 7 using conditions such as
those described in Example #1, General Procedures B, OO, OO.1, or
ZZZZ, or by methods known to one skilled in the art (for example,
Bioorganic & Medicinal Chemistry Letters 2007, 17(12),
3373-3377 or Journal of Medicinal Chemistry 1990, 33(9), 2326-34).
Further functionalization of hydrazides 6 or
pyrrolotriazolopyrazines 7 can be performed, if desired, using
reactions known to one skilled in the art (for example, Larock, R.
C. referenced above). For example, formation of amides, ureas,
sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,
substituted amines, squaramides, or guanidines can be prepared from
pyrrolotriazolopyrazines 7 containing a primary or secondary amine
(for example General Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1,
L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or
EEEEE). Also, deprotection of hydrazides 6 or
pyrrolotriazolopyrazines 7 containing a protected primary or
secondary amine can be performed using conditions such as those
described in Greene, T. W. and Wuts, P. G. M. referenced above or
in General Procedures E, E.1, F, F.1, or BB. For example, for R'''
containing a protecting group such as a benzyloxycarbonyl (Cbz)
group, the protecting group can be removed to yield the unprotected
amine (for example General Procedures F, F.1, and DDDDD) and the
deprotected compounds 7 may then be reacted further as described
above. In some cases, additional reactions may also occur without
isolation of initial pyrrolotriazolopyrazines 7 as seen in General
Procedure C. Alternatively, hydrazinylpyrrolopyrazines 5 may be
directly cyclized to pyrrolotriazolopyrazines 7 (Scheme I, step i)
using conditions such as those described in General Procedure
BBBBB. Removal of the sulfonamide protecting group of
pyrrolotriazolopyrazines 7 may be accomplished using conditions
such as those described in Example #1, General Procedures D, XXX,
AAAA, BBBB, or CCCC or by methods known to one skilled in the art
(for example, the books from Larock, R. C. or Greene, T. W. and
Wuts, P. G. M. referenced above) to give pyrrolotriazolopyrazines 8
(Scheme I, step g). Further functionalization of the R' group in
pyrrolotriazolopyrazines 8 can be performed, if desired, using
reactions known to one skilled in the art (for example, Larock, R.
C. referenced above). For example, amides, ureas, sulfonamides,
aryl amines, heteroaryl amines, sulfonyl ureas, substituted amines,
squaramides, or guanidines can be prepared from
pyrrolotriazolopyrazines 8 with an R' containing a primary or
secondary amine (for example Examples #8-9 or General Procedures G,
H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by
AAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also, deprotection of the
R''' group in pyrrolotriazolopyrazines 8 to yield an unprotected
compound can be performed using conditions such as those described
in Greene, T. W. and Wuts, P. G. M. referenced above or in General
Procedures E, E.1, F, F.1, Y, or BB. For example, a protecting
group such as a benzyloxycarbonyl (Cbz) group can be removed from a
protected amine to yield the unprotected amine (for example General
Procedures F, F.1, and DDDDD) and the deprotected compounds 8 may
then be reacted further as described above.
##STR00022##
[1004] Methods for preparing imidazo[1,2-a]pyrrolo[2,3-e]pyrazines
compounds of the invention are illustrated in Scheme II. In step a,
Pd-mediated carbonylation of pyrrolopyrazines 3 gives esters 9
using methods known to one skilled in the art such as those
described in Example #3; U.S. Pat. Appl. Publ., US 2007293509; or
U.S. Pat. Appl. Publ., US 2008248537. Hydrolysis of esters 9 gives
acids 10 (Scheme II, step b) using well known conditions such as
those described in Example #3 or General Procedure Z. A Curtius
rearrangement is used to prepare carbamates 11 as shown in Scheme
II, step c using conditions such as those described in Example #3
or referenced in Li, J. J. "Name Reactions. A Collection of
Detailed Reaction Mechanisms, 2.sup.nd edition", 2003, Springer:
New York. Alkylation of pyrrolopyrazin-2-ylcarbamates 11 with
appropriately substituted 2-halomethyl ketones (which may be
prepared via procedures such as those described in General
Procedures R and LLLL; Tetrahedron Letters, 1992, (33), 309-312) by
methods known to one skilled in the art (for example General
Procedures S or S.1; Tetrahedron Letters, 2006, 47(34), 6113-6115;
or Journal of Medicinal Chemistry, 2005, 48(14), 4535-4546) yields
pyrrolopyrazines 12 (Scheme II, step d). The deprotection of
pyrrolopyrazines 12 to pyrrolopyrazines 13 (Scheme II, step e) is
accomplished using conditions such as those described in General
Procedures E and E.1, or in Greene, T. W. and Wuts, P. G. M.
referenced above. As shown in Scheme II, step f, cyclization of
pyrrolopyrazines 13 to imidazopyrrolopyrazines 14 can be
accomplished by methods known to one skilled in the art (for
example, General Procedures T or MUCK; Example #3, European Journal
of Medicinal Chemistry, 2001, 36(3), 255-264; or Bioorganic and
Medicinal Chemistry Letters, 2007, 17(5), 1233-1237). Further
functionalization of the R''' group in imidazopyrrolopyrazines 14
can be performed, if desired, using reactions known to one skilled
in the art (for example, Larock, R. C. referenced above). For
example, amides, ureas, sulfonamides, aryl amines, heteroaryl
amines, sulfonyl ureas, substituted amines, squaramides, or
guanidines can be prepared from imidazopyrrolopyrazines 14 with an
R''' group containing a primary or secondary amine (for example,
Example #3, Example #7, or General Procedures G, H, I, J, J.1, XXX,
EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X,
X.1, TTTT, or EEEEE). Also, deprotection of the R''' group in
imidazopyrrolopyrazines 14 to yield deprotected compounds 14 can be
performed using conditions such as those described in Greene, T. W.
and Wuts, P. G. M. referenced above or in General Procedures E,
E.1, F, F.1, Y, or BB and the deprotected compounds 14 may then be
reacted further as described above. Removal of the sulfonamide
protecting group of imidazopyrrolopyrazines 14 may be accomplished
using conditions such as those described in Example #3, General
Procedures D, XXX, AAAA, BBBB, or CCCC or by methods known to one
skilled in the art (for example, the books from Larock, R. C. or
Greene, T. W. and Wuts, P. G. M. referenced above) to give
imidazopyrrolopyrazines 15 (Scheme II, step g).
##STR00023##
[1005] Methods for preparing imidazo[1,5-a]pyrrolo[2,3-e]pyrazines
compounds of the invention are illustrated in Scheme III. In step
a, Pd-mediated cyanation of bromides 3 gives the corresponding
nitriles 16 (for example Example #5 or Tetrahedron Letters 1999,
40(47), 8193-8195). Subsequent reduction of nitriles 16 gives
amines 17 (Scheme III, step b) using methods known to one skilled
in the art (for example Example #5 or Journal of Medicinal
Chemistry 2003, 46(4), 461-473). The coupling of amines 17 with
acids provides amides 18 (Scheme III, step c) using well known
conditions such as those given in Example #5 or General Procedure
H. As shown in Scheme III, step d, the cyclization of amides 18 can
be accomplished by conversion to the thioamide followed by
treatment with an activating agent (such as a mercury salt, a
silver salt or a copper salt) providing the
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 (for example Example #5 or
General Procedure Q). Alternatively, if R''' contains a nitrogen
such that the compounds 18 are ureas instead of amides, then
cyclization to imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 may be
accomplished using POCl.sub.3 as described in General Procedure OO
or OO.1. Deprotection of the sulfonamide of compounds 19 to yield
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 20 (Scheme III, step e) can
be performed using conditions such as those described in Greene, T.
W. and Wuts, P. G. M. "Protective Groups in Organic Synthesis,
3.sup.rd Edition", 1999, Wiley-Interscience, General Procedures D,
XXX, AAAA, BBBB, or CCCC, or Example #5. Further functionalization
of the R''' group in imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 or
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 20 can be performed, if
desired, using reactions known to one skilled in the art (for
example, Larock, R. C. referenced above). For example, formation of
amides, ureas, sulfonamides, aryl amines, heteroaryl amines,
sulfonyl ureas, substituted amines, squaramides, or guanidines can
be prepared from compounds 19 or 20 with an R''' group containing a
primary or secondary amine (for example, Example #6, or General
Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY,
ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also,
deprotection of the R''' group in compounds 19 or 20 to yield an
unprotected compound can be performed using conditions such as
those described in Greene, T. W. and Wuts, P. G. M. referenced
above or in General Procedures E, E.1, F or F.1 and the deprotected
compounds may then be reacted further as described above.
##STR00024##
[1006] Methods for preparing 4-substituted piperidine-3-carboxylic
acid compounds of the invention are illustrated in Scheme IV. In
step a, 4-substituted nicotinic acids 21 may be fully saturated
using methods that are known to one skilled in the art (for
example, General Procedure O or Bioorganic and Medicinal Chemistry
Letters 2004, 14(17), 4453-4459). The resulting piperidines 22 may
be protected with a suitable amine protecting group (Scheme IV,
step b) such as those described in Greene, T. W. and Wuts, P. G. M.
"Protective Groups in Organic Synthesis, 3rd Edition", 1999,
Wiley-Interscience; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2.sup.nd
edition", 1999, Wiley-VCH or General Procedures M, M.1, or N to
give protected piperidines 23.
##STR00025##
[1007] Methods for preparing amino-substituted cyclopentyl
carboxylic acids 32 for use in the preparation of compounds of the
invention are illustrated in Scheme V. In step a, .beta.-ketoesters
24 may be condensed with an alkyl 4-chloroacetoacetate 25 to give
cyclic .beta.-ketoester enolate salts 26 (for example, General
Procedure U). Decarboxylation of compounds 26 to give
.alpha.,.beta.-unsaturated ketones 27 (Scheme V, step b) is
accomplished by standard methods known to one skilled in the art
(for example, General Procedure V). As shown in step c,
hydrogenation of .alpha.,.beta.-unsaturated ketones 27 provides the
saturated ketones 28 (for example, General Procedures W or W.1).
Reductive amination of ketones 28 with dibenzylamine yields
compounds 29 (Scheme V, step d) using conditions such as those
described in General Procedures X or X.1. The debenzylation of
compounds 29 may be accomplished via hydrogenation as described in
General Procedure Y to give amines 30 (Scheme V, step e). Alternate
conditions may be used to access amines 30 from ketones 28, for
example, as described in Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2.sup.nd
edition", 1999, Wiley-VCH (Scheme V, step h) Amines 30 may undergo
further functionalization using reactions known to one skilled in
the art (for example, Larock, R. C. referenced above). For example,
amides, ureas, sulfonamides, aryl amines, heteroaryl amines,
sulfonyl ureas, substituted amines, squaramides, or guanidines can
be prepared from amines 30 (for example, General Procedures G, H,
I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by
AAA, CCC, YYY, X, X.1, TTTT, or EEEEE) to give compounds 31 (Scheme
V, step f). The ester of compounds 31 may be hydrolyzed under
aqueous base or acid conditions to give the desired carboxylic
acids 32 (Scheme V, step g) using conditions such as those
described in General Procedures Z or TT or Larock, R. C. referenced
above). Alternatively, the ester of compounds 29 may be hydrolyzed
to give intermediate carboxylic acids 32' as shown in Scheme V,
step i, using aqueous base or acid conditions (for example,
Preparation #TT.1).
##STR00026##
[1008] Methods for preparing ether-substituted
1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
compounds of the invention are illustrated in Scheme VI. As shown
in step a, reduction of .alpha.,.beta.-unsaturated ketones 27 with
concomitant reduction of the ketone provides the saturated alcohols
33 (for example, the chiral reduction conditions described in
Example #4). Alternate conditions may be used to access alcohols 33
from ketones 28 via reduction (Scheme VI, step b) as described in
General Procedure P or in Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2.sup.nd
edition", 1999, Wiley-VCH. The alcohols 33 may be reacted to give
ethers 34 (Scheme VI, step c) using conditions such as those
described in General Procedure EE (which may require first making
the 2,2,2-trichloroimidate as described in General Procedure UU),
II, JJ, or VV followed by General Procedure FFF or by methods known
to one skilled in the art (for example, Tet. Lett. 1983, 24(48),
5363 or Greene, T. W. and Wuts, P. G. M. "Protective Groups in
Organic Synthesis, 3.sup.rd Edition", 1999, Wiley-Interscience).
The ester of compounds 34 may be hydrolyzed under aqueous base or
acid conditions to give the desired carboxylic acids 35 (Scheme VI,
step d), using conditions such as those described in General
Procedure Z or TT or Larock, R. C. referenced above. The formation
of hydrazides 36 from hydrazinylpyrrolopyrazines 5 and carboxylic
acids 35 (Scheme VI, step e) may be accomplished by a variety of
methods known to one skilled in the art such as those described in
General Procedure A or standard peptide coupling methods such as
those found in Larock, R. C. referenced above. The hydrazides 36
may be cyclized to pyrrolotriazolopyrazines 37 (Scheme VI, step f)
using conditions such as those described in General Procedures B or
ZZZZ or by methods known to one skilled in the art (for example,
Bioorganic & Medicinal Chemistry Letters 2007, 17(12),
3373-3377 or Journal of Medicinal Chemistry 1990, 33(9),
2326-2334). Removal of the sulfonamide protecting group of
pyrrolotriazolopyrazines 37 may be accomplished using conditions
such as those described in General Procedures D, AAAA, BBBB, or
CCCC or by methods known to one skilled in the art (for example,
the books from Larock, R. C. or Greene, T. W. and Wuts, P. G. M.
referenced above) to give pyrrolotriazolopyrazines 38 as final
products or intermediates (Scheme VI, step g). The
pyrrolotriazolopyrazines 38 may be SEM protected (Scheme VI, step
h) using conditions such as those described in General Procedure
KK, or as described in Greene, T. W. and Wuts, P. G. M. referenced
above. If the R'' group in pyrrolotriazolopyrazines 37 or 39 is a
protecting group, it may be deprotected to yield alcohols 40
(Scheme VI, step k) or 43 (Scheme VI, step i), respectively, using
conditions such as those described in Greene, T. W. and Wuts, P. G.
M. referenced above. For example, a protecting group such as a
p-methoxybenzyl (PMB) group can be removed from a PMB-ether to
yield the unprotected alcohol (for example General Procedure FF)
and the deprotected compounds 40 or 43 may then be reacted further.
Mitsunobu reaction of alcohols 40 or 43 may be used to prepare
ethers or esters 41 (Scheme VI, step 1), 44 (Scheme VI, step j), or
45 (Scheme VI, step n) with inversion at the reacting center using
conditions such as those described in General Procedure II or by
methods known to one skilled in the art such as those found in
Larock, R. C. referenced above. Additionally, ethers 44 may be
prepared from alcohols 43 via alkylation using conditions such as
those described in General Procedure HHHH Alternatively, alcohols
40 or 43 may be converted to carbamates 41 or 44 using well-known
conditions such as those described in General Procedures OOO, WWW
and PPPP. Removal of the sulfonamide protecting group of
pyrrolotriazolopyrazines 41 may be accomplished using conditions
such as those described in General Procedures D, AAAA, BBBB, CCCC
or PPPP, or by methods known to one skilled in the art (for
example, the books from Larock, R. C. or Greene, T. W. and Wuts, P.
G. M. referenced above) to give pyrrolotriazolopyrazines 42 (Scheme
VI, step m). The ester group of esters 45 may by cleaved to yield
the unprotected alcohols 46 (Scheme VI, step o) using conditions
such as those described in General Procedure SS. The alcohols 46
can be reacted further to ethers 44 (Scheme VI, step p) via
Mitsunobu chemistry (in a manner as described for Scheme VI, step
j) or by conditions such as those described in General Procedure EE
(which may require first making the 2,2,2-trichloroimidate as
described in General Procedure UU) or JJ or by methods known to one
skilled in the art (for example, the book from Larock, R. C.
referenced above). The SEM protecting group of
pyrrolotriazolopyrazines 44 may be removed by methods such as those
described in General Procedures LL and LL.1, or using conditions
such as described in Greene, T. W. and Wuts, P. G. M. referenced
above to give pyrrolotriazolopyrazines 42 (Scheme VI, step q).
##STR00027##
[1009] An alternate method for preparing ether-substituted
1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
compounds of the invention is illustrated in Scheme VII. As shown
in step a, the ester of compounds 33 may be hydrolyzed under
aqueous base or acid conditions to give the desired carboxylic
acids 47, using conditions such as those described in General
Procedures Z or TT or Larock, R. C. referenced above. The formation
of lactones 48 from carboxylic acids 47 (Scheme VII, step b) may be
accomplished by methods such as those described in Example #4,
General Procedure GG, or by methods known to one skilled in the art
such as those found in Larock, R. C. referenced above. The
formation of hydrazides 49 from hydrazinylpyrrolopyrazines 5 and
lactones 48 (Scheme VII, step c) may be accomplished by a variety
of methods known to one skilled in the art such as those described
in Example #4 or General Procedure HH. The alcohols 49 may be
reacted to form ethers 50 (Scheme VII, step d) using conditions
such as those described in General Procedures VV (which may require
first making the 2,2,2-trichloroimidate as described in General
Procedure UU) or JJ, or by methods known to one skilled in the art
(for example, Tet. Lett. 1983, 24(48), 5363). Mitsunobu reaction of
alcohols 49 may be used to prepare ethers 51 (Scheme VII, step f)
with inversion at the reacting center using conditions such as
those described in Example #4, General Procedure II, or by methods
known to one skilled in the art such as those found in Larock, R.
C. referenced above. The hydrazides 50 or 51 may be cyclized to
pyrrolotriazolopyrazines 37 (Scheme VII, step e) or 41 (Scheme VII,
step g) using conditions such as those described in Example #4,
General Procedures B or ZZZZ, or by methods known to one skilled in
the art (for example, Bioorganic & Medicinal Chemistry Letters
2007, 17(12), 3373-3377 or Journal of Medicinal Chemistry 1990,
33(9), 2326-2334). Further elaboration of 37 or 41 may be performed
as described in Scheme VI.
##STR00028##
[1010] Methods for preparing
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine compounds of the
invention are illustrated in Scheme VIII. As shown in step a,
4-chloro-3-iodopyridin-2-amine 52 may be nitrated to give
4-chloro-3-iodo-5-nitropyridin-2-amine 53 as described in Example
#21 or in Larock, R. C. "Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, 2.sup.nd edition", 1999,
Wiley-VCH. 4-Chloro-3-iodo-5-nitropyridin-2-amine 53 is reacted
with a (trimethylsilyl)acetylene via a Sonogashira cross coupling
using methods known to one skilled in the art (for example Example
#21 or WO2006058120A1) to give
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine 54
(Scheme VIII, step b). As shown in step c,
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine 54 is
deprotected to give the 4-chloro-3-ethynyl-5-nitropyridin-2-amine
55 as described in Example #21 or using methods known to one
skilled in the art (for example, the books from Greene, T. W. and
Wuts, P. G. M. "Protective Groups in Organic Synthesis, 3.sup.rd
Edition", 1999, Wiley-Interscience or Larock, R. C. referenced
above). 4-Chloro-3-ethynyl-5-nitropyridin-2-amine 55 is cyclized,
as shown in step d, to give
4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine 56 as described in
Example #21, or by methods known to one skilled in the art (for
example, as described in WO2008004117). As shown in step e,
amino-substituted 1H-pyrrolo[2,3-b]pyridines 57 are prepared using
methods known to one skilled in the art (for example, Example #21
or Larock, R. C. referenced above). Diamino-substituted
1H-pyrrolo[2,3-b]pyridines 58 (Scheme VIII, step f) are prepared
from the reduction of nitro-containing 1H-pyrrolo[2,3-b]pyridines
57 using methods known to one skilled in the art (for example,
Example #21, General Procedure BBB, or Larock, R. C. referenced
above). As shown in step g, diamino-substituted
1H-pyrrolo[2,3-b]pyridines 58 can be cyclized as described in
Example #21 or General Procedure DDD to give
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59. Further
functionalization of the R group in
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 can be
performed, if desired, using reactions known to one skilled in the
art (for example, Larock, R. C. referenced above). For example,
amides, ureas, sulfonamides, aryl amines, heteroaryl amines,
sulfonyl ureas, substituted amines, squaramides, or guanidines can
be prepared from 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine 59
with an R group containing a primary or secondary amine (for
example General Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L,
DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or
EEEEE). Also, deprotection of the R group in
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 to yield an
unprotected compound can be performed using conditions such as
those described in Greene, T. W. and Wuts, P. G. M. referenced
above or in General Procedures E, E.1, F, F.1, Y, or BB. For
example, a protecting group such as a benzyloxycarbonyl (Cbz) group
can be removed from a protected amine to yield the unprotected
amine (for example General Procedures F, F.1, or Y) and the
deprotected compounds 59 may then be reacted further as described
above. Alternatively, intei mediates 56 or 57 may be sulfonamide
protected using reactions known to one skilled in the art (for
example, Greene, T. W. and Wuts, P. G. M. referenced above or
General Procedure K.1) to give sulfonamides 134 and 135
respectively (Scheme VII, steps h and m). As shown in step i,
amino-substituted 1H-pyrrolo[2,3-b]pyridines 135 may also be
prepared from chloro-substituted 1H-pyrrolo[2,3-b]pyridines 134
using methods known to one skilled in the art (for example, Example
#23 or Larock, R. C. referenced above). Diamino-substituted
1H-pyrrolo[2,3-b]pyridines 136 are prepared from the reduction of
nitro-containing 1H-pyrrolo[2,3-b]pyridines 135 using methods known
to one skilled in the art (for example, Example #23, General
Procedure BBB, or Larock, R. C. referenced above). As shown in step
k, diamino-substituted 1H-pyrrolo[2,3-b]pyridines 136 can be
cyclized as described in Example #23 or General Procedure DDD to
give sulfonamide-protected
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 137. Deprotection
of the sulfonamide of compounds 137 to yield
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridines 59 (Scheme VIII,
step 1) can be performed using conditions such as those described
in Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic
Synthesis, 3.sup.rd Edition", 1999, Wiley-Interscience, General
Procedures D, XXX, AAAA, BBBB, or CCCC or Example #23.
##STR00029##
[1011] Methods for preparing substituted cyclopentyl amines 61 for
use in the preparation of compounds of the invention are
illustrated in Scheme IX. In step a, carboxylic acids 32 are
subjected to a Curtius rearrangement as described in General
Procedure NNN to form isocyanates 60. The hydrolysis of isocyanates
60 yields amines 61 (for example, General Procedure 000).
##STR00030##
[1012] Methods for preparing
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanones
and their derivatives as compounds of the invention are illustrated
in Scheme X. In step a, ketones 28 are protected as ketals 62 using
conditions as described in General Procedure WW or as those
described in Greene, T. W. and Wuts, P. G. M. referenced above. The
ester of compounds 62 may be hydrolyzed under aqueous base
conditions to give the desired carboxylic acids 63 (Scheme X, step
b), using conditions such as those described in General Procedure Z
or Larock, R. C. referenced above. The formation of hydrazides 64
from hydrazinylpyrrolopyrazines 5 and carboxylic acids 63 (Scheme
X, step c) may be accomplished by a variety of methods known to one
skilled in the art such as those described in General Procedure A
or standard peptide coupling methods such as those found in Larock,
R. C. referenced above. The hydrazides 64 may be cyclized to
pyrrolotriazolopyrazines 65 (Scheme X, step d) using conditions
such as those described in General Procedures B or ZZZZ or by
methods known to one skilled in the art (for example, Bioorganic
& Medicinal Chemistry Letters 2007, 17(12), 3373-3377 or
Journal of Medicinal Chemistry 1990, 33(9), 2326-2334). Ketals 65
may be deprotected to yield ketones 66 as described in Preparation
#25 or Greene, T. W. and Wuts, P. G. M. referenced above.
Deprotection of the sulfonamide protecting group of
pyrrolotriazolopyrazines 66 may be accomplished using conditions
such as those described in General Procedures D, AAAA, BBBB, or
CCCC or by methods known to one skilled in the art (for example,
Greene, T. W. and Wuts, P. G. M. referenced above) to give
pyrrolotriazolopyrazines 67 as final products or intermediates
(Scheme X, step f). For example, step g illustrates the formation
of oxime ethers 68 from ketones 67 which may be accomplished using
conditions such as those described in General Procedure PPP or
Larock, R. C. referenced above.
##STR00031##
[1013] Methods for preparing acetic acid and acetamide derivatives
from
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanones
as compounds of the invention are illustrated in Scheme XI. As
shown in step a, Horner-Wadsworth-Emmons reaction of ketones 66 to
give alkenes 69 may be accomplished using procedures known to one
skilled in the art such as those described in General Procedure
III. Deprotection of the sulfonamide protecting group of
pyrrolotriazolopyrazines 69 may be accomplished using conditions
such as those described in General Procedures D, AAAA, BBBB, or
CCCC or by methods known to one skilled in the art (for example,
Greene, T. W. and Wuts, P. G. M. referenced above) to give
pyrrolotriazolopyrazines 70 (Scheme XI, step b). Hydrogenation of
alkenes 70 as described in General Procedures W or W.1 yields
pyrrolotriazolopyrazines 71 (Scheme XI, step c). Hydrolysis of
esters 71 gives acids 72 (Scheme XI, step d) using well known
conditions such as those described in General Procedure Z. The
acids 72 may be further reacted to give amides 73 as shown in step
e using conditions such as those described in General Procedure
H.
##STR00032##
[1014] Methods for preparing
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentylamines
as compounds of the invention are illustrated in Scheme XII. As
shown in step a, reductive amination of ketones 66 to give amines
74 may be accomplished using well known conditions such as those
described in General Procedures X or X.1. Deprotection of the
sulfonamide protecting group of pyrrolotriazolopyrazines 74 may be
accomplished using conditions such as those described in General
Procedures D, AAAA, BBBB, or CCCC or by methods known to one
skilled in the art (for example, Greene, T. W. and Wuts, P. G. M.
referenced above) to give pyrrolotriazolopyrazines 75 (Scheme XII,
step b).
##STR00033##
[1015] Methods for preparing
dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine compounds of the
invention are illustrated in Scheme XIII. In step a, reaction of
5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 76
with a substituted aldehyde provides alcohols 77 using procedures
such as those described in Example #29, Example #30, or in
WO2009152133. Preparation of ketones 78 (step b) can be
accomplished by treatment of alcohols 77 with an oxidizing agent by
methods known to one skilled in the art (for example, Example #29,
Example #30, or Larock, R. C. referenced above). Ketones 78 can
then be converted to hydrazones 79 with the loss of the TIPS
protecting group through reaction with hydrazine using conditions
such as those described in Example #29, Example #30 or General
Procedure XXXX. Cyclization of hydrazones 79 to provide
dihydropyrazolo[4,3-a]pyrrolo[2,3-b]pyridines 80 can be
accomplished via an intramolecular Buchwald-Hartwig cyclization
(for example, General Procedure XX or Organic Letters, 2008,
10(18), 4109-4112). Further functionalization of the R''' group in
dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 can be performed,
if desired, using reactions known to one skilled in the art (for
example, Larock, R. C. referenced above). For example, amides,
ureas, sulfonamides, aryl amines, heteroaryl amines, sulfonyl
ureas, substituted amines, squaramides, or guanidines can be
prepared from dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 with
an R''' group containing a primary or secondary amine (for example,
General Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ,
RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE).
Also, deprotection of the R''' group in
dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 80 to yield
deprotected compounds 80 can be performed using conditions such as
those described in Greene, T. W. and Wuts, P. G. M. referenced
above or in General Procedures E, E.1, F, F.1, Y, or BB and the
deprotected compounds 80 may then be reacted further as described
above.
##STR00034##
[1016] Methods for preparing
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine compounds of
the invention are illustrated in Scheme XIV. In step a,
o-lithiation of
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 81
followed by trapping of the anion with ethyl chloroformate yields
ethyl
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
82 using conditions described in Example #28. The removal of the
TIPS group of 82 may be accomplished as shown in step b to give
ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 83 using
conditions well known in the literature (for example, Greene, T. W.
and Wuts, P. G. M. referenced above or Example #28). In step c,
sulfonamide protected compounds 84 are prepared using reactions
known to one skilled in the art (for example, Greene, T. W. and
Wuts, P. G. M. referenced above or Example #28). As shown in step
d, amino-substituted 1H-pyrrolo[2,3-b]pyridines 85 are prepared
using methods known to one skilled in the art (for example, Example
#28 or Larock, R. C. referenced above). The reduction of esters 85
to alcohols 86 (Scheme XIV, step e) may be accomplished using
conditions well known in the literature (for example, Example #28
or Larock, R. C. referenced above). In step f, alcohols 86 are
oxidized to aldehydes 87 using methods known to one skilled in the
art (for example, Example #28 or Larock, R. C. referenced above).
The Wittig reaction of aldehydes 87 with
((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (Scheme
XIV, step g) yields alkenes 88 using conditions such as those
described in Example #28. Reduction of alkenes 88 may be
accomplished using conditions such as those described in Example
#28 or General Procedures W or W.1 (Scheme XIV, step h). The
cyclization of aminoacetals 89 to give protected
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 90 is
accomplished using conditions described in Example #28 (scheme XIV,
step i). Deprotection of the sulfonamide protecting group of
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 90 may be
accomplished using conditions such as those described in General
Procedures D, AAAA, BBBB, or CCCC or by methods known to one
skilled in the art (for example, Greene, T. W. and Wuts, P. G. M.
referenced above) to give
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 (Scheme
XIV, step j). Further functionalization of the R' group in
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 can be
performed, if desired, using reactions known to one skilled in the
art (for example, Larock, R. C. referenced above). For example,
amides, ureas, sulfonamides, aryl amines, heteroaryl amines,
sulfonyl ureas, substituted amines, squaramides, or guanidines can
be prepared from
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 with an
R' group containing a primary or secondary amine (for example,
General Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ,
RR, YY, ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE).
Also, deprotection of the R' group in
2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridines 91 to yield
deprotected compounds 91 can be performed using conditions such as
those described in Greene, T. W. and Wuts, P. G. M. referenced
above or in General Procedures E, E.1, F, F.1, Y, or BB and the
deprotected compounds 91 may then be reacted further as described
above.
##STR00035##
[1017] Methods for preparing substituted
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines compounds of the invention
are illustrated in Scheme XV. As shown in step a,
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 19 may be halogenated using
conditions such as those described in General Procedure MM to give
3-halo-imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 92. The
3-halo-imidazo[1,5-a]pyrrolo-[2,3-e]pyrazines 92 may undergo a
variety of reactions known to one skilled in the art (for example,
Larock, R. C. referenced above) including, but not limited to,
cyanation as described in General Procedure HHH (Scheme XVI, step
c) or Suzuki coupling reactions such as those described in General
Procedures UUU or VVV (Scheme XV, step b). Deprotection of the
sulfonamide protecting group of
imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 93 may be accomplished using
conditions such as those described in General Procedures D, UUU,
AAAA, BBBB, or CCCC, or by methods known to one skilled in the art
(for example, Greene, T. W. and Wuts, P. G. M. referenced above) to
give imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 94 (Scheme XV, step
c).
##STR00036##
[1018] Methods for preparing
pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compounds of the
invention are illustrated in Scheme XVI. Pyrrolotriazolopyrazines 8
may be halogenated using conditions such as those described in
General Procedures GGG or GGG.1 to give
8-halopyrrolotriazolo-pyrazines 95 (Scheme XVI, step a). In step b,
8-halopyrrolotriazolopyrazines 95 may be protected with a SEM group
using conditions known in the literature such as those found in
Greene, T. W. and Wuts, P. G. M. referenced above or as in General
Procedure KK. The resulting SEM-protected
8-halopyrrolotriazolopyrazines 96 may undergo a variety of
reactions known to one skilled in the art (for example, Larock, R.
C. referenced above) including, but not limited to, cyanation as
described in General Procedure HHH (Scheme XVI, step c), Suzuki
coupling reactions as described in Preparation #23, formation of a
carboxylic ester as described in General Procedure AAAAA, or Stille
coupling reactions as described in General Procedure CCCCC (Scheme
XVI, step e). The resulting products 97 or 99 may be deprotected
using conditions such as those described in General Procedure LL,
LL.1, or by methods known to one skilled in the art (for example,
Greene, T. W. and Wuts, P. G. M. referenced above) to give
pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines 98 or 100 (Scheme XV,
steps d and f, respectively). Additionally, compounds 99 and 100
may undergo further functionalization, if desired, using reactions
known to one skilled in the art (for example, Larock, R. C.
referenced above). For example, for R=CO.sub.2Et, the compound may
be hydrolyzed using conditions such as those described in General
Procedure D and then undergo amide bond formation as described in
General Procedure H.
##STR00037##
[1019] Methods for preparing substituted
4-(sulfonamidomethyl)cyclopentanecarboxylic acids 110 for use in
the preparation of compounds of the invention are illustrated in
Scheme XVII. In step a, 5-substituted-bicyclo[2.2.1]hept-2-enes 101
are oxidized to dicarboxylic acids 102 using known conditions such
as those described in Preparation #11, Bioorganic & Medicinal
Chemistry, 2007, 15, 7581, or Journal of Organic Chemistry, 1993,
58, 4745. Formation of the mono-esters 103 are achieved through the
cyclic anhydride as described in Preparation #11 (Scheme XVII, step
b). The t-butyl esters 104 are prepared in step c using standard
condition such as those described in Preparation #11 or Larock, R.
C. referenced above. Reduction of the methyl ester of compounds 104
to alcohols 105 is achieved using well known conditions such as
those found in Preparation #21 (Scheme XVII, step d). The mesylates
106 are prepared as described in Preparation #21 or by methods
known to one skilled in the art (Scheme XVII, step e). As shown in
step f, the mesylates 106 may be used to form azides 107 using well
known conditions such as those described in Preparation #21 or
Larock, R. C. referenced above (Scheme XVII, step f). The reduction
of azides 107 to amines 108 is a standard transformation that may
be accomplished as described in Preparation #21 or using conditions
such as those described in General Procedure TTT or in Larock, R.
C. referenced above (Scheme XVII, step g). Step h shows the
formation of sulfonamides 109 from amines 108 which is achieved as
described in General Procedures K or K.1 or by methods known to one
skilled in the art (for example, Greene, T. W. and Wuts, P. G. M.
referenced above). The acidic cleavage of t-butyl esters 109 to
give 4-(sulfonamidomethyl)cyclopentanecarboxylic acids 110 (Scheme
XVII, step i) may be done with the conditions described in General
Procedure QQQ or with methods known to one skilled in the art (for
example, the books from Larock, R. C. or Greene, T. W. and Wuts, P.
G. M. referenced above).
##STR00038##
[1020] Methods for preparing
4-((dibenzylamino)methyl)-2-substituted-cyclopentanecarboxylic
acids 115 for use in the preparation of compounds of the invention
are illustrated in Scheme XVIII. Reduction of the methyl ester of
compounds 103 to alcohols 111 is achieved using well known
conditions such as those found in Preparation #22 or Larock, R. C.
referenced above (Scheme XVIII, step a). Step b illustrates the
formation of esters 112 which is achieved as described in
Preparation #22 or Larock, R. C. referenced above. In step c,
alcohols 112 are oxidized to aldehydes 113 using known conditions
such as those described in Preparation #22 or Larock, R. C.
referenced above. The reductive amination of aldehydes 113 using
conditions such as those described in General Procedures X or X.1
gives amines 114 (Scheme XVIII, step d). In step e, esters 114 are
hydrolyzed to give
4-((dibenzylamino)methyl)-2-substituted-cyclopentanecarboxylic
acids 115 using conditions such as those described in General
Procedures Z or TT or known to one skilled in the art (for example,
the books from Larock, R. C. or Greene, T. W. and Wuts, P. G. M.
referenced above).
##STR00039##
[1021] Methods for preparing
3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine compounds of the
invention are illustrated in Scheme XIX. Alkylation of
pyrrolopyrazin-2-ylcarbamates 11 with t-butyl 2-bromoacetate, by
methods known to one skilled in the art (for example, General
Procedures S or S.1), gives pyrrolopyrazines 116 (Scheme XIX, step
a). The double deprotection of pyrrolopyrazines 116 to aminoacetic
acids 117 may be accomplished using conditions such as those
described in General Procedures E, E.1, or QQQ (Scheme XIX, step
b). The coupling of acids 117 with amines provides amides 118
(Scheme XIX, step c) using well known conditions such as those
given in General Procedure H or Larock, R. C. referenced above. As
shown in step d, the cyclization of amides 118 to
imidazopyrrolopyrazin-8-amines 119 may be accomplished using
conditions such as those described in General Procedures OO or
OO.1. Further functionalization of the R' or R'' group in
imidazopyrrolopyrazin-8-amines 119 can be performed, if desired,
using reactions known to one skilled in the art (for example,
Larock, R. C. referenced above). For example, amides, ureas,
sulfonamides, aryl amines, heteroaryl amines, sulfonyl ureas,
substituted amines, squaramides, or guanidines can be prepared from
imidazopyrrolopyrazin-8-amines 119 with an R' or R'' group
containing a primary or secondary amine (for example, General
Procedures G, H, I, J, J.1, XXX, EEEE, K, K.1, L, DD, QQ, RR, YY,
ZZ followed by AAA, CCC, YYY, X, X.1, TTTT, or EEEEE). Also,
deprotection of the of the R' or R'' group in
imidazopyrrolopyrazin-8-amines 119 to yield deprotected compounds
119 can be performed using conditions such as those described in
Greene, T. W. and Wuts, P. G. M. referenced above or in General
Procedures E, E.1, F, F.1, Y, or BB and the deprotected compounds
119 may then be reacted further as described above. Removal of the
sulfonamide protecting group of imidazopyrrolopyrazin-8-amines 119
may be accomplished using conditions such as those described in
General Procedures D, XXX, AAAA, BBBB, or CCCC or by methods known
to one skilled in the art (for example, the books from Larock, R.
C. or Greene, T. W. and Wuts, P. G. M. referenced above) to give
imidazopyrrolopyrazin-8-amines 120 (Scheme XIX, step e).
##STR00040##
[1022] Methods for preparing pyrrolidine-3-carboxylic acids 125 for
use in the preparation of compounds of the invention are
illustrated in Scheme XX. In step a, alkynes 121 are reduced to
alkenes 122 as described in General Procedure RRR or using methods
known to one skilled in the art (for example, Larock, R. C.
referenced above). The 1,3-dipolar cycloaddition of alkenes 122 and
N-substituted-1-methoxy-N-((trimethylsilyl)methyl)methanamine 123
to give pyrrolidines 124 (Scheme XX, step b) can be accomplished by
methods known to one skilled in the art (for example, General
Procedure SSS or Journal of Medicinal Chemistry, 2009, 52(24),
7946-7949). The ester of compounds 124 may be hydrolyzed under
aqueous base or acid conditions to give carboxylic acids 125
(Scheme XX, step c) using conditions such as those described in
General Procedures Z or TT or Larock, R. C. referenced above.
##STR00041##
[1023] Methods for preparing sulfone-substituted
1-cyclopentyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
compounds of the invention are illustrated in Scheme XXI. As shown
in step a, Mitsunobu reaction of alcohols 46 with appropriate
thiols gives sulfides 126 using conditions such as those described
in General Procedure MMM or by methods known to one skilled in the
art (for example, Larock, R. C. referenced above). The oxidation of
sulfides 126 to sulfones 127 (Scheme XXI, step b) is accomplished
as described in General Procedure LLL or by methods known to one
skilled in the art (for example, Larock, R. C. referenced above).
The SEM protecting group of pyrrolotriazolopyrazines 127 may be
removed by methods such as those described in General Procedures LL
and LL.1, or using conditions such as described in Greene, T. W.
and Wuts, P. G. M. referenced above to give
pyrrolotriazolopyrazines 128 (Scheme XXI, step c).
##STR00042##
[1024] Methods for preparing sulfonyl chlorides 133 for use in the
preparation of compounds of the invention are illustrated in Scheme
XXII. In step a, sulfonates 130 are prepared from sulfonyl
chlorides 129 using known reaction conditions such as those
described in Preparation #6 Step A, WO2007014011, or WO2009018238.
An additional substitutent is added to sulfonates 130 to give
sulfonates 131 via alkylation as described in General Procedure
KKK, WO2007014011, or WO2009018238 (Scheme XXII, step b). In step
c, potassium sulfonates 132 are prepared from sulfonates 131 with
aqueous potassium cyanate using conditions such as those in General
Procedure JJJ, WO2007014011, or WO2009018238. Potassium sulfonates
132 are converted to sulfonyl chlorides 133 (Scheme XXII, step d)
using thionyl chloride as described in General Procedure EEE,
WO2007014011, or WO2009018238.
##STR00043##
[1025] Methods for preparing imidazopyrrolo[2,3-e]pyrazines
compounds of the invention are illustrated in Scheme XXIII.
Imidazopyrrolopyrazines 15 [T=N, U.dbd.CH] or 20 [T=CH, U.dbd.N]
may be halogenated using conditions such as those described in
General Procedures GGG or GGG.1 to give
8-haloimidazopyrrolopyrazines 138 (Scheme XXIII, step a). In step
b, 8-haloimidazopyrrolopyrazines 138 may be protected with a SEM
group using conditions known in the literature such as those found
in Greene, T. W. and Wuts, P. G. M. referenced above or as in
General Procedure KK. The resulting SEM-protected
8-haloimidazopyrrolopyrazines 139 may undergo a variety of
reactions known to one skilled in the art (for example, Larock, R.
C. referenced above) including, but not limited to, cyanation as
described in General Procedure HHH (Scheme XXIII, step c) or Suzuki
coupling reactions as described in General Procedure WV or Stille
coupling reactions as described in General Procedure CCCCC (Scheme
XXIII, step e). The resulting products 140 or 142 may be
deprotected using conditions such as those described in General
Procedures LL and LL.1, or by methods known to one skilled in the
art (for example, Greene, T. W. and Wuts, P. G. M. referenced
above) to give imidazopyrrolo[2,3-e]pyrazines 141 or 143 (Scheme
XXIII, steps d and f, respectively).
##STR00044##
[1026] Methods for preparing compounds of the invention from a
common ketone intermediate are illustrated in Scheme XXIV. As shown
in scheme XXIV, step a, ketones 144 may be reacted with an alkyl
lithium or a Grignard reagent to give alcohols 145 using conditions
known to one skilled in the art (for example, Larock, R. C.
referenced above or General Procedure ZZZ). Alternatively, ketones
144 may undergo a Horner-Wadsworth-Emmons reaction with a reagent
such as ethyl 2-(diethoxyphosphoryl)acetate (R'''=CO.sub.2Et) or
diethyl cyanomethylphosphonate (R'''.dbd.CN) as described in
General Procedure III to give alkenes 146 (Scheme XXIV, step b).
Alkenes 146 may be hydrogenated to alkanes 147 using well-known
conditions such as those described in General Procedure W and W.1
(Scheme XXIV, step c). The R''' group may be further functionalized
using a variety of reactions such as those described in Larock, R.
C. referenced above. For example, for R'''=CO.sub.2Et, alcohols 148
can be prepared as described in General Procedure ZZZ (Scheme XXIV,
step d) or oxadiazoles 149 may be prepared as described in General
Procedure DDDD (Scheme XXIV, step e). As shown in scheme XXIV, step
f, ketones 144 may also be reduced to alcohols 150 as described in
General Procedure P or in Larock, R. C. referenced above. Mesylates
151 are formed from alcohols 150 using conditions known to one
skilled in the art such as those described in General Procedure
IIII (Scheme XXIV, step g) and can be reacted with a variety of
nucleophiles (Nu) as described in General Procedure JJJJ (Scheme
XXIV, step h) to give compounds 152. Depending on the nucleophile
used, further functionalization can be done to give compounds 153
(Scheme XXIV, step i). These functionalizations may be accomplished
using methods such as those described in Larock, R. C. referenced
above or General Procedures QQQQ or UUUU.
##STR00045##
[1027] Methods for preparing
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine compounds of
the invention are illustrated in Scheme XXV. Diamines 136 (Scheme
XVIII) may be reacted with cyanogen bromide as described in General
Procedure RRRR (Scheme XXV, step a). The resulting
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 154 may be
further further functionalized, if desired, using reactions known
to one skilled in the art (see, for example, Larock, R. C. above)
to give 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 155
(Scheme XXV, step b). Removal of the sulfonamide protecting group
of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 155 or
154 may be accomplished using conditions such as those described in
General Procedures D, AAAA, BBBB, or CCCC or by methods known to
one skilled in the art (for example, the books from Larock, R. C.
or Greene, T. W. and Wuts, P. G. M. referenced above) to give
1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 156 or 157,
respectively (Scheme XXV, steps c and d).
##STR00046##
[1028] Methods for preparing
1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridine compounds
of the invention are illustrated in Scheme XXV. Diamines 136
(Scheme XVIII) may be reacted with sodium nitrite as described in
General Procedure SSSS to give
1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridines 158
(Scheme XXVI, step a). Removal of the sulfonamide protecting group
of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amines 158 may
be accomplished using conditions such as those described in General
Procedures D, AAAA, BBBB, or CCCC or by methods known to one
skilled in the art (for example, the books from Larock, R. C. or
Greene, T. W. and Wuts, P. G. M. referenced above) to give
1,6-dihydropyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridines 159
(Scheme XXV, step b).
##STR00047##
[1029] Alternate methods for preparing the ketone intermediate used
to make dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine compounds of
the invention are illustrated in Scheme XXVII. In step a,
carboxylic acids 160 are converted to the corresponding acid
chlorides 161 using conditions widely known to one skilled in the
art such as those described in General Procedure WWWW. Acid
chlorides 161 are reacted with
5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 162 as
described in General Procedure VVVV (Scheme XXVII, step b) to give
ketones 78 which may be further reacted as described in Scheme
XIII.
##STR00048##
[1030] Alternate methods for preparing
imidazo[1,2-a]pyrrolo[2,3-e]pyrazines compounds of the invention
are illustrated in Scheme XXVIII. In step a, carboxylic acids 160
are converted to the corresponding sulfoxonium ylides 163 using
conditions such as those described in General Procedure FFFFF or J.
Org. Chem. 2004, 69, 1629. Pyrrolopyrazin-2-amines 164 may be
prepared from pyrrolopyrazin-2-ylcarbamates 11 (Scheme II) using
conditions known to one skilled in the art such as those described
in General Procedure E or Greene, T. W. and Wuts, P. G. M.
referenced above (Scheme XXVIII, step b). Sulfoxonium ylides 163
are reacted with pyrrolopyrazin-2-amines 164 using conditions such
as those described in General Procedure GGGGG or Org. Lett. 2009,
11, 3566 to give pyrrolopyrazines 13 which may be further reacted
as described in Scheme II (Scheme XXVIII, step c). Alternatively,
as shown in step d, pyrrolopyrazin-2-amines 164 may be reacted with
an .alpha.-haloaldehyde using conditions such as those given in
General Procedure YYYY to give imidazopyrrolopyrazines 14 which may
be further reacted as described in Scheme II.
##STR00049##
[1031] If desired, chiral separation of any of the chiral compounds
in Schemes I-XXVIII may be done using methods known to one skilled
in the art such as chiral preparative HPLC or chiral SFC (for
example, General Procedure AA) or crystallization of diastereomeric
salts as described in Example #5. Further functionalization of any
of the R groups above (e.g. R, R'', R''', R'', and R''') can be
performed, if desired, using reactions known to one skilled in the
art (for example, Larock, R. C. referenced above). For example,
formation of amides, ureas, sulfonamides, aryl amines, heteroaryl
amines, sulfonyl ureas, substituted amines, squaramides, or
guanidines can be prepared with an R group containing a primary or
secondary amine (for example, General Procedures G, H, I, J, J.1,
XXX, EEEE, K, K.1, L, DD, QQ, RR, YY, ZZ followed by AAA, CCC, YYY,
X, X.1, TTTT, or EEEEE). Also, deprotection of an R group to yield
deprotected compounds may be performed using conditions such as
those described in Greene, T. W. and Wuts, P. G. M. referenced
above or in General Procedures E, E.1, F, F.1, Y, or BB and the
deprotected compounds may then be reacted further as described
above.
GENERAL PROCEDURES AND EXAMPLES
[1032] The general synthetic schemes that were utilized to
construct the majority of compounds disclosed in this application
are described below in Schemes 1-111. These schemes are provided
for illustrative purposes only and are not to be construed as
limiting the scope of the invention.
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List of General Procedures
[1033] General Procedure A Formation of a hydrazide from a
carboxylic acid [1034] General Procedure B Cyclization of a
hydrazide [1035] General Procedure C Cyclization of a hydrazide
with loss of Boc-protecting group [1036] General Procedure D
Hydrolysis of a sulfonamide [1037] General Procedure E Acidic
cleavage of a Boc-protected amine [1038] General Procedure E.1
Acidic cleavage of a Boc-protected amine [1039] General Procedure F
Deprotection of a Cbz-protected amine using HBr in AcOH [1040]
General Procedure G Formation of an acetamide [1041] General
Procedure H Formation of an amide from a carboxylic acid and an
amine [1042] General Procedure I Formation of a urea from an amine
and a carbamoyl chloride [1043] General Procedure J Formation of a
urea or thiourea using CDI or thiocarbonyl diimidazole,
respectively [1044] General Procedure K Formation of a sulfonamide
from an amine [1045] General Procedure K.1 Formation of a
sulfonamide from an amine or nitrogen containing heterocycle [1046]
General Procedure L Displacement of an aryl or heteroaryl halide
with an amine [1047] General Procedure M Boc-protection of an amine
[1048] General Procedure M.1 Boc-protection of a
nitrogen-containing compound [1049] General Procedure N
Cbz-protection of an amine [1050] General Procedure O Reduction of
a pyridine [1051] General Procedure P Reduction of carbonyl to an
alcohol [1052] General Procedure Q Cyclization of an amide using a
dithiaphosphetane reagent [1053] General Procedure R Formation of a
bromomethyl ketone from an acid [1054] General Procedure S
N-Alkylation using an alkyl halide or .alpha.-haloketone [1055]
General Procedure T Cyclization of a ketone using a
dithiaphosphetane reagent [1056] General Procedure U Knoevenagel
condensation to form a substituted cyclopentadiene [1057] General
Procedure V Decarboxylation of a .beta.-ketoester enolate [1058]
General Procedure W Hydrogenation of an alkene [1059] General
Procedure W.1 Hydrogenation of an alkene [1060] General Procedure X
Reductive amination of a ketone or aldehyde [1061] General
Procedure X.1 Reductive amination of a ketone or aldehyde [1062]
General Procedure Y Hydrogenation of a benzyl- or Cbz-protected
amine [1063] General Procedure Z Basic hydrolysis of an ester to a
carboxylic acid [1064] General Procedure AA Chiral preparative HPLC
separation of stereoisomers [1065] General Procedure BB Acidic
hydrolysis of an acetyl protected amine [1066] General Procedure CC
Formation of a sulfamoyl chloride [1067] General Procedure DD
Formation of a sulfonylurea [1068] General Procedure EE Ether
formation from a trichloroacetimidate derivative [1069] General
Procedure FF Deprotection of a PMB-protected alcohol [1070] General
Procedure GG Formation of a lactone [1071] General Procedure HH
Opening of a lactone with an amine or hydrazine [1072] General
Procedure II Mitsunobu reaction of an alcohol [1073] General
Procedure JJ Displacement of a halide with an alcohol [1074]
General Procedure KK SEM protection of a nitrogen [1075] General
Procedure LL SEM deprotection of a nitrogen [1076] General
Procedure MM Halogenation of an imidazole [1077] General Procedure
NN Formation of an amide from a carboxylic acid and an amine with
loss of a sulfonamide protecting group [1078] General Procedure OO
Cyclization with POCl.sub.3 [1079] General Procedure OO.1
Cyclization with POCl.sub.3 [1080] General Procedure PP Reaction of
an amine with an aryl boronic acid [1081] General Procedure QQ
Formation of a urea from an amine and an isocyanate [1082] General
Procedure RR Formation of a urea from an amine, a heteroaryl amine
and phenyl chloro fog mate [1083] General Procedure SS Hydrolysis
of an ester to an alcohol [1084] General Procedure TT Acid-mediated
conversion of an ester to a carboxylic acid [1085] General
Procedure UU Formation of a 2,2,2-trichloroacetimidate [1086]
General Procedure VV Formation of a TBDMS-protected alcohol [1087]
General Procedure WW Formation of a ketal [1088] General Procedure
XX Palladium catalyzed coupling of a hydrazone [1089] General
Procedure YY Michael addition of an amine to an
.alpha.,.beta.-unsaturated sulfonamide [1090] General Procedure ZZ
Formation of an oxazolidinone sulfonourea [1091] General Procedure
AAA Formation of a sulfonylurea from an oxazolidinone sulfonourea
[1092] General Procedure BBB Reduction of a nitro group [1093]
General Procedure CCC Formation of an amide [1094] General
Procedure DDD Cyclization to form a fused imidazole [1095] General
Procedure EEE Formation of a sulfonyl chloride [1096] General
Procedure FFF Generation of an ether under reductive conditions
[1097] General Procedure GGG Iodination, chlorination or
bromination of a heterocycle or halogenation of a heterocycle
[1098] General Procedure GGG.1 Iodination of a heterocycle or
halogenation of a heterocycle [1099] General Procedure HHH
Cyanation of a heterocycle [1100] General Procedure III
Horner-Wadsworth-Emmons reaction of a ketone [1101] General
Procedure JJJ Formation of a potassium sulfonate [1102] General
Procedure KKK Alkylation of a sulfonate [1103] General Procedure
LLL Oxidation of a thioether to a sulfone [1104] General Procedure
MMM Mitsunobu reaction using a thiol [1105] General Procedure NNN
Curtius reaction to form an isocyanate [1106] General Procedure OOO
Hydrolysis of an isocyanate [1107] General Procedure PPP Formation
of an oxime ether from a ketone [1108] General Procedure QQQ
TFA-mediated conversion of a t-butyl ester to a carboxylic acid
[1109] General Procedure RRR Reduction of an alkyne to an alkene
[1110] General Procedure SSS 1,3-Dipolar cycloaddition to form a
pyrrolidine [1111] General Procedure TTT Hydrogenation of an azide
to an amine [1112] General Procedure UUU Reaction of an aryl or
heteroaryl halide with a boronic acid or boronate ester followed by
tosyl deprotection [1113] General Procedure VVV Reaction of an aryl
or heteroaryl halide with a boronic acid or boronate ester [1114]
General Procedure WWW Formation of a carbamate [1115] General
Procedure XXX Urea formation with loss of protecting group [1116]
General Procedure YYY Michael addition [1117] General Procedure ZZZ
Grignard or alkyl lithium addition to a carbonyl-containing
compound [1118] General Procedure AAAA Deprotection of a
sulfonamide with DBU [1119] General Procedure BBBB Deprotection of
a sulfonamide with TBAF [1120] General Procedure CCCC Deprotection
of a sulfonamide with KCN [1121] General Procedure DDDD Formation
of an oxadiazole [1122] General Procedure EEEE Formation of a urea
using phosgene [1123] General Procedure FFFF Formation of an amide
from an ester [1124] General Procedure GGGG Formation of a nitrile
from a primary amide [1125] General Procedure HHHH O-alkylation
with KOH or NaOH and TBAB [1126] General Procedure IIII Formation
of a mesylate [1127] General Procedure JJJJ Displacement of an
alkyl mesylate, tosylate, or halide with a nucleophile [1128]
General Procedure KKKK Cyclization of a ketone using TFAA or PFPAA
[1129] General Procedure LLLL Formation of a bromoketone from a
ketone or an aldehyde [1130] General Procedure MMMM Formation of a
ketone from a Weinreb amide [1131] General Procedure NNNN Formation
of .beta.-hydroxysulfonamide from a ketone [1132] General Procedure
OOOO Formation of a phenyl carbonate [1133] General Procedure PPPP
Formation of a carbamate followed by sulfonamide hydrolysis [1134]
General Procedure QQQQ Oxidation of an alkyl thioacetate to an
alkyl sulfonic acid [1135] General Procedure RRRR Cyclization of a
diamine with cyanogen bromide [1136] General Procedure SSSS
Cyclization of a diamine with NaNO.sub.2 [1137] General Procedure
TTTT Formation of a squaramide [1138] General Procedure UUUU
Reduction of an azide to an amine [1139] General Procedure VVVV
Formation of a ketone from a heteroaryl halide [1140] General
Procedure WWWW Formation of an acid chloride [1141] General
Procedure XXXX Formation of a hydrazone [1142] General Procedure
YYYY Cyclization with an .alpha.-haloaldehyde [1143] General
Procedure ZZZZ Cyclization of a hydrazide followed by hydrolysis of
a sulfonamide [1144] General Procedure AAAAA Formation of a
carboxylic acid or ester from an aryl halide [1145] General
Procedure BBBBB Cyclization with an orthoformate [1146] General
Procedure CCCCC Stille coupling of an aryl or heteroaryl halide
[1147] General Procedure DDDDD Deprotection of a Cbz-protected
amine using triethylsilane [1148] General Procedure EEEEE Formation
of a guanidine [1149] General Procedure FFFFF Formation of a
sulfoxonium ylide [1150] General Procedure GGGGG Reaction of a
sulfoxonium ylide with an amine
[1151] The following examples are ordered according to the final
general procedure used in their preparation. The synthetic routes
to any novel intermediates are detailed by sequentially listing the
general procedure (letter codes) in parentheses after their name
with additional reactants or reagents as appropriate. A worked
example of this protocol is given below using Preparation #Z.1 as a
non-limiting illustration. Preparation #Z.1 is
(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carbox-
ylic acid, which was prepared from (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane carboxylate using
General Procedure Z as represented in Scheme A.
##STR00161##
The precursor to Preparation #Z.1, (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate, was
prepared (as shown in Scheme B) by initially reacting ethyl
4-amino-2-ethylcyclopentanecarboxylate (Preparation #Y.1) with the
commercially available cyclopropanesulfonyl chloride, following the
conditions given in General Procedure K, to give ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a
mixture of stereoisomers. This mixture of stereoisomers is
separated as described in General Procedure AA, using the
conditions from Method 1 in Table 2, to give the precursor to
Preparation #Z.1, (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate as a
single enantiomer with a retention time of 9.5 minutes and a
negative optical rotation. The reaction sequence to synthesize the
precursor to Preparation #Z.1, (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate,
(detailed above) is consequently translated in the preparations and
examples section to: (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate
(prepared using K from Preparation #Y.1 and cyclopropanesulfonyl
chloride, AA [Table 2, Method 1, R.sub.t=9.5 min, or =negative]).
Hence the Preparation #Z.1 would be written as: Preparation #Z.1
was prepared from (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane carboxylate
(prepared using K from Preparation #Y.1 and cyclopropanesulfonyl
chloride, AA [Table 2, Method 1, R.sub.t=9.5 min, or =negative])
using General Procedure Z.
##STR00162##
Analytical Methods
[1152] Analytical data was included within the procedures below, in
the illustrations of the general procedures, or in the tables of
examples. Unless otherwise stated, all .sup.1H NMR data were
collected on a Varian Mercury Plus 400 MHz or a Varian Inova 600
MHz instrument and chemical shifts are quoted in parts per million
(ppm). LC/MS and HPLC data are referenced to the table of LC/MS and
HPLC conditions using the lower case method letter provided in
Table 1.
TABLE-US-00003 TABLE 1 LC/MS and HPLC methods Method Conditions a
LC/MS: The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min
with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile
phase A was 10 mM NH.sub.4OAc, mobile phase B was HPLC grade MeCN.
The column used for the chromatography is a 4.6 .times. 50 mm
MAC-MOD Halo C18 column (2.7 .mu.m particles). Detection methods
are diode array (DAD) and evaporative light scattering (ELSD)
detection as well as positive/negative electrospray ionization. b
LC/MS: The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min
with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile
phase A was 10 mM NH.sub.4OAc, mobile phase B was HPLC grade MeCN.
The column used for the chromatography is a 4.6 .times. 50 mm
MAC-MOD Halo C8 column (2.7 .mu.m particles). Detection methods are
diode array (DAD) and evaporative light scattering (ELSD) detection
as well as positive/negative electrospray ionization. c LC/MS: The
gradient was 5-60% B in 0.75 min then 60-95% B to 1.15 min with a
hold at 95% B for 0.75 min (1.3 mL/min flow rate). Mobile phase A
was 10 mM NH.sub.4OAc, mobile phase B was HPLC grade MeCN. The
column used for the chromatography was a 4.6 .times. 50 mm MAC-MOD
Halo C8 column (2.7 .mu.m particles). Detection methods are diode
array (DAD) and evaporative light scattering (ELSD) detection as
well as positive/negative electrospray ionization. d HPLC: The
gradient was 5-100% B over 40 min, hold at 100% for 5 min, 2 min
back to 5% B, hold at 5% B for 4 min (21 mL/min flow rate). Mobile
phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC
grade MeCN. The column used for the chromatography was a 21.2
.times. 250 mm Hypersil C18 HS column (8 .mu.m particles).
Detection method was UV. e HPLC: The gradient was 1-5% B over 3 min
then 5-55% B over 6 min with a hold at 55% B for 0.10 min then
55-95% B over 1.5 min (22.5 mL/min flow rate). Mobile phase A was
50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC grade MeCN,
the column used for the chromatography was a 19 .times. 50 mm
Waters Atlantis T3 OBD C18 column (5 .mu.m particles), detection
methods are Photodiode array DAD and Waters ZQ 2000 mass
spectrometer. f HPLC: The gradient was 10-75% B over 9 min with a
hold at 75% for 0.10 min then 75%-100% B over 1.5 min (22.5 mL/min
flow rate). Mobile phase A was 50 mM NH4OAc (pH 4.5) and mobile
phase B was HPLC grade MeCN, the column used for the chromatography
was a 19 .times. 50 mm Waters Atlantis T3 OBD C18 column (5 .mu.m
particles), detection methods were Photodiode array DAD and Waters
ZQ 2000 mass spectrometer. g HPLC: The gradient was 10% B over 2.5
min then 10-15% B over 0.50 min then 15-75% B over 3 min then
75-85% B over 3.10 min then 85%-100% B over 1.5 min (22.5 mL/min
flow rate). Mobile phase A was 50 mM NH.sub.4OAc (pH 4.5) and
mobile phase B was HPLC grade MeCN, the column used for the
chromatography was a 19 .times. 50 mm Waters Atlantis T3 OBD C18
column (5 .mu.m particles), detection methods were Waters 2996
photodiode array DAD and Waters ZQ 2000 mass spectrometer. h HPLC:
The gradient was 10-85% B over 9.00 min then 85-95% B over 0.10 min
then held at 95% B for 1.50 min (25.0 mL/min flow rate). Mobile
phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC
grade MeCN, the column used for the chromatography was a 19 .times.
50 mm Waters Atlantis T3 OBD C18 column (5 .mu.m particles),
detection methods were Waters 2996 photodiode array DAD and Waters
ZQ 2000 mass spectrometer. i HPLC: The gradient was 10-35% B over
45 min (25 mL/min flow rate). Mobile phase A was 50 mM NH.sub.4OAc
(pH 4.5) and mobile phase B was HPLC grade MeCN. The column used
for the chromatography was a 21.2 .times. 250 mm Hypersil C18 HS
column (8 .mu.m particles). Detection method was UV. j HPLC: The
gradient was 5-75% B over 25 min (21 mL/min flow rate). Mobile
phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC
grade MeCN. The column used for the chromatography was a 21.2
.times. 250 mm Hypersil C18 HS column (8 .mu.m particles).
Detection method was UV. k HPLC: The gradient was 20-40% B over 30
min (21 mL/min flow rate). Mobile phase A was 50 mM NH.sub.4OAc (pH
4.5) and mobile phase B was HPLC grade MeCN. The column used for
the chromatography was a 21.2 .times. 250 mm Hypersil C18 HS column
(8 .mu.m particles). Detection method was UV. l HPLC: The gradient
was 0-100% B over 30 min (21 mL/min flow rate). Mobile phase A was
50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC grade MeCN.
The column used for the chromatography was a 21.2 .times. 250 mm
Hypersil C18 HS column (8 .mu.m particles). Detection method was
UV. m HPLC: The gradient was 5% B, hold for 5 min, 5-100% B over 40
min, hold at 100% for 5 min, 2 min back to 5% B, hold at 5% B for 4
min, (21 mL/min flow rate). Mobile phase A was 50 mM NH.sub.4OAc
(pH 4.5) and mobile phase B was HPLC grade MeCN. The column used
for the chromatography was a 21.2 .times. 250 mm Hypersil C18 HS
column (8 .mu.m particles). Detection method was UV. n LC/MS: The
gradient was 5-60% B in 0.60 min then 60-95% B to 1.0 min with a
hold at 95% B for 0.30 min (1.25 mL/min flow rate). Mobile phase A
was 10 mM NH.sub.4OAc, mobile phase B was HPLC grade MeCN. The
column used for the chromatography is 2.1 .times. 30 mm Acquity
UPLC HSS T3 column (1.8 .mu.m particles). Detection methods are
diode array (DAD) and evaporative light scattering (ELSD) detection
as well as positive/negative electrospray ionization. o LC/MS: The
gradient was 60-95% B in 1.15 min with a hold at 95% B for 3 min
(1.3 mL/min flow rate). Mobile phase A was 10 mM NH.sub.4OAc,
mobile phase B was HPLC grade MeCN. The column used for the
chromatography is a 4.6 .times. 50 mm MAC-MOD Halo C8 column (2.7
.mu.m particles). Detection methods are diode array (DAD) and
evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization. p LC/MS: The gradient
was 5% B, hold for 0.2 min, 5-95% B over 1.7 min, hold at 95% for
1.3 min, back to 5% B within 0.01 min, (2.3 mL/min flow rate).
Mobile phase A was water (0.05% TFA) and mobile phase B was HPLC
grade MeCN (0.05% TFA). The column used for the chromatography was
a 4.6 .times. 50 mm XBridge C18 column (3.5 .mu.m particles).
Temperature 50.degree. C. Detection method was UV. q HPLC: The
gradient was 10-75% B over 10 min (22.5 mL/min flow rate). Mobile
phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC
grade MeCN, the column used for the chromatography was a 19 .times.
50 mm Waters Atlantis T3 OBD C18 column (5 .mu.m particles),
detection methods were Photodiode array DAD and Waters ZQ 2000 mass
spectrometer. r LC/MS: The gradient was 80-65% B in 1.80 min then
65-40% B to 2.80 min with a hold at 40% for another 1.20 min (1.3
mL/min flow rate). The column used for the chromatography is a 4.6
.times. 50 mm X-bridge hilic column (3.5 .mu.m particles). Mobile
phase A was 10 mM ammonium acetate, mobile phase B was HPLC grade
acetonitrile. Detection methods are diode array (DAD) and
evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization. s HPLC: The gradient was
0-100% B over 15 min, hold at 100% for 15 min (21 mL/min flow
rate). Mobile phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile
phase B was HPLC grade MeCN. The column used for the chromatography
was a 21.2 .times. 250 mm Hypersil C18 HS column (8 .mu.m
particles). Detection method was UV. t HPLC: The gradient was 24% B
over 2 min then 24-55% B over 7.6 min then 55- 98% B over 1 min (25
mL/min flow rate). Mobile phase A was 50 mM NH.sub.4OAc (pH 4.5)
and mobile phase B was HPLC grade MeCN, the column used for the
chromatography was a 19 .times. 50 mm Waters Atlantis T3 OBD C18
column (5 .mu.m particles), detection methods were Waters 2996
photodiode array DAD and Waters ZQ 2000 mass spectrometer. u LC/MS:
The gradient was 0-0.1 min 10% A, 0.1-1.1 min 10-100% A, 1.1-1.3
min 100% A, then 1.3-1.4 min 100-10% A. Flow rate was 1 mL/min.
Mobile phase A was HPLC grade acetonitrile and mobile phase B was
0.1% trifluoroacetic acid in water. The column used was a Waters
BEH C8, 1.7 .mu.m (2.1 mm .times. 30 mm) at a temperature of
55.degree. C. Detection methods were diode array (DAD) and
evaporative light scattering (ELSD) detection as well as positive
APCI ionization. v The gradient was 0-0.1 min 10% A, 0.1-2.6 min
10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A then 0.5 min
post-run delay. Flow rate was 2 mL/min. Mobile phase A was HPLC
grade acetonitrile and mobile phase B was 0.1% trifluoroacetic acid
in water. The column used for the chromatography was a Phenomenex
Luna Combi-HTS C8(2) 5 .mu.m 100 .ANG. (2.1 mm .times. 50 mm), at a
temperature of 55.degree. C. Detection methods were diode array
(DAD) and evaporative light scattering (ELSD) detection as well as
positive APCI ionization. w HPLC: The gradient was 15% B over 3.5
min then 15-46% B over 6.1 min then 46- 98% B over 1.2 min (25
mL/min flow rate). Mobile phase A was 50 mM NH.sub.4OAc (pH 4.5)
and mobile phase B was HPLC grade MeCN, the column used for the
chromatography was a 19 .times. 50 mm Waters Atlantis T3 OBD C18
column (5 micron particles), detection methods were Waters 2996
photodiode array DAD and Waters ZQ 2000 mass spectrometer. x HPLC:
The gradient was 0-80% B over 5 min, hold at 80% for 4 min, 0.1 min
at 90% B, then 90 to 0% B for 2.9 min, hold at 0% B for 2 min (1
mL/min flow rate). Mobile phase A was 0.1% H.sub.3PO.sub.4 in water
and mobile phase B was HPLC grade MeCN. The column used for the
chromatography was a 4.6 .times. 150 mm Ascentis Express column
(2.8 .mu.m particles). Detection method was UV. y HPLC: The
gradient was 0-50% B over 45 min (25 mL/min flow rate). Mobile
phase A was 50 mM NH.sub.4OAc (pH 4.5) and mobile phase B was HPLC
grade MeCN. The column used for the chromatography was a 21.2
.times. 250 mm Hypersil C18 HS column (8 .mu.m particles).
Detection method was UV.
TABLE-US-00004 TABLE 2 Chiral HPLC methods Method Conditions 1
Isocratic 50% A for 25 min (20 mL/min flow rate). Mobile phase A
was a 50:50 mixture of HPLC grade MeOH and EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IA, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection as well as optical rotation. 2
Isocratic 100% EtOH (200 proof) for 13 min (10 mL/min flow rate).
The column used for the chromatography was a Daicel IC, 20 .times.
250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 3 Isocratic 20% A for 10-23 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IC, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 4 Isocratic 70% A for
25 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.12% diethylamine
added. The column used for the chromatography was a Daicel IA, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 5 Isocratic 50% A for 20 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 6 Isocratic 25% A for
18 min (20 mL/min flow rate). Mobile phase A was a 50:50 mixture of
HPLC grade MeOH and EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 7 Isocratic 30% A for
18 min (20 mL/min flow rate). Mobile phase A was a 50:50 mixture of
HPLC grade MeOH and EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 8 The gradient was
15-54% A in 16 min then step to 90% A in 0.5 min, with a hold at
90% for 4.3 min (20 mL/min flow rate). Mobile phase A was a 50:50
mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.1% diethylamine added. The column used
for the chromatography was a Daicel IA, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 9 The
gradient was 10-70% A in 16 min then re-equilibrated at 10% A for 9
min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.1% diethylamine added.
The column used for the chromatography was a Daicel IA, 20 .times.
250 mm column (5 .mu.m particles). Detection methods were UV,
.lamda. = 315 nm. 10 The gradient was 10-50% A in 19 min with a
hold at 50% for 2 min (20 mL/min flow rate). Mobile phase A was
EtOH (200 proof), mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 11 Isocratic 60% A for 20 min (20 mL/min flow
rate). Mobile phase A was EtOH (200 proof), mobile phase B was HPLC
grade heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were UV, .lamda. = 300 nm. 12
Isocratic 30% A for 25 min (20 mL/min flow rate). Mobile phase A
was HPLC grade IPA, mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 13 Isocratic 20% A for 20 min (20 mL/min flow
rate). Mobile phase A was HPLC grade IPA, mobile phase B was HPLC
grade heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 14 Isocratic 100%
EtOH (200 proof) for 20 min (13 mL/min flow rate). The column used
for the chromatography was a Daicel IC, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 15
Isocratic 50% A for 20 min (20 mL/min flow rate). Mobile phase A
was HPLC grade IPA, mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 16 Isocratic 30% A for 18 min (20 mL/min flow
rate). Mobile phase A was a 50:50 mixture of HPLC grade MeOH and
EtOH (200 proof), mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 17 The gradient was 10-50% A in 19 min with a
hold at 50% for 2 min then re- equilibrated at 10% A for 11 min (20
mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IC, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection as well as optical rotation. 18
The gradient was 10-50% A in 19 min with a hold at 50% for 1.5 min
(20 mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IA, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 19 The gradient was 10-50% A in 19 min
then re-equilibrated at 10% A for 6 min (20 mL/min flow rate).
Mobile phase A was HPLC grade IPA, mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IC, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 20 Isocratic 40% A
for 16 min (20 mL/min flow rate). Mobile phase A was HPLC grade
IPA, mobile phase B was HPLC grade heptane with 0.1% diethylamine
added. The column used for the chromatography was a Daicel IA, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 21 Isocratic 40% A for 15-25 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection, and/or UV (variable wavelength) as well as
optical rotation. 22 The gradient was 10-40% A in 19 min (20 mL/min
flow rate). Mobile phase A was EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.1% diethylamine added. The column used
for the chromatography was a Daicel IB, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 23 The
gradient was 15-70% A in 19 min (20 mL/min flow rate). Mobile phase
A was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.1% diethylamine added. The column used for the chromatography was
a Daicel IA, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection as well as optical rotation. 24 Isocratic 15% A for 14
min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.12% diethylamine
added. The column used for the chromatography was a Daicel IC, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 25 Isocratic 30% A for 10 min (20 mL/min flow rate).
Mobile phase A was HPLC grade IPA, mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IB, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 26 Isocratic 40% A
for 5 min then gradient 40 to 95% A in 2 min, with a hold at 95%
for 11 min (20 mL/min flow rate). Mobile phase A was a 50:50
mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.1% diethylamine added. The column used
for the chromatography was a Daicel IA, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 27 The
gradient was 10-50% A in 19 min (20 mL/min flow rate). Mobile phase
A was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.1% diethylamine added. The column used for the chromatography was
a Daicel IB, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection as well as optical rotation. 28 Isocratic 15% A for 35
min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.12% diethylamine
added. The column used for the chromatography was a Daicel IA, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 29 The gradient was 10-50% A in 19 min with a hold at 50%
for 3 min then re-
equilibrate at 10% A for 13 min (1 mL/min flow rate). Mobile phase
A was IPA, mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IC, 4.6 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 30 Isocratic 20% A for 20 min (1 mL/min flow
rate). Mobile phase A was IPA, mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IC, 4.6 .times. 250 mm column (5 .mu.m
particles). Detection methods were UV, .lamda. = 230 nm as well as
positive electrospray ionization. 31 Isocratic 20% A for 10 min (20
mL/min flow rate). Mobile phase A was ethanol (200 proof), mobile
phase B was HPLC grade heptane with 0.12% diethylamine added. The
column used for the chromatography was a Daicel IA, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection as well as optical rotation. 32
The gradient was 10-70% A in 19 min then re-equilibrate at 10% A
for 11 min (20 mL/min flow rate). Mobile phase A was ethanol (200
proof), mobile phase B was HPLC grade heptane with 0.1%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were ELSD and optical rotation. 33 Isocratic 30% A for
20-30 min (20 mL/min flow rate). Mobile phase A was ethanol (200
proof), mobile phase B was HPLC grade heptane with 0.12%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection, and/or
UV (variable wavelength) as well as optical rotation. 34 Isocratic
40% A for 10-30 min (20 mL/min flow rate). Mobile phase A was
ethanol (200 proof), mobile phase B was HPLC grade heptane with
0.12% diethylamine added. The column used for the chromatography
was a Daicel IC, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection as well as optical rotation. 35 Isocratic 15% A for 22.5
min then step to 60% A and hold for 5 min (20 mL/min flow rate).
Mobile phase A was HPLC grade IPA, mobile phase B was HPLC grade
heptane with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection method was UV, .lamda. = 325 nm 36 Isocratic
40% A for 20 min (20 mL/min flow rate). Mobile phase A was a 50:50
mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.1% diethylamine added. The column used
for the chromatography was a Daicel IA, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 37 The
gradient was 10-70% A in 19 min (20 mL/min flow rate). Mobile phase
A was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.1% diethylamine added. The column used for the chromatography was
a Daicel IC, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection as well as optical rotation. 38 Isocratic 35% A for 25
min (20 mL/min flow rate). Mobile phase A was HPLC grade IPA,
mobile phase B was HPLC grade heptane with 0.1% diethylamine added.
The column used for the chromatography was a Daicel IC, 20 .times.
250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 39 Isocratic 70% A for 7 min then gradient 70-95% A in 3
min and hold at 95% A for 12 min (20 mL/min flow rate). Mobile
phase A was EtOH (200 proof), mobile phase B was HPLC grade heptane
with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection, and/or UV (variable wavelength) as well as
optical rotation. 40 Isocratic 25% A for 25 min (20 mL/min flow
rate). Mobile phase A was HPLC grade IPA, mobile phase B was HPLC
grade heptane with 0.12% diethylamine added. The column used for
the chromatography was a Daicel IA, 20 .times. 250 mm column (5
.mu.m particles). Detection method was UV, .lamda. = 325 nm 41
Isocratic 10% A for 25 min (20 mL/min flow rate). Mobile phase A
was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.12% diethylamine added. The column used for the chromatography
was a Daicel IA, 20 .times. 250 mm column (5 .mu.m particles).
Detection method was UV, .lamda. = 320 nm 42 Isocratic 20% A for 20
min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.1% diethylamine added.
The column used for the chromatography was a Daicel IA, 20 .times.
250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection as well as optical
rotation. 43 Isocratic 15% A for 30 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IB, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 44 Isocratic 25% A
for 25 min (20 mL/min flow rate). Mobile phase A was EtOH (200
proof), mobile phase B was HPLC grade heptane with 0.12%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 45 The gradient was 10-60% A in 20 min (20
mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IC, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 46 The gradient was 10-50% A in 13 min
(20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IA, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 47 The gradient was 10-50% A in 17 min
(20 mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IA, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 48 The gradient was 15-60% A in 17 min
(20 mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLC
grade MeOH and EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.1% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection, and/or UV (variable wavelength) as well as
optical rotation. 49 Isocratic 25% A for 17 min then step to 60% A
and hold for 10 min (20 mL/min flow rate). Mobile phase A was HPLC
grade IPA, mobile phase B was HPLC grade heptane with 0.12%
diethylamine added. The column used for the chromatography was a
Daicel IC, 20 .times. 250 mm column (5 .mu.m particles). Detection
method was UV, .lamda. = 340 nm 50 Isocratic 20% A for 20 min (20
mL/min flow rate). Mobile phase A was EtOH (200 proof), mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The
column used for the chromatography was a Daicel IB, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 51 Isocratic 10% A for 60 min (20
mL/min flow rate). Mobile phase A was a 50:50 mixture of HPLC grade
MeOH and EtOH (200 proof), mobile phase B was HPLC grade heptane
with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IA, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection as well as optical rotation. 52 Isocratic 50% A
for 20 min (20 mL/min flow rate). Mobile phase A was a 50:50
mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.12% diethylamine added. The column used
for the chromatography was a Daicel IC, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection as well as optical rotation. 53 The
gradient was 30-70% A in 18 min with a hold at 70% for 4 min then
re- equilibrate at 30% A for 13 min (20 mL/min flow rate). Mobile
phase A was IPA, mobile phase B was HPLC grade heptane with 0.12%
diethylamine added. The column used for the chromatography was a
Daicel IC, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection as well
as optical rotation. 54 Isocratic 30% A for 30 min (20 mL/min flow
rate). Mobile phase A was ethanol (200 proof), mobile phase B was
HPLC grade heptane with 0.12% diethylamine added. The column used
for the chromatography was a Daicel IC, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection, and/or UV (variable wavelength) as
well as optical rotation. 55 Isocratic 30% A for 30 min (20 mL/min
flow rate). Mobile phase A was ethanol (200 proof), mobile phase B
was HPLC grade heptane with 0.12% diethylamine added. The column
used for the chromatography was a (R,R) Whelk-O1, 21 .times. 250 mm
column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 56 Isocratic 35% A for 30 min (20
mL/min flow rate). Mobile phase A was ethanol (200 proof), mobile
phase B was HPLC grade heptane with 0.12% diethylamine added. The
column used for the chromatography was a Daicel IC, 20 .times. 250
mm column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 57 Isocratic 30% A for 30 min (20
mL/min flow rate). Mobile phase A was a 50:50
mixture of HPLC grade MeOH and EtOH (200 proof), mobile phase B was
HPLC grade heptane with 0.12% diethylamine added. The column used
for the chromatography was a Daicel IC, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection, and/or UV (variable wavelength) as
well as optical rotation. 58 Isocratic 15% A for 11 min then step
to 50% A in 0.5 min and hold for 4.5 min (20 mL/min flow rate).
Mobile phase A was HPLC grade ethanol (200 proof), mobile phase B
was HPLC grade heptane with 0.12% diethylamine added. The column
used for the chromatography was a Daicel IA, 20 .times. 250 mm
column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 59 The gradient was 10-95% A in 17 min
with a hold at 95% for 2 min (20 mL/min flow rate). Mobile phase A
was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.12% diethylamine added. The column used for the chromatography
was a Daicel IA, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection, and/or UV (variable wavelength) as well as optical
rotation. 60 Isocratic 20% A for 10 min then step to 60% A in 0.5
min and hold at 60% for 5.5 min (20 mL/min flow rate). Mobile phase
A was HPLC grade IPA, mobile phase B was HPLC grade heptane with
0.12% diethylamine added. The column used for the chromatography
was a Daicel IA, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection, and/or UV (variable wavelength) as well as optical
rotation. 61 The gradient was 10-20% A in 28 min, hold at 20% for 2
min then 20-70% A in 5 min (20 mL/min flow rate). Mobile phase A
was EtOH (200 proof), mobile phase B was HPLC grade heptane with
0.12% diethylamine added. The column used for the chromatography
was a Daicel IC, 20 .times. 250 mm column (5 .mu.m particles).
Detection methods were evaporative light scattering (ELSD)
detection, and/or UV (variable wavelength) as well as optical
rotation. 62 Isocratic 22% A for 30 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IB, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection, and/or UV (variable wavelength) as well as
optical rotation. 63 Isocratic 25% A for 30 min (20 mL/min flow
rate). Mobile phase A was EtOH (200 proof), mobile phase B was HPLC
grade heptane with 0.12% diethylamine added. The column used for
the chromatography was a Daicel IB, 20 .times. 250 mm column (5
.mu.m particles). Detection methods were evaporative light
scattering (ELSD) detection, and/or UV (variable wavelength) as
well as optical rotation. 64 Isocratic 65% A for 30 min (20 mL/min
flow rate). Mobile phase A was ethanol (200 proof), mobile phase B
was HPLC grade heptane with 0.12% diethylamine added. The column
used for the chromatography was a (R,R) Whelk-O1, 21 .times. 250 mm
column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 65 Isocratic 65% A for 6 min then step
to 90% A in 0.5 min and hold at 90% for 6.5 min (20 mL/min flow
rate). Mobile phase A was ethanol (200 proof), mobile phase B was
HPLC grade heptane with 0.12% diethylamine added. The column used
for the chromatography was a (R,R) Whelk-O1, 21 .times. 250 mm
column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 66 Isocratic 30% A for 30 min (20
mL/min flow rate). Mobile phase A was HPLC grade IPA, mobile phase
B was HPLC grade heptane with 0.12% diethylamine added. The column
used for the chromatography was a Daicel IC, 20 .times. 250 mm
column (5 .mu.m particles). Detection methods were evaporative
light scattering (ELSD) detection, and/or UV (variable wavelength)
as well as optical rotation. 67 Isocratic 55% A for 8 min then step
to 90% A in 1 min and hold at 90 for 7 min (20 mL/min flow rate).
Mobile phase A was EtOH (200 proof), mobile phase B was HPLC grade
heptane with 0.12% diethylamine added. The column used for the
chromatography was a Daicel IC, 20 .times. 250 mm column (5 .mu.m
particles). Detection methods were evaporative light scattering
(ELSD) detection, and/or UV (variable wavelength) as well as
optical rotation. 68 The gradient was 60-90% A in 4 min with a hold
at 90% for 6 min (20 mL/min flow rate). Mobile phase A was EtOH
(200 proof), mobile phase B was HPLC grade heptane with 0.12%
diethylamine added. The column used for the chromatography was a
Daicel IA, 20 .times. 250 mm column (5 .mu.m particles). Detection
methods were evaporative light scattering (ELSD) detection, and/or
UV (variable wavelength) as well as optical rotation. 69 Isocratic
20% A for 12 min then step to 50% A in 0.5 min and hold at 50% for
3.5 min (20 mL/min flow rate). Mobile phase A was EtOH (200 proof),
mobile phase B was HPLC grade heptane with 0.12% diethylamine
added. The column used for the chromatography was a Daicel IA, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection, and/or UV (variable
wavelength) as well as optical rotation. 70 The gradient was 20-50%
B over 10 min (0.6 mL/min flow rate). Mobile phase A was 10 mM
KH.sub.2PO.sub.4 buffer (pH = 6.9) and mobile phase B was HPLC
grade MeCN. The column used for the chromatography was a 4.6
.times. 150 mm Chiralpak AS-RH, Diacel col. Detection method was
UV. 71 The gradient was 15-85% A in 37 min with a hold at 85% A for
0.5 min (20 mL/min flow rate). Mobile phase A was HPLC grade IPA,
mobile phase B was HPLC grade heptane with 0.12% diethylamine
added. The column used for the chromatography was a Daicel IC, 20
.times. 250 mm column (5 .mu.m particles). Detection methods were
evaporative light scattering (ELSD) detection, and/or UV (variable
wavelength) as well as optical rotation.
Purification Methods
[1153] For the general procedures, the intermediates and final
compounds may be purified by any technique or combination of
techniques known to one skilled in the art. Some examples that are
not limiting include flash chromatography with a solid phase (e.g.
silica gel, alumina, etc.) and a solvent (or combination of
solvents) that elutes the desired compounds (e.g. heptane, EtOAc,
DCM, MeOH, MeCN, water, etc.); preparatory TLC with a solid phase
(e.g. silica gel, alumina etc.) and a solvent (or combination of
solvents) that elutes the desired compounds (e.g. heptane, EtOAc,
DCM, MeOH, MeCN, water, etc.); reverse phase HPLC (see Table 1 for
some non-limiting conditions); recrystallization from an
appropriate solvent or combination of solvents (e.g. MeOH, EtOH,
IPA, EtOAc, toluene, etc.) or combination of solvents (e.g.
EtOAc/heptane, EtOAc/MeOH, etc.); chiral LC with a solid phase and
an appropriate solvent (see Table 2 for some non-limiting
conditions) to elute the desired compound; chiral SFC with a solid
phase and CO.sub.2 with an appropriate modifier (e.g. MeOH, EtOH,
IPA with or without additional modifier such as diethylamine, TFA,
etc.); precipitation from a combination of solvents (e.g.
DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with an
appropriate solvent (e.g. EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-IPA,
etc.); extractions by dissolving a compound in a liquid and washing
with an appropriately immiscible liquid (e.g. DCM/water,
EtOAc/water, DCM/saturated aqueous NaHCO.sub.3, EtOAc/saturated
aqueous NaHCO.sub.3, DCM/10% aqueous HCl, EtOAc/10% aqueous HCl,
etc.); distillation (e.g. simple, fractional, Kugelrohr, etc.); gas
chromatography using an appropriate temperature, carrier gas and
flow rate; sublimation at an appropriate temperature and pressure;
filtration through a media (e.g. Florosil.RTM., alumina,
Celite.RTM., silica gel, etc.) with a solvent (e.g. heptane,
hexanes, EtOAc, DCM, MeOH, etc.) or combination of solvents; salt
formation with solid support (resin based, e.g. ion exchange) or
without. Compounds of interest may be isolated as a salt without
the use of a specific salt formation purication method. For
example, on occasions where purification is accomplished with
reverse phase HPLC with an aqueous TFA buffer, the TFA salt may be
isolated. Some descriptions of these techniques can be found in the
following references: Gordon, A. J. and Ford, R. A. "The Chemist's
Companion", 1972; Palleros, D. R. "Experimental Organic Chemistry",
2000; Still, W. C., Kahn and M. Mina, A. J. Org. Chem. 1978, 43,
2923; Yan, B. "Analysis and Purification Methods in Combinatorial
Chemistry", 2003; Harwood, L. M., Moody, C. J. and Percy, J. M.
"Experimental Organic Chemistry: Standard and Microscale, 2.sup.nd
Edition", 1999; Stichlmair, J. G. and Fair, J. R. "Distillation;
Principles and Practices", 1998; Beesley, T. E. and Scott, R. P. W.
"Chiral Chromatography", 1999; Landgrebe, J. A. "Theory and
Practice in the Organic Laboratory, 4.sup.th Ed.", 1993; Skoog, D.
A. and Leary, J. J. "Principles of Instrumental Analysis, 4.sup.th
Ed.", 1992; G. Subramanian, "Chiral Separation Techniques, 3.sup.rd
Edition", 2007; Y. Kazakevich, R. Lobrutto, "HPLC for
Pharmaceutical Scientists", 2007.
PREPARATIONS AND EXAMPLES
[1154] The general synthetic methods used in each General Procedure
follow and include an illustration of a compound that was
synthesized using the designated General Procedure. None of the
specific conditions and reagents noted herein are to be construed
as limiting the scope of the invention and are provided for
illustrative purposes only. All starting materials are commercially
available from Sigma-Aldrich (including Fluka and Discovery CPR)
unless otherwise noted after the chemical name. Reagent/reactant
names given are as named on the commercial bottle or as generated
by IUPAC conventions, CambridgeSoft.RTM. ChemDraw Ultra 9.0.7,
CambridgeSoft.RTM. Chemistry E-Notebook 9.0.127, or AutoNom 2000.
Compounds designated as salts (e.g. hydrochloride, acetate) may
contain more than one molar equivalent of the salt. Compounds of
the invention where the absolute stereochemistry has been
determined by the use of a commercially available enantiomerically
pure starting material or a stereochemically defined intermediate,
or by X-ray diffraction are denoted by an asterisk after the
example number.
Preparation #1: cis-3-(4-cyanobenzyloxy)cyclobutanecarboxylic
acid
##STR00163##
[1155] Step A: cis-ethyl 3-hydroxycyclobutanecarboxylate
##STR00164##
[1157] A solution of ethyl 3-oxocyclobutanecarboxylate (2.90 g,
20.4 mmol, Parkway) in EtOH (30 mL) at ambient temperature was
treated with NaBH.sub.4 (0.77 g, 20 mmol). The reaction was stirred
for about 1 h and then 2 N aqueous HCl was added to adjust the pH
to about 2. The reaction was concd in vacuo. The reaction was
partitioned with DCM (50 mL) and brine (50 mL). The organic layer
was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered then
concd in vacuo. The resulting residue was purified on silica gel
(80 g) using 20-40% EtOAc in DCM to give cis-ethyl
3-hydroxycyclobutanecarboxylate (2.75 g, 66%) as a clear oil:
.sup.1H NMR (DMSO-d.sub.6) .delta. 5.17 (d, 1H), 4.09-3.99 (m, 2H),
3.99-3.90 (m, 1H), 2.57-2.47 (m, 1H), 2.42-2.29 (m, 2H), 1.98-1.89
(m, 2H), 1.17 (m, 3H).
Step B: cis-ethyl 3-(4-cyanobenzyloxy)cyclobutanecarboxylate
##STR00165##
[1159] To a solution of cis-ethyl 3-hydroxycyclobutanecarboxylate
(0.17 g, 1.2 mmol) in DMF (4 mL) was added K.sub.2CO.sub.3 (0.24 g,
1.8 mmol) followed by 4-(bromomethyl)benzonitrile (0.28 g, 1.4
mmol). The reaction was stirred at about 25.degree. C. for about 16
h. The reaction was partitioned between EtOAc (50 mL) and brine (50
mL). The layers were separated and the organic layer was washed
with additional brine (50 mL). The organic layer was then dried
over anhydrous Na.sub.2SO.sub.4, filtered, and concd in vacuo to
give cis-ethyl 3-(4-cyanobenzyloxy)-cyclobutanecarboxylate (0.29 g,
95%) as an oil: .sup.1H NMR (DMSO-d.sub.6) .delta. 7.82 (d, J=8.5
Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 4.02 (q, J=7.1 Hz,
2H), 3.93 (m, 1H), 2.58-2.45 (m, 1H), 2.41-2.28 (m, 2H), 1.98-1.85
(m, 2H), 1.20-1.08 (t, J=7.1 Hz, 3H).
Step C: cis-3-(4-cyanobenzyloxy)cyclobutanecarboxylic acid
##STR00166##
[1161] To a solution of cis-ethyl
3-(4-cyanobenzyloxy)cyclobutanecarboxylate (0.44 g, 1.70 mmol) in
1,4-dioxane (10 mL) was added aqueous NaOH (1 N, 2.0 mL). The
reaction was stirred at about 25.degree. C. for about 16 h. The
reaction was partitioned between 10% aqueous AcOH (20 mL) and EtOAc
(25 mL). The layers were separated and the aqueous layer was
extracted with additional EtOAc (25 mL). The combined organic
extracts were washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered then concd in vacuo to give
cis-3-(4-cyanobenzyloxy)-cyclobutanecarboxylic acid (0.24 g, 60%):
LC/MS (Table 1, Method b) R.sub.t=1.67 min; MS m/z: 232
(M+H).sup.+.
Preparation #2*:
(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane
##STR00167##
[1162] Step A:
3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentyl)propane-1-sulfonamide
##STR00168##
[1164] To a suspension of
(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanamine hydrochloride (0.05 g, 0.11 mmol, prepared using E
from Preparation #B.1 and HCl) and TEA (0.03 mL, 0.21 mmol) in DCM
(5 mL) at about 0.degree. C. was added 3-chloropropane-1-sulfonyl
chloride (0.02 g, 0.11 mmol) dropwise. The reaction mixture was
stirred at about 0.degree. C. for about 1.5 h. The reaction mixture
was diluted with 5% aqueous citric acid (10 mL), and the layers
were separated. The organic layer was washed with saturated aqueous
NaHCO.sub.3 (10 mL), water (10 mL), brine (10 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give
3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentyl)propane-1-sulfonamide (0.052 g, 91%) as a
brown residue: LC/MS (Table 1, Method a) R.sub.t=2.18 min; MS m/z:
537 (M+H).sup.+.
Step B:
(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyraz-
in-1-yl)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane
##STR00169##
[1166] To a solution of
3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentyl)propane-1-sulfonamide (0.11 g, 0.21 mmol) in
DMF (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.04 mL,
0.27 mmol crude). The reaction mixture was stirred at ambient
temperature for about 16 h. The solvent was removed under reduced
pressure to give
(1S,3R)-1-[3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)-isothiazolidin-2-yl-1,1-dioxide]cyclopentane (0.106 g, 99%):
LC/MS (Table 1, Method a) R.sub.t=2.04 min; MS m/z: 501
(M+H).sup.+.
Preparation #3*:
1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine
##STR00170##
[1168] A solution of 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1
mmol) in water (3 mL) was heated at about 100.degree. C. for about
1.5 h. The solution was cooled to ambient temperature. A suspension
of
(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clo-pentanamine hydrochloride (0.10 g, 0.21 mmol, prepared using E
from Preparation #B.1 and HCl) and NaOAc (0.05 g, 0.61 mmol) in DCM
(5 mL) was added to the aqueous solution. The reaction mixture was
stirred at ambient temperature for about 1 h followed by addition
of additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol). The
reaction mixture was heated to about 40.degree. C. for about 15 h.
Additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) was
added and the reaction mixture was stirred at about 40.degree. C.
for about 8 h then at about 35.degree. C. for about 48 h. The
reaction was diluted with DCM (10 mL) and water (10 mL). The layers
were separated and the organic layer was washed with water
(2.times.10 mL) and brine (10 mL), dried over anhydrous MgSO.sub.4,
filtered, and the solvent was removed under reduced pressure to
give
1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine (0.095 g, 99%) as a yellow residue: LC/MS
(Table 1, Method a) R.sub.t=2.42 min; MS m/z: 447 (M+H).sup.+.
Preparation #4*:
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)-1H-pyrrole-3-carbonitrile
##STR00171##
[1169] Step A:
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)-1H-pyrrole-3-carbaldehyde
##STR00172##
[1171] To a suspension of
(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanamine hydrochloride (0.175 g, 0.373 mmol, prepared using E
from Preparation #B.1 and HCl) and NaOAc (0.100 g, 1.22 mmol) in
DCM (3 mL) and water (2 mL) was added
2,5-dimethoxytetrahydrofuran-3-carbaldehyde (0.600 g, 3.37 mmol).
The reaction was heated to about 40.degree. C. for about 24 h. The
reaction mixture was diluted with DCM (30 mL) and washed with water
(4.times.20 mL). The organic layer was dried over anhydrous
MgSO.sub.4, filtered, and the solvent was removed under reduced
pressure to give a brown residue. The crude material was purified
by flash chromatography on silica gel eluting with a gradient of
20-100% EtOAc in DCM to give
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.059 g, 33%) as a yellow
amorphous solid: LC/MS (Table 1, Method a) R.sub.t=2.10 min; MS
m/z: 475 (M+H).sup.+.
Step B:
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyraz-
in-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile
##STR00173##
[1173] To a solution of
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.050 g, 0.105 mmol) in
THF (2 mL) was added iodine (0.083 g, 0.327 mmol) and aqueous
NH.sub.4OH (28-30% w/v, 0.733 mL, 5.27 mmol). The reaction mixture
was stirred at ambient temperature for about 24 h. The reaction
mixture was diluted with saturated aqueous Na.sub.2SO.sub.3 (30 mL)
and EtOAc (30 mL). The layers were partitioned and the organic
layer was dried over anhydrous MgSO.sub.4, filtered, and the
solvent was removed under reduced pressure to give
1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile (0.05 g, 100%):
LC/MS (Table 1, Method a) R.sub.t=2.33 min; MS m/z: 472
(M+H).sup.+.
Preparation #5:
3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide
##STR00174##
[1174] Step A:
1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate
##STR00175##
[1176] To a solution of 1,1'-sulfonyldiimidazole (3.50 g, 17.7
mmol) in DCM (75 mL) at about 0.degree. C. was added methyl
trifluoromethanesulfonate (1.94 mL, 17.7 mmol). The reaction
mixture was stirred at about 0.degree. C. for about 1 h, then
warmed to ambient temperature and stirred for about 5 h. The solid
was collected by vacuum filtration and washed with DCM (10 mL) to
give 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate (6.35 g, 98%) as a white solid: LC/MS
(Table 1, Method a) R.sub.t=0.082 min; MS m/z 213 (M+H).sup.+.
Step B: 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole
##STR00176##
[1178] A solution of 3,3-difluoroazetidine hydrochloride (1.00 g,
7.72 mmol) and DIEA (1.5 mL, 8.6 mmol) in MeCN (5 mL) was stirred
for about 5 min and then was added to a solution of
1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate (4.20 g, 11.6 mmol) in MeCN (10 mL) at
about 0.degree. C. The reaction mixture was stirred at about
0.degree. C. for about 1 h, and then warmed to ambient temperature
and stirred for about 16 h. The reaction mixture was then concd
under reduced pressure. The crude material was purified by flash
chromatography on silica gel eluting with a gradient of 5-100%
EtOAc in DCM to give
1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.95 g, 55%) as
a yellow solid: LC/MS (Table 1, Method c) R.sub.t=1.16 min; MS m/z
224 (M+H).sup.+.
Step C:
1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate
##STR00177##
[1180] To a solution of
1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.500 g, 2.24
mmol) in DCM (5 mL) at about 0.degree. C. was added methyl
trifluoromethanesulfonate (0.27 mL, 2.46 mmol) dropwise over about
3 min. The reaction mixture was stirred at about 0.degree. C. for
about 2 h. The solid was collected by vacuum filtration, washed
with DCM (10 mL), and dried under vacuum to give
1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate (0.79 g, 90%) as a white solid: LC/MS
(Table 1, Method c) R.sub.t=1.12 min; MS m/z 238 (M+H).sup.+.
Step D:
3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide
##STR00178##
[1182] To a solution of
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]-octan-1-amine (0.20 g, 0.46 mmol, Example #9, Step F) in MeCN
(5 mL) was added
1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-iu- m
trifluoromethanesulfonate (0.19 g, 0.50 mmol). The reaction mixture
was heated to about 70.degree. C. for about 24 h. The solvent was
removed under reduced pressure. The residue was partitioned between
EtOAc (30 mL) and water (10 mL). The layers were separated and the
organic layer was washed with water (10 mL) and brine (2.times.10
mL), dried over anhydrous MgSO.sub.4, filtered, and the solvent was
removed under reduced pressure. The crude material was purified by
flash chromatography on silica gel eluting with a gradient of 0-10%
MeOH in DCM to give
3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide (0.119 g,
38%): LC/MS (Table 1, Method a) R.sub.t=2.32 min; MS m/z 592
(M+H).sup.+.
Preparation #6: 1-methylcyclopropane-1-sulfonyl chloride
##STR00179##
[1183] Step A: butyl cyclopropanesulfonate
##STR00180##
[1185] To a solution of cyclopropanesulfonyl chloride (5.00 g, 35.6
mmol) in n-BuOH (20 mL) at -20.degree. C., pyridine (5.75 mL, 71.1
mmol) was added dropwise. The resulting mixture was stirred for
about 16 h while warming slowly to ambient temperature. The
solvents were removed under reduced pressure and the residue was
partitioned between DCM and water (50 mL each). The organic phase
was further washed with brine (40 mL), dried over anhydrous
MgSO.sub.4 and concd under reduced pressure to yield butyl
cyclopropanesulfonate (4.7 g, 74%) as a yellow oil. 1H NMR
(DMSO-d.sub.6) .delta. 4.2 (t, 2H), 2.82 (m, 1H), 1.64 (m, 2H),
1.35 (m, 2H), 1.08 (m, 2H), 1.01 (m, 2H), 0.89 (t, 3H).
Step B: butyl 1-methylcyclopropane-1-sulfonate
##STR00181##
[1187] To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4
mmol) in THF (8 mL) at about -78.degree. C., n-BuLi (1.6 M in
hexanes, 5.26 mL, 8.42 mmol) and iodomethane (0.684 mL, 10.9 mmol)
were added simultaneously and the resulting mixture was stirred at
about -78.degree. C. for about 2 h and then at ambient temperature
for about 2 h. The reaction was quenched by the addition of
saturated aqueous NH.sub.4Cl (7 mL) and the layers were separated.
The aqueous layer was back extracted with EtOAc (15 mL) and the
combined organic extracts were dried over anhydrous MgSO.sub.4 and
concd under reduced pressure. The residue was subjected to silica
gel column chromatography (5 to 25% EtOAc in heptane over 30 min)
to yield butyl 1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a
colorless oil. .sup.1H NMR (DMSO-d.sub.6) .delta. 4.17 (t, 2H),
1.62 (m, 2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m,
2H), 0.88 (t, 3H).
Step C: 1-methylcyclopropane-1-sulfonyl chloride
##STR00182##
[1189] A mixture of butyl 1-methylcyclopropane-1-sulfonate (0.80 g,
4.2 mmol) and potassium thiocyanate (0.404 g, 4.16 mmol) in
1,4-dioxane/water (1:1, 10 mL) was heated at reflux for about 8 h.
The reaction was cooled to ambient temperature and the solvents
were concd under reduced pressure to yield crude potassium
1-methylcyclopropane-1-sulfonate which was suspended in thionyl
chloride (7 mL). DMF (0.05 mL) was added and the mixture was heated
at reflux for about 8 h and then cooled. The volatiles were removed
under reduced pressure and the residue was dissolved in DCM (20
mL), washed with water (15 mL), dried over anhydrous MgSO.sub.4 and
concd under reduced pressure to yield
1-methylcyclopropane-1-sulfonyl chloride (0.56 g, 86%) as a yellow
oil. .sup.1H NMR (DMSO-d.sub.6) .delta. 1.82 (br s, 2H), 1.79 (s,
3H), 1.15 (m, 2H).
Preparation #7: ethyl
4-(cyclopropanesulfonamido)-2-ethyl-1-fluorocyclopentanecarboxylate
##STR00183##
[1191] A solution of ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (0.630
g, 2.18 mmol, prepared using K from Preparation #Y.1 and
cyclopropanesulfonyl chloride) in THF (14.5 mL) was cooled to about
-78.degree. C. and then LDA (1.8 M in THF/hexane, 3.63 mL, 6.53
mmol) was added dropwise to the reaction mixture over about 30 min.
The reaction mixture was stirred at about -78.degree. C. for about
50 min before a solution of
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.06 g, 6.53 mmol)
in THF (7.3 mL) was added dropwise over about 30 min. The reaction
mixture was stirred at about -78.degree. C. for about 1 h and then
was warmed to ambient temperature and stirred for about 16 h.
Saturated aqueous NH.sub.4Cl (100 mL) was added. The reaction
mixture was partitioned with EtOAc (50 mL). The aqueous layer was
further extracted with EtOAc (2.times.50 mL). The combined organic
layers were concd under reduced pressure. The residue was purified
by silica gel chromatography eluting with a gradient of 0-60% EtOAc
in heptane to yield ethyl
4-(cyclopropanesulfonamido)-2-ethyl-1-fluorocyclopentanecarboxylate
(0.41 g, 46%) as clear oil: LC/MS (Table 1, Method b) R.sub.t=2.12
min; MS m/z: 306 (M-H).sup.-.
Preparation #8: (1S,2R,4R)-ethyl
2-methyl-4-(phenylamino)cyclopentanecarboxylate and
(1R,2S,4S)-ethyl
2-methyl-4-(phenylamino)cyclopentanecarboxylate
##STR00184##
[1193] A solution of ethyl
4-hydroxy-2-methylcyclopentanecarboxylate (1.81 g, 10.5 mmol,
prepared using P from Example #7, step G and NaBH.sub.4) and
pyridine (1.28 mL, 15.8 mmol) in THF (52.5 mL) was cooled to about
0.degree. C. Methanesulfonyl chloride (0.90 mL, 12 mmol) was added
dropwise. The reaction mixture was stirred at ambient temperature
for about 16 h then partitioned between water (50 mL) and DCM (30
mL). The layers were separated and the aqueous layer was extracted
with DCM (2.times.30 mL). The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4 and concd under reduced pressure to
give a white solid. The resulting solid was mixed with aniline
(78.0 g, 841 mmol) and heated at about 90.degree. C. for about 16
h. The reaction mixture was coned under reduced pressure and
purified by silica gel chromatography eluting with a gradient of
20-100% EtOAc in DCM to yield (1S,2R,4R)-ethyl
2-methyl-4-(phenylamino)cyclopentanecarboxylate and
(1R,2S,4S)-ethyl 2-methyl-4-(phenylamino)cyclopentanecarboxylate
with 29 mol % aniline as an excipient (2.73 g, 75%) as a dark oil:
LC/MS (Table 1, Method b) R.sub.t=2.67 min; MS m/z: 248
(M+H).sup.+.
Preparation #9: 1-tert-butyl 3-ethyl
4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate
##STR00185##
[1194] Step A: 1-tert-butyl 3-ethyl
4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate
##STR00186##
[1196] To a solution of 1-tert-butyl 3-ethyl
4-oxopiperidine-1,3-dicarboxylate (11.50 g, 42.4 mmol, ASDI) in
MTBE (500 mL) at about -78.degree. C. was added NaHMDS (1 M in THF,
53.0 mL, 53.0 mmol). After about 1 h, diethyl phosphorochloridate
(7.62 mL, 53.0 mmol) was added to the reaction mixture. After about
30 min, the reaction mixture was allowed to warm to ambient
temperature and stirred for about 16 h. The reaction mixture was
partitioned between saturated aqueous NH.sub.4Cl (100 mL) and EtOAc
(50 mL). The layers were separated. The aqueous layer was further
extracted with EtOAc (2.times.50 mL). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4, filtered, and coned
under reduced pressure. The crude material was purified by silica
gel chromatography eluting with a gradient of 0-100% EtOAc in
heptane to yield 1-tert-butyl 3-ethyl
4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate
(8.55 g, 49%) as a yellow oil: LC/MS (Table 1, Method b)
R.sub.t=2.35 min; MS m/z: 408 (M+H).sup.+.
Step B: 1-tert-butyl 3-ethyl
4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate
##STR00187##
[1198] To a slurry of CuI (4.21 g, 22.12 mmol) in THF (61.4 mL) at
about 0.degree. C. was added ethylmagnesium bromide (1.0 M in THF,
44.2 mL, 44.2 mmol) dropwise. After about 30 min, the reaction
mixture was cooled to about -78.degree. C. and a solution of
1-tert-butyl 3-ethyl
4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate
(7.51 g, 18.43 mmol) in THF (61 mL) was added slowly. The reaction
mixture was stirred at about -78.degree. C. for about 1 h then
warmed to about 0.degree. C. The reaction mixture was stirred at
about 0.degree. C. for about 1.5 h, then warmed to ambient
temperature and stirred for about 1 h. The reaction mixture was
cooled to about -78.degree. C. and saturated aqueous NH.sub.4Cl
(100 mL) was slowly added. The reaction mixture was allowed to
wall)) to ambient temperature and stirred for about 16 h. The
mixture was extracted with Et.sub.2O (100 mL). The aqueous layer
was further extracted with Et.sub.2O (2.times.50 mL). The organic
layers were combined, washed with saturated aqueous NH.sub.4Cl (50
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concd under
reduced pressure and purified by silica gel chromatography eluting
with a gradient of 0-30% EtOAc in heptane to yield 1-tert-butyl
3-ethyl 4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (0.785 g,
15%) as a clear oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.23 (d,
J=7.1 Hz, 2H), 4.12 (s, 2H), 3.48 (t, J=5.8 Hz, 2H), 2.52 (q, J=7.5
Hz, 2H), 2.28 (t, J=5.8 Hz, 2H), 1.51 (s, 9H), 1.32 (t, J=7.1 Hz,
3H), 1.09 (t, J=7.5 Hz, 3H).
Preparation #10:
1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridi-
ne
##STR00188##
[1199] Step A: tert-butyl
2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate
##STR00189##
[1201] A mixture of 1-benzylpiperidin-3-one hydrochloride (1.00 g,
4.10 mmol), tert-butyl hydrazinecarboxylate (0.596 g, 4.51 mmol),
and AcOH (0.470 mL, 8.21 mmol) in DCE (20 mL) was stirred at
ambient temperature for about 1 h then NaCNBH.sub.3 (0.258 g, 4.10
mmol) was added. The reaction mixture was stirred at ambient
temperature for about 16 h. The reaction mixture was quenched by
the addition of saturated aqueous NaHCO.sub.3 (50 mL). The organic
layer was separated, concd under reduced pressure and purified by
RP-HPLC (Table 1, Method h) to afford tert-butyl
2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 100%) as a
clear oil: LC/MS (Table 1, Method b) R.sub.t=1.66 min; MS m/z: 306
(M+H).sup.+.
Step B: 1-benzyl-3-hydrazinylpiperidine hydrochloride
##STR00190##
[1203] A solution of tert-butyl
2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 4.10 mmol)
in aqueous HCl (6 N, 6.83 mL, 41.0 mmol) was stirred at ambient
temperature for about 8 h. The solvent was removed under reduced
pressure to give crude 1-benzyl-3-hydrazinylpiperidine
hydrochloride (1.45 g, 112%) as a white solid which was used
without further purification: LC/MS (Table 1, Method b)
R.sub.t=0.66 min; MS m/z: 206 (M+H).sup.+.
Step C:
1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b-
]pyridine
##STR00191##
[1205] 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.40 g,
2.21 mmol, Adesis) and 1-benzyl-3-hydrazinylpiperidine
hydrochloride (1.39 g, 4.43 mmol) were suspended in n-BuOH (11.1
mL). The mixture was heated at about 90.degree. C. for about 3 h
and then heated at about 120.degree. C. for about 5 h. The reaction
mixture was cooled to ambient temperature and the solvent was
removed under reduced pressure. The residue was purified by silica
gel chromatography eluting with a gradient of 0-5% MeOH in DCM to
yield
1-(1-benzylpiperidin-3-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-
-b]pyridine (0.105 g, 14%) as a brown oil: LC/MS (Table 1, Method
b) R.sub.t=1.53 min; MS m/z: 332 (M+H).sup.+.
Preparation #11: cis-3-tert-butyl 1-methyl
4-ethylcyclopentane-1,3-dicarboxylate
##STR00192##
[1206] Step A:
cis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid
##STR00193##
[1208] Ruthenium (III) chloride hydrate (0.203 g, 0.900 mmol) was
added to a mixture of 5-ethylbicyclo[2.2.1]hept-2-ene (5.00 g, 40.9
mmol, ChemSampCo) and sodium periodate (35.0 g, 164 mmol) in water
(117 mL), MeCN (78 mL) and EtOAc (78 mL). The reaction mixture was
stirred at ambient temperature for about 16 h. The reaction mixture
was filtered, extracted with Et.sub.2O (2.times.100 mL). The
aqueous layer was further extracted with Et.sub.2O (3.times.100
mL). The organic layers were combined, washed with brine (100 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The residue was dissolved in Ac.sub.2O (20 mL, 24 mmol)
and heated at reflux for about 4 h. The reaction mixture was cooled
to ambient temperature and the solvent was removed under reduced
pressure. MeOH (40 mL) was added and the reaction mixture was
heated at reflux for about 6 h. The solvent was removed under
reduced pressure to yield
cis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (4.84 g,
59%) as a brown oil: LC/MS (Table 1, Method b) R.sub.t=1.91 min; MS
m/z: 201 (M+H).sup.+.
Step B: cis-3-tert-butyl 1-methyl
4-ethylcyclopentane-1,3-dicarboxylate
##STR00194##
[1210] A mixture of
cis-2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (4.50 g,
22.47 mmol) in SOCl.sub.2 (8.20 mL, 112 mmol) was stirred at
ambient temperature for about 16 h. The solvent was removed under
reduced pressure. The resulting residue was dissolved in t-BuOH
(22.5 mL). The reaction mixture was stirred at ambient temperature
for about 16 h. The solvent was removed under reduced pressure. The
residue was dissolved in water (50 mL) and DCM (100 mL). The
organic layer was separated, washed with saturated aqueous
NaHCO.sub.3 (50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd under reduced pressure to give cis-3-tert-butyl
1-methyl 4-ethylcyclopentane-1,3-dicarboxylate (3.94 g, 68%) as a
dark brown oil: LC/MS (Table 1, Method b) R.sub.t=2.86 min; MS m/z:
257 (M+H).sup.+.
Preparation #12:
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine
hydrochloride
##STR00195##
[1211] Step A: (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR00196##
[1213] To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
(3.1 g, 8.8 mmol, Example #1, Step B), PdCl.sub.2(dppf).DCM (0.719
g, 0.880 mmol) and (E)-styrylboronic acid (2.60 g, 17.6 mmol) in
THF (3 mL) and water (2 mL) was added Na.sub.2CO.sub.3 (2.33 g,
22.0 mmol). The reaction mixture was degassed with argon for about
5 min. The reaction mixture was heated at about 50.degree. C. After
about 24 h, additional PdCl.sub.2(dppf).DCM (0.719 g, 0.880 mmol),
(E)-styrylboronic acid (2.60 g, 17.6 mmol) and Na.sub.2CO.sub.3
(2.33 g, 22.0 mmol) were added to the reaction mixture. After
heating at about 50.degree. C. for about 48 h, the reaction mixture
was cooled to ambient temperature and diluted with DCM (200 mL) and
water (200 mL). The organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4, filtered, and coned under reduced
pressure. Purification by chromatography over silica gel eluting
with a gradient of 20-60% EtOAc in heptane containing 5% DCM
provided (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a yellow
solid (1.2 g, 36%): LC/MS (Table 1, Method a) R.sub.t=2.99 min; MS
m/z: 376 (M+H).sup.+.
Step B: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde
##STR00197##
[1215] To a solution of
(E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.2 g, 3.2 mmol) in
1,4-dioxane (20 mL) and water (2.0 mL) was added sodium periodate
(2.73 g, 12.8 mmol) followed by osmium tetroxide (2.5 wt % in
t-BuOH, 4.01 mL, 0.320 mmol). The reaction mixture was stirred for
about 1 day at ambient temperature and then additional sodium
periodate (2.73 g, 12.78 mmol) and osmium tetroxide (2.5 wt % in
t-BuOH, 4.01 mL, 0.320 mmol) were added. After stirring for about 2
days, a solution of 10% aqueous Na.sub.2S.sub.2O.sub.3 (100 mL) and
EtOAc (100 mL) was added. The organic layer was separated, dried
over anhydrous Na.sub.2SO.sub.4, filtered, and coned under reduced
pressure to give a solid, which was triturated with heptane to
remove benzaldehyde. The resulting solid was dried in vacuo to
provide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde as a brown
solid (0.77 g, 80%): LC/MS (Table 1, Method a) R.sub.t=2.01 min; MS
m/z: 334 (M+H).sup.+.
Step C: 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol
##STR00198##
[1217] To a solution of
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.1 g, 17 mmol)
in THF (100 mL) and water (33.3 mL) was added 3-bromoprop-1-ene
(2.86 mL, 33.9 mmol) followed by indium (3.89 g, 33.9 mmol). The
reaction mixture was stirred for about 15 h at ambient temperature
and then aqueous HCl (1 N, 150 mL) and EtOAc (150 mL) were added.
The organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered, coned in vacuo and purified by
chromatography on silica gel eluting with 20-60% EtOAc in heptane
to provide 1-(5-tosyl-5H-pyrrolo[2,3-]pyrazin-2-yl)but-3-en-1-ol (4
g, 69%) as a thick oil: LC/MS (Table 1, Method a) R.sub.t=2.30 min;
MS m/z: 344 (M+H).sup.+.
Step D: 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR00199##
[1219] To a solution of
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (0.14 g,
0.41 mmol) in DCM (10 mL) was added thionyl chloride (0.045 mL,
0.61 mmol). The reaction mixture was stirred for about 8 h at
ambient temperature and then EtOAc and saturated aqueous
NaHCO.sub.3 (10 mL each) were added. The organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concd in vacuo. The crude chloride was dissolved in DMF (10 mL) and
sodium azide (0.159 g, 2.45 mmol) was added to the reaction
mixture. The reaction mixture was stirred for about 15 h at ambient
temperature and then EtOAc and saturated aqueous NaHCO.sub.3 (10 mL
each) were added to the reaction mixture. The organic layer was
separated, concd in vacuo, and purified by chromatography on silica
gel eluting with 10-60% EtOAc in heptane to provide
2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.153 g,
87%) as an oil: LC/MS (Table 1, Method a) R.sub.t=2.84 min; MS m/z:
369 (M+H).sup.+.
Step E: 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine
hydrochloride
##STR00200##
[1221] To a solution of
2-(1-azidobut-3-enyl)-3-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.90 g,
10.6 mmol) in THF (60 mL) and water (30 mL) was added
triphenylphosphine (3.33 g, 12.7 mmol). The reaction mixture was
heated to about 50.degree. C. for about 15 h. The reaction mixture
was cooled to ambient temperature and concd in vacuo. The residue
was dissolved in EtOAc (30 mL) and HCl (gas) was added until a pH
of about 1 was maintained followed by the addition of Et.sub.2O to
induce precipitate formation. After stirring for about 15 h, the
precipitate was collected by filtration to provide
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine
hydrochloride (2.5 g, 62%) as a tan solid: LC/MS (Table 1, Method
a) R.sub.t=1.80 min; MS m/z: 343 (M+H).sup.+.
Preparation #13:
N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide
##STR00201##
[1223] To a slurry of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(0.50 g, 1.476 mmol, Example #5, Step C) in DCM (10 mL) was added
cyclohexanecarbonyl chloride (0.221 mL, 1.623 mmol) followed by
DIEA (0.644 mL, 3.69 mmol). The reaction mixture was stirred for
about 4 h at ambient temperature and then saturated aqueous
NaHCO.sub.3 (20 mL) and DCM (20 mL) were added to the reaction
mixture. The organic layer was separated, concd in vacuo, and
purified by chromatography on silica gel (40 g) eluting with 20-80%
EtOAc in DCM to provide
N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide
(0.49 g, 80%) as a colorless solid: LC/MS (Table 1, Method a)
R.sub.t=2.40 min; MS m/z: 413 (M+H).sup.+.
Preparation #14*: (2R,4S)-tert-butyl
4-(cyclopropanesulfonamido)-2-methylpyrrolidine-1-carboxylate
##STR00202##
[1225] To a slurry of 20 wt % Pd(OH).sub.2 on C (0.605 g, 0.862
mmol) in EtOH (75 mL) was added a solution of (2R,4S)-tert-butyl
4-azido-2-methylpyrrolidine-1-carboxylate (3.9 g, 17 mmol,
synthesized as described in Rosen, T.; Chu, D. T. W.; Lico, I. M.;
Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G.
J. Med. Chem. 1988, 31, 1598-1611) in EtOH (25 mL). The reaction
mixture was sparged with hydrogen and an atmosphere of hydrogen was
maintained via balloon. The reaction mixture was stirred for about
2 h at ambient temperature and then was filtered and concd in
vacuo. The residue was dissolved in DCM (100 mL), cooled to about
0.degree. C. and TEA (6.01 mL, 43.1 mmol) was added followed by
cyclopropanesulfonyl chloride (2.67 g, 19.0 mmol). The reaction
mixture was stirred at ambient temperature for about 15 h,
saturated aqueous NaHCO.sub.3 (50 mL) was added to the reaction
mixture and the organic layer was separated, concd in vacuo, and
purified by chromatography on silica gel (80 g) eluting with 20-80%
EtOAc in heptane to provide (2R,4S)-tert-butyl
4-(cyclopropanesulfonamido)-2-methylpyrrolidine-1-carboxylate (2.55
g, 48%) as an oil: LC/MS (Table 1, Method a) R.sub.t=1.98 min
(ELSD); MS m/z: 305 (M+H).sup.+.
Preparation #15*: (2R,4S)-tert-butyl
4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate
##STR00203##
[1227] To a slurry of 20 wt % Pd(OH).sub.2 on C (0.044 g, 0.062
mmol) in EtOH (30 mL) was added a solution of (2R,4S)-tert-butyl
4-azido-2-ethylpyrrolidine-1-carboxylate (1.5 g, 6.2 mmol,
synthesized as described in Rosen, T.; Chu, D. T. W.; Lico, I. M.;
Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G.
J. Med. Chem. 1988, 31, 1598-1611) in EtOH (10 mL). The reaction
mixture was sparged with hydrogen and an atmosphere of hydrogen was
maintained via balloon. The reaction mixture was stirred for about
4 h at ambient temperature and then was filtered and concd in
vacuo. The residue was dissolved in pyridine (30 mL) and
cyclopropanesulfonyl chloride (1.05 g, 7.49 mmol) was added. The
reaction mixture was stirred for about 15 h at ambient temperature
and then was partitioned between EtOAc (50 mL) and saturated
aqueous CuSO.sub.4 (50 mL). The organic layer was separated, washed
with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, concd in vacuo, and purified by chromatography on silica
gel (80 g) eluting with 20-80% EtOAc in heptane to provide
(2R,4S)-tert-butyl
4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95
g, 48%) as an oil: LC/MS (Table 1, Method a) R.sub.t=2.12 min
(ELSD); MS m/z: 319 (M+H).sup.+.
Preparation #16: tert-butyl
1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcar-
bamate
##STR00204##
[1229] To a solution of tert-butyl
1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-pyrrolidin-
-3-ylcarbamate (0.54 g, 1.0 mmol, Preparation #J.1) in THF (15 mL)
was added DIEA (0.444 mL, 2.54 mmol) followed by mercury (II)
trifluoroacetate (0.478 g, 1.12 mmol). The reaction mixture was
stirred at ambient temperature for about 2 h and then saturated
aqueous NaHCO.sub.3 (30 mL) and EtOAc (30 mL) were added. The
organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd in vacuo. The crude material was purified by
chromatography on silica gel (40 g) eluting with 10-40% EtOAc in
DCM to provide tert-butyl
1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcar-
bamate (0.411 g, 81%) as a yellow glass: LC/MS (Table 1, Method a)
R.sub.t=2.50 min; MS m/z: 497 (M+H).sup.+.
Preparation #17:
N-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyra-
zin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide
##STR00205##
[1231] To a solution of
N-(4-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo-
-[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 0.47 mmol,
prepared using E with
4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid
[Prime Organics], K with cyclopropylsulfonyl chloride, H from
Preparation #12, HATU and DIEA, Q with Lawesson's reagent and
mercury (II) trifluoroacetate) in 1,4-dioxane (10 mL) and water (1
mL) was added N-methylmorpholine-N-oxide (0.22 g, 1.8 mmol)
followed by osmium tetroxide (4 wt % in water, 0.36 mL, 0.047
mmol). The reaction mixture was stirred for about 15 h and then DCM
(20 mL) and water (10 mL) were added to the reaction mixture. The
organic layer was separated, concd in vacuo, and purified by
chromatography on silica gel eluting with 10-50% MeCN in DCM, to
provide
N-(4-(3-(2,3-dihydroxypropyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyra-
zin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.009 g,
3%): LC/MS (Table 1, Method a) R.sub.t=1.90 min; MS m/z: 612
(M-H).sup.-.
Preparation #18:
2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR00206##
[1232] Step A: 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine
##STR00207##
[1234] To a solution of 3,5-dibromopyrazin-2-amine (10.0 g, 39.5
mmol) in THF (200 mL) was added copper (I) iodide (0.377 g, 1.98
mmol), bis (triphenylphosphine)palladium (II) dichloride (1.39 g,
1.98 mmol) and TEA (16.5 mL, 119 mmol). The reaction mixture was
cooled to about 0.degree. C. and degassed with Ar. The reaction
mixture was stirred for about 5 min and then the reaction mixture
was sparged with propyne and a propyne atmosphere was maintained
via balloon. The reaction mixture was stirred for about 30 min at
about 0.degree. C. and then was allowed to warm to ambient
temperature. The reaction mixture was stirred for about 2 h and
then EtOAc (100 mL) and water (100 mL) were added to the reaction
mixture. The organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd in vacuo. The crude mixture
was purified by chromatography on silica gel (120 g) eluting with
10-60% EtOAc in DCM (dry loaded) to provide
5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 84%) as a yellow
solid: LC/MS (Table 1, Method a) R.sub.t=1.79 min; MS m/z: 212, 214
(1:1) (M+H).sup.+.
Step B: 2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR00208##
[1236] To a slurry of NaH (60% dispersion in mineral oil, 2.00 g,
49.9 mmol) in NMP (100 mL) was slowly added a solution of
5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 33.2 mmol) in NMP
(20 mL). The reaction mixture was stirred at ambient temperature
for about 20 min and then a solution of p-toluenesulfonyl chloride
(6.97 g, 36.6 mmol) in NMP (20 mL) was added. The reaction mixture
was stirred at ambient temperature for about 20 h and then aqueous
HCl (1 N, 100 mL) was added to the reaction mixture. The resulting
solids were collected by filtration. The brown solid was triturated
with DCM/EtOAc (1:1, 30 mL) and collected by filtration to provide
2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (9.0 g, 74%) as
a brown solid: LC/MS (Table 1, Method a) R.sub.t=2.68 min; MS m/z:
366, 368 (1:1) (M+H).sup.+.
Step C: tert-butyl
2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR00209##
[1238] Tris(dibenzylideneacetone)dipalladium(0) (0.250 g, 0.273
mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl
(0.232 g, 0.546 mmol) were combined in 1,4-dioxane (15 mL). The
flask was evacuated with some bubbling of solvent and then
carefully refilled with nitrogen (3 times). Nitrogen was then
bubbled directly into the reaction mixture. The mixture was then
heated at about 80.degree. C. for about 10 min and then removed
from the heating source.
2-Bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 2.73
mmol), tert-butyl hydrazinecarboxylate (0.541 g, 4.10 mmol) and
NaOt-Bu (0.501 mL, 4.10 mmol) were added and the reaction was
heated at about 80.degree. C. for about 1 h. The reaction was
cooled to ambient temperature and the solvents removed under
reduced pressure. The black residue was then taken up in EtOAc (50
mL) and filtered. The filtrate was washed with saturated aqueous
NH.sub.4Cl (50 mL), EDTA (1.0 M aqueous, 50 mL) and saturated
aqueous NaHCO.sub.3 (50 mL). The solution was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd under reduced pressure. The
material was purified by chromatography on silica gel (80 g)
eluting with 25-100% EtOAc in heptane to provide tert-butyl
2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
(0.160 g, 14%) as a brown oil: LCMS (Table 1, Method a)
R.sub.t=2.51 min; MS m/z: 418 (M+H).sup.+.
Step D: 2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR00210##
[1240] tert-Butyl
2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazine
carboxylate (0.16 g, 0.38 mmol) was stirred in 1,4-dioxane (1.9 mL)
in a sealed vial to give a brown solution. HCl (4 M in 1,4-dioxane,
0.958 mL, 3.83 mmol) was added and the reaction stirred at ambient
temperature for about 20 h. The solvents were removed under reduced
pressure. The residue was partitioned between saturated aqueous
NaHCO.sub.3 (10 mL) and EtOAc (10 mL). The layers were separated
and the aqueous layer was extracted with EtOAc (2.times.10 mL). The
combined organic extracts were washed with brine (20 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered, and concd in vacuo to
provide 2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
(0.089 g, 73%): LC/MS (Table 1, Method a) R.sub.t=1.92 min; MS m/z:
318 (M+H).sup.+.
Preparation #19
Preparation #19.1:
(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)cyclopentanamine
Preparation #19.2:
(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentanamine
##STR00211##
[1242] To a mixture of
N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentyl)acetamide (1.52 g, 3.36 mmol, prepared
using Y from Example #7, step H and Pd/C, G, AA [Table 2, Method 3,
R.sub.t=6.1 min, or =ND], Z with NaOH, A with Example #1 Step D,
HATU, and TEA, and B with TEA) and 1,4-dioxane (25 mL) was added
aqueous HCl (6 N, 25 mL, 150 mmol). The reaction was heated at
about 100.degree. C. for about 14 h and then was cooled to ambient
temperature and concd under reduced pressure. To the resulting
brown residue was added MeOH (30 mL) and the solution was concd
under reduced pressure. To the resulting residue was added MeOH (5
mL) followed by slow addition of Et.sub.2O (20 mL). Initially a
cloudy solution formed and then a dark oil/gum formed and the
mixture was concd under reduced pressure. To the resulting brown
residue was added MeOH (30 mL),
(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3--
a]pyrazin-1-yl)cyclopentan-amine (1.35 g, 2.50 mmol, UV purity 75%)
from a separate reaction, and silica gel (7 g). The mixture was
concd under reduced pressure and purified by silica gel
chromatography eluting with a gradient of 0-100% (DCM/[2 M NH.sub.3
in MeOH] (9:1)) in DCM, the column was further flushed with MeOH
then MeOH/aqueous NH.sub.4OH (9:1), to give
(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-y-
l)cyclopentanamine [Preparation #19.1] (0.092 g, 5%) as a dark
brown solid: LC/MS (Table 1, Method a) R.sub.t=1.35 min; MS m/z:
257 (M+H).sup.+ and 2.9 g of brown residue that was partitioned
between DCM and saturated aqueous NaHCO.sub.3 (50 mL each). The
layers were separated and the aqueous layer was extracted with
additional DCM (2.times.50 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and concd
under reduced pressure to give
(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentanamine [Preparation #19.2] (1.94 g, 78%) as a
taupe foam: LC/MS (Table 1, Method a) R.sub.t=1.80 min; MS m/z: 411
(M+H).sup.+.
Preparation #20:
3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopenty-
l benzoate
##STR00212##
[1244] To a mixture of
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentyl benzoate (5.00 g, 7.84 mmol, prepared from Example #4
Step J using II with benzoic acid, and B) in MeOH (16 mL) was added
a solution of potassium cyanide (0.74 mL, 17.2 mmol) in MeOH (16
mL). The reaction was stirred at ambient temperature for about 16
h. The reaction mixture was concd under reduced pressure to afford
a residue. The residue was partitioned between water (20 mL) and
DCM (20 mL). The layers were separated and the aqueous layer was
extracted with DCM (3.times.10 mL). The extract was then washed
with saturated aqueous NaHCO.sub.3, dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to afford a
crude oil. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to
3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopenty-
l benzoate (2.30 g, 78%) as a red tinted solid. LC/MS (Table 1,
Method a) R.sub.t=2.08 min; MS m/z: 376 (M+H).sup.+.
Preparation #21: tert-butyl
4-(aminomethyl)-2-ethylcyclopentanecarboxylate
##STR00213##
[1245] Step A: tert-butyl
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate
##STR00214##
[1247] A solution of 3-tert-butyl 1-methyl
4-ethylcyclopentane-1,3-dicarboxylate (3.88 g, 15.1 mmol,
Preparation #11, Step B) in Et.sub.2O (150 mL) was cooled to about
-40.degree. C. LAH (2 N in THF, 8.32 mL, 16.6 mmol) was added
dropwise. The reaction mixture was stirred at about -40.degree. C.
for about 1 hour. The reaction mixture was partitioned between
saturated aqueous NaHCO.sub.3 (50 mL) and EtOAc (3.times.50 mL).
The combined organic extracts were concd under reduced pressure.
The crude material was purified by silica gel chromatography
eluting with a gradient of 0-100% EtOAc/heptane to give tert-butyl
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (1.00 g, 29%) as a
brown oil: LC/MS (Table 1, Method a) R.sub.t=2.37 min; MS m/z: 229
(M+H).sup.+.
Step B: tert-butyl
2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate
##STR00215##
[1249] To a solution of tert-butyl
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (0.220 g, 0.964
mmol) in DCM (5 mL) was added TEA (0.16 mL, 1.15 mmol) and
methanesulfonyl chloride (0.083 mL, 1.06 mmol) at about 0.degree.
C. The reaction mixture was allowed to warm to about 25.degree. C.
and stirred at about 25.degree. C. for about 16 h. The reaction
mixture was partitioned between water (20 mL) and DCM (20 mL). The
aqueous solution was washed with DCM (2.times.20 mL). The combined
organic extracts were dried over anhydrous MgSO.sub.4, filtered,
and concd under reduced pressure to give tert-butyl
2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295
g, 100%): LC/MS (Table 1, Method b) R.sub.t=2.55 min; MS m/z: 307
(M+H).sup.+.
Step C: tert-butyl
4-(aminomethyl)-2-ethylcyclopentanecarboxylate
##STR00216##
[1251] To a solution of tert-butyl
2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295
g, 0.964 mmol) in DMF (5 mL) was added sodium azide (0.313 g, 4.82
mmol). The reaction was heated at about 50.degree. C. for about 16
h and then cooled to about 15-20.degree. C. Water (40 mL) was added
to the reaction mixture. The aqueous solution was extracted with
DCM (3.times.30 mL). The combined organic extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give a dark brown oil. The brown oil was dissolved in THF (6.5 mL)
and water (3.5 mL). Triphenylphosphine (0.316 g, 1.205 mmol) was
added. The reaction mixture was stirred at about 25.degree. C. for
about 15 h. The organic solvent was removed under reduced pressure
and the residue partitioned between saturated aqueous NaHCO.sub.3
(20 mL) and DCM (20 mL). The organic phase was concd under reduced
pressure. The resulting residue was purified using silica gel
chromatography eluting with a gradient of 0-20% (20% (7 N ammonium
in MeOH) in MeOH)) in DCM to give tert-butyl
4-(aminomethyl)-2-ethylcyclopentanecarboxylate (0.102 g, 46%) as a
brown oil: LC/MS (Table 1, Method b) ft, =1.72 min; MS m/z: 228
(M+H).sup.+.
Preparation #22: ethyl 2-ethyl-4-formylcyclopentanecarboxylate
##STR00217##
[1252] Step A: 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic
acid
##STR00218##
[1254] To a solution of
2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (8.34 g,
41.7 mmol, Preparation #11, Step A) in THF (208 mL) was added
LiBH.sub.4 (0.907 g, 41.7 mmol) at about -20.degree. C. The
reaction mixture was stirred at about -20.degree. C. for about 1 h.
The reaction mixture was allowed to warm to about 25.degree. C.
then was stirred at about 25.degree. C. for about 16 h. Additional
LiBH.sub.4 (0.907 g, 41.7 mmol) was added. The reaction mixture was
stirred at about 25.degree. C. for about 4 h. Water (10 mL) was
added slowly to quench the reaction. The solid was removed by
vacuum filtration. The filtrate was concd under reduced pressure.
The resulting residue was partitioned between water (50 mL) and DCM
(3.times.50 mL). The combined organic extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g,
100%): LC/MS (Table 1, Method n) R.sub.t=0.44 min; MS m/z: 173
(M+H).sup.+.
Step B: ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate
##STR00219##
[1256] HCl gas was bubbled through a solution of
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 42.3
mmol) in EtOH (60 mL) at about 25.degree. C. for about 10 min. The
reaction mixture was stirred at about 25.degree. C. for about 72 h.
The solvent was removed under reduced pressure. The crude residue
was partitioned between water (30 mL) and DCM (3.times.30 mL). The
combined organic extracts were concd under reduced pressure. The
crude material was purified by silica gel chromatography eluting
with a gradient of 0-100% EtOAc/heptane to give ethyl
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.89 g, 58%) as a
yellow oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.23-4.02 (m, 2H),
3.74-3.47 (m, 2H), 2.96-2.83 (m, 1H), 2.31-2.17 (m, 1H), 2.15-1.98
(m, 2H), 1.97-1.84 (m, 1H), 1.79-1.66 (m, 1H), 1.65-1.50 (m, 1H),
1.49-1.37 (m, 1H), 1.30-1.21 (m, 5H), 1.04-0.82 (m, 3H).
Step C: ethyl 2-ethyl-4-formylcyclopentanecarboxylate
##STR00220##
[1258] To a solution of ethyl
2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.84 g, 24.2
mmol) in DCM (100 mL) was added pyridinium chlorochromate (10.42 g,
48.3 mmol). The reaction mixture was stirred at about 25.degree. C.
for about 3 h. Silica gel (1 g) was added. The mixture was stirred
at about 25.degree. C. for about 30 min. The solid was removed by
vacuum filtration, while rinsing with DCM (100 mL). The filtrate
was concd under reduced pressure. The resulting residue was
purified using silica gel chromatography eluting with a gradient of
0-40% EtOAc/Heptane to give ethyl
2-ethyl-4-formylcyclopentanecarboxylate (3.03 g, 63%) as a clear
oil: .sup.1H NMR (DMSO-d.sub.6) .delta. 9.66-9.47 (m, 1H),
4.12-3.94 (m, 2H), 2.94-2.73 (m, 2H), 2.19-1.90 (m, 4H), 1.55-1.65
(m, 1H), 1.37-1.23 (m, 1H), 1.23-1.06 (m, 4H), 0.96-0.82 (m,
3H).
Preparation #23:
N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trim-
ethylsilyl)ethoxy)methyl)cyclopropanesulfonamide
##STR00221##
[1260] Cesium carbonate (0.274 g, 0.841 mmol),
tricyclohexylphosphine (20 wt % solution in toluene, 0.094 g, 0.067
mmol), Pd.sub.2(dba).sub.3 (0.039 g, 0.042 mmol) and
trimethylborate (0.069 g, 0.547 mmol) were added to a solution of
N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-p-
yrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trimet-
hylsilyl)ethoxy)methyl)cyclopropanesulfonamide (0.32 g, 0.421 mmol,
prepared using KK from Preparation #GGG.1) in 1,4-dioxane (8 mL).
The mixture was degassed and heated at about 85.degree. C. for
about 2 h. The solvent was removed and the residue was partitioned
between EtOAc and water (20 mL each). The organic phase was washed
with brine (15 mL), dried over anhydrous MgSO.sub.4, filtered and
concd. The resulting mixture was purified by silica gel flash
chromatography (40 to 100% of EtOAc in heptane) to yield
N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-
-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-((2-(trim-
ethylsilyl)ethoxy)methyl)cyclopropanesulfonamide (0.21 g, 77%) as a
yellow amorphous solid. LC/MS (Table 1, Method a) R.sub.t=3.39 min;
MS m/z: 650 (M+H).sup.+.
Preparation #24: diethyl
2-(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)-2-oxoethylphospho-
nate
##STR00222##
[1261] Step A: methyl
4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate
##STR00223##
[1263] To a solution of methyl
4-aminobicyclo[2.2.2]octane-1-carboxylate (500 mg, 2.73 mmol) (Yeh,
V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.;
Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H. L.; Link,
J. T. Bioorg. and Med. Chem. Let, 2006, vol. 16, i#20 p. 5408-5413)
in DCM (10 mL) at rt was added TEA (0.76 mL, 5.46 mmol) and DMAP
(50 mg, 0.41 mmol). Cyclopropanesulfonyl chloride (764 mg, 5.46
mmol, Matrix) was added dropwise by syringe. The reaction mixture
was stirred for about 15 h at rt. The mixture was washed with water
(10 mL), and the aqueous layer was extracted with DCM (2.times.10
mL), the organic layers were combined and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concd in vacuo. The crude materials
was purified by silica gel chromatography eluting with a gradient
of 20-35% EtOAc in hexanes to afford methyl
4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (410
mg, 52% yield). LC/MS (Table 1, Method p) R.sub.t=1.68 min; MS m/z:
288 (M+H).sup.+.
Step B: diethyl
(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate
##STR00224##
[1265] A solution of diethyl methylphosphonate (1.27 g, 8.36 mmol)
was dissolved in THF (20 mL) and cooled to about -78.degree. C. in
a dry ice-acetone bath under nitrogen. Then n-BuLi (9.77 mmol, 3.9
mL, 2.5M in hexane) was added dropwise over about 5 min. The
reaction mixture was stirred for about 3 h, keeping the temperature
below about -70.degree. C. Then a solution of methyl
4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (800
mg, 2.79 mmol) in THF (10 mL) was added, keeping the temperature at
about -78.degree. C. The solution was stirred for about 15 h,
allowing the temperature to rise slowly to rt. To the reaction
mixture was added saturated aqueous NH.sub.4Cl (30 mL) and
extracted with EtOAc (3.times.30 mL). The organic layers were
combined and washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concd to provide diethyl
(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate
(1.30 g, 100% yield). The crude product was used in next step
without further purification. LC/MS (Table 1, Method p)
R.sub.t=1.62 min; MS m/z: 408 (M+H).sup.+.
Preparation #25:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone
##STR00225##
[1266] Step A: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR00226##
[1268] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22,
Step B) in DCM (22 mL). To the flask were added ethylene glycol
(0.91 mL, 16 mmol), triethylorthoformate (2.0 mL, 12 mmol), and
p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The reaction
mixture was stirred at rt for about 24 h. The solution was concd
under reduced pressure to give a brown oil that was dissolved in
EtOAc and purified by flash silica gel chromatography (Silicycle 25
g column) eluting with a gradient of 0-50% EtOAc in heptane. The
product containing fractions were combined and concd to dryness
under reduced pressure to give ethyl
2-ethyl-4-oxocyclopentanecarboxylate as a light yellow oil (1.6 g,
83%): LC/MS (Table 1, Method c) MS m/z 229 (M+H).sup.1; .sup.1H NMR
(CDCl) .delta. 4.14 (q, 2H), 3.90 (m, 4H), 2.99 (q, 1H), 2.32-2.27
(m, 1H), 2.26-2.11 (m, 1H), 2.05-1.99 (m, 1H), 1.96-1.91 (m, 1H),
1.83-1.78 (m, 1H), 1.46-1.39 (m, 1H), 1.31-1.24 (m, 1H), 1.26 (t,
3H), 0.90 (t, 3H).
Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid
##STR00227##
[1270] A round bottom flask was charged with ethyl
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol)
and aqueous 1 N sodium hydroxide (14.0 mL, 14.0 mmol). The solution
was stirred overnight at rt. To the solution was added DCM (30 mL)
followed by the addition of 20% aqueous citric acid (about 20 mL)
to reach pH of about 2. The layers were separated and the aqueous
solution was extracted with DCM (2.times.30 mL) and DCM/EtOAc (1:1,
30 mL). The combined extracts were dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure to give
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid as a clear,
colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c) R.sub.t=1.20
min; MS m/z: 201 (M+H).sup.+.
Step C:
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[-
4.4]nonane-7-carbohydrazide
##STR00228##
[1272] A 50 mL round bottom flask was charged with
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,
Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic
acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction
mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6
mmol) and the resulting yellow suspension was stirred at rt for
about 3 h. To the reaction solution was added DCM (25 mL) and the
solution was washed with water and brine (20 mL each). The organic
layer was dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a brown oil. The crude product was
purified by flash silica gel chromatography (25 g Silicycle column)
eluting with a gradient of: 0-10% MeOH in DCM over 25 min. The
product containing fractions were concd under reduced pressure to
give
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]non-
ane-7-carbohydrazide as a foam (0.50 g, 89%): LC/MS (Table 1,
Method c) R.sub.t=1.49 min; MS m/z: 486 (M+H).sup.+.
Step D:
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine
##STR00229##
[1274] A round bottom flask was charged with
8-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nona-
ne-7-carbohydrazide (4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To
the flask was added DIEA (8.81 mL, 50.5 mmol) followed by the
addition of thionyl chloride (0.770 mL, 10.6 mmol). The mixture was
heated to about 75.degree. C. for about 90 min. Additional thionyl
chloride (0.074 mL, 1.0 mmol) was added and heating was continued
for about 1 h. The reaction was cooled to rt and stirred overnight.
The solution was diluted with DCM (75 mL) and washed with water (50
mL). The layers were separated and the organic layer was dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give a dark brown oil. The crude product was purified via flash
silica gel chromatography eluting with a gradient of 0-60% acetone
in heptane with a hold at 60% acetone in heptane. The product
containing fractions were combined and concd to give material that
was loaded onto a second column (Silicycle, 40 g column), eluting
with a gradient of 0-60% acetone in heptane. The product containing
fractions were combined and concd under reduced pressure to give
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine as a tan powder (3.0 g, 64%): LC/MS (Table
1, Method c) R.sub.t=1.44 min; MS m/z: 468 (M+H).sup.+.
Step E:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentanone
##STR00230##
[1276] A round bottom flask was charged with
1-47S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine (3.56 g, 7.61 mmol) and THF (20
mL). To the solution was added aqueous HCl (6N, 3.81 mL, 22.8 mmol)
and the mixture was stirred at rt for about 2 h. The solvent was
removed under reduced pressure and DCM (75 mL) and water (50 mL)
were added. The layers were separated and the organic solution was
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure to give
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone as a brown foam (2.99 g, 93%): LC/MS (Table 1, Method
c) R.sub.t=1.40 min; MS m/z: 424 (M+H).sup.+.
Preparation #26: 3,3-difluoro-1-(vinylsulfonyl)pyrrolidine
##STR00231##
[1278] A solution of 3,3-difluoropyrrolidine hydrochloride (0.3 g,
2.1 mmol, Matrix) and DIEA (0.37 mL, 2.1 mmol) in MeCN (5 mL) was
stirred at about 50.degree. C. for about 30 min. The reaction was
cooled to ambient temperature and concd under reduced pressure. The
solid was dissolved in MeCN (2 mL) and a solution of
2-chloroethanesulfonyl chloride (0.22 mL, 2.1 mmol) in Et.sub.2O (3
mL) was added at about -78.degree. C. and stirred for about 2 h. To
the reaction mixture was added DIEA (0.6 mL, 3.4 mmol) and stirred
for about 1 h. The reaction was warmed to ambient temperature and
the solvent was removed under reduced pressure. The residue was
partitioned between DCM (5 mL) and water (2.times.2 mL). The
combined organic layers were dried over anhydrous MgSO.sub.4,
filtered and concd under reduced pressure to give crude
3,3-difluoro-1-(vinylsulfonyl)pyrrolidine (0.11 g, 27%) which was
used without further purification: LC/MS (Table 1, Method b)
R.sub.t=2.04 min; MS m/z: 198 (M+H).sup.+.
Preparation #27: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
##STR00232##
[1279] Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine
##STR00233##
[1281] A solution of 4-chloro-3-iodopyridin-2-amine (0.25 g, 0.982
mmol, Boa Pharma) in concd H.sub.2SO.sub.4 (1.95 mL) was cooled to
about 0.degree. C. before the portion wise addition of potassium
nitrate (0.21 g, 2.2 mmol) over 10 min. The reaction was stirred
for about 4 h at about 0.degree. C. The reaction mixture was slowly
pipetted over a solution of ammonium hydroxide and crushed ice (10
mL) in an ice bath. The pH of the reaction was maintained above 9
by the incremental addition of ammonium hydroxide. The resulting
precipitate was filtered and dried to afford
4-chloro-3-iodo-5-nitropyridin-2-amine (0.085 g, 29%) as a
green-tinted solid LC/MS (Table 1, Method n) R.sub.t=0.64 min; MS
m/z: 298 (M-H).sup.-.
Step B:
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine
##STR00234##
[1283] To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine
(5.30 g, 17.7 mmol) in THF (90 mL) was added TEA (15.0 mL, 108
mmol). The reaction mixture was degassed and purged with nitrogen 3
times. Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g,
0.88 mmol, Strem), copper(I) iodide (0.17 g, 0.89 mmol), and
trimethylsilylacetylene (5.4 mL, 39 mmol) were added to the
reaction mixture. The mixture was degassed and purged 3 times with
nitrogen. The reaction was heated at about 60.degree. C. for about
16 h. The reaction mixture was cooled to ambient temperature. The
reaction mixture was filtered and washed with THF (200 mL). The
filtrate was coned under reduced pressure. DCM (100 mL) was added
to the residue and the precipitate that formed was filtered and
collected to give
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77
g). The remaining filtrate was coned under reduced pressure and the
crude material was purified by flash chromatography on silica gel
eluting with a gradient of 0-100% EtOAc in DCM. The purified
material was combined with the 0.77 g of precipitate to afford
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22
g, 47%) as a yellow solid: LC/MS (Table 1, Method c) R.sub.t=1.62
min; MS m/z 268 (M-H).sup.-.
Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine
##STR00235##
[1285] To a solution of
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98
g, 7.34 mmol) in DMF (25 mL) was added potassium fluoride on
alumina (40 wt %, 2.67 g, 18.35 mmol). The suspension was stirred
at ambient temperature for about 1 h. Activated charcoal (0.3 g)
was added and the suspension was filtered through Celite.RTM.,
washing with DMF (150 mL). The solvent was removed under reduced
pressure and the crude material was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to
afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g, 71%) as a
yellow solid: LC/MS (Table 1, Method n) R.sub.t=0.59 min; MS m/z:
196 (M-H).sup.-.
Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
##STR00236##
[1287] To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine
(0.16 g, 0.81 mmol) in DMF (3 mL) was added
chloro(1,5-cyclooctadiene) rhodium (I) dimer (0.02 g, 0.04 mmol)
and tris(4-fluorophenyl)phosphine (0.128 g, 0.405 mmol). The
reaction mixture was degassed by bubbling argon for 15 min. The
reaction mixture was heated at about 80.degree. C. for about 45
min. The reaction was cooled to ambient temperature and the solvent
was removed under reduced pressure and the residue was suspended in
ether (10 mL). The precipitate was collected by filtration and
dried to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g,
83%, contains approximately 6% mol of DMF and approximately 3% mol
of tris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1,
Method a) R.sub.t=2.05 min; MS m/z 198 (M+H).sup.+.
Preparation #28*:
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide
##STR00237##
[1289] To a solution of
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (115 mg, 0.271 mmol, Preparation #BB.1*)
in DCM (1.5 mL) was added DIEA (0.071 mL, 0.406 mmol) followed by
2-methylpropane-2-sulfinic chloride (0.037 mL, 0.298 mmol). After
about 4 h the reaction mixture was diluted with EtOAc (10 mL) and
aqueous saturated NaHCO.sub.3 (10 mL). The organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concd in vacuo. The crude residue was dissolved in DCM (1.5 mL) and
a freshly prepared solution of m-chloroperbenzoic acid (0.271 mL,
0.271 mmol, 1M in DCM) was added. After about 2 h the reaction
mixture was diluted with EtOAc (10 mL) and saturated aqueous
NaHCO.sub.3 (10 mL). The organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concd in vacuo. The crude
residue was purified by chromatography on silica gel eluting with
EtOAc to provide
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)-2-methylpropane-2-sulfonamide (95 mg, 64%
yield) as an oil. LC/MS (Table 1, Method a) R.sub.t=2.40 min; MS
m/z: 545 (M+H).sup.+.
Preparation #29*:
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione
##STR00238##
[1291] To a solution of
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (0.40 g, 0.942 mmol, Example #8 Step M)
in MeOH (3 mL) was added 3,4-dimethoxycyclobut-3-ene-1,2-dione
(0.14 g, 0.98 mmol) and DIEA (0.18 mL, 1.0 mmol). The reaction was
stirred at rt for about 16.5 h. Then the solid from the reaction
mixture was collected via vacuum filtration, while washing with
cold MeOH (about 4.degree. C., 10 mL), and dried in a vacuum oven
at about 60.degree. C. to give crude
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione
(0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) R.sub.t=2.13
min; MS m/z: 535 (M+H).sup.+.
Preparation #30:
3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-amine
hydrochloride
##STR00239##
[1292] Step A:
N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamin-
e
##STR00240##
[1294] To a solution of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (2.00 g, 6.61
mmol, Example #5 Step C) in DCM (30 mL) was added
diphenylmethanimine (1.16 mL, 6.61 mmol). After about 2 d, the
reaction mixture was concd in vacuo to provide
N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamin-
e (2.75 g, 89%) as a foam and used without further purification.
LC/MS (Table 1, Method a) R.sub.t=3.02 min; MS m/z: 467
(M+H).sup.+.
Step B:
3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1--
amine, hydrochloride
##STR00241##
[1296] To a solution of
N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamin-
e (0.722 g, 1.55 mmol) in THF (3 mL) at about -78.degree. C. was
added NaHMDS (0.5 M in THF, 1.55 mL, 1.55 mmol). After about 30
min, 1,1,1-trifluoro-2-iodoethane (1.51 mL, 15.5 mmol) was added to
the reaction mixture. After about 4 h, the reaction mixture was
allowed to warm to rt slowly over night. After about 15 h, EtOAc
(30 mL) and saturated aqueous NaHCO.sub.3 (30 mL) were added. The
organic layer was separated, concd in vacuo and purified by
chromatography on silica gel eluting with EtOAc/heptane (20-50%) to
provide the crude alkylated imine. The imine was dissolved in
isopropyl acetate (30 mL) and concd HCl (0.50 mL) was added. The
reaction mixture was spun on a rotory evaporator for 1 h prior to
partial concentration to approx 10 mL. Additional isopropyl acetate
(30 mL) was added and the solvent was partially removed in vacuo
until approx. 10 mL remained. Et.sub.2O (30 mL) was added and the
solution was allowed to age for about 30 min. The resulting solids
were collected by filtration and dried in vacuo to provide
3,3,3-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-amine
hydrochloride (0.150 g, 23%) as a colorless solid. LC/MS (Table 1,
Method a) R.sub.t=1.88 min; MS m/z 385 (M+H).sup.+.
Preparation #31:
(1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic
acid
##STR00242##
[1297] Step A: (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol
##STR00243##
[1299] To a solution of (1S,2R)-ethyl
2-ethyl-4-oxocyclopentanecarboxylate (5 g, 27.1 mmol, Example #22
step B) in THF (100 mL) at about -78.degree. C. was added LAH (2 M
in THF, 54.3 mL, 109 mmol). After about 1 h, the reaction mixture
was allowed to warm to rt slowly. After about 4 h, water (4.8 mL)
followed by aqueous NaOH (15% w/v, 4.8 mL) followed by water (9.6
mL) was added to the reaction mixture. After about 15 h, anhydrous
Na.sub.2SO.sub.4 was added and the slurry was filtered and concd in
vacuo to provide crude
(3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (3.9 g, 100%) as an
oil which was used without further purification. LC/MS (Table 1,
Method a) R.sub.t=2.40 min; MS m/z: 145 (M+H).sup.+.
Step B: (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone
##STR00244##
[1301] To a solution of
(3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (4.00 g, 27.7 mmol)
in MeCN (70 mL) and water (30.0 mL) was added potassium bromate
(1.487 mL, 29.1 mmol) and CAN (0.760 g, 1.387 mmol). The reaction
mixture was heated to about 80.degree. C. After about 2 h, the
reaction mixture was cooled to rt and Et.sub.2O (100 mL) was added.
The organic layer was separated, washed with brine (30 mL), concd
in vacuo and purified by chromatography on silica gel eluting with
EtOAc/heptane (20-60%) to provide
(3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.4 g, 61%) as an
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.79 (dd, J=10.5,
5.3 Hz, 1H), 3.70 (dd, J=10.5, 6.5 Hz, 1H), 2.55-2.44 (m, 1H),
2.41-2.25 (m, 4H), 2.15-2.05 (m, 1H), 1.55-1.65 (m, 2H), 1.43-1.30
(m, 1H), 0.97 (t, J=7.3 Hz, 3H).
Step C:
(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentano-
ne
##STR00245##
[1303] To a solution of
(3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.60 g, 18.3 mmol)
in DMF (30 mL) was added imidazole (1.87 g, 27.4 mmol) followed by
tert-butylchlorodimethylsilane (3.03 g, 20.1 mmol). After about 4
h, heptane (50 mL) was added. The heptane layer was removed and
washed with brine. The brine layer was combined with the DMF layer
and extracted with EtOAc/heptane (1:1, 30 mL). The heptane and
EtOAc layers were combined, concd in vacuo and purified by
chromatography on silica gel eluting with EtOAc/heptane (0-30%) to
provide
(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone
(3.5 g, 75%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.77 (dd, J=10.5, 4.3 Hz, 1H), 3.64 (dd, J=10.5, 4.0 Hz,
1H), 2.40-2.20 (m, 5H), 2.18-2.02 (m, 1H), 1.65-1.55 (m, 1H),
1.52-1.37 (m, 1H), 0.97 (t, J=7.4 Hz, 3H), 0.87 (s, 9H), 0.43 (s,
3H), 0.03 (s, 3H).
Step D: ethyl
2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene-
)acetate
##STR00246##
[1305] To a slurry of NaH (60% dispersion in mineral oil, 0.608 g,
15.2 mmol) in THF (50 mL) was added ethyl
2-(diethoxyphosphoryl)acetate (3.25 mL, 16.2 mmol). After about 30
min, the phosphonate solution was added to a flask charged with
(3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone
(2.6 g, 10.14 mmol). After about 20 h, EtOAc (20 mL) and saturated
aqueous NH.sub.4Cl (20 mL) were added. The organic layer was
removed concd in vacuo and purified by chromatography on silica gel
eluting with EtOAc/heptane (20-60%) to provide ethyl
2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene-
)acetate (3.3 g, 100%) as an oil. LC/MS (Table 1, Method a)
R.sub.t=3.91, 3.96 min; MS m/z: 327 (M+H).sup.+.
Step E: ethyl
2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate
##STR00247##
[1307] To a solution of ethyl
2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene-
)acetate (1.00 g, 3.06 mmol) in THF (20 mL) was added TBAF (1M in
THF, 4.59 mL, 4.59 mmol). After 6 h, EtOAc and water were added.
The organic layer was separated, concd in vacuo and purified by
chromatography on silica gel eluting with EtOAc/heptane to provide
ethyl 2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate
(0.620 g, 95%) as an oil. LC/MS (Table 1, Method a) R.sub.t=1.96,
2.08 min; MS m/z: 213 (M+H).sup.+.
Step F: ethyl
2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate
##STR00248##
[1309] To a solution of ethyl
2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate (0.160
g, 0.754 mmol) in DCM (3 mL) was added Crabtree's catalyst (0.030
g, 0.038 mmol). The reaction mixture was sparged with hydrogen for
about 5 min and an atmosphere of hydrogen was maintained via
balloon. After about 24 h, the reaction mixture was concd in vacuo
and purified by chromatography on silica gel eluting with
EtOAc/heptane (30-80%) to provide ethyl
2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate (0.140
g, 87%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.12
(q, J=7.1 Hz, 2H), 3.71-3.64 (dd, J=10.5, 8.0 Hz, 1H), 3.47 (dd,
J=10.5, 8.0 Hz, 1H), 2.55-2.41 (m, 1H), 2.32 (d, J=6.7 Hz, 2H),
2.02-1.89 (m, 1H), 1.88-1.76 (m, 1H), 1.70-1.60 (m, 1H), 1.48-1.33
(m, 4H), 1.26 (t, J=7.1 Hz, 3H), 1.22-1.07 (m, 1H), 0.90 (t, J=7.4
Hz, 3H).
[1310] Step G:
(1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic
acid
##STR00249##
[1311] To a solution of ethyl
2-((1R,3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentyl)acetate (0.140
g, 0.653 mmol) in MeCN (2 mL), water (4 mL) and EtOAc (2 mL) was
added sodium periodate (0.349 g, 1.633 mmol) followed by
ruthenium(III) chloride hydrate (0.0015 g, 0.0065 mmol). After
about 2 h, the reaction mixture was diluted with EtOAc (20 mL) and
water (10 mL). The organic layer was separated and extracted with
aqueous NaOH (1 N, 10 mL). The pH of the aqueous layer was adjusted
to about 1 with concd HCl and extracted with EtOAc (20 mL). The
organic layer was dried over anhydrous MgSO.sub.4, filtered, and
concd in vacuo to provide
(1S,2R,4R)-4-(2-ethoxy-2-oxoethyl)-2-ethylcyclopentanecarboxylic
acid (0.150 g, 101%) as an oil which was used without further
purification. .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 10.68 (bs,
1H), 4.13 (q, J=7.1 hz, 2H), 2.99-2.95 (m, 1H), 2.76-2.64 (m, 1H),
2.31 (d, J=7.6 Hz, 2H), 2.24 (ddd, J=13.5, 8.7, 4.8 Hz, 1H),
2.18-2.11 (m, 1H), 1.81 (dt, J=13.0, 8.4 Hz, 1H), 1.55-1.45 (m,
3H), 1.31-1.27 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), (t, J=7.4 Hz,
3H).
Preparation #32:
2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanamine,
hydrochloride
##STR00250##
[1312] Step A:
(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propan-
e-2-sulfinamide
##STR00251##
[1314] To a solution of
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (8.66 g, 28.7
mmol, Preparation #12Step B) and (S)-2-methylpropane-2-sulfinamide
(4.18 g, 34.5 mmol) in DCM (20 mL) at ambient temperature was added
anhydrous powdered copper(II) sulfate (13.8 g, 86 mmol). After
about 20 h, the reaction mixture was filtered and partially concd
in vacuo. Heptane was added to the solution and the resulting
solids were collected by filtration and dried in vacuo to provide
(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylen-
e)propane-2-sulfinamide (11.5 g, 99%) as a solid. LC/MS (Table 1,
Method a) R.sub.t=2.50 min; MS m/z: 405 (M+H).sup.+.
Step B:
(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazi-
n-2-yl)ethyl)propane-2-sulfinamide
##STR00252##
[1316] To a dry flask charged with 4 .ANG. molecular sieves (5 g)
and tetramethyl-ammonium fluoride (0.553 g, 5.93 mmol) was added
THF (20 mL). The reaction mixture was stirred for about 30 min
after which it was cooled to about -78.degree. C. and a solution of
(S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propan-
e-2-sulfinamide (1.20 g, 2.97 mmol) in THF (10 mL) was added. After
about 15 min trimethyl(trifluoromethyl)silane (0.877 mL, 5.93 mmol)
was added to the reaction mixture. The mixture was allowed to warm
to -35 to -45.degree. C. After about 3 h, the reaction mixture was
cooled to -78.degree. C. and aqueous NH.sub.4Cl was added. The
reaction mixture was allowed to warm to rt. EtOAc (30 mL) and brine
(30 mL) were added. The organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concd in vacuo to provide
crude
(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-
ethyl)propane-2-sulfinamide (1.4 g, 99%) as a foam sulfonamide
which was used without further purification. LC/MS (Table 1, Method
a) R.sub.t=2.49 min; MS m/z 475 (M+H).sup.+.
Step C:
2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanamin-
e hydrochloride
##STR00253##
[1318] To a solution of
(S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-
ethyl)propane-2-sulfinamide (1.40 g, 2.95 mmol) in MeOH (20 mL) was
added HCl (4 N in 1,4-dioxane, 7.38 mL, 29.5 mmol). After about 2
h, the reaction mixture was partially concd in vacuo and diluted
with Et.sub.2O until solids began to form. After about 30 min, the
resulting solids were collected by filtration and dried in vacuo to
provide
2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanamine
hydrochloride (0.840 g, 70%) as a solid. LC/MS (Table 1, Method a)
R.sub.t=2.16 min; MS m/z 371 (M+H).sup.+.
Preparation #33:
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic
acid
##STR00254##
[1319] Step A:
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate.(R)-1-phenyl-
ethanamine
##STR00255##
[1321] To a solution of
4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (1240 g, 1499
mmol, prepared using X with Example #24 Step H and dibenzylamine
and TT) in THF (8.0 L) was added (R)-(+)-1-phenylethylamine (0.193
L, 1499 mmol). The mixture was warmed to reflux to dissolve the
solids, and was then cooled to ambient temperature. After about 15
h, the reaction mixture was filtered, washed THF (800 mL) and dried
in a vacuum oven to afford
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate.(R)-1-phenyl-
ethanamine (565 g, 85%, 97. 5% ee): LC/MS (Table 2, Method 70)
R.sub.t=8.49 min. The mother liquor was coned. The residue was
dissolved in THF (1 L), heated to dissolve the solids, and cooled
to ambient temperature. After about 15 h, the reaction mixture was
filtered, washed THF (800 mL) and dried in a vacuum oven to afford
additional
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate.(R)-1-phenyl-
ethanamine (78.5 g, 12%, 95.2% ee): HPLC (Table 2, Method 70)
R.sub.t=8.57 min
Step B: (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic
acid
##STR00256##
[1323] Phosphoric acid (11.40 mL, 196 mmol) was added to a flask
containing water (500 mL). The solution was stirred for about 5
min.
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate.(R)-1-phenyl-
ethanamine (83 g, 187 mmol) was added to the solution in small
portions. MTBE (500 mL) was added and the contents were mixed well,
dissolving the solid. The phases were settled and separated. The
aqueous layer was back extracted with MTBE (150 mL). The combined
organic phases were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo to afford
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
(60 g, 99%) as an oil: HPLC (Table 1, Method x) R.sub.t=4.57
min.
Preparation #34: 3,3-difluorocyclobutane-1-sulfonyl chloride
##STR00257##
[1324] Step A: 3-bromo-1,1-difluorocyclobutane
##STR00258##
[1326] To a vigorously stirred solution of 3-bromocyclobutanone
(18.0 g, 121 mmol, prepared as described in J. Am. Chem. Soc.,
1971, 93, 2481) in DCM (375 mL) at about 0.degree. C. was added
dropwise via an addition funnel DAST (36.9 mL, 279 mmol) over about
1 h. The reaction mixture continued stirring at about 0.degree. C.
for about 2 h and at ambient temperature for about 14 h. The
reaction was cooled to about -5.degree. C. in an ice/acetone bath
and a saturated aqueous solution of NaHCO.sub.3 (400 mL) was added
dropwise via addition funnel. The bilayers remained vigorously
stirring for about 1 h. The layers were partitioned and the aqueous
layer was extracted with DCM (4.times.200 mL). The combined organic
layers were dried over anhydrous MgSO.sub.4, filtered, and solvent
removed under reduced pressure (180 mm Hg maximum, 30.degree. C.
water bath) to afford 3-bromo-1,1-difluorocyclobutane (15.3 g, 59%)
as a light brown oil as product: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.28-4.14 (m, 1H), 3.35-3.16 (m, 2H), 3.06-2.87 (m,
2H).
Step B: S-3,3-difluorocyclobutyl ethanethioate
##STR00259##
[1328] To a solution of 3-bromo-1,1-difluorocyclobutane (13.8 g,
64.7 mmol) in DMSO (24.6 mL) was added potassium thioacetate (22.2
g, 194 mmol). The solution was heated at about 45.degree. C. for
about 16 h. Water (20 mL) and Et.sub.2O (50 mL) were added. The
layers were partitioned and the aqueous layer was extracted with
Et.sub.2O (7.times.50 mL). The combined organic layers were dried
over anhydrous MgSO.sub.4, filtered, and solvent removed under
reduced pressure (60 mm Hg maximum, 30.degree. C. water bath) to
afford crude S-3,3-difluorocyclobutyl ethanethioate (13.09 g, 78%)
as an oil: .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 3.84-3.69
(m, 1H), 3.14 (ddd, J=13.0, 7.5, 3.9 Hz, 2H), 2.66-2.55 (m, 2H),
2.33 (s, 3H).
Step C: potassium 3,3-difluorocyclobutane-1-sulfonate
##STR00260##
[1330] To a solution of crude S-3,3-difluorocyclobutyl
ethanethioate (13.0 g, 39.1 mmol) in acetic acid (100 mL) was added
H.sub.2O.sub.2 (24.0 mL, 235 mmol, 30% in water). After about 4 h,
an exotherm was noted which generated enough heat to reflux the
reaction mixture. After about 20 h, the reaction mixture was
diluted with toluene (500 mL) and partially concd in vacuo. This
process was repeated (5.times.). The solution was diluted with EtOH
(about 500 mL) and KOH (4.4 g, 78 mmol) was added to the reaction
mixture. The precipitate was collected by filtration and discarded.
Additional KOH (4.4 g, 78 mmol) was added to the filtrate and the
precipitate was collected by filtration. The solution was partially
concd in vacuo. The solution was diluted with EtOH (approx. 500 mL)
and partially concd again (3.times.). The precipitate was collected
by filtration. The last 2 collected solids were dried in vacuo and
combined to provide potassium 3,3-difluorocyclobutane-1-sulfonate
(3.5 g, 42.6%). Additional KOH (4.39 g, 78 mmol) and the solution
was partially concd in vacuo. The solution was diluted with EtOH
(approx. 500 mL) and concd again (3.times.). The resulting solids
were collected by filtration to provide potassium
3,3-difluorocyclobutane-1-sulfonate (1.6 g, 19%): .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 3.01 (ddd, J=13.5, 6.3, 2.5 Hz, 1H),
2.72-2.59 (m, 4H).
Step D: 3,3-difluorocyclobutane-1-sulfonyl chloride
##STR00261##
[1332] To a suspension of potassium
3,3-difluorocyclobutane-1-sulfonate (0.250 g, 1.189 mmol) in
thionyl chloride (2.60 mL, 35.7 mmol) was added DMF (3 drops). The
reaction was heated to about 60.degree. C. for about 21 h. The
solvent was removed under reduced pressure and the residue was used
in the next reaction without further workup or purification to
afford crude 3,3-difluorocyclobutane-1-sulfonyl chloride (0.227 g,
100%) as product. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
4.33-4.17 (m, 1H), 3.28 (dd, J=11.1, 7.6 Hz, 2H), 3.21-3.05 (m,
2H).
Preparation #35: isopropyl
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylcarbamate
##STR00262##
[1334] To a solution of
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (0.080 g, 0.19 mmol, Preparation #BB.1*)
in THF (2 mL) was added TEA (0.079 mL, 0.565 mmol) and the solution
was stirred at ambient temperature for about 10 min. To the
reaction was added isopropyl chloroformate (1 M in toluene, 0.18
mL, 0.18 mmol) and the reaction mixture was stirred for about 1 h.
The solvent was removed under reduced pressure and DCM (5 mL) and
saturated aqueous NaHCO.sub.3 (2 mL) were added. The layers were
separated and the organic layer was washed with brine (2 mL), dried
over MgSO.sub.4, filtered and concentrated under reduced pressure
to give crude isopropyl
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylcarbamate (0.080 g, 60%) which was used without
further purification: LC/MS (Table 1, Method b) R.sub.t=2.33 min;
MS m/z: 511 (M+H).sup.+.
Preparation #36: 3-(aminomethyl)cyclobutanecarboxylic acid
##STR00263##
[1336] To a flask charged with 10% palladium on carbon (0.20 g,
0.19 mmol) was added a solution of benzyl
3-(azidomethyl)cyclobutanecarboxylate (2.00 g, 8.15 mmol, prepared
using IIII from benzyl 3-(hydroxymethyl)cyclobutanecarboxylate
(Parkway Scientific), JJJJ with sodium azide) in MeOH (100 mL). The
reaction mixture was sparged with hydrogen and an atmosphere of
hydrogen was maintained via a balloon. The reaction mixture was
stirred for about 4 h at ambient temperature and then was filtered
through a pad of Celite.RTM., washed with MeOH and concentrated in
vacuo to give the crude 3-(aminomethyl)cyclobutanecarboxylic acid
(1.08 g, 100%) which was used without further purification: LC/MS
(Table 1, Method r) R.sub.t=2.41 min (ELSD); MS m/z: 130
(M+H).sup.+.
Preparation #37: ethyl
3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate
##STR00264##
[1338] 3-Bromo-2-oxo-propionic acid ethyl ester (0.090 mL, 0.72
mmol) was added to a mixture of
5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (0.180 g, 0.624 mmol,
prepared using E from Example #3 Step E and HCl) and 1,4-dioxane
(3.5 mL) under nitrogen. After about 3 days, the volatiles were
removed under reduced pressure. The residue was slurried in
Et.sub.2O (5 mL) and then filtered to afford a tan powder. The
solid was slurried in MeCN (3.50 mL) under nitrogen. PFPAA (0.40
mL, 2.1 mmol) was added. After about 30 min, the volatiles were
removed under reduced pressure. The residue was dissolved in DCM
(20 mL) and washed with saturated aqueous NaHCO.sub.3/water (2:1,
20 mL). The aqueous layer was extracted with DCM (20 mL). The
combined organics were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluting with a gradient of
20-100% EtOAc/heptane to afford ethyl
3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate
(0.181 g, 75%): LC/MS (Table 1, Method n) R.sub.t=0.70 min; MS m/z:
385 (M+H).sup.+.
Preparation #38:
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde
##STR00265##
[1340] Water (1.0 mL) was added to a mixture of
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.200 g, 1.26
mmol, prepared using D from Preparation #BBBBB.1 and NaOH) and
hexamethylenetetramine (0.264 g, 1.89 mmol). Acetic acid (0.5 mL)
was added. The reaction vessel was sealed and the mixture was
warmed to about 100.degree. C. After about 8 h, the solution was
allowed to cool to ambient temperature. After sitting for about 13
h, the mixture was cooled to about 0.degree. C. The resulting
mixture was diluted with water (1 mL) and then filtered rinsing
with water. The solid was dried to afford
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde
(0.041 g, 18%): LC/MS (Table 1, Method n) R.sub.t=0.23 min; MS m/z
188 (M+H).sup.+.
Preparation #39:
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine
##STR00266##
[1342] 1-Methylpiperazine (0.160 mL, 1.44 mmol) was added to a
solution of 2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.250
g, 0.481 mmol, synthesized as described in Majeed, A. J., et al.
Tetrahedron 1989, 45, 993-1006) and 1,4-dioxane (1.0 mL) under
nitrogen. After about 2 h, the solution was warmed to about
50.degree. C. After about 30 min, the solution was warmed to about
80.degree. C. After about 30 min, a reflux condenser was attached
and the solution was warmed to about 100.degree. C. After about 16
h, the brown solution was allowed to cool to ambient temperature.
Water (5 mL) was added. The mixture was extracted with EtOAc
(2.times.5 mL). The combined organics were dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel chromatography eluting with a gradient of
2-10% MeOH/DCM to afford
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.127 g,
56%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (d, J=4.6 Hz,
1H), 6.63 (d, J=4.6 Hz, 1H), 3.98-3.82 (m, 4H), 2.63-2.48 (m, 4H),
2.40 (s, 3H), 1.70-1.43 (m, 6H), 1.42-1.20 (m, 6H), 1.18-0.97 (m,
6H), 0.88 (t, J=7.3 Hz, 9H).
Preparation #40:
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline
##STR00267##
[1343] Step A: 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline
##STR00268##
[1345] 2,4-Dichloroquinazoline (2.00 g, 10.1 mmol, prepared as
described in Prasad, M., et al. Org. Process Res. Dev. 2004, 8,
330-340) was slurried in 1,4-dioxane (20.0 mL).
1,4-Dimethylpiperazine (1.44 mL, 10.6 mmol) was added. The mixture
was heated in a CEM microwave at about 150.degree. C. for about 5
min. The material was poured into saturated aqueous
NaHCO.sub.3/water (1:1, 150 mL). The mixture was extracted with
EtOAc (5.times.100 mL). 20 g of silica gel was added to the
combined organics and the volatiles were removed under reduced
pressure. The resulting solid was purified by silica gel
chromatography eluting with a gradient of 2-10% MeOH/DCM to afford
4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36 g, 52%): LC/MS
(Table 1, Method n) R.sub.t=0.51 min; MS m/z 263 (M+H).sup.+.
Step B: 4-iodo-2-(4-methylpiperazin-1-yl)quinazoline
##STR00269##
[1347] Hydrogen iodide (55% aqueous solution, 4.00 mL, 29.3 mmol)
was slowly added to 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline
(1.36 g, 5.18 mmol) under air while cooling in an ambient
temperature water bath. After about 5 min, the bath was removed,
the reaction vessel was wrapped in aluminum foil, and the mixture
was stirred at ambient temperature for about 5 h. DCM (4.0 mL) was
added and the mixture was stirred for about 39 h. Hydrogen iodide
(55% aqueous solution, 8.0 mL, 110 mmol) was added and the mixture
was stirred for about 71 h. The mixture was slowly added to
saturated aqueous NaHCO.sub.3 (200 mL) and EtOAc (200 mL). After
completion of the quench, the layers were separated. The organics
were washed with saturated aqueous NaHCO.sub.3/water (1:1, 200 mL).
The organics were dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. The residue was purified
by silica gel chromatography eluting with a gradient of 2-5%
MeOH/DCM to afford (1.18 g, 69%) as a 3:1 mixture of
4-iodo-2-(4-methylpiperazin-1-yl)quinazoline to
4-chloro-2-(4-methylpiperazin-1-yl)quinazoline.
4-iodo-2-(4-methylpiperazin-1-yl)quinazoline: LC/MS (Table 1,
Method n) R.sub.t=0.55 min; MS m/z 355 (M+H).sup.+.
Step C:
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline
##STR00270##
[1349] Bis(triphenylphosphine)palladium(II) acetate (0.063 g, 0.085
mmol) was added to 3:1 mixture of
4-iodo-2-(4-methylpiperazin-1-yl)quinazoline:4-chloro-2-(4-methylpiperazi-
n-1-yl)quinazoline (0.300 g) under nitrogen. Bis(tributyltin)
(0.855 mL, 1.69 mmol) was added. TBAF (1.0 M solution in THF, 2.54
mL, 2.54 mmol) was added. The mixture was purged with nitrogen for
about 20 min and then stirred under nitrogen at ambient temperature
for about 7 h. Saturated aqueous NaHCO.sub.3/water (1:1, 20 mL) and
EtOAc (50 mL) were added. The mixture was filtered through a
syringe filter, the layers were separated and the organics were
washed with water (2.times.10 mL). The organics were dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography eluting with a gradient of 5-10% MeOH/DCM to afford
a sticky brown solid. The material was dissolved in EtOAc (10 mL)
and washed with water (2.times.5 mL). The organics were dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to afford a
1:1 mix of
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline:4-chloro-2-(4-m-
ethylpiperazin-1-yl)quinazoline (0.058 g, 17%).
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)quinazoline: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.69-7.64 (m, 1H), 7.61-7.57
(m, 1H), 7.49-7.44 (m, 1H), 7.31-7.26 (m, 1H), 3.95-3.83 (m, 4H),
2.44-2.35 (m, 4H), 2.22 (s, 3H), 1.66-1.48 (m, 6H), 1.37-1.18 (m,
12H), 0.82 (t, J=7.3 Hz, 9H).
Preparation #41: 4-(methylsulfonyl)morpholine
##STR00271##
[1351] To a solution of morpholine (2.00 mL, 22.96 mmol) in DCM (40
mL) was added TEA (3.20 mL, 22.96 mmol) at about -20.degree. C.,
then methanesulfonyl chloride (2.68 mL, 34.4 mmol) was added
dropwise at about -20.degree. C. The reaction mixture was stirred
at about -20.degree. C. for about 2 h, then warmed to rt. The
mixture was partitioned with saturated aqueous NH.sub.4Cl (100 mL)
and DCM (3.times.50 mL). The combined organic layers were
concentrated and purified by silica gel chromatography eluting with
a gradient of 0-100% EtOAc/heptane to give
4-(methylsulfonyl)morpholine (3.95 g, 100%) as a white solid:
.sup.1H NMR (DMSO-d.sub.6) .delta. 3.70-3.60 (m, 4H), 3.12-3.04 (m,
4H), 2.89 (s, 3H).
Preparation #42: methyl
5-(chloromethyl)-3-methylfuran-2-carboxylate
##STR00272##
[1353] To a solution of methyl 3-methylfuran-2-carboxylate (8.00 g,
57.1 mmol) in DCM (285 mL) was added zinc chloride (2.14 g, 15.7
mmol) and paraformaldehyde (2.2 mL, 82 mmol). The solution was
warmed to about 35.degree. C. HCl gas was bubbled through the
reaction mixture for about 20 min. The mixture was partitioned with
water (50 mL) and DCM (3.times.30 mL). The combined organic layers
were concentrated and purified by silica gel chromatography eluting
with a gradient of 0-50% EtOAc/heptane to give methyl
5-(chloromethyl)-3-methylfuran-2-carboxylate (8.24 g, 77%) as a
white solid: LC/MS (Table 1, Method n) R.sub.t=0.69 min; MS m/z:
189 (M+H).sup.+.
Preparation #43: cis-methyl
5-((t-butoxycarbonylamino)methyl)-3-methyltetrahydrofuran-2-carboxylate
##STR00273##
[1355] A solution of methyl
5-(azidomethyl)-3-methylfuran-2-carboxylate (3.10 g, 15.88 mmol,
prepared using General Procedure JJJJ from Preparation #42 and
sodium azide) in MeOH (50 mL) was added to a suspension of 5% Rh/C
(0.31 g, 3.01 mmol) and di-tert-butyl dicarbonate (4.16 g, 19.06
mmol) in a 50 mL pressure bottle. The reaction mixture was stirred
under 40 psi of hydrogen at about 50.degree. C. for about 3.5 days.
The mixture was filtered through a nylon membrane. The organic
solvent was concentrated under reduced pressure to give cis-methyl
5-((t-butoxycarbonylamino)methyl)-3-methyltetrahydrofuran-2-carboxylate
(4.19 g, 81%) as a brown oil: .sup.1H NMR (CDCl.sub.3) .delta. 5.70
(s, 1H), 4.43-4.46 (d, 1H), 4.28-4.12 (m, 1H), 3.75 (s, 3H),
3.50-3.30 (m, 2H), 2.75-2.55 (m, 1H), 1.95-2.05 (m, 1H), 1.65-1.48
(m, 1H), 1.45 (s, 9H), 1.03-0.97 (d, 3H).
Preparation #44:
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentanamine and
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine
##STR00274##
[1357] To a mixture of
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)acetamide (5.0 g, 10.7 mmol, Example #8
Step L) and THF (110 mL) was added aqueous HCl (6 N, 63 mL, 375
mmol). The reaction was heated at about 95.degree. C. for about 20
h and then cooled to ambient temperature and concd under reduced
pressure. To the resulting brown residue was added DCM (100 mL) and
the solution was washed with saturated NaHCO.sub.3 (3.times.50 mL).
The aqueous portion was extracted with DCM (3.times.50 mL). The
combined organic layers were washed with brine (100 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The material was purified by chromatography on silica gel eluting
with 0-100% DCM/MeOH/NH.sub.4OH (950:45:5) to give a mixture of
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentanamine and
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (3.2 g, 70%) in a 1:10 ratio based on
H-NMR as an off-white solid: LC/MS (Table 1, Method a) R.sub.t=1.75
min; MS m/z: 425 (M+H).sup.+.
Preparation #45: Methyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate
##STR00275##
[1359] CO was bubbled into an orange solution of
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (550.0 g, 142 mmol,
Example #7, step B) in DMF (2.50 L) within a 5 L round bottom flask
for about 2 min. Bis(triphenylphosphine)-palladium(II) dichloride
(9.96 g, 14.2 mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259
mmol) were added and the flask was fitted with a balloon of CO. The
mixture was heated at about 95.degree. C. under an atmosphere of CO
(1 atmosphere). After stirring overnight, the reaction mixture was
cooled to ambient temperature overnight and poured into ice water
(3.2 L). The mixture was stirred for about 10 min and the
precipitate was collected by filtration, while washing with water,
and dried for 1 h. The crude material was dissolved in DCM,
separated from residual water, dried over anhydrous MgSO.sub.4,
filtered, added silica gel, and concd under reduced pressure to
prepare for chromatography. The crude material was purified by
silica gel column chromatography eluting with 0-5% MeOH in DCM to
yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5
mol % DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table
1, Method a) R.sub.t=2.35 min; MS m/z 332 (M+H).sup.+.
Preparation #46: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic
acid
##STR00276##
[1361] HCl (6 N aqueous, 714 mL) was added to a yellow solution of
methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g,
53.6 mmol, Preparation #45) in 1,4-dioxane (715 mL) within a 2 L
round bottom flask, and the mixture was heated at about 60.degree.
C. for about 16 h. The reaction mixture was cooled to ambient
temperature. The organic solvent was removed under reduced pressure
and the precipitate was collected, washed with water, and dried to
yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g,
85%) as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.63 min;
MS m/z 316 (M-H).sup.-.
Preparation #47: tert-Butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
##STR00277##
[1363] In a 500 mL round bottom flask,
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3
mmol, Preparation #46), diphenylphosphoryl azide (9.78 mL, 45.3
mmol) and TEA (13.9 mL, 100 mmol) in t-BuOH (200 mL) were added to
give an orange suspension. The mixture was heated at about
70.degree. C. for about 16 h, cooled to ambient temperature and the
insoluble material was filtered off. The solvent was removed under
reduced pressure and the crude material was purified by silica gel
column chromatography eluting with 25-60% EtOAc in heptane over 30
min to yield tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as an
off-white solid: LC/MS (Table 1, Method a) R.sub.t=2.79 min; MS m/z
389 (M+H).sup.+.
Preparation #48:
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone
##STR00278##
[1365] Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a
solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
(7.34 g, 22.7 mmol, Example #7, step I) in DCM (100 mL), (note:
mild gas evolution) followed by a dropwise addition of DMF (0.26
mL, 3.41 mmol). The mixture was stirred at ambient temperature for
about 14 h. The solvent was removed under reduced pressure to yield
a beige amorphous solid, which was dissolved in THF and MeCN (1:1,
100 mL) and added to a solution of trimethylsilyldiazomethane (2 M
in Et.sub.2O, 39.7 mL, 79 mmol) in THF and MeCN (1:1, 100 mL) at
about 0.degree. C. The resulting mixture was stirred at about
0.degree. C. for about 3 h and then was quenched by a dropwise
addition of HBr (48% aqueous, 25 mL, 221 mmol). The resulting
mixture was neutralized by a dropwise addition of saturated aqueous
NaHCO.sub.3 (300 mL) and the layers were separated. The organic
layer was dried over anhydrous MgSO.sub.4 and concd under reduced
pressure. The residue was purified by silica gel flash
chromatography eluting with 5% to 45% of EtOAc in heptane to yield
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g,
69%) as a yellow oil: LC/MS (Table 1, Method a) R.sub.t=2.90 min;
MS m/z 400, 402 (M+H).sup.+.
Preparation #49: tert-Butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate
##STR00279##
[1367] A solution of tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol,
Example #7, Step C) in DMF (5 mL) was added dropwise to a
suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45
mmol) in DMF (5 mL), at about 0.degree. C. The resulting mixture
was stirred at about 0.degree. C. for about 30 min and then added
dropwise to a solution of
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g,
1.8 mmol) in DMF (10 mL) at about 0.degree. C. The resulting
mixture was stirred at about 0.degree. C. for about 1 h and the
solvent was removed under reduced pressure. The residue was
partitioned between saturated aqueous NaHCO.sub.3 and EtOAc (100 mL
each). The organic phase was separated, dried over anhydrous
MgSO.sub.4 and concd under reduced pressure to yield tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous
solid: LC/MS (Table 1, Method a) R.sub.t=3.30 min; MS m/z 708
(M+H).sup.+.
Preparation #50:
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone
##STR00280##
[1369] tert-Butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate (6.19 g, 8.75 mmol, Preparation #49)
was dissolved in HCl (4 N in 1,4-dioxane, 25 mL). The reaction
mixture was stirred at ambient temperature for about 2 h. The
solvent was removed under reduced pressure and the residue
partitioned between saturated aqueous NaHCO.sub.3 and EtOAc (100 mL
each). The organic phase was washed with brine (80 mL), dried over
anhydrous MgSO.sub.4 and coned under reduced pressure to yield
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.2 g, 98%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=3.00 min; MS m/z 608
(M+H).sup.+.
Preparation #51:
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)cyclopentanamine
##STR00281##
[1371] A mixture of
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.32 g, 8.75 mmol, Preparation #50) and
Lawesson's reagent (1.88 g, 4.64 mmol) was heated at about
60.degree. C. for about 2 h. Lawesson's reagent (1.88 g, 4.64 mmol)
was added. The reaction mixture was stirred at about 60.degree. C.
for about 1 h. The solvent was removed under reduced pressure and
the residue purified by silica gel flash chromatography eluting
with a gradient of 0-8% MeOH in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=2.99 min; MS m/z 590
(M+H).sup.+.
Preparation #52:
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentanamine
##STR00282##
[1373]
N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyr-
azin-8-yl)cyclopentan-amine (4.47 g, 7.58 mmol, Preparation #51)
was dissolved in 1,4-dioxane (40 mL). NaOH (2 N aqueous, 4 mL) was
added and the reaction mixture was heated at about 90.degree. C.
for about 80 min. The organic solvent was removed under reduced
pressure and the residue was treated with saturated aqueous
NH.sub.4Cl (70 mL) and extracted with DCM (2.times.60 mL). The
combined organic extracts were washed with brine (70 mL), dried
over anhydrous MgSO.sub.4 and coned under reduced pressure.
Purification by silica gel flash chromatography eluting with a
gradient of 0-8% MeOH in DCM yielded
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentan-amine (1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method
a) R.sub.t=2.31 min; MS m/z 436 (M+H).sup.+.
Preparation #53:
3-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine
##STR00283##
[1375] To a mixture of
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentanamine (1.84 g, 4.22 mmol, Preparation #52) in EtOH (50 mL)
was added 20 wt % Pd(OH).sub.2 on C (0.43 g, 0.61 mmol) and the
resulting mixture was shaken under hydrogen pressure of about 50
psi on a Parr shaker at about 50.degree. C. for about 2 h. The
catalyst was filtered off using a pad of Celite.RTM., 20 wt %
Pd(OH).sub.2 on C (0.43 g, 0.61 mmol) was added, and the mixture
was shaken under hydrogen pressure of about 50 psi on a Parr shaker
at about 50.degree. C. for about 16 h. The catalyst was filtered
off using a pad of Celite.RTM., 20 wt % Pd(OH).sub.2 on C (0.43 g,
0.61 mmol) was added, and the mixture was shaken under hydrogen
pressure of about 50 psi on a Parr shaker at about 50.degree. C.
for about 4 h. The catalyst was filtered off using a pad of
Celite.RTM. and the filtrate was concd under reduced pressure to
yield
3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine
(0.88 g, 82%) as an off-white amorphous solid: LC/MS (Table 1,
Method a) R.sub.t=0.75 min and 0.87 min; MS m/z 256
(M+H).sup.+.
General Procedure A: Formation of a Hydrazide from a Carboxylic
Acid
[1376] To a mixture of a 2-hydrazinylpyrrolo[2,3-b]pyrazine
(preferably 1 equiv) and a carboxylic acid (1-2 equiv, preferably
1.1-1.3 equiv) in an organic solvent (such as DCM, DMF or THF,
preferably DMF) is added a coupling agent such as EDC.HCl or HATU
(1.0-2.0 equiv, preferably 1.2-1.6 equiv) with or without an
organic base (such as TEA or DIEA, 2-5 equiv, preferably 3-4
equiv). After about 1-72 h (preferably 2-16 h) at about
20-60.degree. C. (preferably about ambient temperature), the
reaction is worked up using one of the following methods. If DMF is
the solvent, the reaction is first concd under reduced pressure.
Method 1: Water is added and the layers are separated. Optionally,
the mixture may be filtered through Celite.RTM. prior to the
separation of the layers. The aqueous layer is then extracted with
an organic solvent such as EtOAc or DCM. The combined organic
layers are optionally washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or decanted, and concd
under reduced pressure. Method 2: The reaction is diluted with an
organic solvent such as EtOAc or DCM and is washed with either
water or brine or both. The aqueous layer is optionally further
extracted with an organic solvent such as EtOAc or DCM. Then the
organic layer or combined organic layers are optionally washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered or decanted, and concd under reduced pressure. Method 3:
The reaction is diluted with an organic solvent such as EtOAc or
DCM and water is added. The layers are separated and the organic
layer is concd under reduced pressure and directly purified by
chromatography.
Illustration of General Procedure A
Preparation #A.1*: (S)-tert-butyl
3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyr-
rolidine-1-carboxylate
##STR00284##
[1378] To a solution of
(S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(0.756 g, 3.30 mmol, AstaTech) and
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.3 mmol,
Example #1, Step D) in DMF (33 mL) was added TEA (1.38 mL, 9.89
mmol) followed by the addition of HATU (1.25 g, 3.30 mmol). The
resulting mixture was stirred at ambient temperature for about 15 h
then concd under reduced pressure. The residue was taken up in
EtOAc (100 mL) and washed with water (100 mL). The organic portion
was separated, washed with brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd under reduced pressure to
give (S)-tert-butyl
3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyr-
rolidine-1-carboxylate as a sticky brown solid (1.90 g, 100%). This
material was used without further purification: LC/MS (Table 1,
Method c) R.sub.t=1.38 min; MS m/z: 515 (M+H).sup.+.
[1379] General Procedure B: Cyclization of a Hydrazide
[1380] To a solution of a 2-hydrazidyl-5H-pyrrolo[2,3-b]pyrazine
(preferably 1 equiv) in an organic solvent (for example
1,4-dioxane) is added a base (such as TEA or DIEA, 1-5 equiv,
preferably 2-4 equiv) and SOCl.sub.2 (1-5 equiv, preferably 1-2
equiv). The mixture is heated at about 60-100.degree. C.
(preferably about 80.degree. C.) for about 1-16 h (preferably about
1-2 h). The reaction mixture is cooled to ambient temperature and
worked up using one of the following methods. Method 1: An organic
solvent (such as EtOAc or DCM) and water are added. The layers are
separated and the aqueous layer is optionally extracted with
additional organic solvent. The combined organic layers may be
optionally washed with aqueous base (such as NaHCO.sub.3) and/or
brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, then
decanted or filtered prior to concentrating under reduced pressure.
Method 2: An organic solvent (such as EtOAc or DCM) is added and
the organic layer is optionally washed with brine or water, dried
over anhydrous MgSO.sub.4 or Na.sub.2SO.sub.4, filtered or
decanted, and concd under reduced pressure. Method 3: The reaction
mixture is partitioned between an organic solvent (such as EtOAc or
DCM) and saturated aqueous NaHCO.sub.3 or brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, then decanted or filtered
prior to concentrating under reduced pressure.
Illustration of General Procedure B
Preparation #B.1*: tert-butyl
(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentylcarbamate
##STR00285##
[1382] To a solution of tert-butyl
(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyc-
lopentylcarbamate (9.30 g, 18.1 mmol, prepared using A from Example
#1 Step D, and
(1R,3S)-3-tert-butoxycarbonylamino)cyclopentanecarboxylic acid
[Peptech]) in 1,4-dioxane (100 mL) was added TEA (10.0 mL, 72.3
mmol) and SOCl.sub.2 (2.11 mL, 28.9 mmol). The mixture was heated
at about 80.degree. C. for about 1.5 h. The reaction mixture was
cooled to ambient temperature, EtOAc (200 mL) and water (200 mL)
were added, and the layers were separated. The aqueous portion was
extracted with EtOAc (2.times.100 mL) and the combined organic
extracts were washed with saturated aqueous NaHCO.sub.3 (100 mL)
and brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
25-100% EtOAc in DCM to give
tert-butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylcarbamate (7.65 g, 85%): LC/MS (Table 1, Method
a) R.sub.t=2.37 min; MS m/z: 497 (M+H).sup.+.
[1383] General Procedure C: Cyclization of a Hydrazide with Loss of
Boc-Protecting Group
[1384] To a solution of an appropriately substituted
2-hydrazidyl-5H-pyrrolo[2,3-b]pyrazine containing a Boc protecting
group (preferably 1 equiv) and TEA or DIEA (0-6 equiv, preferably 4
equiv) in an organic solvent (such as 1,4-dioxane or DCM,
preferably 1,4-dioxane) is added SOCl.sub.2 (2.0-6.0 equiv,
preferably 2.5 equiv). The reaction is heated at about
60-120.degree. C. (preferably about 80-90.degree. C.) for about 1-8
h (preferably about 2-4 h) and then worked up using one of the
following methods. Method 1: The reaction mixture is filtered and
washed with a suitable organic solvent (such as EtOAc or DCM) to
give the target compound with no further purification. Method 2:
The crude material is diluted with a suitable organic solvent (such
as EtOAc or DCM) and saturated aqueous NaHCO.sub.3 is added, the
layers are separated and the organic portion is dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure. Method 3: The reaction mixture is washed with a
basic aqueous solution (preferably saturated aqueous NaHCO.sub.3)
and filtered to give the Boc-deprotected target compound with no
further purification. If partial Boc-deprotection occurs, the
filtrate is extracted with a suitable organic solvent (such as
EtOAc or DCM), the layers are separated and the organic portion is
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd under reduced pressure to give the remaining Boc-protected
compound. The crude Boc-protected material or partially
Boc-protected material obtained above is dissolved in 1,4-dioxane
or DCM (preferably 1,4-dioxane) and added to a solution of HCl in
an organic solvent (1-6 N, preferably 4 N HCl in 1,4-dioxane) and
heated to about 30-60.degree. C. (preferably about 50.degree. C.)
for about 1-5 h (preferably about 3 h). If a precipitate forms, it
is collected and then dissolved in a suitable organic solvent (such
as EtOAc or DCM) and washed with a basic aqueous solution
(preferably saturated aqueous NaHCO.sub.3). If no precipitate
forms, the reaction mixture is washed with a basic aqueous solution
(preferably saturated aqueous NaHCO.sub.3). In either case, the
layers are separated and the organic portion is dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure.
Illustration of General Procedure C
Preparation #C.1
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-amine
##STR00286##
[1386] To a solution of tert-butyl
4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.-
2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol, Example #9, Step E), and
TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) was added
SOCl.sub.2 (2.0 mL, 27.5 mmol). The reaction mixture was heated at
about 80.degree. C. for about 2 h then cooled to ambient
temperature. The reaction mixture was washed with saturated aqueous
NaHCO.sub.3 (3.times.50 mL). The layers were separated and the
aqueous portion was filtered to give
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1,
Method a) R.sub.t=1.28 min; MS m/z: 437 (M+H).sup.+. The remaining
filtrate was extracted with EtOAc (10 mL). The combined organic
layer was dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to afford crude tert-butyl
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material
was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8
mL) was added. The reaction mixture was heated to about 50.degree.
C. for about 3 h. The precipitate formed was collected by
filtration. The solid was dissolved in DCM (50 mL), and washed with
saturated aqueous NaHCO.sub.3 (3.times.20 mL). The layers were
separated and the organic portion was dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to give
additional
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS
(Table 1, Method a) R.sub.t=1.28 min; MS m/z: 437 (M+H).sup.+.
[1387] General Procedure D: Hydrolysis of a Sulfonamide
[1388] To a flask containing a sulfonamide, for example, a
sulfonyl-protected pyrrole, (preferably 1 equiv) in an organic
solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably
1,4-dioxane) is added an aqueous base (such as aqueous
Na.sub.2CO.sub.3 or aqueous NaOH, 1-30 equiv, preferably 2-3 equiv
for aqueous NaOH, preferably 15-20 equiv for aqueous
Na.sub.2CO.sub.3). The mixture is stirred at about 25-100.degree.
C. (preferably about 60.degree. C.) for about 1-72 h (preferably
about 1-16 h). In cases where the reaction does not proceed to
completion as monitored by TLC, LC/MS, or HPLC, additional aqueous
base (such as aqueous Na.sub.2CO.sub.3, 10-20 equiv, preferably 10
equiv or aqueous NaOH, 1-5 equiv, preferably 1-2 equiv) and/or a
cosolvent (such as EtOH) is added. The reaction is continued at
about 25-100.degree. C. (preferably about 60.degree. C.) for about
0.25-3 h (preferably about 1-2 h). In any case where an additional
base labile group is present (for example, an ester a
trifluoromethyl, or a cyano group), this group may also be
hydrolyzed. The reaction is worked up using one of the following
methods. Method 1. The organic solvent is optionally removed under
reduced pressure and the aqueous solution is neutralized with the
addition of a suitable aqueous acid (such as aqueous HCl). A
suitable organic solvent (such as EtOAc or DCM) and water are
added, the layers are separated, and the organic solution is dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd
to dryness under reduced pressure to give the target compound.
Method 2. The organic solvent is optionally removed under reduced
pressure, a suitable organic solvent (such as EtOAc or DCM) and
water are added, the layers are separated, and the organic solution
is dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered,
and concd to dryness under reduced pressure to give the target
compound. Method 3. The reaction mixture is concd under reduced
pressure and directly purified by one of the subsequent
methods.
Illustration of General Procedure D
Preparation #D.1*:
(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-meth-
ylpiperidine-1-carboxylate
##STR00287##
[1390] To a solution of (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate (40 g, 78 mmol, Example #5 Step H) in 1,4-dioxane
(160 mL) was added NaOH (1 N aqueous, 157 mL). The reaction was
heated at about 60.degree. C. for about 1 h. The reaction was
allowed to cool to ambient temperature. The reaction was
neutralized with aqueous HCl (4 N, 50 mL). The layers and extracted
with DCM (2.times.300 mL). The combined organic extracts were
washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered then coned in vacuo. The product was purified by
chromatography on silica gel (330 g) using 1-5% MeOH in DCM to give
(3R,4R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (30 g, 99%): LC/MS (Table 1, Method b) R.sub.t=2.00 min; MS
m/z: 356 (M+H).sup.+.
TABLE-US-00005 TABLE D.1 Examples prepared using General Procedure
D with NaOH R.sub.t min (Table 1, m/z ESI+ Sulfonamide Product Ex #
Method) (M + H).sup.+ (S)-1-((1-(cyclopropylsulfonyl)
pyrrolidin-3-yl)methyl)-6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine (prepared using C from
Preparation #A.1, and K with cyclopropanesulfonyl chloride and TEA)
##STR00288## D.1.1* 1.34 (a) 347 N-(1-((6-tosyl-6H-pyrrolo[2,3-e]
[1,2,4]triazolo[4,3-a]pyrazin- 1-yl)methyl)cyclobutyl)-
cyclopropanesulfonamide (prepared using A from Example #1 Step D
and 2-(1- (tert-butoxycarbonyl-amino) cyclobutyl)acetic acid
[prepared as described in Eur. J. Med. Chem, 1999, 34, 363] with
EDC.cndot.HCl, B with TEA, E with HCl, K with cyclopropanesulfonyl
chloride and DIEA) ##STR00289## D.1.2 1.60 (a) 347
N-((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo
[4,3-a]pyrazin-1- yl)cyclopentyl)cyclo- propanecarboxamide
(prepared using E from Preparation #B.1 with HCl, H with
cyclopropanecarboxylic acid, EDC, and DIEA) ##STR00290## D.1.3*
1.15 (c) 311 2-cyclopropyl-N-((1S,3R)-3-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)acetamide
(prepared using using E from Preparation #B.1 with HCl, H with
cyclopropylacetic acid [Lancaster], EDC, and DIEA) ##STR00291##
D.1.4* 1.17 (c) 325 4-fluoro-N-((1R,3R)-3-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline
(prepared using PP with Example #2 Step F, 4- fluorophenyl boronic
acid, and DIEA) ##STR00292## D.1.5* 1.91 (a) 337
4-chloro-N-((1R,3R)-3-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline
(prepared using PP with Example #2 Step F, 4- chlorophenylboronic
acid and DIEA) ##STR00293## D.1.6* 2.07 (a) 353
3,4-dichloro-N-((1R,3R)-3-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline
(prepared using PP with Example #2 Step F, 3,4-
dichlorophenylboronic acid and DIEA) ##STR00294## D.1.7* 2.24 (a)
387 4-methoxy-N-((1R,3R)-3-(6- tosyl-6H-pyrrolo[2,3-e]
[1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)aniline (prepared
using PP with Example #2 Step F, 4- methoxyphenyl boronic acid and
DIEA) ##STR00295## D.1.8* 1.74 (a) 349
4-methoxy-N-(4-methoxyphenyl)- N-((1R,3R)-3-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)aniline (prepared using PP with Example #2 Step F,
4- methoxyphenyl boronic acid and DIEA) ##STR00296## D.1.9* 2.30
(a) 455 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)azetidine-1-
sulfonamide (Preparation #DD.1) ##STR00297## D.1.10* 1.81 (a) 390
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3,3-difluoroazetidine-1- sulfonamide (prepared using DD with
Example #8 Step M, 3,3-difluoroazetidine-1- sulfonyl chloride
[prepared from CC with 3,3- difluoroazetidine hydrochloride
[Matrix] and DIEA] and TEA) ##STR00298## D.1.11* 1.97 (a) 426
(S)-N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a] pyrazin-1-yl)cyclopentyl)-2-
(trifluoromethyl)pyrrolidine- 1-sulfonamide (prepared using DD with
Example #8 Step M, (S)-2- (trifluoromethyl)pyrrolidine- 1-sulfonyl
chloride [prepared from CC with (S)-(-)-2-
(trifluoromethyl)pyrrolidine and DIEA] and TEA) ##STR00299##
D.1.12* 2.13 (a) 472 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3,3-difluoropyrrolidine-1- sulfonamide (prepared using DD with
Example #8 Step M, 3,3-difluoropyrrolidine-1- sulfonyl chloride
[prepared from CC with 3,3- difluoropyrrolidine hydrochloride and
DIEA] and TEA) ##STR00300## D.1.13* 1.98 (a) 440
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
4,4-difluoropiperidine-1- sulfonamide (prepared using DD with
Example #8 Step M, 4,4-difluoropiperidine-1- sulfonyl chloride
[prepared from CC with 4,4- difluoropiperidine hydrochloride and
DIEA] and TEA) ##STR00301## D.1.14* 2.01 (a) 454
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline
(prepared using PP from Preparation #19.2, phenylboronic acid, and
DIEA) ##STR00302## D.1.15* 2.01 (a) 333 4-methyl-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)aniline (prepared using PP from
Preparation #19.2, p- tolylboronic acid and DIEA) ##STR00303##
D.1.16* 2.08 (a) 347 4-chloro-N-((1S,3R,4S)-3-methyl-
4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)aniline (prepared using PP from Preparation #19.2,
4- chlorophenylboronic acid, and DIEA) ##STR00304## D.1.17* 2.25
(a) 367 4-fluoro-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)aniline
(prepared using PP from Preparation #19.2, 4- fluorophenylboronic
acid, and DIEA) ##STR00305## D.1.18* 2.05 (a) 351
1-(3,3-difluorocyclobutyl)-6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine (prepared using H from Example #5 Step C
and 3,3- difluorocyclobutanecarboxylic acid [Waterstone], HATU, and
DIEA; Q with Lawesson's reagent and mercury (II) trifluoroacetate)
##STR00306## D.1.19 1.63 (b) 249 4-((cis-3-(6-tosyl-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclobutoxy)methyl)benzo- nitrile (prepared using H from Example
#5 Step C and Preparation #1 with HATU and DIEA; Q with Lawesson's
reagent and mercury (II) trifluoroacetate) ##STR00307## D.1.20 1.81
(b) 344 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- N-
methylcyclopropanesulfon- amide (prepared using A from Example #1
Step D and Preparation #Z.1 with HATU and TEA, B with TEA, S with
iodomethane and NaH) ##STR00308## D.1.21* 1.75 (a) 389
N-(cyclopropylmethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)cyclo- propanesulfonamide (prepared using A from
Example #1 Step D and Preparation #Z.1 with HATU and TEA, B with
TEA, S with (bromomethyl)- cyclopropane and NaH) ##STR00309##
D.1.22* 1.98 (a) 429 1-methyl-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)- 1H-pyrazole-4-sulfonamide (prepared
using K from Preparation #19.2, 1-methyl- 1H-pyrazole-4-sulfonyl
chloride [Oakwood] and DIEA) ##STR00310## D.1.23* 1.60 (a) 401
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3,3,3-trifluoropropane-1- sulfonamide (prepared using K from
Example #8 Step M and 3,3,3-trifluoropropane-1- sulfonyl chloride
[Matrix] and DIEA) ##STR00311## D.1.24* 2.05 (a) 431
N-((3S,5R)-5-ethyl-1-(3-tosyl-3H- imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)pyrrolidin-3- yl)cyclopropanesulfonamide (prepared
using S from Example #3 Step E and tert- butyl bromoacetate, E with
HCl, H with Preparation #E.1, OO) ##STR00312## D.1.25* 1.60 (a) 375
N-((1R,3S,4R)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopentane-
sulfonamide and N- ((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopentane-
sulfonamide (prepared using K from Preparation #Y.1 and
cyclopentanesulfonyl chloride, Z with NaOH, A with Example #1 Step
D, HATU, and TEA, B with TEA) ##STR00313## D.1.26 1.77 (a) 403
(1S,3R)-1-[3-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)- isothiazolidin-2-yl-1,1- dioxide]cyclopentane
(Preparation #2) ##STR00314## D.1.27* 1.47 (a) 347
1-((1R,3S)-3-(1H-pyrrol-1- yl)cyclopentyl)-6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine (Preparation #3) ##STR00315##
D.1.28* 1.82 (a) 293 N-(4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)bicyclo[2.2.2]octan-1-
yl)azetidine-1-sulfonamide (prepared using DD with Example #9, Step
F and Preparation #CC.1) ##STR00316## D.1.29 1.44 (a) 402
3,3-difluoro-N-(4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo
[4,3-a]pyrazin-1- yl)bicyclo[2.2.2]octan-1-
yl)azetidine-1-sulfonamide (Preparation #5) ##STR00317## D.1.30
1.61 (a) 438 2-(N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclo-
propanesulfonamido)ethyl acetate (prepared using A from Preparation
#Z.1, Example #1, Step D, HATU, and TEA, B with TEA, S with
2-bromoethyl acetate) ##STR00318## D.1.31* 1.54 (a) 419
1-((1S,2R,4S)-2-ethyl-4-(4- methoxybenzyloxy)cyclopent-
yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine and
1-((1R,2S,4R)- 2-ethyl-4-(4- methoxybenzyloxy)cyclo-
pentyl)-6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazine
(prepared using Z from Preparation #EE.1, A from Example #1, Step
D, HATU, and TEA, B with DIEA) ##STR00319## D.1.32 2.02 (b) 392
1-methyl-N-(4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo
[4,3-a]pyrazin-1- yl)bicyclo[2.2.2]octan-1- yl)cyclopropane-1-
sulfonamide (prepared using K from Preparation #C.1 and Preparation
#6) ##STR00320## D.1.33 1.48 (a) 401
4-methyl-N-((1R,3R)-3-(6-tosyl- 6H-pyrrolo[2,3-e][1,2,4]
triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)aniline (prepared using PP
from Example #2, Step F and p- tolylboronic acid) ##STR00321##
D.1.34* 1.89 (b) 333 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-methylcyclopropane-1- sulfonamide (prepared using K from Example
#8, Step M and Preparation #6) ##STR00322## D.1.35* 1.66 (a) 389
1-((1S,2R,4S)-4-(benzyloxy)-2- ethylcyclopentyl)-6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine and 1-((1R,2S,4R)-
4-(benzyloxy)-2- ethylcyclopentyl)-6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine (prepared using EE from benzyl
2,2,2- trichloroacetimidate and Preparation #FF.1) ##STR00323##
D.1.36 2.15(b) 362 N-(4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)bicyclo[2.2.2]octan-1-
yl)pyrrolidine-1-carboxamide (prepared using I from methyl
4-aminobicyclo[2.2.2]octane- 1-carboxylate hydrochloride [Prime
Organics], pyrrolidine-1-carbonyl chloride and TEA, Z with NaOH, A
from Example #1, Step D, HATU and TEA, B with TEA)) ##STR00324##
D.1.37 1.65 (a) 380 1-((1R,2R,4S)-2-ethyl-4-(4-
methoxybenzyloxy)cyclopent- yl)-6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine and 1-((1S,2S,4R)- 2-ethyl-4-(4-
methoxybenzyloxy)cyclopent- yl)-6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine (prepared using Z from
Preparation #EE.1, A from Example #1, Step D, HATU, and TEA, B with
DIEA) ##STR00325## D.1.38 2.14 (b) 392
N-(4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)bicyclo[2.2.2]octan-1- yl)cyclobutanesulfonamide (prepared using
K from methyl 4- aminobicyclo[2.2.2]octane-1- carboxylate
hydrobromide [Prime Organics], cyclobutanesulfonyl chloride [Hande]
and TEA, Z with NaOH, A from Example #1, Step D, HATU and TEA, B
with TEA)) ##STR00326## D.1.39 1.71 (a) 401
N-(4-(3-allyl-6-tosyl-6H- imidazo[1,5,-a]pyrrolo[2,3,- e]pyrazin-1-
yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (prepared
using E with 4-(tert- butoxycarbonylamino)- bicyclo[2.2.2]octane-1-
carboxylic acid [Prime Organics], K with cyclopropylsulfonyl
chloride, H from Preparation #12, HATU and DIEA, Q with Lawesson's
reagent and mercury (II) trifluoroacetate) ##STR00327## D.1.40 1.89
(a) 426 N-(4-(3-(2,3-dihydroxypropyl)-6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)bicyclo[2.2.2]octan-1-
yl)cyclopropanesulfonamide (Preparation #17) ##STR00328## D.1.41
1.37 (a) 460 tert-butyl 1-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3-
e]pyrazin-1-yl)pyrrolidin-3- ylcarbamate (Preparation #16)
##STR00329## D.1.42 1.78 (a) 343 3-bromo-1-cyclohexyl-6-tosyl-
6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine (Preparation #MM.1)
##STR00330## D.1.43 2.38 (a) 319, 321 (1:1)
N-((1S,3S,4R)-3-(3-chloro-6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1-yl)- 4-ethylcyclopentyl)-
cyclopropanesulfonamide (prepared using H from Example #5, Step C
and Preparation #Z.1, HATU and DIEA, Q with Lawesson's reagent and
mercury (II) trifluroacetate, MM with NCS) ##STR00331## D.1.44*
2.01(a) 408 N-((1S,3S,4R)-3-(3-bromo-6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1-yl)- 4-ethylcyclopentyl)-
cyclopropanesulfonamide (prepared using H from Example #5, Step C
and
Preparation #Z.1, HATU and DIEA, Q with Lawesson's reagent and
mercury (II) trifluroacetate, MM with NBS ##STR00332## D.1.45* 2.05
(a) 452, 454 (1:1) N-((3S,5R)-5-ethyl-1-(6-tosyl-
6H-imidazo[1,5-a]pyrrolo [2,3-e]pyrazin-1- yl)pyrrolidin-3-
yl)cyclopropanesulfonamide, (prepared using E from Preparation #15,
J from Example #5, Step C with CDI, OO) ##STR00333## D.1.46* 1.63
(a) 375 N-((3S,5R)-5-methyl-1-(6-tosyl- 6H-imidazo[1,5-a]pyrrolo
[2,3-e]pyrazin-1- yl)pyrrolidin-3- yl)cyclopropanesulfonamide,
(prepared using E from Preparation #14, J from Example #5, Step C
with CDI, OO) ##STR00334## D.1.47* 1.31 (a) 359
N-((1S,3R,4S)-3-ethyl-4-(7- methyl-6-tosyl-6H-pyrrolo
[2,3-e][1,2,4]triazolo[4,3-a] pyrazin-1-yl)cyclopentyl)
cyclo-propanesulfonamide (prepared using A with Preparation #18 and
Preparation #Z.1, B with thionyl chloride and TEA) ##STR00335##
D.1.48* 1.74 (a) 389 4-((4-(6-tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)cubanyl)methoxy)benzonitrile
(prepared using H from (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2-
yl)methanamine hydrochloride (Example #5, Step C) and 4-
methoxycarbonylcubanecarboxylic acid [Boron Molecular] with
EDC.cndot.HCl and DIEA; P with DIBAL-H; II with 4-
hydroxybenzonitrile, triphenylphosphine and DIAD; Q with Lawesson's
reagent and mercury (II) trifluoroacetate) ##STR00336## D.1.49 2.05
(b) 392 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
4-methylpiperazine-1- sulfonamide (prepared using ZZ from
Preparation BB.1, AAA with 1- methylpiperazine) ##STR00337##
D.1.50* 1.32 (a) 433 1-cyclohexyl-2-methyl-6-tosyl-
1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridine (prepared using
K.1 from Example #21, Step E with 4- methylbenzene-1-sulfonyl
chloride, L with cyclohexylamine, BBB, G with acetic anhydride and
OO) ##STR00338## D.1.51 1.86 (a) 255 1-cyclohexyl-6-tosyl-2-
(trifluoromethyl)-1,6- dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridine
(prepared using prepared using K.1 from Example #21, Step E with 4-
methylbenzene-1-sulfonyl chloride, L with cyclohexylamine, BBB, G
with trifluoroacetic anhydride, DDD with 2,4,6- tripropyl-
[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide) ##STR00339##
D.1.52 2.37 (a) 309 N-((1S,3R,4S)-3-methyl-4-(2-
methyl-6-tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared from Preparation
#27 and Preparation #OOO.1 using L and DIEA, K.1 with TsCl and NaH,
BBB, H with acetic anhydride, and DDD with POCl.sub.3) ##STR00340##
D.1.53 * 1.59(a) 374 1-((1S,2R,4S)-4- (cyclopropylmethoxy)-2-
methylcyclopentyl)-6-tosyl- 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazine (prepared using P from Example #24 Step H and
NaBH.sub.4, VV, FFF with 2- cyclopropylacetaldehyde, Z with NaOH, A
with Example #1 Step D, HATU and TEA, B with SOCl.sub.2 and DIEA)
##STR00341## D.1.54 1.73 (a) 312 1-methyl-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared from
5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride
(WO2009152133) and (1S,2R,4S)-4-acetamido-2-
methylcyclopentanecarboxylic acid [prepared from ethyl 4-
amino-2-methyl- cyclopentanecarboxylate (WO2009152133) using G, AA
[Table 2, Method 3, R.sub.t = 6.1 min, or = ND], and Z using H, OO,
BB, and K with 3-chlorophenysulfonyl chloride) ##STR00342## D.1.55*
2.17 (a) 430 N-((1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl) cyclopentyl)-2-
hydroxyethylamino-1- sulfonamide (Preparation #ZZ.1) ##STR00343##
D.1.56* 1.33 (a) 394 N-((1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-2-
methoxyethanesulfonamide (prepared using K from Example #8 Step M
and 2-methoxyethane- 1-sulfonyl chloride [Focus Synthesis] with
TEA) ##STR00344## D.1.57* 1.53 (b) 393 N-((1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-
1-yl)cyclopentyl)-2-(1H-1,2,3- triazol-1-yl)ethanesulfonamide
(prepared using K.1 from Example #8 Step M and 2-
chloroethanesulfonyl chloride with TEA, YY with 1H-1,2,3- triazole
and DIEA) ##STR00345## D.1.58* 1.45 (b) 430
N-((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-2-(2H-1,2,3-
triazol-2-yl)ethanesulfonamide (prepared using K.1 from Example #8
Step M and 2- chloroethanesulfonyl chloride with TEA, YY with
1H-1,2,3- triazole and DIEA) ##STR00346## D.1.59* 1.58 (b) 430
2-(4,4-difluoropiperidin-1-yl)-N- ((1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)ethanesulfon- amide (prepared using K.1 from Example
#8 Step M and 2-chloroethanesulfonyl chloride with TEA, YY with
4,4-difluoropiperidine hydrochloride and DIEA) ##STR00347## D.1.60*
1.76 (b) 482 N-((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-
morpholinoethanesulfonamide (prepared using K.1 from Example #8
Step M and 2- chloroethanesulfonyl chloride with TEA, YY with
morpholine) ##STR00348## D.1.61* 1.35 (b) 448 (1S,3R,4S)-N-(2-(3,3-
difluoropyrrolidin-1- ylsulfonyl)ethyl)-3-ethyl-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanamine (prepared
using YY from Preparation #26 and Example #8 Step M with DIEA)
##STR00349## D.1.62* 1.53 (b) 468 (cis)-6-tosyl-1-(5-(3,3,3-
trifluoropropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-
yl)-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine (prepared using K from
(cis)- tert-butyl 2,5-diazabicyclo [2.2.1]heptane-2-carboxylate
(US2003/225268) and 3,3,3- trifluoropropane-1-sulfonyl chloride
(Matrix), E with HCl, J with CDI and (5-tosyl-5H-
pyrrolo[2,3-b]pyrazin-2- yl)methanamine hydrochloride (Example #5,
Step C) with DIEA, OO). ##STR00350## D.1.63 1.85 415
(cis)-6-tosyl-1-(5-(3,3,3- trifluoropropylsulfonyl)hexahy-
dropyrrolo[3,4-c]pyrrol-2(1H)- yl)-6H-imidazo[1,5-a]pyrrolo
[2,3-e]pyrazine (prepared using K from (cis)-tert-butyl
hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate and
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), E with HCl, J
with CDI and (5- tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine
hydrochloride (Example #5, Step C) with DIEA, OO). ##STR00351##
D.1.64 1.80 429 1-(6-fluoro-4-(3,3,3- trifluoropropylsulfonyl)-1,4-
diazepan-1-yl)-6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazine
(prepared using K from tert-butyl 6-fluoro-1,4-
diazepane-1-carboxylate (WO2007/126935) and 3,3,3-
trifluoropropane-1-sulfonyl chloride (Matrix), E with HCl, J with
CDI and (5-tosyl-5H- pyrrolo[2,3-b]pyrazin-2- yl)methanamine
hydrochloride (Example #5, Step C) with DIEA, OO). ##STR00352##
D.1.65 1.86 435 trans-N-(4-methyl-1-(3,3,3-
trifluoropropylsulfonyl)piperi- din-3-yl)-6-tosyl-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-amine (prepared using K from
trans-tert-butyl 4-methylpiperidin-3- ylcarbamate (WO2009/140320)
and 3,3,3- trifluoropropane-1-sulfonyl chloride (Matrix), E with
HCl, J with CDI and (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2-
yl)methanamine hydrochloride (Example #5, Step C) with DIEA, OO).
##STR00353## D.1.66 1.89 431 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)-2- methylpropane-2-sulfonamide (Preparation #28)
##STR00354## D.1.67 * 1.76 391 6-tosyl-1-(2-(3,3,3-
trifluoropropylsulfonyl)-2,5- diazaspiro[3.5]nonan-5-yl)-
6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazine (prepared using K from 5
benzyl-2,5-diazaspiro[3.5] nonane (WO2008/60767) and
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), Y with
Pd(OH).sub.2, J with CDI and (5-tosyl-5H-pyrrolo[2,3-
b]pyrazin-2-yl)methanamine hydrochloride (Example #5, Step C) with
DIEA, OO). ##STR00355## D.1.68 2.07 443
6-tosyl-1-((trans)-4-(3,3,3- trifluoropropylsulfonyl)octa-
hydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazine (prepared using K from
(trans)-tert-butyl octahydro-1H-pyrrolo[3,2-
b]pyridine-1-carboxylate (WO2009/140320) and 3,3,3-
trifluoropropane-1-sulfonyl chloride (Matrix), E with HCl, J with
CDI and (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine
hydrochloride (Example #5, Step C) with DIEA, OO). ##STR00356##
D.1.69 1.94 443 1-(7-methyl-4-(3,3,3- trifluoropropylsulfonyl)-1,4-
diazepan-1-yl)-6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazine
(prepared using K from benzyl 7-methyl-1,4-
diazepane-1-carboxylate, Hydrochloric Acid (Wlodarczyk, N.;
Gilleron, P.; Millet, R.; Houssin, R.; Henichart, J.-P. Tet. Let.,
2007, vol. 48, # 14 p. 2583-2586) and 3,3,3-trifluoropropane-1-
sulfonyl chloride (Matrix), Y with Pd(OH).sub.2, J with CDI and
(5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride
(Example #5, Step C) with DIEA, OO). ##STR00357## D.1.70 1.97 431
6-tosyl-1-(5-(3,3,3- trifluoropropylsulfonyl)-2,5-
diazaspiro[3.5]nonan-2-yl)- 6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine (prepared using K from tert- butyl 2,5-
diazaspiro[3.5]nonane-2- carboxylate (WO2008/60767) and
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), E with HCl, J
with CDI and (5- tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine
hydrochloride (Example #5, Step C) with DIEA, OO). ##STR00358##
D.1.71 2.03 443 3,3,3-trifluoro-N-(1-(6-tosyl-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-yl)piperidin-3-
yl)propane-1-sulfonamide (prepared using K tert-butyl
3-aminopiperidine-1- carboxylate (3B-Scientific Corp.) and 3,3,3-
trifluoropropane-1-sulfonyl chloride (Matrix), E with HCl, J with
CDI and (5-tosyl- 5H-pyrrolo[2,3-b]pyrazin-2- yl)methanamine
hydrochloride (Example #5, Step C) with DIEA, OO). ##STR00359##
D.1.72 1.76 417 6-tosyl-1-(2-(3,3,3- trifluoropropylsulfonyl)-2,6-
diazabicyclo[3.2.1]octan-6- yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine (prepared using K from benzyl 2,6-
diazabicyclo[3.2.1]octane-6- carboxylate (Pharmabridge) and
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), Y with
Pd(OH).sub.2, J with CDI and (5-tosyl-5H-pyrrolo[2,3-
b]pyrazin-2-yl)methanamine hydrochloride (Example #5, Step C) with
DIEA, OO). ##STR00360## D.1.73 1.91 429
N-((3R,5R)-1-ethyl-5-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-3-
yl)cyclopropanesulfonamide (prepared using K with
(2R,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2- dicarboxylate
Hydrochloric Acid (Acesys Pharmatech Corp) and
cylcopropylsulfonylchloride and TEA, Z with NaOH, A with Example #8
Step M, B, E with HCl, X with acetaldehyde. ##STR00361## D.1.74*
1.32 376 (cis)-tert-butyl 3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1- carboxylate
(prepared using SSS from N-benzyl-1- methoxy-N-
((trimethylsilyl)methyl)meth- anamine and (Z)-ethyl pent-2- enoate
(Lee, R.D.; Kassahun, K.; Abbott, F.S. J. of Pharm. Sci., 1989,
vol. 78, #8 p. 667-671), TT, Y, M, A, B, E and K with
cyclopropylmethanesulfonyl chloride and TEA ##STR00362## D.1.75
1.66 375 N-(4-(3-tosyl-3H-dipyrrolo[1,2- a:2',3'-e]pyrazin-8-
yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (prepared
using III from 5- tosyl-5H-pyrrolo[2,3- b]pyrazine-2-carbaldehyde
(Preparation #12: step B) and diethyl 2-(4-
(cyclopropanesulfonamido) bicyclo[2.2.2]octan-1-yl)-2-
oxoethylphosphonate (Preparation #24), W, T with Lawesson's
reagent). ##STR00363## D.1.76 1.97 385 1-methyl-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared from
5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride
(WO2009152133) and (1S,2R,4S)-4-acetamido-2-
methylcyclopentanecarboxylic acid [prepared from ethyl 4-
amino-2-methyl- cyclopentanecarboxylate (WO2009152133) using G, AA
[Table 2, Method 3, R.sub.t = 6.1 min, or = ND], and Z] using H,
OO, BB, and K from Preparation #6 and TEA) ##STR00364## D.1.77*
1.87 (a) 374 3,3-difluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)azetidine-1-
sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-
b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and
(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid
[prepared from ethyl 4- amino-2-methyl- cyclopentanecarboxylate
(WO2009152133) using G, AA[Table 2, Method 3, R.sub.t = 6.1 min, or
= ND], and Z using H, OO, BB, ZZ and AAA with 3,3-
difluoroazetidine hydrochloride and TEA) ##STR00365## D.1.78*
1.99(a) 411 3,3,3-trifluoro-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- yl)cyclopentyl)propane-1-
sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-
b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and
(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid
[prepared from ethyl 4- amino-2-methyl- cyclopentanecarboxylate
(WO2009152133) using G, AA [Table 2, Method 3, R.sub.t = 6.1 min,
or = ND], and Z using H, OO, BB, and K from
3,3,3-trifluoro-propane- 1-sulfonyl chloride [Matrix]and TEA)
##STR00366## D.1.79* 2.00(a) 416 3,3-difluoro-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)pyrrolidine-1- sulfonamide (prepared from
5-tosyl-5H-pyrrolo[2,3- b]pyrazin-2-yl)methanamine hydrochloride
(WO2009152133) and (1S,2R,4S)-4-acetamido-2-
methylcyclopentanecarboxylic acid [prepared from ethyl 4-
amino-2-methyl- cyclopentanecarboxylate (WO2009152133) using G, AA
[Table 2, Method 3, R.sub.t = 6.1 min, or = ND], and Z] using H,
OO, BB, ZZ and AAA with 3,3- difluoropyrrolidine hydrochloride
and
TEA) ##STR00367## D.1.80* 2.01 (a) 425
(R)-N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)-2-
(trifluoromethyl)pyrrolidine- 1-sulfonamide sulfonamide
(Preparation #AAA.1) ##STR00368## D.1.81* 2.16 (a) 457
1-ethyl-N-((1S,3R,4S)-3-ethyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)
cyclopropane-1-sulfonamide (prepared from Example #8 Step M and
Preparation #EEE.1 using K and TEA) ##STR00369## D.1.82* 1.90 (a)
403 1-ethyl-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)cyclopropane-
1-sulfonamide (prepared from 5-tosyl-5H-pyrrolo[2,3-
b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and
(1S,2R,4S)-4-acetamido-2- methylcyclopentanecarboxylic acid
[prepared from ethyl 4- amino-2-methyl- cyclopentanecarboxylate
(WO2009152133) using G, AA [Table 2, Method 3, R.sub.t = 6.1 min,
or = ND], and Z] using H, OO, BB, and K using Preparation #EEE.1
and TEA) ##STR00370## D.1.83* 1.96 (a) 388
1-butyl-N-((1S,3R,4S)-3-ethyl-4- (6-tosyl-6H-pyrrolo[2,3-e]
[1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)cyclopropane-1-
sulfonamide (prepared from Example #8 Step M and 1-
butylcyclopropane-1-sulfonyl chloride [prepared from Preparation #6
Step A and1,1,1- trifluoro-2-iodoethane, KHMDS using KKK, JJJ, and
EEE with TEA] using K and TEA) ##STR00371## D.1.84* 2.13 (a) 431
N-((1S,3R,4S)-3-methyl-4-(6- tosylimidazo[4,5-
d]pyrrolo[2,3-b]pyridin- 1(6H)- yl)cyclopentyl)cyclopropane-
sulfonamide (Preparation #DDD.1) ##STR00372## D.1.85* 1.65 (a) 360
N-((1S,3S,4R)-3-(2-cyclopropyl- 6-tosylimidazo[4,5-
d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4- methylcyclopentyl)cyclopro-
panesulfonamide (prepared from Preparation #27 and Preparation
#OOO.1 using L and DIEA, K.1 with TsCl and NaH, BBB, H with
cyclopropanecarboxylic acid, HATU, and TEA, and DDD with
POCl.sub.3) ##STR00373## D.1.86* 1.74 (a) 400
N-((1S,3R,4S)-3-ethyl-4-(6- tosylpyrrolo[2,3-
b][1,2,3]triazolo[4,5- d]pyridin-1(6H)- yl)cyclopentyl)cyclo-
propanesulfonamide (Preparation #SSSS.1) ##STR00374## D.1.87* 1.82
(a) 375 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)pentane-2-
sulfonamide (prepared using K from Example #8 Step M and
pentane-2-sulfonyl chloride) ##STR00375## D.1.88 1.88 (b) 405
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3-phenylpropane-1- sulfonamide (prepared using K from Example #8
Step M and 3-phenylpropane-1- sulfonyl chloride) ##STR00376##
D.1.89* 1.98 (b) 453 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
4,4,4-trifluorobutane-1- sulfonamide (prepared using K from Example
#8 Step M and 4,4,4-trifluorobutane-1- sulfonyl chloride)
##STR00377## D.1.90* 1.85 (b) 445 2-ethyl-N-((1S,3R,4S)-3-ethyl-4-
(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)cyclopropane- 1-sulfonamide (prepared using K from
Example #8 Step M and 2- ethylcyclopropane-1-sulfonyl chloride)
##STR00378## D.1.91 1.81 (b) 403 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
2-methylpropane-1- sulfonamide (prepared using K from Example #8
Step M and 2-methylpropane-1- sulfonyl chloride) ##STR00379##
D.1.92* 1.77 (b) 391 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
2-phenylethanesulfonamide (prepared using K from Example #8 Step M
and 2- phenylethanesulfonyl chloride) ##STR00380## D.1.93* 1.92 (b)
439 1-cyclohexyl-N-((1S,3R,4S)-3- ethyl-4-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methanesulfon-
amide (prepared using K from Example #8 Step M and
cyclohexylmethanesulfonyl chloride) ##STR00381## D.1.94 * 2.04 (b)
431 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)butane-1-
sulfonamide (prepared using K from Example #8 Step M and
butane-1-sulfonyl chloride) ##STR00382## D.1.95* 1.78 (b) 391
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-2-
sulfonamide (prepared using K from Example #8 Step M and
propane-2-sulfonyl chloride) ##STR00383## D.1.96* 1.61 (b) 377
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-phenylmethanesulfonamide (prepared using K from Example #8 Step M
and phenylmethanesulfonyl chloride) ##STR00384## D.1.97* 1.82 (b)
425 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-
sulfonamide (prepared using K from Example #8 Step M and
propane-1-sulfonyl chloride) ##STR00385## D.1.98* 1.64 (b) 377
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3-methylbutane-1- sulfonamide (prepared using K from Example #8
Step M and 3-methylbutane-1- sulfonyl chloride) ##STR00386##
D.1.99* 1.90 (b) 405 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1,1- difluoromethanesulfonamide (prepared using K from Example #8
Step M and difluoromethanesulfonyl chloride) ##STR00387## D.1.100*
1.75 (b) 385 4-cyano-N-((1S,3R,4S)-3-ethyl-4-
(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)butane-1- sulfonamide (prepared using K from Example
#8 Step M and 4-cyanobutane-1-sulfonyl chloride) ##STR00388##
D.1.101* 1.56 (b) 416 2-ethoxy-N-((1S,3R,4S)-3-ethyl-
4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)ethanesulfon- amide (prepared using K from Example
#8 Step M and 2- ethoxyethanesulfonyl chloride) ##STR00389##
D.1.102* 1.62 (b) 407 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-(tetrahydrofuran-2- yl)methanesulfonamide (prepared using K from
Example #8 Step M and (tetrahydrofuran-2- yl)methanesulfonyl
chloride) ##STR00390## D.1.103 1.58 (b) 419
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)tetrahydro-2H-
pyran-4-sulfonamide (prepared using K from Example #8 Step M and
tetrahydro-2H-pyran-4- sulfonyl chloride) ##STR00391## D.1.104*
1.50 (b) 419 3-cyano-N-((1S,3R,4S)-3-ethyl-4-
(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)propane-1- sulfonamide (prepared using K from
Example #8 Step M and 3-cyanopropane-1- sulfonyl chloride)
##STR00392## D.1.105* 1.51 (b) 402
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-(5-methylisoxazol-3- yl)methanesulfonamide (prepared using K from
Example #8 Step M and (5- methylisoxazol-3- yl)methanesulfonyl
chloride) ##STR00393## D.1.106* 1.66 (b) 430
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-(tetrahydro-2H-pyran-2- yl)methanesulfonamide (prepared using K
from Example #8 Step M and (tetrahydro-2H-pyran-2-
yl)methanesulfonyl chloride) ##STR00394## D.1.107 1.73 (b) 433
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-(pyridin-2-
yl)ethanesulfonamide (prepared using K from Example #8 Step M and
2- (pyridin-2-yl)ethanesulfonyl chloride) ##STR00395## D.1.108*
1.58 (b) 440 1-(2,2-dichlorocyclopropyl)-N-
((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methanesulfon
amide (prepared using K from Example #8 Step M and (2,2-
dichlorocyclopropyl)methane sulfonyl chloride) ##STR00396## D.1.109
1.91 (b) 457 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3-phenylpropane-1- sulfonamide (prepared using K from Preparation
#19.2 and 3-phenylpropane-1-sulfonyl chloride) ##STR00397##
D.1.110* 1.90 (b) 439 4,4,4-trifluoro-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)butane-1- sulfonamide (prepared using K
from Preparation #19.2 and 4,4,4-trifluorobutane-1- sulfonyl
chloride) ##STR00398## D.1.111* 1.76 (b) 431
2-ethyl-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopropane-
1-sulfonamide (prepared using K from Preparation #19.2 and 2-
ethylcyclopropane-1-sulfonyl chloride) ##STR00399## D.1.112 1.70
(b) 389 2-methyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)propane-1- sulfonamide (prepared using K from
Preparation #19.2 and 2-methylpropane-1-sulfonyl chloride)
##STR00400## D.1.113* 1.67 (b) 377 N-((1S,3R,4S)-3-methyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)- 2-phenylethanesulfonamide (prepared
using K from Preparation #19.2 and 2- phenylethanesulfonyl
chloride) ##STR00401## D.1.114* 1.83 (b) 425
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)butane-2-
sulfonamide (prepared using K from Preparation #19.2 and
2-(methylsulfonyl)butane) ##STR00402## D.1.115 1.63 (b) 377
1-cyclohexyl-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methanesulfon-
amide (prepared using K from Preparation #19.2 and
cyclohexylmethanesulfonyl chloride) ##STR00403## D.1.116* 1.94 (b)
417 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)butane-1-
sulfonamide (prepared using K from Preparation #19.2 and
butane-1-sulfonyl chloride) ##STR00404## D.1.117* 1.67 (b) 377
2-methoxy-N-((1S,3R,4S)-3- methyl-4-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)ethanesulfon-
amide (prepared using K from Preparation #19.2 and 2-
methoxyethanesulfonyl chloride) ##STR00405## D.1.118* 1.38 (b) 379
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-2-
sulfonamide (prepared using K from Preparation #19.2 and
propane-2-sulfonyl chloride) ##STR00406## D.1.119* 1.50 (b) 363
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-phenylmethanesulfonamide (prepared using K from Preparation #19.2
and phenylmethanesulfonyl chloride) ##STR00407## D.1.120* 1.72 (b)
411 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-
sulfonamide (prepared using K from Preparation #19.2 and
propane-1-sulfonyl chloride) ##STR00408## D.1.121* 1.53 (b) 363
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3-methylbutane-1- sulfonamide (prepared using K from Preparation
#19.2 and 3-methylbutane-1-sulfonyl chloride) ##STR00409## D.1.122*
1.80 (b) 391 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-e]
[1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)-1,1-
difluoromethanesulfonamide (prepared using K from Preparation #19.2
and difluoromethanesulfonyl chloride) ##STR00410## D.1.123* 1.64
(b) 371 4-cyano-N-((1S,3R,4S)-3-methyl-
4-(6-tosyl-6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]pyrazin-
1-yl)cyclopentyl)butane-1- sulfonamide (prepared using K from
Preparation #19.2 and 4-cyanobutane-1-sulfonyl chloride)
##STR00411## D.1.124 * 1.45 (b) 402 2-ethoxy-N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)ethanesulfon- amide (prepared using K
from Preparation #19.2 and 2- ethoxyethanesulfonyl chloride)
##STR00412## D.1.125* 1.50 (b) 393 N-((1S,3R,4S)-3-methyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)- 1-(tetrahydrofuran-2-
yl)methanesulfonamide (prepared using K from Preparation #19.2 and
(tetrahydrofuran-2- yl)methanesulfonyl chloride) ##STR00413##
D.1.126 1.46 (b) 405 N-((1S,3R,4S)-3-methyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)tetrahydro-2H- pyran-4-sulfonamide (prepared using K
from Preparation #19.2 and tetrahydro-2H-pyran-4- sulfonyl
chloride) ##STR00414## D.1.127* 1.39 (b) 405
3-fluoro-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-
sulfonamide (prepared using K from Preparation #19.2 and
3-fluoropropane-1-sulfonyl chloride) ##STR00415## D.1.128* 1.48 (b)
381
3-cyano-N-((1S,3R,4S)-3-methyl- 4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)propane-1-
sulfonamide (prepared using K from Preparation #19.2 and
3-cyanopropane-1-sulfonyl chloride) ##STR00416## D.1.129* 1.39 (b)
388 N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-(5-methylisoxazol-3- yl)methanesulfonamide (prepared using K from
Preparation #19.2 and (5- methylisoxazol-3- yl)methanesulfonyl
chloride) ##STR00417## D.1.130* 1.55 (b) 416
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
1-(tetrahydro-2H-pyran-2- yl)methanesulfonamide (prepared using K
from Preparation #19.2 and (tetrahydro-2H-pyran-2-
yl)methanesulfonyl chloride) ##STR00418## D.1.131 1.63 (b) 419
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- 2-(pyridin-2-
yl)ethanesulfonamide (prepared using K from Preparation #19.2 and
2- (pyridin-2-yl)ethanesulfonyl chloride) ##STR00419## D.1.132*
1.47 (b) 426 1-(benzo[d]isoxazol-3-yl)-N-
((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methane-
sulfonamide (prepared using K from Preparation #19.2 and
benzo[d]isoxazol-3- ylmethanesulfonyl chloride) ##STR00420##
D.1.133* 1.77 (b) 452 1-(2,2-dichlorocyclopropyl)-N-
((1S,3R,4S)-3-methyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methane-
sulfonamide (prepared using K from Preparation #19.2 and (2,2-
dichlorocyclopropyl)methane- sulfonyl chloride) ##STR00421##
D.1.134 1.81 (b) 443 tert-butyl 3-(N-((1S,3R,4S)-3-
methyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)sulfamoyl) azetidine-1-carboxylate
(prepared using K from Preparation #19.2 and tert-butyl 3-
(chlorosulfonyl)azetidine-1- carboxylate) ##STR00422## D.1.135*
1.78 (b) 476 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- N-(4,4,4-
trifluorobutyl)oxetan-3-amine (prepared using X from Example #8
Step M with oxetan-3-one [PharmaBlock R&D], X with 4,4,4-
trifluorobutanal [Matrix]) ##STR00423## D.1.136* 1.75 (a) 437
N-((1S,3S,4R)-3-(2-amino-6- tosylimidazo[4,5-
d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4-
ethylcyclopentyl)cyclopropane- sulfonamide (Preparation #RRRR.1)
##STR00424## D.1.137* 1.30 (a) 389
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)- N-(3,3,3-
trifluoropropyl)oxetan-3- amine (prepared using X from Example #8
Step M with oxetan-3-one [PharmaBlock], and X with 3,3,3-
trifluoropropanal [Apollo Sci]) ##STR00425## D.1.138* 1.91 (b) 423
(3R,4S)-N-cyclopropyl-3-ethyl-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentane- 1-sulfonamide
(prepared using EEE from Preparation #QQQQ.1; K with
cyclopropylamine) ##STR00426## D.1.139 1.53 (b) 375
N-((3R,5R)-1-(2,2-difluoroethyl)- 5-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-3-
yl)cyclopropanesulfonamide (prepared using K from
(2R,4R)-1-tert-butyl-4- aminopyrrolidine-1,2- dicarboxylate
hydrochloric acid (Acesys Pharmatech Corp) and
cylcopropylsulfonylchloride, TEA, Z with NaOH, A with Example #1
Step D, HATU and TEA, B with SOCl.sub.2 and TEA, E with HCl, S with
1,1- difluoro-2-iodoethane) ##STR00427## D.1.140* 1.46 (a) 412
N-((3R,5R)-1-ethyl-5-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-3- yl)-N-
methylcyclopropanesulfon- amide (prepared using K with
(2R,4R)-1-tert-butyl-4- aminopyrrolidine-1,2- dicarboxylate
Hydrochloric Acid (Acesys Pharmatech Corp), d
cylcopropylsulfonylchloride and TEA, Z with NaOH, A with Example #1
Step D, HATU and TEA, B, E with HCl, X with acetaldehyde, S with
iodomethane) ##STR00428## D.1.141* 1.44 (a) 390
1-((cis)-1-(cyclopropylsulfonyl)- 4-ethylpyrrolidin-3-yl)-6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared
using K with Example #36 Step F and cylcopropylsulfonylchloride
(Matrix) and TEA) ##STR00429## D.1.142 1.50 (a) 361
1-((cis)-1-benzyl-4- isopropylpyrrolidin-3-yl)-6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared
using A with (Example #1, Step D) and (cis)-1- benzyl-4-
isopropylpyrrolidine-3- carboxylic acid hydrochloride (prepared
using SSS with (Z)- ethyl 4-methylpent-2-enoate and
N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)meth- anamine
(Aldrich)), B with TEA) ##STR00430## D.1.143 0.47(a) 361
N-((1S,3R,4R)-3-ethyl-4-(6-tosyl- 3-(trifluoromethyl)-6H-
imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H with
Preparation #32 and Preparation #Z.1, OO) ##STR00431## D.1.144 *
2.12 (a) 442 N-((1S,3R,4R)-3-ethyl-4-(6-tosyl-
3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H with
Preparation #32 and Preparation #Z.1, OO ##STR00432## D.1.145 *
1.59 (a) 418 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using H with
Preparation #32 and Preparation #Z.1, OO ##STR00433## D.1.146 *
1.45 (a) 418 N-((1S,3R,4S)-3-methyl-4-(6-
tosyl-3-(trifluoromethyl)-6H- imidazo[1,5-a]pyrrolo[2,3-
e]pyrazin-1- yl)cyclopentyl)cyclopropane- sulfonamide (prepared
using Y from Example #24 Step J, K with cyclopropylsulfonyl
chloride (Matrix), H from Preparation #32 and OO) ##STR00434##
D.1.147* 2.03 (a) 428 1-((cis)-4-ethylpyrrolidin-3-yl)-6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazine.cndot.hydrochloride (prepared using K from Example #36,
Step F, 3,3,3- trifluoropropane-1-sulfonyl chloride [Matrix] and
TEA) ##STR00435## D.1.148 1.86 (a) 417 1-((cis)-4-ethyl-1-(3,3,3-
trifluoropropyl)pyrrolidin-3- yl)-6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- ajpyrazine (prepared using X from Example
#36, Step F, 3,3,3-trifluoropropanal [Alfa Aesar], sodium
triacetoxyborohydride and DIEA) ##STR00436## D.1.149 1.54 (a) 353
4-(2-((cis)-3-ethyl-4-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-1-
yl)ethyl)morpholine (prepared using X from Example #36, Step F, 2-
morpholinoacetaldehyde [Matrix], sodium triacetoxyborohydride and
DIEA) ##STR00437## D.1.150 1.35 (a) 370
2-cyclopropyl-1-((cis)-3-ethyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidin-1- yl)ethanone
(prepared using H from Example #36, Step F, 2-cyclopropylacetic
acid, HATU [Novabiochem] and DIEA) ##STR00438## D.1.151 1.54 (a)
339 1-((cis)-4-ethylpyrrolidin-3-yl)-6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine.cndot.hydrochloride (prepared
using H from Example #36, Step F, 2- (tetrahydro-2H-pyran-4-
yl)acetic acid [Astatech], HATU [Novabiochem] and DIEA)
##STR00439## D.1.152 1.54 (a) 383 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
3,3-difluorocyclobutane-1- sulfonamide (prepared using K from
Example 8, Step M, Preparation #34, and DIEA) ##STR00440## D.1.153
1.75 (a) 425 1-((cis)-4-ethylpyrrolidin-3-yl)-6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazine.cndot.hydrochloride (prepared using K from Example #36,
Step F, Preparation #34, and DIEA) ##STR00441## D.1.154 1.90 (a)
411 isopropyl (1S,3R,4S)-3-ethyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylcarbamate
sulfonamide (Preparation #35) ##STR00442## D.1.155* 1.74 (b) 357
3-tosyl-8-(2-tosyl-2- azaspiro[3.3]heptan-6-yl)-3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (Preparation #KKKK.1)
##STR00443## D.1.156 1.99 (a) 294 (M - H).sup.-
4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)bicyclo[2.2.2]octan-1- amine (Example #9 Step F) ##STR00444##
D.1.157 2.72 (r) 283 8-(piperidin-1-yl)-3-tosyl-3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (prepared using S from
Example #3, Step E and 1-(bromoacetyl)piperidine [ChemBridge], E
with HCl, OO.1) ##STR00445## D.1.158 1.78 (a) 242
8-(2-(4-methylpiperazin-1- yl)pyrimidin-4-yl)-6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (Preparation
#CCCCC.1) ##STR00446## D.1.159 1.00 (a) 336
8-(2-(4-methylpiperazin-1- yl)quinazolin-4-yl)-6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine (prepared using D
from Preparation #BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl
and NaH, CCCCC with Preparation #40, tetrakis(triphenylphosphine)
palladium(0), LiCl, CsF, and CuI ##STR00447## D.1.160 1.16 (a) 386
8-(2-methoxypyridin-4-yl)-6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazine (prepared using D from
Preparation #BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl and
NaH, CCCCC with 2- methoxy-4- (tributylstannyl)pyridine
[Synthonix], tetrakis(triphenylphosphine) palladium(0), LiCl, CsF,
and CuI ##STR00448## D.1.161 1.28 (a) 267
8-(1-benzylpyrrolidin-3-yl)-3- tosyl-3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazine (prepared using R from 1-
benzylpyrrolidine-3- carboxylic acid, S from Example #3 Step E, E
with TFA, KKKK with PFPAA) ##STR00449## D.1.162 1.40 (b) 317
2-(3-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)oxetan-
3-yl)acetonitrile (prepared using YYY from Preparation #BB.1* and
2-(oxetan-3- yliden)acetonitrile (J. Med. Chem, 2010, 53(8) 3227-
3246) with Hunig's base) ##STR00450## D.1.163* 1.35 (a) 366
N-((1S,3R,4S)-3-methyl-4-(6- tosyl-2- (trifluoromethyl)imidazo[4,5-
d]pyrrolo[2,3-b]pyridin- 1(6H)- yl)cyclopentyl)cyclopropane-
sulfonamide (prepared using L from Preparation #27 and Preparation
#OOO.1 and DIEA, K with TsCl and NaH, BBB, CCC with TFAA, DDD with
HCl) ##STR00451## D.1.164 1.95 (a) 428 N-(3-ethyl-4-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-
yl)cyclopentyl)-N-(4,4,4- trifluorobutyl)acetamide (prepared using
X from Example #8 Step M and 4,4,4-trifluorobutanal [Matrix], CCC
with Ac.sub.2O) ##STR00452## D.1.165* 1.85 (a) 423
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
N-((tetrahydro-2H-pyran-4- yl)methyl)acetamide (prepared using X
from Example #8 Step M and tetrahydro-2H-pyran-4- carbaldehyde
[Pharmacore], CCC with Ac.sub.2O) ##STR00453## D.1.166* 1.61 (a)
411 N-(cyclopropylmethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)acetamide (prepared using X from Example #8 Step M
and cyclopropanecarbaldehyde, CCC with Ac.sub.2O) ##STR00454##
D.1.167* 1.73 (a) 367 N-((1S,3S,4R)-3-(2- (difluoromethyl)-6-
tosylimidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)-4-
ethylcyclopentyl)cyclopropane- sulfonamide (prepared using H from
Example #23 Step I, difluoroacetic acid, HATU, and TEA, DDD with
TPP) ##STR00455## D.1.168 1.76 (a) 424
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentyl)-
N-methyloxetan-3-amine (prepared using X from Preparation #25 and
N- methyloxetan-3-amine [Synthonix]) ##STR00456## D.1.169 1.02 (a)
341 (1S,3R,4S)-3-ethyl-N-((3- methyloxetan-3-yl)methyl)-4-
(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentanamine (prepared using X from Preparation #25 and (3-
methyloxetan-3- yl)methanamine [Synthonix]) ##STR00457## D.1.170
1.11 (a) 355 N-((1S,3R,4S)-3-ethyl-4-(2- methyl-6-tosylimidazo[4,5-
d]pyrrolo[2,3-b]pyridin- 1(6H)- yl)cyclopentyl)cyclopropane-
sulfonamide (prepared using CCC from Example #23 Step I and
Ac.sub.2O, DDD with TPP) ##STR00458## D.1.171 1.53 (a) 358
N-(cyclopropylmethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)- 3-methyloxetan-3-amine (prepared using
X from Preparation #25 and 3- methyloxetan-3-amine [Synthonix], X
using cyclopropanecarbaldehyde) ##STR00459## D.1.172 1.23 (a) 395
N-(2-cyclopropylethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)- 3-methyloxetan-3-amine (prepared using
X from Preparation #25 and 3- methyloxetan-3-amine [Synthonix], X
using 2- cyclopropylacetaldehyde [Anichem]) ##STR00460## D.1.173
1.40 (a) 409 N-((1S,3R,4S)-3-ethyl-4-(6-tosyl- 2-
(trifluoromethyl)imidazo[4,5- d]pyrrolo[2,3-b]pyridin- 1(6H)
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using CCC from
Example #23 Step I and TFAA, DDD with HCl) ##STR00461## D.1.174
1.95 (a) 442 34(1R,3R,4S)-3-ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyloxy)propanenit rile (prepared using YYY
from Example #41Step I and acrylonitrile, Z with NaOH, A with
Example #1 Step D, HATU and TEA, B with thionyl chloride and TEA)
##STR00462## D.1.175 1.72 (b) 325
TABLE-US-00006 TABLE D.2 Examples prepared using General Procedure
D with Na.sub.2CO.sub.3 R.sub.t min Example (Table 1,) m/z ESI+
Sulfonamide Product # Method) (M + H).sup.+ (S)-5-(3-((6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)methyl)pyrrolidin-1- yl)pyrazine-2-carbonitrile (Preparation
#L.1) ##STR00463## D.2.1* 1.46 (a) 346 2-(4-cyanophenyl)-N-
((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)acetamide (prepared using E from
Preparation #B.1 with HCl, and H with 4- cyanophenylacetic acid,
EDC and DIEA) ##STR00464## D.2.2* 1.20 (c) 386
4-cyano-N-((1S,3R)-3-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazoIo[4,3- a]pyrazin-1- yl)cyclopentyl)benzamide
(prepared using E from Preparation #B.1 with HCl, H with
4-cyanobenzoic acid, EDC, and DIEA) ##STR00465## D.2.3* 1.16 (c)
372 3-((1R,3R)-3-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentylamino) benzonitrile (prepared using PP
with Example #2, Step F, 3-cyanophenylboronic acid and DIEA)
##STR00466## D.2.4* 1.91 (a) 344 3-cyano-N-((1S,3R,4S)-3-
ethyl-4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]
triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)azetidine-1- sulfonamide
(prepared using DD with Example #8, Step M, 3-cyanoazetidine-
1-sulfonyl chloride [prepared from CC with azetidine-3-carbonitrile
hydrochloride (Astatech) and DIEA] and TEA) ##STR00467## D.2.5*
1.82 (a) 415 3-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
benzonitrile (prepared using PP from Preparation #19.2,
3-cyanophenyl boronic acid, and DIEA) ##STR00468## D.2.6* 2.04 (a)
358 5-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
pyrazine-2-carbonitrile (prepared using L from Preparation #19.2,
2- chloro-5-cyanopyrazine [ArkPharm], and DIEA) ##STR00469## D.2.7*
1.89 (a) 360 6-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
nicotinonitrile (prepared using L from Preparation #19.2,
5-cyano-2- fluoropyridine[Matrix] and DIEA) ##STR00470## D.2.8*
1.81 (a) 359 2-((1S,3R,4S)-3-methyl-4- (6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
thiazole-5-carbonitrile (prepared using L from Preparation #19.2,
2- chlorothiazole-5- carbonitrile [ArkPharm] and DIEA) ##STR00471##
D.2.9* 1.89 (a) 365 6-((1R,3R,4R)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyloxy) nicotinonitrile and 6- ((1S,3S,4S)-3-
ethyl-4-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyloxy)- nicotinonitrile (prepared using II
from 6- hydroxynicotinonitrile [Asta Tech], Preparation #FF.1 and
DEAD) ##STR00472## D.2.10 2.01 (b) 374 5-((1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentylamino)- pyrazine-2-carbonitrile (prepared using L
from Example #8, Step M and 2- chloro-5-cyanopyrazinc [ArkPharm]
and DIEA) ##STR00473## D.2.11* 1.94 (a) 374
1-((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)-1H-pyrrole- 3-carbonitrile
(Preparation #4) ##STR00474## D.2.12* 1.92 (a) 318
5-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentylamino)pyrazine-
2-carbonitrile (prepared using H from Example #8, Step K, Example
#5, Step C, HATU and TEA, Q with Lawesson's reagent and mercury
(II) trifluoroacetate, BB with HCl, L with 2-chloro-5-
cyanopyrazine [ArkPharm] ##STR00475## D.2.13* 2.10 (a) 373 and
DIEA) 5-(((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-
amino)pyrazine-2- carbonitrile (prepared using M from (1R,3S)-3-
(aminomethyl)cyclo- pentanecarboxylic acid (AFID), A from Example
#1, Step D, HATU and TEA, C with TEA, L with
2-chloro-5-cyanopyrazine ##STR00476## D.2.14* 1.79 (a) 360
[ArkPharm] and DIEA) 5-(((1S,3S)-3-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methyl-
amino)pyrazine-2- carbonitrile and 5- (((1S,3R)-3-(6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)methyl- amino)pyrazine-2- carbonitrile (prepared
using ##STR00477## D.2.15* 1.84 (a) 359 M from (1R,3S)-3-
(aminomethyl)cyclo- pentanecarboxylic acid (AFID), H from Example
#5, Step C, HATU and TEA, Q wilh Lawesson's reagent and mercury(II)
trifluoroacetate, E with HCl, L with 5- chloropyrazine-2-
carbonitrile [ArkPharm] and DIEA) 5-(((1S,3S)-3-(6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)methyl- amino)pyrazine-2- carbonitrile and 5-
(((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3- e][1,2,41triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)methyl- amino)pyrazine-2- carbonitrile
(prepared using ##STR00478## D.2.16* 1.73 (a) 359 M frorn(1R,3S)-3-
(aminomethyl)cyclo- pentanecarboxylic acid (AFID), H from Example
#5, Step C, HATU and TEA, Q with Lawesson's reagent and mercury(II)
trifluoroacetate, L with 5- chloropyrazine-2- carbonitrile
[ArkPharm] and DIEA) 6-(cis-3-methyl-4-(6-tosyl- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
nicotinonitrile (prepared using Y from Preparation #46 with
Pd(OH).sub.2 on C, Z with NaOH, M, A from Example #1, Step D, HATU,
and TEA, C with TEA, L with 6- fluoronicotinonitrile [Matrix] and
DIEA) ##STR00479## D.2.17 1.74 (a) 359 5-((cis-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyl)methoxy)- pyrazine-2-carbonitrile (prepared using P
from Preparation #11 with LAH, JJ with 2-chloro-5- cyanopyrazine
[ArkPharm], TT with HCl, A from Example #1, Step D with HATU and
TEA, B with TEA) ##STR00480## D.2.18 1.81 (a) 407
6-((1S,3R,4S-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
nicotinonitrile (prepared using L from Example #8, Step M and 6-
fluoronicotinonitrile [Matrix] and DIEA) ##STR00481## D.2.19* 2.02
(a) 373 5-((1R,3R)-3-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentylamino)-
pyrazine-2-carbonitrile (prepared using L from Example #2, Step F,
5- chloropyrazine-2- carbonitrile[Ark Pharm] and DIEA) ##STR00482##
D.2.20* 1.57 (b) 346 5-((1S,3R,4S)-3-methyl-4-
(6-tosyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)cyclopentylamino)pyrazine- 2-carbonitrile (prepared using L from
Preparation #19.2, 2-chloropyrazine-2- carbonitrile [Ark Pharm] and
DIEA) ##STR00483## D.2.21* 1.97 (b) 359 6-((1R,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyloxy)- nicotinonitrile and 6-
((1S,3S,4R)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyloxy)-
nicotinonitrile (prepared using II from 6- hydroxynicotino-nitrile
[Asta Tech], Preparation #FF.1 and DEAD) ##STR00484## D.2.22 1.99
(b) 374 2-(((1S,3R)-3-(6-tosyl-6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)methylamino)
isonicotinonitrile (prepared using A from Example #1, Step D,
Preparation #M.1, HATU and TEA, B with TEA; L with 2-
fluoroisonicotinonitrile) ##STR00485## D.2.23* 1.69 (a) 159
4-((1R,4S)-3-ethyl-4-(6- tosyl-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyloxy)benzonitrile (prepared
from prepared from 5-tosyl-5H- pyrrolo[2,3-b]pyrazin-2-
yl)methanamine hydrochloride (WO2009152133) and Preparation #GG.1
using HH with TMA and DIEA, II with 4-cyanophenol, DEAD, PPh.sub.3,
and TEA, and ##STR00486## D.2.24 2.28 (a) 372 Q with Lawesson's
reagent and and mercury (II) trifluoroacetate) N-(cyanomethyl)-N-
((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)
cyclopropanesulfonamide (prepared using S.1 from N-
((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclo-
propanesulfonamide [WO2009152133A1] and 2-iodoacetonitrile)
##STR00487## D.2.25* 1.74 (a) 414 (1S,3R,4S)-N-(2-
cyclopropylethyl)-3-ethyl- 4-(6-tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)-N-(2,2,2-
trifluoroethyl)cyclopentanamine (prepared using X from Preparation
#25 with 2,2,2-trifluoroethanamine, X with 2-
cyclopropylacelaldehyde [Anichem]) ##STR00488## D.2.26 * 2.49 (a)
421 (1S,3R,4S)-N- (cyclopropylmethyl)-3- ethyl-4-(6-tosyl-6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)-N-(2,2,2-
trifluoroethyl)cyclopentanamine (prepared using X from Preparation
#25 with 2,2,2-trifluoroethanamine, X with
cyclopropanecarbaldehyde) ##STR00489## D.2.27* 2.31 (a) 407
N-((1S,3R,4S)-3-ethyl-4-(6- tosyl-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)cyclopropane-
sulfonamide (prepared using K from Example #8, Step M and
cyclopropropanesulfonyl chloride; YYY from acrylontrile with DBU]
##STR00490## D.2.28* 1.70 (b) 428 (1S,3R,4S)-3-ethyl-4-(6-
tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentanamine (prepared using K from Example #8, Step M and
3- fluoropropane-1-sulfonyl chloride [Hande]) ##STR00491## D.2.29*
1.59 (b) 395 1-((cis)-4-ethylpyrrolidin-3-
yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine
.cndot. hydrochloride (prepared using L from Example #36, Step F,
6- fluoronicotinonitrile [Matrix], and TEA) ##STR00492## D.2.30
1.81 (a) 359 1-((cis)-4-ethylpyrrolidin-3-
yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine
.cndot. hydrochloride (prepared using X from Example #36, Step F,
4- formylbenzonitrile, sodium triacetoxyborohydride and DIEA)
##STR00493## D.2.31 1.53 (a) 372 1-((cis)-4-ethylpyrrolidin-3-
yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine
.cndot. hydrochloride (prepared using H from Example #36, Step F,
2- cyanoacetic acid, HATU [Novabiochem] and DIEA) ##STR00494##
D.2.32 1.49 (a) 324 1-((cis-4-ethylpyrrolidin-3-
yl)-6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazine
.cndot. hydrochloride (prepared using YYY from Example #36, Step F,
2- (oxetan-3- ylidene)acetonilrile [J. Med. Chem, 2010, 53,
3227-3246], and DIEA) ##STR00495## D.2.33 1.55 (a) 352
(1S,3R,4S-3-ethyl-4-(6H- pyrrolo[2,3- e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl phenylcarbamate (prepared using WWW from
Example #42 Step N and phenylamine) ##STR00496## D.2.34* 2.04 (b)
391
TABLE-US-00007 TABLE D.3 Examples prepared using General Procedure
D with Na.sub.2CO.sub.3 followed by NaOH R.sub.t min (Table 1, m/z
ESI+ Sulfonamide Product Ex # Method) (M + H).sup.+
3-(cyclopropylmethylamino)-4- ((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
al]pyrazin-a-yl)cyclopentylamino)- cyclobut-3-ene-1,2-dione
(prepared using TTTT from Preparation #29 and
cyclopropylmethanamine) ##STR00497## D.3.1* 1.71 (a) 420
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentylamino)-4-
(oxetan-3-ylamino)cyclobut-3-ene-1,2- dione (prepared using TTTT
from Preparation #29 and oxetan-3-amine [Synthonix]) ##STR00498##
D.3.2* 1.55 (a) 422 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentylamino)-4-
(3,3,3-trifluoropropylamino)cyclobut-3- ene-1,2-dione(Preparation
#TTTT.1) ##STR00499## D.3.3* 1.58 (a) 462
3-(cyclopropylamino)-4-((1S,3R,4S)-3-
ethyl-4-(6-tosyl-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentylamino)cyclobut-3-ene- 1,2-dione (prepared using TTTT
from Preparation #29 and cyclopropylamine) ##STR00500## D.3.4* 1.65
(a) 406
[1391] General Procedure E: Acidic Cleavage of a Boc-Protected
Amine
[1392] To a solution of a Boc-protected amine (preferably 1 equiv)
in an organic solvent (such as DCM, 1,4-dioxane, or MeOH) is added
TFA or HCl (preferably 4 N HCl in 1,4-dioxane, 2-35 equiv,
preferably 2-15 equiv). The reaction is stirred at about
20-100.degree. C. (preferably ambient temperature to about
60.degree. C.) for about 1-24 h (preferably about 1-6 h). In any
case where an additional acid labile group is present (for example,
a t-butyl ester), this group may also be cleaved during the
reaction. Optionally, additional TFA or HCl (preferably 4 N HCl in
1,4-dioxane solution, 2-35 equiv, preferably 2-15 equiv) may be
added to the reaction mixture in cases where the reaction does not
proceed to completion as monitored by TLC, LC/MS, or HPLC. Once the
reaction has proceeded to an acceptable level, the reaction mixture
can be concd in vacuo to provide the amine as a salt.
Alternatively, the reaction may be partitioned between an organic
solvent (such as EtOAc, DCM or 1,4-dioxane) and an aqueous base
(such as saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2CO.sub.3, preferably saturated aqueous NaHCO.sub.3). The
aqueous layer can be optionally extracted with additional organic
solvent such as EtOAc or DCM. The combined organic layers may
optionally be washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, then decanted or filtered, prior to
concentrating under reduced pressure to give the target
compound.
Preparation #E.1:
N-((3S,5R)-5-ethylpyrrolidin-3-yl)cyclopropanesulfonamide
hydrochloride
##STR00501##
[1394] To a solution of (2R,4S)-tert-butyl
4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95
g, 2.98 mmol, Preparation #15) in 1,4-dioxane (7.5 mL) was added
HCl (4 N in 1,4-dioxane, 7.46 mL, 29.8 mmol). The reaction mixture
was heated to about 60.degree. C. After about 4 h, the reaction
mixture was cooled to ambient temperature and concd in vacuo to
provide crude
N-((3S,5R)-5-ethylpyrrolidin-3-yl)cyclopropanesulfonamide
hydrochloride (0.38 g, 50%) as a brown residue: LC/MS (Table 1,
Method a) R.sub.t=0.63 min; MS m/z: 219 (M+H).sup.+.
TABLE-US-00008 TABLE E.1 Examples prepared using General Procedure
E with HCl R.sub.t min (Table 1, m/z ESI+ Boc-protected Amine
Product Ex # Method) (M + H).sup.+ (R)-tert-butyl 3-((3R,4R)-3-(6H-
imidazo[1,5-a]pyrrolo[2,3-c]pyrazin-1- yl)-4-methylpiperidine-1-
carbonyl)morpholine-4-carboxylate (prepared using H from Example
#5, Step J and (R)4-(tert- butoxycarbonyl)morpholine-3- carboxylic
acid [Tyger] with EDO.cndot.HCl and DIEA) ##STR00502## E.1.1* 1.16
(b) 369 tert-butyl 2-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-ylamino)-2- oxoethylcarbamate (prepared
using H from Preparation #OO.1.1, tert- butoxycarbonylaminoacetic
acid [TCI], HATU and TEA, D with NaOH) ##STR00503## E.1.2 1.72 (r)
231 tert-butyl 3-(3H-imidazo[1,2-
a]pyrrolo[2,3-c]pyrazin-8-ylamino)-3- oxopropylearbamate (prepared
using H from Preparation #OO.1.1, 3-tert-
butoxycarbonylaminopropionic acid, HATU and TEA, D with NaOH)
##STR00504## E.1.3 2.09 (r) 245 tert-butyl 4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazine-8- carbonyl)piperazine-1-carboxylate
(prepared using D from Preparation #YYY.1 and NaOH, H with
piperidin- 4-yl-carbamic acid tert-butyl ester [Tyger], EDC, HOBt,
and TEA) ##STR00505## E.1.4 2.75 (r) 271 tert-butyl
1-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazine-8-
carbonyl)piperidin-4-ylcarbamate (prepared using D from Preparation
#YYYY.l and NaOH, H with piperazine-1-carboxylic acid tert-butyl
ester, EDC, HOBt, and TEA) ##STR00506## E.1.5 2.81 (r) 285
tert-butyl 4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazine-7-
carbonyl)piperazine-1-carboxylate (prepared using D from
Preparation #37 and NaOH, H with piperazine-1- carboxylic acid
tert-butyl ester, EDC, HOBt, and TEA) ##STR00507## E.1.6 2.68 (r)
271 tert-butyl trans-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine-8-
carboxamido)cyclohexyl)methylcarbamate (Preparation #LL.1.1)
##STR00508## E.1.7 0.74 (a) 314 tert-butyl
(trans-4-((6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)
methylamino)cyclohexyl)methylcarbamate (Preparation #X.1.1)
##STR00509## E.1.8 2.66 (r) 300 tert-butyl
(trans-4-((6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)methyl)cyclohexyl)methylcarbamate (Preparation #ZZZZ.1)
##STR00510## E.1.9 1.01 (a) 285 t-butyl 2-(4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin- 1-yl)ethylcarbamate
(prepared using R from 1-(benzyloxycarbonyl)piperidine-
4-carboxylic acid (Matrix), S from Example #3 Step E, E with TFA,
KKKK with PFPAA, D with NaOH, F, X with t-butyl
2-oxoethylcarbamate) ##STR00511## E.1.10 2.28 (r) 285 tert-butyl
4-((3,6-dihydropyrazolo[4,3- d]pyrrolo[2,3-b]pyridin-1-
yl)methyl)piperidine-1-carboxylate (prepared using XX from
Preparation #XXXX.1) ##STR00512## E.1.11 1.30 (a) 256
[1395] General Procedure E.1: Acidic Cleavage of a Boc-Protected
Amine
[1396] To a solution of a Boc-protected amine (preferably 1 equiv)
in an organic solvent (such as DCM, 1,4-dioxane, MeOH, or THF) is
added an acid (such as TFA, HCl, or H.sub.3PO.sub.4 (preferably
H.sub.3PO.sub.4, 1-50 equiv, preferably 5-10 equiv). The reaction
is stirred at about 20-100.degree. C. (preferably ambient
temperature to about 65.degree. C.) for about 1-24 h (preferably
about 1-6 h). In any case where an additional acid labile group is
present (for example, a t-butyl ester), this group may also be
cleaved during the reaction. Optionally, additional TFA, HCl, or
H.sub.3PO.sub.4 may be added to the reaction mixture in cases where
the reaction does not proceed to completion as monitored by TLC,
LC/MS, or HPLC. Once the reaction has proceeded to an acceptable
level, the reaction mixture can be concd in vacuo to provide the
amine as a salt. Alternatively, the reaction may be cooled to about
-10-25.degree. C. before the addition of an aqueous base (such as
saturated aqueous NaHCO.sub.3, saturated aqueous Na.sub.2CO.sub.3,
or aqueous K.sub.3PO.sub.4, preferably aqueous K.sub.3PO.sub.4) and
optionally partitioned between an organic solvent (such as EtOAc,
DCM, THF, or 1,4-dioxane). The aqueous layer can be optionally
extracted with additional organic solvent such as EtOAc or DCM. The
combined organic layers may optionally be washed with brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, then decanted or
filtered, prior to concentrating under reduced pressure to give the
target compound.
Preparation #E.1.1 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine
##STR00513##
[1398] To a solution of tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.35 g, 31.8 mmol,
Example #3 Step E) in THF (35 mL) was added H.sub.3PO.sub.4 (20.16
mL, 350 mmol). The reaction mixture was heated to about 65.degree.
C. After about 90 min, the reaction mixture was cooled to about
0.degree. C. and a solution of K.sub.3PO.sub.4 (29.0 mL, 350 mmol)
in water (100 mL) was added. A white precipitate was removed by
filtration. The organic layer was separated, dried over anhydrous
MgSO.sub.4, and concd in vacuo to provide crude
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (8.58 g, 94%) as a tan
solid: LC/MS (Table 1, Method a) R.sub.t=1.85 min; MS m/z: 289
(M+H).sup.+.
[1399] General Procedure F: Deprotection of a Cbz Protected Amine
Using HBr in AcOH
[1400] To a Cbz protected amine (preferably 1 equiv) is added HBr
in AcOH (40-400 equiv, preferably 70-90 equiv of 33% HBr in AcOH)
at about 0.degree. C. to 40.degree. C. (preferably at ambient
temperature) and the mixture is stirred at this temperature for
about 5-45 min (preferably about 10 min). The precipitate is
collected by filtration and extensively washed with an organic
solvent such as Et.sub.2O, EtOAc, 1,4-dioxane, THF or MeCN
(preferably EtOAc or MeCN) to yield the target compound.
Illustration of General Procedure F
Preparation #F.1:
4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-amin-
e hydrobromide
##STR00514##
[1402] Benzyl
4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-ylca-
rbamate (0.22 g, 0.529 mmol, prepared using Z from Preparation #N.1
and NaOH, R with diazomethane, S from Example #3, Step E, T with
Lawesson's reagent and D with NaOH) was dissolved in HBr (33% in
AcOH, 10 mL) and the mixture was stirred for about 10 min at
ambient temperature. The reaction was then diluted with EtOAc (30
mL) and the precipitate was collected by filtration, extensively
washed with MeCN and dried to yield
4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)bicyclo[2.2.2]octan-1-amin-
e hydrobromide (0.16 g, 83%) as a yellow solid: LC/MS (Table 1,
Method a) R.sub.t=1.67 min; MS m/z 282 (M+H).sup.+.
TABLE-US-00009 TABLE F.1 Examples prepared using General Procedure
F with HBr in AcOH Rt min (Table 1, m/z ESI+ Cbz-protected Amine
Product Ex # Method) (M + H).sup.+ benzyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclohexylcarbamate (prepared using N
from (cis)-4- aminocyclohexanecarboxylic acid with benzyl
2,5-dioxopyrrolidin-1-yl carbonate and Na.sub.2CO.sub.3, R with
(trimethylsilyl)diazomethane, S with Example#3 Step E, E with HCl,
T with Lawesson's reagent, D with NaOH) ##STR00515## F.1.1 0.69 (a)
256 benzyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclohexylcarbamate (prepared using N from (cis)-4-
aminoyclohexanecarboxylic acid with benzyl 2,5-dioxopyrrolidin-1-yl
carbonate and Na.sub.2CO.sub.3, R with
(trimethylsilyl)diazomethane, S with Exainple#3 Step E, E with HCl,
T with Lawesson's reagent, D with NaOH) ##STR00516## F1.2 2.77 (r)
256 benzyl 3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)pyrrolidine-1-carboxylate (prepared using R from 1-
(benzyloxycarbonyl)pyrrolidine-3- carboxylie acid (Astatech), S
from Example #3 Step E, E with TFA, KKKK with PFPAA) ##STR00517##
F.1.3 2.83 (r) 228 benzyl 4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine- 1-carboxylate (prepared
using R from 1- (benzyloxycarbonyl)piperidine-4- carboxylic acid
(Matrix), S from Example #3 Step E, E with TFA, KKKK with PFPAA)
##STR00518## F.1.4 2.82 (r) 242
[1403] General Procedure F.1: Deprotection of a Cbz Protected Amine
Using HBr in AcOH
[1404] To a Cbz protected amine (preferably 1 equiv) is added HBr
in acetic acid (5-400 equiv, 33% HBr in AcOH) at about 0.degree. C.
to 40.degree. C. (preferably at ambient temperature) and the
mixture is stirred at this temperature for about 0.5-5 h
(preferably about 1 h). The reaction is worked up using one of the
following methods. Method 1: The precipitate is collected by
filtration and extensively washed with an organic solvent such as
Et.sub.2O, EtOAc, 1,4-dioxane, THF or MeCN (preferably EtOAc or
MeCN) to yield the target compound. Method 2: The reaction mixture
is diluted with water and a suitable organic solvent (such as
Et.sub.2O). The layers are stirred for short period and the organic
layer is decanted. This is repeated (3-10.times.) and the organic
layer is discarded. The aqueous layer is basified with an aqueous
base (such as saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2CO.sub.3, preferably saturated aqueous NaHCO.sub.3) and
extracted with a suitable organic solvent (such as EtOAc, DCM or
Et.sub.2O). The combined organic layers may optionally be washed
with brine and coned in vacuo or dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4 and then decanted or filtered prior
to concentrating under reduced pressure to give the target
compound.
Illustration of General Procedure F.1
Preparation #F.1.1:
8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]p-
yrazine
##STR00519##
[1406] To a solution of (cis)-benzyl
3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-
e-1-carboxylate (0.838 g, 1.541 mmol, prepared using E from Example
#36 Step D with TFA, N, R, S.1 with Example #3 Step E, and T with
Lawesson's reagent) was added a solution of HBr (2.50 mL, 15.19
mmol, 33% in acetic acid). The reaction mixture was stirred at
ambient temperature for about 1 h. The reaction was diluted with
Et.sub.2O (50 mL) and water (20 mL). The layers were stirred for
about 3 min and the organic layer was decanted then the procedure
was repeated 5 times. The aqueous layer was cooled to about
0.degree. C. was basified with saturated aqueous NaHCO.sub.3
solution (10 mL) to about pH 7. The aqueous layer was extracted
with EtOAc (3.times.50 mL), combined, and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concd to give a brown solid. The
solid was dissolved in DCM (50 mL) and washed with water
(3.times.20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concd to afford
8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]p-
yrazine (0.453, 61%) as a brown residue: LC/MS (Table 1, Method a)
R.sub.t=1.73 min; MS m/z: 410 (M+H).sup.+.
[1407] General Procedure G: Formation of an Acetamide
[1408] To a solution of amine (preferably 1 equiv) in pyridine
(5-25 equiv, preferably 10 equiv) at about 0-25.degree. C.
(preferably about 0.degree. C.) is added Ac.sub.2O (2-10 equiv,
preferably 5 equiv). If the reaction is cooled, stirring is
continued at the lower temperature for about 5-30 min (preferably
10-15 min) and then warmed to ambient temperature. After about 1-24
h (preferably 2-16 h), the reaction is concd under reduced pressure
and partitioned between an organic solvent such as EtOAc or DCM
(preferably EtOAc) and aqueous acid such as aqueous HCl (1-6 N,
preferably 1 N). The layers are separated and the organic layer is
optionally washed with aqueous acid such as aqueous HCl (1-6 N,
preferably 1 N), aqueous base such as aqueous NaHCO.sub.3 or
aqueous Na.sub.2CO.sub.3 (preferably saturated aqueous
NaHCO.sub.3), and brine. The organic layer is then dried over
anhydrous MgSO.sub.4, filtered through a pad of Florisil.RTM. while
washing with additional organic solvent such as EtOAc or DCM
(preferably EtOAc), and concd under reduced pressure.
Illustration of General Procedure G
Preparation #G.1*: (1S,2R,4S)-ethyl
4-acetamido-2-ethylcyclopentanecarboxylate
##STR00520##
[1410] A solution of ethyl 4-amino-2-ethylcyclopentanecarboxylate
(49.0 g, 264 mmol, Example #8, Step I) in pyridine (214 mL, 2645
mmol) was cooled to about 0.degree. C. Ac.sub.2O (125 mL, 1322
mmol) was added and stirring was continued at about 0.degree. C.
for about 15 min. The resulting solution was warmed to ambient
temperature and stirred for about 12 h. The reaction was concd
under reduced pressure and EtOAc (500 mL) and aqueous HCl (1 N, 200
mL) were added. The layers were separated and the organic layer was
washed with aqueous HCl (1 N, 200 mL), saturated aqueous
NaHCO.sub.3 (2.times.200 mL) and brine (150 mL), dried over
anhydrous MgSO.sub.4, filtered through a pad of Florisil.RTM. while
washing with EtOAc (600 mL), and concd under reduced pressure to
give an off-white solid (52 g) that was purified by using General
Procedure AA (Table 2, Method 24, R.sub.t=8.2 min, or =positive) to
give (1S,2R,4S)-ethyl 4-acetamido-2-ethylcyclopentanecarboxylate
(20.3 g, 34%): LC/MS (Table 1, Method a) R.sub.t=1.82 min; MS m/z:
228 (M+H).sup.+.
TABLE-US-00010 TABLE G.1 Examples prepared using General Procedure
G R.sub.t min (Table 1, m/z ESI+ Amine Product Ex. # Method) (M +
H).sup.+ N-((3R,5R)-5-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-3-
yl)cyclopropanesulfonamide (prepared using K from
(2R,4R)-1-tert-butyl-4- aminopyrrolidine-1,2-dicarboxylate
hydrochloric acid (Acesys Pharmatech Corp) and
cylcopropylsulfonylchloride, TEA, Z with NaOH, A with HATU and TEA,
B with SOCl.sub.2 and TEA, E with HCl. ##STR00521## G.1.1* 1.13
390
[1411] General Procedure H: Formation of an Amide from a Carboxylic
Acid and an Amine
[1412] To a solution or suspension of a carboxylic acid (1-5 equiv,
preferably 1.0 equiv) and an amine or an amine salt (1-5 equiv,
preferably 1 equiv) in an organic solvent (such as DCM, DCE, THF,
or 1,4-dioxane, preferably DCM) is added a peptide coupling reagent
(such as BOP-Cl, IBCF, HATU, or EDC.HCl, preferably HATU, 1-10
equiv, preferably 1-1.5 equiv), a base (such as TEA, DIEA, or
pyridine, preferably DIEA, 0-20 equiv, preferably 3 equiv). The
reaction mixture is then stirred at ambient temperature for about
15 min to 24 h (preferably about 45 min-16 h). The reaction mixture
is then worked up using one of the following methods. Method 1: The
reaction mixture is diluted with water or saturated aqueous
NaHCO.sub.3. The layers are separated. The aqueous layer is
optionally extracted with additional organic solvent such as EtOAc
or DCM. The organic layer is (or combined layers are) optionally
washed with water, saturated aqueous NaHCO.sub.3 and/or brine,
dried over anhydrous MgSO.sub.4 or Na.sub.2SO.sub.4, filtered or
decanted, and concd under reduced pressure. Method 2: The crude
reaction mixture is filtered through a pad of silica gel, washing
with a suitable solvent (such as EtOAc, MeOH, or DCM, preferably
MeOH), and concd under reduced pressure. Method 3: The crude
reaction mixture is directly purified by chromatography without a
work up.
Illustration of General Procedure H
Preparation #H.1*: (3R,4R)-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperi-
dine-1-carboxylate
##STR00522##
[1414] To a slurry of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(34.0 g, 100 mmol, Example #5, Step C),
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid (24.43 g, 100 mmol, Example #5, Step F) and HATU (38.2 g, 100
mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The
reaction was stirred at ambient temperature for about 45 min. The
reaction was washed with saturated aqueous NaHCO.sub.3 (300 mL).
The organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd in vacuo. The resulting
residue was purified by chromatography on silica gel (330 g) using
33-100% EtOAc in heptanes to give
(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)met-
hylcarbamoyl)-piperidine-1-carboxylate (53 g, 96%) as a pale-yellow
foam: LC/MS (Table 1, Method b) R.sub.t=2.40 min; MS m/z: 528
(M+H).sup.+.
TABLE-US-00011 TABLE H.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (Example #5, Step J) using General Procedure H with
EDC.cndot.HCl and DIEA R.sub.t min Example (Table 1, m/z ESI+
Carboxylic Acid Product # Method) (M + H).sup.+ 4,4-
difluorocyclohexane- carboxylic acid ##STR00523## H.1.1* 1.82 (b)
402 3,3,3-trifluoropropanoic acid ##STR00524## H.1.2* 1.68 (b) 366
3-hydroxy-3- methylbutanoic acid (Fluka) ##STR00525## H.1.3* 1.49
(b) 356 2-methoxyacetic acid ##STR00526## H.1.4* 1.39 (b) 328
3-methoxypropanoic acid ##STR00527## H.1.5* 1.44 (b) 342
pent-4-ynoic acid (Fluka) ##STR00528## H.1.6* 1.59 (b) 336
2-(4-chlorophenyl)acetic acid ##STR00529## H.1.7* 1.90 (b) 408
2-(3-chlorophenyl)acetic acid ##STR00530## H.1.8* 1.91 (b) 408
4-cyanobenzoic acid ##STR00531## H.1.9* 1.68 (b) 385
3-(3-chloroisoxazol-5- yl)propanoic acid (Matrix) ##STR00532##
H.1.10* 1.78 (b) 413 2-(3-cyanophenyl)acetic acid ##STR00533##
H.1.11* 1.71 (b) 399 2-(4-cyanophenyl)acetic acid ##STR00534##
H.1.12* 1.70 (b) 399 2-(1H-pyrrol-2-yl)acetic acid (Tyger)
##STR00535## H.1.13* 1.62 (b) 363 2-(pyrazin-2-yl)acetic acid
(Astatech) ##STR00536## H.1.14* 1.37 (b) 376
2-(tetrahydro-2H-pyran-4- yl)acetic acid (Astatech) ##STR00537##
H.1.15* 1.49 (b) 382 2-(pyrimidin-2-yl)acetic acid (Caymen
Chemical) ##STR00538## H.1.16* 1.56 (b) 376 3-acetamidopropanoic
acid ##STR00539## H.1.17* 1.29 (b) 369 tetrahydrofuran-2-
carboxylic acid ##STR00540## H.1.18* 1.45 (b) 354
tetrahydrofuran-3- carboxylic acid ##STR00541## H.1.19* 1.43 (b)
354 3-methoxycyclo- hexanecarboxylic acid ##STR00542## H.1.20*
1.62, 1.69 (b) 396 ##STR00543## 3,3- difluoro-
cyclobutanecarboxylic acid (Waterstone) ##STR00544## H.1.21* 1.75
(b) 374 4,4,4-trifluorobutanoic acid (Matrix) ##STR00545## H.1.22*
1.78 (b) 380 tetrahydro-2H-pyran-4- carboxylic acid (Matrix)
##STR00546## H.1.23* 1.75 (b) 368 tetrahydro-2H-pyran-3- carboxylic
acid (Chem Impex) ##STR00547## H.1.24* 1.74 (b) 368
3-cyanopropanoic acid (Tyger) ##STR00548## H.1.25* 1.65 (b) 337
tetrahydro-2H-pyran-2- carboxylic acid (Acella Chembio Co.)
##STR00549## H.1.26* 1.76 (b) 368 3-(methyl- sulfonyl)propanoic
acid (Enamine) ##STR00550## H.1.27* 1.36 (b) 390
1,4-dioxane-2-carboxylic acid (Enamine) ##STR00551## H.1.28* 1.41
(b) 370 tetrahydrothiophene-3- carboxylic acid-1,1- dioxide
##STR00552## H.1.29* 1.41 (b) 402 1-methylpyrrolidine-3- carboxylic
acid (Chembridge) ##STR00553## H.1.30* 1.18 (b) 367
1-methylpiperidine-4- carboxylic acid (Astatech) ##STR00554##
H.1.31* 1.19 (b) 381
TABLE-US-00012 TABLE H.2 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride
(prepared using A from Example #1, Step D and Example #5, Step F,
HATU and DIEA; B with DIEA; D with NaOH; E with HCl) using General
Procedure H with EDC.cndot.HCl and DIEA R.sub.t min Carboxylic
Example (Table 1, m/z ESI+ Acid Product # Method) (M + H).sup.+
2-cyanoacetic acid ##STR00555## H.2.1* 1.23 (b) 324
TABLE-US-00013 TABLE H.3 Examples prepared from
1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (prepared using D from Preparation #Q.1 with NaOH,
and E with 4 N HCl in 1,4-dioxane) using General Procedure H with
HATU and DIEA R.sub.t min Example (Table 1, m/z ESI+ Carboxylic
Acid Product # Method) (M + H).sup.+ 2,4-difluorobenzoic acid
##STR00556## H.3.1 1.79 (b) 396 4-(trifluoromethyl) benzoic acid
##STR00557## H.3.2 1.96 (b) 428 nicotinic acid ##STR00558## H.3.3
1.41 (b) 361 3-(trifluoromethyl) benzoic acid ##STR00559## H.3.4
1.97 (b) 428 pyrazine-2- carboxylic acid ##STR00560## H.3.5 1.40
(b) 362 pyrimidine-5- carboxylic acid [Frontier Scientific]
##STR00561## H.3.6 1.37 (b) 362 2-cyclopropylacetic acid
[Lancaster] ##STR00562## H.3.7 1.62 (b) 338 benzoic acid
##STR00563## H.3.8 1.69 (b) 360 2-cyclobutylacetic acid [Beta
Pharmaceuticals] ##STR00564## H.3.9 1.78 (b) 352 3-cyclo-
butylpropanoic acid [ChemBridge] ##STR00565## H.3.10 1.91 (b) 366
1H-pyrazole-4- carboxylic acid ##STR00566## H.3.11 1.32 (b) 350
1H-pyrazole-3- carboxylic acid [Oakwood] ##STR00567## H.3.12 1.34
(b) 350 propionic acid ##STR00568## H.3.13 1.49 (b) 312
1-cyanocyclo- propane carboxylic acid ##STR00569## H.3.14 1.60 (b)
349 1-methyl-1H- pyrazole-4- carboxylic acid ##STR00570## H.3.15
1.37 (b) 364 isonicotinic acid ##STR00571## H.3.16 1.44 (b) 361
2-(3-methylisoxazol- 5-yl)acetic acid ##STR00572## H.3.17 1.52 (b)
379 2-(2,4-difluoro- phenyl)acetic acid ##STR00573## H.3.18 1.84
(b) 410 isoxazole-5- carboxylic acid ##STR00574## H.3.19 1.52 (b)
351
TABLE-US-00014 TABLE H.4 Examples prepared from
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (Example #6, Step H) using General Procedure H with
EDC.cndot.HCl and DIEA R.sub.t min Example (Table 1, m/z ESI+
Carboxylic Acid Product # Method) (M + H).sup.+ 3,3-
difluorocyclobutane- carboxylic acid (Waterstone) ##STR00575##
H.4.1* 1.86 (b) 360
TABLE-US-00015 TABLE H.5 Examples prepared from cyclopropanamine
(Aldrich) using General Procedure H with HATU and TEA R.sub.t min
Example (Table 2, m/z ESI+ Carboxylic Acid Product # Method) (M +
H).sup.+ 2-((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-
e][1,2,4]triazolo[4,3- a]pyrazin-1- yl)cyclopentyl)acetic acid
(Example W.1.2) ##STR00576## H.5.1 1.45 353
[1415] General Procedure I: Formation of a Urea from an Amine and a
Carbamoyl Chloride
[1416] To a flask containing an amine or an amine salt (1 equiv) in
an organic solvent (such as THF or 1,4-dioxane, preferably THF) is
added a base (such as DIEA or TEA, preferably TEA [3-5 equiv,
preferably 4 equiv]) and stirred at ambient temperature for about
0-30 min (preferably about 5 min) then added a carbamoyl chloride
(0.5-2 equiv, preferably 0.75 equiv). The mixture is stirred at
about 0-90.degree. C. (preferably about 45.degree. C.) for about
2-24 h (preferably about 18 h). The reaction mixture is allowed to
reach ambient temperature. The organic solvent is optionally
removed under reduced pressure. The crude material can be
partitioned between an organic solvent (such as EtOAc or DCM) and
water, an aqueous base (such as saturated aqueous NaHCO.sub.3) or
brine. The layers are separated and the organic layer is optionally
washed with water, an aqueous base (such as saturated aqueous
NaHCO.sub.3) or brine, dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, filtered, and coned under reduced pressure to give the
target compound.
Illustration of General Procedure I
Example #I.1.1*
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-
-1-yl)(piperidin-1-yl)methanone
##STR00577##
[1418] A round bottom flask was charged with
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (0.050 g, 0.17 mmol, Example #5, Step J), TEA (0.10
mL, 0.69 mmol) in THF (1.6 mL). The reaction mixture was stirred
for about 5 min at ambient temperature and then
piperidine-1-carbonyl chloride (0.019 g, 0.13 mmol) was added. The
reaction was heated at about 45.degree. C. for about 18 h, cooled
to ambient temperature, and concd under reduced pressure. The crude
product was dissolved in DCM (5 mL) and washed with water (3 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The material was purified by RP-HPLC (Table 1, Method f)
to give
((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidi-
n-1-yl)(piperidin-1-yl)methanone (0.018 g, 8%): LC/MS (Table 1,
Method b) R.sub.t=1.80 min; MS m/z 367 (M+H).sup.+.
TABLE-US-00016 TABLE I.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-
e]pyrazine hydrochloride (Example #5, Step J) using General
Procedure I with TEA R.sub.t min Example (Table 1, m/z ESI+
Carbamoyl chloride Product # Method) (M + H).sup.+
morpholine-4-carbonyl chloride ##STR00578## I.1.2* 1.48 (b) 369
4-methyl-1- piperazinecarbonyl chloride hydrochloride ##STR00579##
I.1.3* 1.22 (b) 382
TABLE-US-00017 TABLE I.2 Examples prepared from
1-(cis-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (prepared using D from Preparation #Q.1 with NaOH,
and E with 4 N HCl in 1,4-dioxane) using General Procedure I with
TEA R.sub.t min Example (Table 1, m/z ESI+ Carbamoyl chloride
Product # Method) (M + H).sup.+ 1-pyrrolidine- carbonyl chloride
##STR00580## I.2.1 1.63 (b) 353 dimethylcarbamoyl chloride
##STR00581## I.2.2 1.52 (b) 327
TABLE-US-00018 TABLE I.3 Example prepared from
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazine
hydrochloride (Example #6, Step H) using General Procedure I with
TEA R.sub.t min Example (Table 1, m/z ESI+ Carbamoyl chloride
Product # Method) (M + H).sup.+ 1-pyrrolidine- carbonyl chloride
##STR00582## I.3.1* 1.53 (b) 339
[1419] General Procedure J: Formation of a Urea or a Thiourea Using
CDI or Thiocarbonyldiimidazole, Respectively
[1420] To a solution or slurry of an amine or amine salt (1-3
equiv, preferably 1 equiv) in an organic solvent such as DCM, THF,
or DMF (preferably DCM) at about -20-40.degree. C. (preferably
about 0.degree. C.) is added an organic base, such as TEA, DIEA,
pyridine (preferably TEA) (1-10 equiv, preferably 1-3 equiv)
followed by CDI or 1,1'-thiocarbonyldiimidazole (0.5-2 equiv,
preferably 1 equiv). After about 0.5-24 h (preferably about 0.5-1
h), a second amine or amine salt (1-10 equiv, preferably 3 equiv)
is added neat or as a solution or slurry in an organic solvent such
as DCM, THF, or DMF (preferably DCM). The reaction is held at about
0.degree. C. for about 10-60 min (preferably about 15-30 min) and
then the reaction is allowed to warm to ambient temperature. After
about 1-48 h (preferably about 12-16 h), the reaction mixture is
partitioned between an organic solvent (such as EtOAc, DCM or
1,4-dioxane) and an aqueous base (such as saturated aqueous
NaHCO.sub.3 or saturated aqueous Na.sub.2CO.sub.3, preferably
saturated aqueous NaHCO.sub.3). Optionally, the reaction mixture is
concd under reduced pressure and the residue is partitioned as
above. In either case, the aqueous layer is then optionally
extracted with additional organic solvent such as EtOAc or DCM. The
combined organic layers may optionally be washed with brine and
concd in vacuo or dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4 and then decanted or filtered prior to concentrating
under reduced pressure to give the target compound. Intermediates
and final compounds prepared via this General Procedure can be
optionally purified using one or more of the Purification Methods
described above.
Preparation #J.1: tert-butyl
1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pyrrolidin--
3-ylcarbamate
##STR00583##
[1422] To a slurry of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(0.50 g, 1.5 mmol, Example #5, Step C) in DCM (10 mL) at about
0.degree. C. was added TEA (0.226 mL, 1.62 mmol). To the
homogeneous reaction mixture was added a solution of
1,1'-thiocarbonyldiimidazole (0.29 g, 1.6 mmol) in DCM (10 mL).
After about 30 min, a slurry of tert-butyl pyrrolidin-3-ylcarbamate
(0.83 g, 4.4 mmol, TCI) in DCM (10 mL) was added to the reaction
mixture. After stirring for about 20 min, the reaction mixture was
allowed to warm to ambient temperature. After stirring for about 15
h, saturated aqueous NaHCO.sub.3 (30 mL) was added to the reaction
mixture. The organic layer was separated, concd in vacuo, and
purified by chromatography on silica gel eluting with 20-40% EtOAc
in DCM to provide tert-butyl
1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pyrrolidin--
3-ylcarbamate (0.54 g, 69%) as a yellow glass: LC/MS (Table 1,
Method a) R.sub.t=2.37 min; MS m/z: 531 (M+H).sup.+.
[1423] General Procedure J.1: Formation of a Urea or a Thiourea
Using CDI or Thiocarbonyldiimidazole, Respectively
[1424] To a solution or slurry of an amine or amine salt (1-3
equiv, preferably 1-2 equiv) in an organic solvent such as DCM,
THF, or DMF (preferably DMF) at about 20-80.degree. C. (preferably
about 65.degree. C.) is optionally added an organic base, such as
TEA, DIEA, pyridine (preferably TEA) (1-10 equiv, preferably 1-5
equiv) followed by CDI or 1,1'-thiocarbonyldiimidazole (0.5-2
equiv, preferably 1 equiv). After about 0.5-24 h (preferably about
1-3 h), a second amine or amine salt (1-10 equiv, preferably 1-3
equiv) is added neat or as a solution or slurry in an organic
solvent such as DCM, THF, or DMF (preferably DMF). The reaction is
held at about 20-80.degree. C. (preferably about 65.degree. C.) for
about 2-24 h (preferably about 3 h). If the reaction mixture is
heated, it is cooled to ambient temperature. The reaction mixture
is partitioned between an organic solvent (such as EtOAc, DCM or
1,4-dioxane) and an aqueous base (such as saturated aqueous
NaHCO.sub.3 or saturated aqueous Na.sub.2CO.sub.3, preferably
saturated aqueous NaHCO.sub.3). Optionally, the reaction mixture is
concd under reduced pressure and the residue is partitioned as
above. In either case, the aqueous layer is then optionally
extracted with additional organic solvent such as EtOAc or DCM. The
combined organic layers may optionally be washed with brine and
concd in vacuo or dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4 and then decanted or filtered prior to concentrating
under reduced pressure to give the target compound. Optionally, the
reaction mixture is concd under reduced pressure and the residue is
directly purified.
Illustration of General Procedure J.1
Preparation #J.1.1:
(cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide
##STR00584##
[1426] To a solution of 2-cyclopropylethanamine (0.068 g, 0.804
mmol, Oakwood) in DMF (3 mL) was added CDI (0.150 g, 0.926 mmol).
The solution was stirred at about 65.degree. C. for about 2 h.
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazine (0.250 g, 0.609 mmol, Example #36, step F) was
added and the reaction mixture continued heating at about
65.degree. C. After about 2 h, the reaction mixture was cooled to
ambient temperature. The solvent was removed under reduced
pressure. The crude material was purified by chromatography on
silica gel eluting with a gradient of 0-10% MeOH in DCM to give
(cis)-N-(2-cyclopropylethyl)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e]-
[1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidine-1-carboxamide (0.238
g, 64%) as product: LC/MS (Table 1, Method a) R.sub.t=2.17 min; MS
m/z: 522 (M+H).sup.+.
TABLE-US-00019 TABLE J.1 Examples prepared from
1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (prepared using D from Preparation #Q.1 with NaOH,
and E with 4 N HCl in 1,4-dioxane) using General Procedure J with
CDI R.sub.t min Amine or Amine Example (Table 1, m/z ESI+
hydrochloride Product # Method) (M + H).sup.+ azetidine-3-
carbonitrile hydrochloride [AstaTech Inc] ##STR00585## J.1.1 1.48
(b) 364 2-aminoacetonitrile ##STR00586## J.1.2 1.37 (b) 338
TABLE-US-00020 TABLE J.2 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-
e]pyrazine hydrochloride (Example #5, Step J) using General
Procedure J with CDI R.sub.t min Amine or Amine Example (Table 1,
m/z ESI+ hydrochloride Product # Method) (M + H).sup.+
pyrrolidine-3- carbonitrile hydrochloride [Tyger] ##STR00587##
J.2.1* 1.51 (b) 378 (R)-pyrrolidine-2- carbonitrile hydrochloride
[AstaTech Inc] ##STR00588## J.2.2* 1.61 (b) 378 (S)-pyrrolidine-2-
carbonitrile hydrochloride [AstaTech Inc] ##STR00589## J.2.3* 1.63
(b) 378 (S)-2-(trifluoro- methyl)pyrrolidine ##STR00590## J.2.4*
1.99 (b) 421 3,3-difluoroazetidine hydrochloride ##STR00591##
J.2.5* 1.71 (b) 375 azetidine ##STR00592## J.2.6* 1.51 (b) 339
(R)-3-fluoropyrrolidine hydrochloride ##STR00593## J.2.7* 1.59 (b)
371 3,3-difluoropyrrolidine hydrochloride ##STR00594## J.2.8* 1.71
(b) 389 (R)-pyrrolidin-2- ylmethanol ##STR00595## J.2.9* 1.45 (b)
383 3-methylpyrrolidine [Tyger] ##STR00596## J.2.10* 1.75 (b) 367
3-fluoroazetidine hydrochloride [Parkway Scientific] ##STR00597##
J.2.11* 1.53 (b) 357 (S)-3-fluoropyrrolidine hydrochloride
##STR00598## J.2.12* 1.56 (b) 371 (R)-2- methylpyrrolidine
##STR00599## J.2.13* 1.74 (b) 367 hexamethyleneimine ##STR00600##
J.2.14* 1.87 (b) 381 (R)-2-(trifluoro- methyl)pyrrolidine
##STR00601## J.2.15* 2.03 (b) 421
TABLE-US-00021 TABLE J.3 Examples prepared from
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (Example #6, Step H) using General Procedure J with
CDI and pyridine R.sub.t min Amine or Amine Example (Table 1, m/z
ESI+ hydrochloride Product # Method) (M + H).sup.+
3,3-difluoroazetidine hydrochloride ##STR00602## J.3.1* 1.56 (b)
361 3,3-difluoropyrrolidine hydrochloride ##STR00603## J.3.2* 1.60
(b) 375 piperidine-3-carbonitrile [ChemBridge-BB] ##STR00604##
J.3.3* 1.55 (b) 378 azetidine-3-carbonitrile hydrochloride
[AstaTech Inc] ##STR00605## J.3.4* 1.36 (b) 350 (R)-2-(trifluoro-
methyl)pyrrolidine ##STR00606## J.3.5* 1.76 (b) 407
3,3-dimethylpyrrolidine hydrochloride [Matrix Scientific]
##STR00607## J.3.6* 1.75 (b) 367 3,3-difluoropiperidine
hydrochloride ##STR00608## J.3.7* 1.71 (b) 389
piperidine-4-carbonitrile [Oakwood] ##STR00609## J.3.8* 1.48 (b)
378 thiomorpholine 1,1- dioxide [TCI-Europe] ##STR00610## J.3.9 *
1.31 (b) 403 4,4-dimethylpiperidine hydrochloride [Matrix
Scientific] ##STR00611## J.3.10* 1.93 (b) 381 4-chloropiperidine
hydrochloride [AstaTech Inc] ##STR00612## J.3.11* 1.72 (b) 387
TABLE-US-00022 TABLE J.4 Examples prepared from
1-((3R,4S)-4-isopropylpyrrolidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4-
,3- a]pyrazine (prepared using Y from Example #D.1.143) using
General Procedure J with CDI R.sub.t min Amine or Amine Example
(Table 1, m/z ESI+ hydrochloride Product # Method) (M + H).sup.+
Cyclobutanamine (Aldrich) ##STR00613## J.4.1 1.58 (a) 368
##STR00614##
[1427] General Procedure K: Formation of a Sulfonamide from an
Amine
[1428] To a mixture of an amine or an amine salt (preferably 1
equiv) in an organic solvent such as THF, DMA, DCM or DMF
(preferably DMF) is added an organic base such as TEA or DIEA (1-10
equiv, preferably 2-4 equiv) or an aqueous base such as saturated
aqueous NaHCO.sub.3 (5-20 equiv, preferably 5-10 equiv) (preferably
an organic base) and a sulfonyl chloride (0.9-3 equiv, preferably
1-1.5 equiv). The reaction mixture is stirred at about
-10-25.degree. C. (preferably at ambient temperature) for about
0.5-150 h (preferably about 144 h). Optionally, additional base
(1-10 equiv) and/or sulfonyl chloride (0.4-2 equiv) may be added at
any point during the reaction time. The reaction is worked up using
one of the following methods. Method 1: The reaction is diluted
with water and extracted with an organic solvent such as DCM or
EtOAc. The combined organic layers are optionally washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered or decanted, and coned under reduced pressure. Method 2:
The crude reaction mixture is purified by preparative HPLC directly
or after the addition of organic solvent such as MeOH or DMF or an
aqueous buffer such as 50 mM NH.sub.4OAc with or without
concentrating the mixture under reduced pressure first. Method 3:
The solvent is removed under reduced pressure and the residue is
partitioned between an organic solvent such as DCM or EtOAc
(preferably EtOAc) and water. The layers are separated and the
organic layer is optionally washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or decanted, and concd
under reduced pressure. Method 4: The reaction is diluted with
water and the resulting solid is collected by vacuum
filtration.
Illustration of General Procedure K
Example #K.1
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentyl)-3,3,3-trifluoropropane-1-sulfonamide
##STR00615##
[1430] 3,3,3-Trifluoropropane-1-sulfonyl chloride (0.194 g, 0.987
mmol, Matrix) was added dropwise to a solution of TEA (0.31 mL, 2.2
mmol) and
3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine
(0.28 g, 1.1 mmol, Preparation #53) in DMF (10 mL). The resulting
mixture was stirred at ambient temperature for about 144 h. The
solvent was removed under reduced pressure and the residue was
partitioned between EtOAc and water (20 mL each). The layers are
separated and the organic layer was washed with brine (30 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The residue was purified by using General Procedure AA
(Table 2, Method 9, R.sub.t=17.7 min, or =negative) to give
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3,3,3-trifluoropropane-1-sulfonamide (0.021 g, 4.6%) as a
white solid: LC/MS (Table 1, Method a) R.sub.t=1.79 min; MS m/z 416
(M+H).sup.+.
TABLE-US-00023 TABLE K.1 Examples prepared from
(1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentanamine (Preparation #19.1) using General
Procedure K R.sub.t min Example (Table 1, m/z ESI+ Sulfonyl
chloride Product # Method) (M + H).sup.+
5-methylisoxazole-4-sulfonyl chloride [Maybridge] ##STR00616##
K.1.1* 1.91 (a) 402
TABLE-US-00024 TABLE K.2 Example prepared from
1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine hydrochloride (prepared using D from
Preparation #Q.1 with NaOH, and E with 4 N HCl in 1,4-dioxane)
using General Procedure K R.sub.t min (Table 1, m/z ESI+ Sulfonyl
chloride Product Example # Method) (M + H).sup.+
cyclopropanesulfonyl chloride ##STR00617## K.2.1 1.66 (b) 360
##STR00618##
TABLE-US-00025 TABLE K.3 Examples prepared from
4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)bicyclo[2.2.2]octan-1-amine hydrobromide (Preparation #F.1)
using General Procedure K R.sub.t min (Table 1, m/z ESI+ Sulfonyl
chloride Product Example # Method) (M + H).sup.+
Cyclopropanesulfonyl chloride ##STR00619## K.3.1 1.59 (a) 386
TABLE-US-00026 TABLE K.4 Examples prepared from
(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a ]pyrrolo[2,3-e]
pyrazin-8-yl)pyrrolidin-3-amine (Preparation #TTT.1) using General
Procedure K R.sub.t min (Table 1, m/z ESI+ Sulfonyl chloride
Product Example # Method) (M + H).sup.+ 3,3,3-trifluoropropane-1-
sulfonyl chloride (Matrix) ##STR00620## K.4.1* 1.86 (a) 431
TABLE-US-00027 TABLE K.5 Examples prepared from
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (Prepared
from Example #8 Step M using D) using General Procedure K R.sub.t
min (Table 1, m/z ESI+ Sulfonyl chloride Product Example # Method)
(M + H).sup.+ 2,2,2-trifluoroethane-1- sulfonyl chloride
##STR00621## K.5.1 1.89 (a) 417
[1431] General Procedure K.1: Formation of a Sulfonamide from an
Amine or Nitrogen Containing Heterocycle (Additional
Conditions)
[1432] To a mixture of an amine, an amine salt or a nitrogen
containing heterocycle (preferably 1 equiv) in an organic solvent
such as THF, DMA, DCM or DMF (preferably DMF) is added an organic
base such as TEA or DIEA (1-10 equiv, preferably 2-4 equiv) or an
aqueous base such as saturated aqueous NaHCO.sub.3 (5-20 equiv,
preferably 5-10 equiv) or an inorganic base such as NaH (1-10
equiv, preferably 1-3 equiv) and a sulfonyl chloride (0.9-3 equiv,
preferably 1-1.5 equiv). The reaction mixture is stirred at about
-10-25.degree. C. (preferably at about 0.degree. C.) for about 5
min-150 h (preferably about 90 min). Optionally, additional base
(1-10 equiv) and/or sulfonyl chloride (0.4-2 equiv) may be added at
any point during the reaction time. In cases where a halogen is
present, the halogen may eliminate and the alkene may be obtained.
The reaction is worked up using one of the following methods.
Method 1: The reaction is diluted with water and extracted with an
organic solvent such as DCM or EtOAc. The combined organic layers
are optionally washed with saturated aqueous base and brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or
decanted, and concd under reduced pressure. Method 2: The crude
reaction mixture is purified by preparative HPLC directly or after
the addition of organic solvent such as MeOH or DMF or an aqueous
buffer such as 50 mM NH.sub.4OAc with or without concentrating the
mixture under reduced pressure first. Method 3: The solvent is
removed under reduced pressure and the residue is partitioned
between an organic solvent such as DCM or EtOAc (preferably EtOAc)
and water. The layers are separated and the organic layer is
optionally washed with brine, dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, filtered or decanted, and concd under reduced
pressure. Method 4: The reaction is diluted with water and the
resulting solid is collected by vacuum filtration.
Illustration of General Procedure K.1
Preparation #K.1:
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylami-
no)cyclopentyl)cyclopropanesulfonamide
##STR00622##
[1434] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclo-
pentyl)cyclopropanesulfonamide (Example #23, Step G) (0.123 g,
0.314 mmol) in DMF (3.0 mL) at about 0.degree. C. was added NaH
(60% in mineral oil, 0.015 g, 0.37 mmol). The reaction mixture was
stirred for about 5 min. 4-Methylbenzene-1-sulfonyl chloride (0.060
g, 0.314 mmol) was added and the reaction mixture was stirred for
about 30 min. NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was
added and the reaction mixture was stirred for about 10 min. NaH
(60% in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction
mixture was stirred for about 15 min. 4-Methylbenzene-1-sulfonyl
chloride (0.012 g, 0.063 mmol) was added and the reaction mixture
was stirred for about 40 min. The reaction mixture was concd under
reduced pressure. The residue was dissolved in EtOAc (25 mL) and
washed with water (15 mL). The organic layer was separated, dried
over anhydrous MgSO.sub.4, filtered and concd under reduced
pressure to give
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4--
ylamino)cyclopentyl)-cyclopropanesulfonamide (0.218 g) as a
red-orange oil containing 40 mol % DMF and 1 equiv EtOAc: LC/MS
(Table 1, Method n) R.sub.t=0.88 min; MS m/z 548 (M+H).sup.+.
[1435] General Procedure L: Displacement of an Aryl or Heteroaryl
Halide with an Amine
[1436] To a microwave vessel or a round bottom flask is added an
amine or an amine salt (preferably 1 equiv), an aryl or heteroaryl
halide (1-10 equiv, preferably 1.5 equiv), a solvent (such as MeCN,
n-PrOH, n-BuOH, toluene, DMSO, DMF, or EtOH, preferably
n-PrOH[microwave] or DMF [thermal heating]), and a base (such as
K.sub.2CO.sub.3, Na.sub.2CO.sub.3, TEA or DIEA, preferably TEA,
DIEA, or K.sub.2CO.sub.3, 1-5 equiv, preferably 2-4 equiv). The
reaction mixture is heated at about 40-220.degree. C. thermally
(preferably about 65.degree. C.) for about 0.5-16 h (preferably
about 8.5 h) or is subjected to microwave heating at about
100-200.degree. C. (preferably about 130-150.degree. C.) for about
0.5-8 h (preferably about 0.5-2 h). In cases where the reaction
does not proceed to completion as monitored by TLC, LC/MS, or HPLC,
the reaction may be resubjected to thermal heating at about
40-220.degree. C. (preferably about 65.degree. C.) for about 0.5-8
h (preferably about 1-2 h) or microwave heating at about
120-200.degree. C. (preferably about 130-150.degree. C.) for an
additional about 1-8 h (preferably about 0.5-2 h) with the optional
addition of more aryl or heteroaryl halide (1-10 equiv, preferably
1.5 equiv) and/or base (such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3,
TEA or DIEA, preferably TEA, DIEA or K.sub.2CO.sub.3, 1-5 equiv,
preferably 2-4 equiv). This process is repeated until the reaction
proceeds no further. After cooling to ambient temperature, the
reaction is worked up using one of the following methods. Method 1:
The reaction is concd under reduced pressure. Method 2: A reaction
mixture containing a precipitate may be filtered to collect the
target compound, while optionally washing with organic solvent or
solvents such as Et.sub.2O, DCM and/or petroleum ether. Method 3:
The reaction mixture is diluted with an organic solvent such as
MeOH, silica gel is added, and the mixture is concd under reduced
pressure to prepare for separation by chromatography with solid
loading. Method 4: The reaction mixture is concd under reduced
pressure prior to the addition of an organic solvent such as EtOAc
or DCM and is then optionally washed with water and/or brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or
decanted, and concd under reduced pressure. Method 5: An organic
solvent such as EtOAc or DCM is added with the optional addition of
water or brine and the layers are separated. The aqueous layer is
then optionally extracted with additional organic solvent such as
EtOAc or DCM. The combined organic layers are optionally washed
with brine or water, dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, filtered or decanted, and concd under reduced
pressure.
Illustration of General Procedure L
Preparation #L.1:
(S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)me-
thyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile
##STR00623##
[1438] A mixture of
(S)-1-(pyrrolidin-3-ylmethyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,-
3-a]pyrazine (0.160 g, 0.404 mmol, prepared using B from
Preparation #A.1 and E with HCl), 2-chloro-5-cyanopyrazine (0.084
g, 0.60 mmol, ArkPharm) and DIEA (0.28 mL, 1.6 mmol) in n-PrOH (2.0
mL) was heated in a CEM microwave at about 150.degree. C. for about
30 min (250 psi maximum pressure, 10 min maximum ramp, 200 maximum
watts). The reaction mixture was cooled to ambient temperature and
DCM (20 mL) was added. The solution was washed with water (20 mL)
and brine (20 mL). The organic layer was separated, dried over
anhydrous MgSO.sub.4, filtered, and coned under reduced pressure.
The residue was taken up in DCM (10 mL), adsorbed onto silica gel
(1 g), and purified by silica gel chromatography eluting with 100%
EtOAc to give a pink solid. The material was triturated with a
mixture of EtOAc (10 mL) and 10% MeOH in DCM (10 mL). The insoluble
material was collected by filtration to give
(S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)me-
thyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile as an off-white solid
(0.056 g, 27%): LC/MS (Table 1, Method c) R.sub.t=1.34 min; MS m/z:
500 (M+H).sup.+.
TABLE-US-00028 TABLE L.1 Examples prepared from
1-(cis)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine hydrochloride (prepared using D from
Preparation #Q.1 with NaOH, and E with 4N HCl in 1,4-dioxane) using
General Procedure L R.sub.t min m/z Example (Table 1, ESI+
Heteroaryl Halide Product # Method) (M + H).sup.+
6-chloropyridazine-3- carbonitrile [ArkPharm] ##STR00624## L.1.1
1.68 (b) 359 ##STR00625## 2-chloro-5- cyanopyrazine [ArkPharm]
##STR00626## L.1.2 1.81 (b) 359 ##STR00627##
6-chloronicotinonitrile ##STR00628## L.1.3 1.88 (b) 358
##STR00629## 2-chlorothiazole-5- carbonitrile [ArkPharm]
##STR00630## L.1.4 1.84 (b) 364 ##STR00631##
TABLE-US-00029 TABLE L.2 Example prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) using
General Procedure L R.sub.t min m/z Example (Table 1, ESI+
Heteroaryl Halide Product # Method) (M + H).sup.+
2-chlorobenzoxazole [TCI America] ##STR00632## L.2.1* 1.94 (b)
373
TABLE-US-00030 TABLE L.3 Examples prepared from
(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine
hydrobromide and
(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine
hydrobromide (Example #3, Step G) using General Procedure L R.sub.t
min m/z Example (Table 1, ESI+ Heteroaryl Halide Product # Method)
(M + H).sup.+ 2-chloro-5-cyanopyrazine [ArkPharm] ##STR00633##
L.3.1 1.71 (a) 345 ##STR00634##
[1439] General Procedure M: Boc-Protection of an Amine
[1440] To a solution of an amine or amine salt (preferably 1 equiv)
in an organic solvent (for example MeCN, 1,4-dioxane or THF,
preferably THF) is added an aqueous base such as Na.sub.2CO.sub.3,
NaOH, K.sub.2CO.sub.3 or NaHCO.sub.3 (2-20 equiv, preferably 2-10
equiv of Na.sub.2CO.sub.3) or an organic base such as TEA or DIEA
(1-5 equiv, preferably 1-2 equiv of TEA) followed by addition of
di-tert-butyl dicarbonate (1-3.0 equiv, preferably 1.2 equiv). The
addition of base is optional if an amine salt is not used. The
reaction is stirred at about 10-40.degree. C. (preferably ambient
temperature) for about 2-24 h (preferably about 2-6 h) and worked
up using one of the following methods. Method 1: An organic solvent
(such as Et.sub.2O, EtOAc or DCM) and water are added and the
layers are separated. The aqueous layer is extracted with
additional organic solvent and the combined organic layers may be
optionally washed with brine, dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, and then decanted or filtered prior to concentrating
under reduced pressure. Method 2: The reaction mixture is
partitioned between an organic solvent (such as Et.sub.2O, EtOAc or
DCM) and aqueous acid (such as HCl). The acidic layer is extracted
with additional organic solvent and the combined organic layers may
be optionally washed with brine. The organic layer is optionally
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, and then
decanted or filtered prior to concentrating under reduced
pressure.
Illustration of General Procedure M
Preparation #M.1*:
(1R,3S)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic
acid
##STR00635##
[1442] To a solution of
(1R,3S)-3-(aminomethyl)cyclopentanecarboxylic acid (0.500 g, 3.49
mmol, AFID) in THF (4 mL) and water (4 mL) was added
Na.sub.2CO.sub.3 (1.11 g, 10.5 mmol) and di-tert-butyl dicarbonate
(0.915 g, 4.19 mmol). The reaction was stirred at ambient
temperature for about 4 h.
[1443] EtOAc (15 mL) and aqueous HCl (1 N, 15 mL) were added and
the layers were separated. The aqueous layer was extracted with
EtOAc (2.times.10 mL) and the combined organic layers were washed
with brine (10 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and coned under reduced pressure to
give (1R,3S)-3-((tert-butoxycarbonylamino)methyl)
cyclopentanecarboxylic acid (0.300 g, 35%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.97 (s, 1H), 6.83 (s, 1H), 2.89-2.86 (t,
J=8.0 Hz, 2H), 2.73-2.58 (m, 1H), 2.04-1.87 (m, 2H), 1.82-1.68 (m,
2H), 1.68-1.58 (m, 1H), 1.37 (s, 9H), 1.34-1.19 (m, 2H).
[1444] General Procedure M.1: Boc-Protection of a
Nitrogen-Containing Compound
[1445] To a nitrogen-containing compound (preferably 1 equiv) in an
organic solvent (for example DCM, MeCN, 1,4-dioxane or THF,
preferably DCM) is added an aqueous base such as Na.sub.2CO.sub.3,
NaOH, K.sub.2CO.sub.3 or NaHCO.sub.3 (preferably Na.sub.2CO.sub.3,
2-20 equiv, preferably 2-10 equiv) or an organic base such as TEA
or DIEA (preferably TEA, 1-5 equiv, preferably 1-2 equiv) followed
by addition of di-tert-butyl dicarbonate (1-3 equiv, preferably 1.2
equiv). DMAP (0.1-2 equiv, preferably 0.1 equiv) is optionally
added to the reaction mixture. The reaction is stirred at about
10-40.degree. C. (preferably rt) for about 0.5-24 h (preferably
about 1 h) and worked up using one of the following methods. Method
1: An organic solvent (such as Et.sub.2O, EtOAc or DCM) and water
are added and the layers are separated. The aqueous layer is
optionally extracted with additional organic solvent and the
combined organic layers may be optionally washed with brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, and then decanted or
filtered prior to concentrating under reduced pressure. Method 2:
The reaction mixture is partitioned between an organic solvent
(such as Et.sub.2O, EtOAc or DCM) and aqueous acid (such as HCl).
The acidic layer is extracted with additional organic solvent and
the combined organic layers may be optionally washed with brine.
The organic layer is optionally dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, and then decanted or filtered prior
to concentrating under reduced pressure. Method 3: Water or an
aqueous solution (such as brine) is added and the layers are
separated. The aqueous layer is optionally extracted with
additional organic solvent (such as Et.sub.2O, EtOAc or DCM) and
the combined organic layers may be optionally washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, and then
decanted or filtered prior to concentrating under reduced
pressure.
Illustration of General Procedure M.1
Preparation #M.1.1: t-butyl
cyclopropylsulfonyl(cis-3-methyl-4-propionylcyclopentyl)carbamate
##STR00636##
[1447] To a solution of
N-(cis-3-methyl-4-propionylcyclopentyl)cyclopropanesulfonamide
(2.70 g, 10.4 mmol, prepared using H from
cis-4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid
(WO2009152133) with N,O-dimethylhydroxylamine hydrochloric acid,
MMMM with ethylmagnesium chloride) in DCM (52 mL) was added TEA
(1.60 mL, 11.5 mmol), di-tert-butyl dicarbonate (2.90 mL, 12.5
mmol), and DMAP (0.127 g, 1.04 mmol). The reaction was stirred at
rt for about 1 h. Water (50 mL) was added and the layers were
separated. The aqueous layer was extracted with DCM (3.times.30 mL)
and the combined organic layer was coned under reduced pressure.
The product was purified by silica gel chromatography eluting with
a gradient of 0-50% EtOAc in heptane to give t-butyl
cyclopropylsulfonyl(cis-3-methyl-4-propionylcyclopentyl)carbamate
(3.71 g, 99%) as a white solid: LC/MS (Table 1, Method b)
R.sub.t=2.62 min; MS m/z: 360 (M+H).sup.+.
[1448] General Procedure N: Cbz-Protection of an Amine
[1449] A solution of an amine or an amine salt (preferably 1 equiv)
and a base (for example, Na.sub.2CO.sub.3 or NaOH, 1-3 equiv,
preferably Na.sub.2CO.sub.3, 1.6 equiv) in water or aqueous organic
solvent (for example, water/1,4-dioxane or water/MeCN, preferably
water/1,4-dioxane) is stirred at ambient temperature for about 1-10
min (preferably 5 min). A solution of benzyl
2,5-dioxopyrrolidin-1-yl carbonate (1-2 equiv, preferably 1.0
equiv) in an organic solvent such as 1,4-dioxane or MeCN is added
to the reaction. The reaction is stirred at ambient temperature for
about 8-144 h (preferably about 72 h). Optionally, the reaction
mixture is concd under reduced pressure. The resulting aqueous
solution is diluted with an organic solvent (such as EtOAc or DCM).
The organic extracts are optionally washed with water and/or brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or
decanted, and concd under reduced pressure. Alternatively, the
resulting aqueous solution is acidified by adding an acid such as
aqueous NH.sub.4Cl or HCl and is then extracted with an organic
solvent (such as EtOAc or DCM).
Illustration of General Procedure N
Preparation #N.1: methyl
4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate
##STR00637##
[1451] To a solution of methyl
4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (1.16 g,
5.29 mmol, Prime Organics) in 1,4-dioxane (15 mL) was added a
solution of Na.sub.2CO.sub.3 (0.90 g, 8.49 mmol) in water (15 mL).
The reaction mixture was stirred for about 5 min at ambient
temperature. Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.32 g,
5.29 mmol) was added and the reaction mixture was stirred at
ambient temperature for about 72 h. The reaction mixture was
diluted with EtOAc (50 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (2.times.20 mL). The
combined organic layers were dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure to give methyl
4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (1.68
g, 95%): LC/MS (Table 1, Method a) R.sub.t=2.44 min; MS m/z: 318
(M+H).sup.+.
[1452] General Procedure O: Reduction of a Pyridine
[1453] A substituted pyridine (preferably 1 equiv) is dissolved in
an organic solvent (such as AcOH, EtOH, or MeOH; preferably AcOH if
using a Parr Shaker or EtOH if using an H-Cube.TM.). A suitable
catalyst such as platinum (IV) oxide or Pd/C (0.05-0.20 equiv,
preferably 0.05-0.10 equiv platinum (IV) oxide for a Parr Shaker
reaction or ThalesNano CatCart.RTM. 10 wt % Pd/C catalyst
cartridges for an H-Cube.TM.) is used for the reduction under an
atmosphere of hydrogen at about 15-1450 psi (preferably about 220
psi for a Parr Shaker or preferably 1305 psi for an H-Cube.TM.).
The reaction is run for about 1-10 d (preferably about 3-5 d) at
about 20-100.degree. C. (preferably about 25.degree. C.) for the
Parr Shaker or at about 1-3 mL/min (preferably 1 mL/min) at about
25-100.degree. C. (preferably about 80.degree. C.) for about 1-10 h
(preferably about 3 h) for an H-Cube.TM.. The reaction mixture is
filtered through Celite.RTM. if run in a Parr shaker and concd
under reduced pressure in either case.
Illustration of General Procedure O
Preparation #O.1: cis-4-(trifluoromethyl)piperidine-3-carboxylic
acid
##STR00638##
[1455] A solution of 4-(trifluoromethyl)nicotinic acid (1.50 g,
7.85 mmol) in EtOH (78 mL) was passed through an H-Cube.TM.
equipped with a ThalesNano CatCart.RTM. 10 wt % Pd/C catalyst
cartridge at about 1.0 mL/min, at about 80.degree. C., under about
1305 psi of hydrogen. After about 3 h, the solvent was removed
under reduced pressure to afford
cis-4-(trifluoromethyl)piperidine-3-carboxylic acid (1.55 g, 100%
crude): LC/MS (Table 1, Method b) R.sub.t=0.54 min; MS m/z: 198
(M+H).sup.+.
[1456] General Procedure P: Reduction of a Carbonyl to an
Alcohol
[1457] A reducing agent (1.0-3.0 equiv, preferably 1.25 equiv),
such as LAH, DIBAL-H, NaBH.sub.4 or LiBH.sub.4 (preferably
DIBAL-H), is added either portionwise as a solid or dropwise as a
solution in an organic solvent (such as THF, Et.sub.2O, EtOH or
MeOH, preferably THF) to a solution of a carbonyl compound
(preferably 1 equiv) in an organic solvent (such as THF, Et.sub.2O,
EtOH or MeOH, preferably MeOH) at about -40-50.degree. C.
(preferably ambient temperature). The reaction mixture is stirred
for about 1-20 h (preferably about 16 h) before quenching with an
aqueous solution (such as NH.sub.4Cl or NaHCO.sub.3, preferably
saturated aqueous NH.sub.4Cl). The reaction is stirred for about 10
min-3 h (preferably about 20-30 min) and then the solution is
partitioned with an organic solvent (such as EtOAc, Et.sub.2O or
DCM, preferably Et.sub.2O). The organic layer is washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd under reduced pressure.
Illustration of General Procedure P
Preparation #P.1: ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate
##STR00639##
[1459] To ethyl 2-ethyl-4-oxocyclopentanecarboxylate (10 g, 54.3
mmol, Example #8, Step G) in MeOH (143 mL) was added NaBH.sub.4
(2.57 g, 67.8 mmol) portionwise. The resulting suspension was
stirred for about 16 h at ambient temperature then saturated
aqueous NH.sub.4Cl (240 mL) was added. The reaction mixture was
stirred for about 20 min then the solution was partitioned with
Et.sub.2O (300 mL). The organic layer was separated and the aqueous
layer was washed with Et.sub.2O (2.times.150 mL). The combined
organic layers were washed with brine (100 mL), dried over
anhydrous MgSO.sub.4, filtered, and coned under reduced pressure.
The product was purified by silica gel chromatography (220 g)
eluting with a gradient of 30-70% EtOAc in heptane to give ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (8.51 g, 84%,
predominantly (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate and (1R,2S,4R)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate) as a clear oil: LC/MS
(Table 1, Method b) R.sub.t=2.02 min; MS m/z: 187 (M+H).sup.+.
TABLE-US-00031 TABLE P.1 Examples prepared using General Procedure
P with DIBAL-H R.sub.t min (Table 1, m/z ESI+ Carbonyl compound
Product Example # Method) (M + H).sup.+ ethyl
2-((1S,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)acetate
(Preparation #W.1.2) ##STR00640## P.1.1 1.47 (b) 300 ethyl
2-((1R,3R,4S)-3-ethyl-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentyl)acetate
(Preparation #W.1.1) ##STR00641## P.1.2 1.47 (b) 300
[1460] General Procedure Q: Cyclization of an Amide Using a
Dithiadiphosphetane Reagent
[1461] To a solution of an amide (preferably 1 equiv) in an organic
solvent (preferably 1,4-dioxane) is added a dithiadiphosphetane
reagent such as Lawesson's reagent or Belleau's reagent
(2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)
(preferably Lawesson's reagent) (0.5-2.0 equiv, preferably 0.6
equiv). The reaction is heated at about 25-120.degree. C.
(preferably about 80.degree. C.) for about 0.5-10 h (preferably
about 1 h). The reaction mixture is cooled to ambient temperature
and is optionally concd under reduced pressure to give a residue.
The reaction mixture or residue is partitioned between an organic
solvent (such as DCM or EtOAc, preferably EtOAc) and water, an
aqueous base (such as saturated aqueous NaHCO.sub.3) or brine. The
layers are separated and the organic layer is optionally washed
with water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd under reduced pressure to give a thioamide. To
a solution of thioamide (preferably 1 equiv) in an organic solvent
(preferably 1,4-dioxane) is added a Lewis acid, such as
diacetoxymercury, mercury dichloride, mercury (II)
trifluoroacetate, silver trifluoroacetate, silver nitrate, copper
bromide (preferably diacetoxymercury or mercury (II)
trifluoroacetate) (1-3 equiv, preferably 1 equiv). The reaction
mixture is stirred at about 20-60.degree. C. (preferably ambient
temperature) for about 0.5-4 h (preferably about 1 h). Optionally,
additional Lewis acid (preferably diacetoxymercury or mercury (II)
trifluoroacetate) (0.2-1.0 equiv, preferably 0.6 equiv) is added
and the reaction is continued for about 10 min-3 h (preferably
about 15 min). The reaction mixture is optionally diluted with
saturated sodium thiosulfate, water, and/or an organic solvent
(preferably EtOAc) and is filtered, preferably through a pad of
Celite.RTM.. The pad of Celite.RTM. can be rinsed with additional
organic solvent (preferably EtOAc or DCM). The filtrate is concd
under reduced pressure. The crude material is optionally
partitioned between an organic solvent (such as EtOAc or DCM) and
washed with saturated sodium thiosulfate and/or water, an aqueous
base (such as saturated aqueous NaHCO.sub.3) and/or brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd
under reduced pressure.
Illustration of General Procedure Q
Preparation #Q.1: cis-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate
##STR00642##
[1463] A round bottom flask was charged with cis-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperi-
dine-1-carboxylate (5.62 g, 10.6 mmol, prepared using O from
4-methylnicotonic acid, M, H from Example #5, Step C, HATU and
DIEA) and Lawesson's reagent (3.0 g, 7.4 mmol) in 1,4-dioxane (100
mL). The reaction was heated at about 80.degree. C. for about 1 h,
cooled to ambient temperature, and concd under reduced pressure.
The crude product was dissolved in EtOAc (200 mL) and washed with
saturated aqueous NaHCO.sub.3 (3.times.100 mL). The organic layer
was separated, dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure. The material was purified by silica gel
chromatography eluting with a gradient of 0-5% MeOH in DCM to
afford cis-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pi-
peridine-1-carboxylate (5.2 g, 90%): LC/MS (Table 1, Method b)
R.sub.t=2.65 min; MS m/z: 544 (M+H).sup.+. A round bottom flask was
charged with cis-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pi-
peridine-1-carboxylate (2.6 g, 4.8 mmol) and mercury (II)
trifluoroacetate (2.1 g, 4.8 mmol) in 1,4-dioxane (72 mL) and
stirred at ambient temperature for about 1 h. The reaction mixture
was filtered through a pad of Celite.RTM.. The Celite.RTM. pad was
rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate was concd
under reduced pressure. The residue was dissolved in DCM (50 mL)
and washed with saturated aqueous sodium thiosulfate (10 mL), and
saturated aqueous NaHCO.sub.3 (25 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The
material was purified by silica gel chromatography eluting with a
gradient of 0-5% MeOH in DCM to afford
cis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.2 g,
90%): LC/MS (Table 1, Method b) R.sub.t=2.57 min; MS m/z: 510
(M+H).sup.+.
[1464] General Procedure R: Formation of a Bromomethyl Ketone from
an Acid
[1465] To a solution of a carboxylic acid (preferably 1 equiv) in
an organic solvent (DCM or DCE, preferably DCM) is slowly added
oxalyl chloride (1.2-3.0 equiv, preferably 2.2 equiv) followed by
dropwise addition of DMF (0.01-0.20 equiv, preferably about 0.15
equiv). The reaction is stirred at about 0-40.degree. C.
(preferably ambient temperature) for about 3-24 h (preferably about
14 h) before it is concd under reduced pressure to a constant
weight to give the crude acid chloride. A solution of a crude acid
chloride (preferably 1 equiv) in an organic solvent (such as THF,
MeCN, Et.sub.2O, or THF/MeCN, preferably THF/MeCN) is added to
trimethylsilyldiazomethane (2.0 M in Et.sub.2O) or diazomethane
solution in Et.sub.2O (prepared from Diazald.RTM. according to
Aldrich protocol or J. Chromatogr. Sci. 1991, 29, 8) (2-10 equiv,
preferably 3.5 equiv of trimethylsilyldiazomethane) at about
-20-20.degree. C. (preferably about 0.degree. C.) in a suitable
organic solvent such as THF, MeCN, Et.sub.2O, or THF/MeCN
(preferably THF/MeCN). The reaction mixture is stirred for about
0.5-5 h (preferably about 3 h) at about -20-20.degree. C.
(preferably about 0.degree. C.) before the dropwise addition of 48%
aqueous HBr (5-40 equiv, preferably about 10 equiv). After about
0-30 min, (preferably about 5 min) the reaction mixture can be
concd to dryness to give the desired product, neutralized by a
dropwise addition of saturated aqueous NaHCO.sub.3 or is optionally
washed with brine after optional addition of an organic solvent
(such as EtOAc or DCM, preferably EtOAc). In cases where the
reaction mixture is subjected to an aqueous work-up, the organic
layer is dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4
(preferably MgSO.sub.4), filtered, and concd under reduced
pressure.
Illustration of General Procedure R
Preparation #R.1:
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone
##STR00643##
[1467] To a solution of
4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7
mmol, Preparation #TT.1) in DCM (100 mL), oxalyl chloride (4.37 mL,
49.9 mmol) was slowly added followed by a dropwise addition of DMF
(0.26 mL, 3.4 mmol). The mixture was stirred at ambient temperature
for about 14 h and the solvent was removed under reduced pressure
to yield 4-(dibenzylamino)-2-methylcyclopentanecarbonyl chloride as
a beige solid. The solid was dissolved in THF and MeCN (1:1, 100
mL) and added to a solution of trimethylsilyldiazomethane (2 M in
Et.sub.2O, 39.7 mL, 79.4 mmol) in 1:1 mixture of THF and MeCN (100
mL) at about 0.degree. C. The resulting mixture was stirred at
about 0.degree. C. for about 3 h and then was quenched by dropwise
addition of 48% aqueous HBr (25 mL, 221 mmol). The resulting
mixture was neutralized by dropwise addition of saturated aqueous
NaHCO.sub.3 (300 mL) and the layers were separated. The organic
layer was dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure. The residue was purified by silica gel
flash chromatography eluting with a gradient of 5-45% EtOAc in
heptane to yield
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g,
69%) as a yellow oil: LC/MS (Table 1, Method a) R.sub.t=2.90 min;
MS m/z 400, 402 (1:1) (M+H).sup.+.
[1468] General Procedure S: N-Alkylation Using Alkyl Halide or
.alpha.-Haloketone
[1469] A round bottom flask is charged with a base such as NaH (60%
dispersion in mineral oil), K.sub.2CO.sub.3, or Cs.sub.2CO.sub.3
(preferably NaH (60% dispersion in mineral oil), 0.9-1.5 equiv,
preferably 0.95 equiv) and an organic solvent (such as DMF or NMP,
preferably DMF). The mixture is cooled to about -10.degree. C. to
10.degree. C. (preferably about 0.degree. C.) and a solution of an
appropriately substituted amine (preferably 1 equiv) in an organic
solvent (such as DMF) is added. The reaction mixture is stirred for
about 5-90 min (preferably about 15-30 min) at about -10.degree. C.
to ambient temperature (preferably about 0.degree. C.) followed by
the addition of an alkyl halide or .alpha.-haloketone (1-2 equiv,
preferably 1.2 equiv). Alternatively, a solution of an amine and a
base in an organic solvent may be added to a solution of an alkyl
halide or .alpha.-haloketone in an organic solvent at about
0.degree. C. The reaction mixture is stirred at about -10.degree.
C. to ambient temperature (preferably ambient temperature) for
about 0.5-2 h (preferably about 1 h). The organic solvent is
removed under reduced pressure. Optionally, the crude mixture may
be diluted with water and an organic solvent (for example, EtOAc or
DCM). The layers are separated and the aqueous layer is extracted
further with organic solvent (such as EtOAc and/or DCM). The
combined organic layers are optionally washed with brine, dried
over anhydrous MgSO.sub.4, filtered, and concd to dryness under
reduced pressure.
Illustration of General Procedure S
Preparation #S.1: tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate
##STR00644##
[1471] To a suspension of NaH (60% dispersion in mineral oil, 0.058
g, 1.45 mmol) in DMF (5 mL) was added a solution of tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol,
Example #3, Step E) in DMF (5 mL) dropwise at about 0.degree. C.
The resulting mixture was stirred at this temperature for about 30
min and then added dropwise to a solution of
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g,
1.823 mmol, Preparation #R.1) in DMF (10 mL). The resulting mixture
was stirred at about 0.degree. C. for about 1 h and the solvent was
removed under reduced pressure. The residue was partitioned between
saturated aqueous NaHCO.sub.3 and EtOAc (100 mL each). The organic
phase was dried over anhydrous MgSO.sub.4 and coned under reduced
pressure to yield tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous
solid: LC/MS (Table 1, Method a) R.sub.t=3.30 min; MS m/z 708
(M+H).sup.+.
[1472] General Procedure S.1: N-Alkylation Using Alkyl Halide,
.alpha.-Haloketone or .alpha.-Haloamide
[1473] A round bottom flask is charged with a base such as NaH (60%
dispersion in mineral oil), K.sub.2CO.sub.3, or Cs.sub.2CO.sub.3
(preferably NaH (60% dispersion in mineral oil), 0.9-1.5 equiv,
preferably 0.95 equiv) and an organic solvent (such as DMF, DCM,
1,4-dioxane, or NMP, preferably DMF). The mixture is cooled to
about -10.degree. C. to ambient temperature (preferably about
0.degree. C.) and a solution of an appropriately substituted amine
(preferably 1 equiv) in an organic solvent (such as DMF) is added.
Alternatively, the base may be added portionwise to a solution of
the amine and an organic solvent at about 0.degree. C. to ambient
temperature. The reaction mixture is stirred for about 5-90 min
(preferably about 15-30 min) at about -10.degree. C. to ambient
temperature (preferably about 0.degree. C.) followed by the
addition of an alkyl halide, .alpha.-haloketone, or
.alpha.-haloamide (1-2 equiv, preferably 1.2 equiv). Alternatively,
a solution of an amine and a base in an organic solvent may be
added to a solution of an alkyl halide, .alpha.-haloketone, or
.alpha.-haloamide in an organic solvent at about 0.degree. C. The
reaction mixture is stirred at about -10.degree. C. to ambient
temperature (preferably ambient temperature) for about 0.5-24 h
(preferably about 1 h). Optionally, the organic solvent may be
removed under reduced pressure. Optionally, the reaction mixture or
residue may be diluted with water, aqueous NH.sub.4Cl, or aqueous
NaHCO.sub.3. If a precipitate forms the solid may be optionally
collected via vacuum filtration to give the target compound.
Alternatively, an organic solvent (such as EtOAc or DCM) is added
to the aqueous mixture and the layers are separated. The aqueous
layer may optionally be extracted further with an organic solvent
(such as EtOAc and/or DCM). The combined organic layers are
optionally washed with additional aqueous solutions such as brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated to dryness under reduced pressure.
Illustration of General Procedure S.1
Preparation #S.1.1: tert-butyl
2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate
##STR00645##
[1475] To a solution of tert-butyl
5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylcarbamate (1.00 g, 2.57 mmol,
Example #3 Step E) and DMF (13 mL) under nitrogen at about
0.degree. C. was added NaH (60% dispersion in mineral oil, 0.113 g,
2.83 mmol) in one portion. After about 30 min, 2-bromoacetamide
(0.391 g, 2.83 mmol) was added in one portion. After about 30 min,
the ice bath was removed and the solution was stirred at ambient
temperature for about 2 h. Saturated aqueous NH.sub.4Cl/water (1:1,
100 mL) was added. After stirring for about 10 min, the mixture was
filtered using water to wash the filter cake. The aqueous phase was
extracted with EtOAc (50 mL). The filter cake was dissolved in
EtOAc and added to the organic layer. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The material was purified by silica gel chromatography
eluting with a gradient of 20-100% EtOAc/heptane to give tert-butyl
2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate
(0.980 g, 82%): LC/MS (Table 1, Method n) R.sub.t=0.70 min; MS m/z
446 (M+H).sup.+.
[1476] General Procedure T: Cyclization of a Ketone Using a
Dithiaphosphetane Reagent
[1477] To a solution of a ketone (preferably 1 equiv) in an organic
solvent such as THF or 1,4-dioxane (preferably 1,4-dioxane) is
added a thiolating reagent such as Lawesson's reagent or Belleau's
reagent
(2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)
(0.5-2.0 equiv, preferably Lawesson's reagent, 0.5-0.6 equiv). The
reaction is heated at about 30.degree. C. to 120.degree. C.
(preferably about 60-70.degree. C.) for about 0.5-10 h (preferably
about 1-2 h). Optionally, additional thiolating reagent (0.5-2.0
equiv, preferably 0.5-0.6 equiv) can be added to the reaction
mixture and heating can be continued for about 0.5-10 h (preferably
about 1-2 h). The reaction mixture is coned under reduced
pressure.
Illustration of General Procedure T
Preparation #T.1:
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)cyclopentanamine
##STR00646##
[1479] A mixture of
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.32 g, 8.75 mmol, Preparation #50) and
Lawesson's reagent (1.88 g, 4.64 mmol) in 1,4-dioxane (60 mL) was
heated at about 60.degree. C. for about 2 h. Lawesson's reagent
(1.88 g, 4.64 mmol) was added and stirring at about 60.degree. C.
was continued for about 1 h. The solvent was removed and the
residue subjected to silica gel flash chromatography eluting with a
gradient of 0-8% MeOH in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyr-
azin-8-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous
solid: LC/MS (Table 1, Method a) R.sub.t=2.99 min; MS m/z 590
(M+H).sup.+.
[1480] General Procedure U: Knoevenagel Condensation to Form a
Substituted Cyclopentadiene
[1481] A round bottom flask is charged with an organic solvent (for
example THF or diethylene glycol dimethyl ether; preferably THF),
followed by the portionwise addition of NaH (60% dispersion in
mineral oil, preferably 1 equiv). An organic solvent can optionally
be added. The reaction mixture is cooled to about -15-5.degree. C.
(preferably about -10-0.degree. C.). A .beta.-keto ester
(preferably 1 equiv) is added dropwise at a rate to keep the
internal temperature below about 10.degree. C. The resulting
mixture is stirred at about 0-60.degree. C. (preferably about
25.degree. C.) for about 0.1-2 h (preferably about 0.5 h), followed
by dropwise addition of an appropriately substituted
.alpha.-haloketone (preferably 0.45-0.55 equiv). The resulting
mixture is heated to about 40-80.degree. C. (preferably about
50.degree. C.) for about 3-24 h (preferably about 19 h). The
organic solvent is removed under reduced pressure and the resulting
crude material is stirred with water while cooling in an ice bath.
The resulting suspension is filtered after about 0.5-3 h
(preferably about 2 h) and the filter cake is washed with water and
dried under vacuum for about 1-3 h (preferably about 1 h). The
resulting solid is suspended in an organic solvent (preferably
Et.sub.2O), collected by vacuum filtration, washed with an organic
solvent (preferably Et.sub.2O), and dried under vacuum to give the
desired product as a sodium salt of the enolate. Optionally,
toluene is added and the water is azetroped. The resulting solid is
re-suspended in an organic solvent (preferably Et.sub.2O),
collected by vacuum filtration, washed with an organic solvent
(preferably Et.sub.2O), and then dried under vacuum.
Illustration of General Procedure U
Preparation #U.1: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR00647##
[1483] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. Ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep internal temperature below about 10.degree. C.
The resulting mixture was stirred at ambient temperature for about
0.5 h to give a clear yellow solution and then methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, coned under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
[1484] General Procedure V: Decarboxylation of a .beta.-Ketoester
Enolate
[1485] A round bottom flask is charged with an appropriate
.beta.-keto ester or its sodium enolate (preferably 1 equiv), an
organic solvent (for example diethylene glycol dimethyl ether or
toluene, preferably toluene), AcOH (2-5 equiv, preferably 3.5
equiv), NaI or KCl (1-5 equiv, preferably 1.4-1.5 equiv of KCl)
with or without water (preferably with water). The reaction is
heated to reflux for about 1-10 h (preferably about 3-6 h). The
reaction is cooled to ambient temperature and is added dropwise
into aqueous NaHCO.sub.3 (preferably 8-10% NaHCO.sub.3). The
resulting mixture is extracted with an organic solvent such as
Et.sub.2O or MTBE (preferably MTBE). The combined organic layers
are dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered,
and concd to dryness under reduced pressure.
Illustration of General Procedure V
Preparation #V.1: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR00648##
[1487] A 5 liter round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol, Preparation #U.1), KCl (126 g, 1687 mmol,
JT-Baker), AcOH (241 mL, 4218 mmol, JT-Baker), toluene (1850 mL)
and water (130 mL). The reaction was heated at reflux for about 6 h
then cooled to ambient temperature and added dropwise to 8% aqueous
NaHCO.sub.3 (3.5 L). The resulting biphasic mixture was extracted
with MTBE (2.times.1.5 L). The combined organic layers were washed
with brine (1 L), dried over anhydrous MgSO.sub.4 and concd under
reduced pressure to give 191 g of crude material that was purified
by vacuum distillation (97-99.degree. C., 0.600 mm Hg) to give
ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H
NMR (CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69
(m, 1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
[1488] General Procedure W: Hydrogenation of an Alkene
[1489] A round bottom flask is charged with 10 wt % Pd/C (about
0.005-0.05 equiv, preferably 0.02 equiv). The flask is evacuated
then flushed with nitrogen 2-5 times (preferably 3 times), then is
optionally cooled to about -10-10.degree. C. (preferably about
0.degree. C.) prior to addition of an organic solvent or mixture of
solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH, preferably EtOAc
or MeOH) under a nitrogen atmosphere. The cooling bath is removed
and to the mixture is added an alkene (preferably 1 equiv) neat or
optionally as a solution in an organic solvent or mixture of
solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH, preferably EtOAc
or MeOH). Hydrogen gas is bubbled through the reaction mixture for
about 1-20 min (preferably about 5 min) and the mixture is stirred
under a hydrogen atmosphere for about 12-60 h (preferably about 48
h). In cases where the reaction does not proceed to completion as
monitored by TLC, LC/MS, or HPLC, the hydrogen source is removed,
the reaction mixture is bubbled with nitrogen for about 1-20 min
(preferably about 5 min) and then filtered through a pad of
Celite.RTM., and the filtrate is concd under reduced pressure. The
crude material is resubjected to the previously described reaction
conditions for about 2-20 h (preferably about 5 h). The hydrogen
source is removed and the mixture is bubbled with nitrogen for
about 1-20 min (preferably about 5 min) and then filtered through a
pad of Celite.RTM.. The filter cake is rinsed with an organic
solvent (such as EtOAc, MeOH or EtOH, preferably the reaction
solvent) and the filtrate is concd under reduced pressure to give
the crude product.
Illustration of General Procedure W
Preparation #W.1: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR00649##
[1491] A round bottom flask was charged with 10 wt % Pd/C (10 g,
9.4 mmol). The flask was cooled to about 0.degree. C. and EtOAc
(400 mL) was added under a nitrogen atmosphere. The cooling bath
was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8
g, 263 mmol, Preparation #V.1) was added. Hydrogen gas was bubbled
through the mixture for about 5 min and the mixture was then
stirred under a hydrogen atmosphere for about 48 h. The hydrogen
source was removed and the mixture was bubbled with nitrogen for
about 5 min and was filtered through a pad of Celite.RTM.. The
filter cake was rinsed with EtOAc (400 mL). The filtrate was concd
under reduced pressure to give ethyl
2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis:trans)
(48.0 g, 99%) as a yellow liquid: .sup.1H NMR (CDCl.sub.3) .delta.
4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m,
3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H),
1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).
TABLE-US-00032 TABLE W.1 Examples prepared with General Procedure W
R.sub.t min (Table 1, m/z ESI+ Alkene Product Ex. # Method) (M +
H).sup.+ N-(4-(3-allyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)bicyclo[2.2.2]octan-1- yl)cyclopropanesulfonamide (Example
#D.1.40) ##STR00650## W.1.1 1.95 (a) 428 2-((3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentylidene)acetic acid (prepared from Preparation #25
using III with triethyl phosphonoacetate, Z with NaOH, D with NaOH)
##STR00651## W.1.2 1.47 314
[1492] General Procedure W.1: Hydrogenation of an Alkene
[1493] A round bottom flask is charged with a slurry of
Pd(OH).sub.2 on carbon or Pd/C (about 0.005-0.10 equiv, preferably
0.05 equiv) in an organic solvent or mixture of solvents (such as
THF, EtOAc, MeOH, EtOH or MeOH/AcOH, preferably THF) under a
nitrogen atmosphere. The mixture is added to an alkene (preferably
1 equiv) neat or optionally as a solution in an organic solvent or
mixture of solvents (such as THF, EtOAc, MeOH, EtOH or MeOH/AcOH,
preferably THF) or optionally the alkene is added to the Pd
mixture. The reaction mixture is sparged with hydrogen. The mixture
is stirred or shaken (preferably stirred when atmospheric hydrogen
is used or shaken when higher pressures of hydrogen is used) under
hydrogen at about atmospheric pressure -60 psi (preferably
atmospheric pressure) at about 20-60.degree. C. (preferably ambient
temperature) for about 0.5-5 days (preferably about 3 days). The
reaction mixture is filtered through a pad of Celite.RTM.. The
filter cake is rinsed with an organic solvent (such as THF, EtOAc,
DCM, MeOH, or EtOH, preferably the reaction solvent) and the
filtrate is coned under reduced pressure to give the crude
product.
Illustration of General Procedure W.1
Preparation #W.1.1 and W.1.2: ethyl
2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate and
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate
##STR00652##
[1495] To a slurry of 20 wt % Pd(OH).sub.2 on carbon (0.134 g,
0.192 mmol) in THF (20 mL) was added a solution of (E)-ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentylidene)acetate (1.3 g, 3.83 mmol, Example #38, Step G) in
THF (5 mL). The reaction mixture was sparged with hydrogen and an
atmosphere of hydrogen was maintained via balloon. After about 3
days, the reaction mixture was filtered through Celite.RTM., coned
under reduced pressure and purified by flash chromatography on
silica gel eluting with EtOAc to afford a dark brown/black solid.
The compound was further by purified by chiral chromatography
(Table 2, Method 47) to afford ethyl
2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate [W.1.1](R.sub.t=12.0 min, or =negative)
(0.400 g, 31%): LC/MS (Table 1, Method a) R.sub.t=1.85 min; MS m/z:
342 (M+H).sup.+ and ethyl
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a-
]pyrazin-1-yl)cyclopentyl)acetate [W.1.2](R.sub.t=13.7 min, or
=negative) (0.420 g, 32%) as a white solid: LC/MS (Table 1, Method
a) R.sub.t=1.85 min; MS m/z: 342 (M+H).sup.+.
[1496] General Procedure X: Reductive Amination of a Ketone or
Aldehyde
[1497] A round bottom flask is charged with a ketone or an aldehyde
(1-40 equiv; preferably 1 equiv) in an organic solvent (such as
DCE, MeCN, MeOH, or MeCN/MeOH; preferably DCE). The mixture is
optionally cooled to about -10-10.degree. C. (preferably about
0.degree. C.) and AcOH (1-3 equiv; preferably 1.5 equiv) and an
amine (1-3 equiv, preferably 1 equiv) are added dropwise, followed
by the portionwise addition of a suitable reducing agent such as
NaBH(OAc).sub.3, Na(CN)BH.sub.3, NaBH.sub.4, preferably
NaBH(OAc).sub.3 (1-6 equiv, preferably 1.5 equiv). Alternatively,
to a solution of an amine (1-3 equiv, preferably 1 equiv) in an
organic solvent (such as DCE, MeCN, or MeOH; preferably DCE) is
added a ketone or an aldehyde (1-40 equiv; preferably 1 equiv)
followed by subsequent portionwise addition of an appropriate
reducing agent such as NaBH(OAc).sub.3, Na(CN)BH.sub.3, NaBH.sub.4,
preferably NaBH(OAc).sub.3 (1-6 equiv, preferably 1.5 equiv). The
mixture is stirred for about 5-20 min (preferably about 15 min)
followed by the dropwise addition of AcOH (1-3 equiv; preferably
1.5 equiv). If the reaction mixture becomes too viscous to stir
freely, additional organic solvent (such as DCE, MeCN, MeOH, or
MeCN/MeOH mixture; preferably DCE) is optionally added to aid
stirring. The reaction mixture is stirred at ambient temperature
for about 1-48 h (preferably about 20 h). The reaction mixture is
slowly poured into a solution of aqueous base (such as saturated
aqueous NaHCO.sub.3) followed by optional addition of solid
NaHCO.sub.3 and stirred for about 0.5-3 h (preferably about 2 h).
The layers are separated and the organic solution is dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd to
dryness under reduced pressure.
Illustration of General Procedure X
Preparation #X.1: ethyl
4-(dibenzylamino)-2-ethylcyclopentanecarboxylate
##STR00653##
[1499] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol, Preparation
#W.1) and DCE (1.8 L). The solution was cooled to about 0.degree.
C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol)
were added dropwise, resulting in formation of a thick suspension.
The reaction mixture was warmed to about 10.degree. C. and
additional DCE (500 mL) was added. NaBH(OAc).sub.3 (166 g, 781
mmol) was added portionwise and the reaction mixture was stirred at
ambient temperature for about 20 h. The reaction mixture was slowly
poured into stirred saturated aqueous NaHCO.sub.3 (1.5 L), followed
by the portionwise addition of solid NaHCO.sub.3 (175 g). The
mixture was stirred for about 2 h and the organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, and concd to
dryness under reduced pressure. The crude yellow oil was purified
by silica gel chromatography eluting with 0-20% EtOAc in heptane to
yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6
g, 72%) as a white solid: LC/MS (Table 1, Method a) R.sub.t=3.26
min; MS m/z: 366 (M+H).sup.+
TABLE-US-00033 TABLE X.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-
6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5,
Step J) using General Procedure X with NaBH.sub.3CN R.sub.t min
Example (Table 1, m/z ESI+ Aldehyde Product # Method) (M + H).sup.+
Benzalde- hyde ##STR00654## X.1.1* 1.51 (b) 346
TABLE-US-00034 TABLE X.2 Examples prepared from acetaldehyde using
General Procedure X with NaBH.sub.3CN R.sub.t min (Table 1, m/z
ESI+ Amine Product Example # Method) (M + H).sup.+
(trans)-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclohexanamine (Example #F.1.2) ##STR00655## X.2.1 0.97 (a)
312
TABLE-US-00035 TABLE X.3 Examples prepared from
4,4,4-trifluorobutyraldehyde [Matrix] using General Procedure X
with Na(OAc).sub.3BH R.sub.t min (Table 1, m/z ESI+ Amine Product
Example # Method) (M + H).sup.+ (1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazin- 1-yl)cyclopentanamine
(Preparation #44) ##STR00656## X.3.1 1.90 (a) 491
TABLE-US-00036 TABLE X.4 Examples prepared from
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentanone (prepared using D from Preparation
#25 using D), and General Procedure X with Na(OAc).sub.3BH R.sub.t
min (Table 1, m/z ESI+ Amine Product Example # Method) (M +
H).sup.+ oxetan-3-amine [Synthonix] ##STR00657## X.4.1 1.01 (a) 327
3-methyloxetan-3-amine [Synthonix] ##STR00658## X.4.2 1.06 (a)
341
[1500] General Procedure X.1: Reductive Amination of a Ketone or
Aldehyde
[1501] A ketone or an aldehyde (1-40 equiv; preferably 1 equiv) is
optionally dissolved or slurried in an organic solvent or solvents
such as DCE, MeCN, MeOH, MeCN/MeOH, EtOH, THF, DMF, AcOH, or DCM
(preferably DCE). The mixture is optionally cooled to about
-10-10.degree. C. (preferably about 0.degree. C.). Optionally, AcOH
(1-3 equiv; preferably 1.5 equiv) is added. An amine (1-3 equiv,
preferably 1 equiv) is added neat or as a solution in an organic
solvent or solvents such as DCE, MeCN, MeOH, EtOH, THF, DMF, AcOH,
or DCM (preferably DCE). Alternatively, a ketone or aldehyde or
solution of ketone or aldehyde may be added to an amine or amine
solution. A dehydrating reagent such as molecular sieves or
titanium(IV) tetraisopropoxide may optionally be added or water may
be removed using a Dean-Stark trap. The solvent is optionally
removed under reduced pressure and an organic solvent or solvents
such as DCE, MeCN, MeOH, EtOH, THF, DMF, AcOH, or DCM may be added.
After stirring for about 5 min-24 h (preferably 15 min) at
0.degree. C. to 100.degree. C. (preferably ambient temperature), a
suitable reducing agent such as NaBH(OAc).sub.3, Na(CN)BH.sub.3,
NaBH.sub.4, preferably NaBH(OAc).sub.3 (1-10 equiv, preferably 1.5
equiv) is added portionwise. If the reaction mixture becomes too
viscous to stir freely, additional organic solvent is optionally
added to aid stirring. The reaction mixture is stirred at ambient
temperature for about 1-72 h (preferably about 20 h). Optionally,
the reaction mixture may be treated with water and then filtered or
the volatiles may be removed under reduced pressure. The reaction
mixture is slowly poured into a solution of aqueous base, water, or
aqueous acid (preferably saturated aqueous NaHCO.sub.3) or
alternatively the aqueous solution is slowly added to the reaction
mixture. Optionally, additional solid NaHCO.sub.3 may be added. The
mixture is vigorously stirred for about 0.5-20 h (preferably about
2 h). The layers are separated and the organic solution is dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated to dryness under reduced pressure.
Illustration of General Procedure X.1
Preparation #X.1.1: tert-butyl
(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamin-
o)cyclohexyl)methylcarbamate
##STR00659##
[1503] tert-Butyl trans-4-aminocyclohexylmethylcarbamate (0.059 g,
0.258 mmol, AMRI) was added to a mixture of
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde
(0.0403 g, 0.215 mmol, Preparation #38) and THF (1.0 mL). The
mixture was stirred at ambient temperature for about 90 min. Sodium
triacetoxyborohydride (0.068 g, 0.32 mmol) was added. After about 3
h, DMF (0.500 mL) was added. After about 15 h, Na(OAc).sub.3BH
(0.091 g, 0.43 mmol) was added. After about 24 h, Na(OAc).sub.3BH
(0.091 g, 0.43 mmol) was added. The mixture was warmed to about
40.degree. C. After about 22 h, the mixture was allowed to cool to
ambient temperature. Saturated aqueous NaHCO.sub.3/water (1:1, 2
mL) was added. After vigorously stirring for about 1 h, the
solution was diluted with water (3 mL) and then extracted with
EtOAc (6.times.10 mL). The combined organics were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified silica gel chromatography
eluting with a gradient of 10-100% [(1% 7 N NH.sub.3 in MeOH) in
10% MeOH/DCM]/DCM to give tert-butyl
(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamin-
o)cyclohexyl)methylcarbamate (0.0476 g, 53%): LC/MS (Table 1,
Method a) R.sub.t=1.24 min; MS m/z 400 (M+H).sup.+.
[1504] General Procedure Y: Hydrogenation of a Benzyl- or
Cbz-Protected Amine
[1505] To a vessel charged with a benzyl- or Cbz-protected amine
(preferably 1 equiv) was added a palladium catalyst (for example
Pd(OH).sub.2 on C or Pd/C; preferably Pd(OH).sub.2 on C) (0.01-0.2
equiv, preferably 0.02-0.15 equiv) and an organic solvent (such as
MeOH or EtOH, preferably EtOH). The mixture is shaken or stirred at
about 25-60.degree. C. (preferably about 50.degree. C.) for about
1-96 h (preferably about 1.5-3 h) at about 15-60 psi hydrogen
(preferably about 30-50 psi hydrogen). In cases where the reaction
does not proceed to completion as monitored by TLC, LC/MS, or HPLC,
the hydrogen source is removed, the reaction mixture is bubbled
with nitrogen for about 5-20 min (preferably about 5 min) and then
filtered through a pad of Celite.RTM., and the filtrate is concd
under reduced pressure. The crude material is resubjected to the
previously described reaction conditions for about 2-20 h
(preferably about 3-5 h). When the reaction is complete as
monitored by TLC, LC/MS, or HPLC, the hydrogen source is removed, a
nitrogen atmosphere is introduced, and the reaction mixture is
filtered through a pad of Celite.RTM.. The filtrate is concd under
reduced pressure to give the desired product.
Illustration of General Procedure Y
Preparation #Y.1: ethyl 4-amino-2-ethylcyclopentanecarboxylate
##STR00660##
[1507] To a vessel containing a slurry of 20 wt % Pd(OH).sub.2 onC
(12.9 g, 18.4 mmol) in EtOH (1.0 L) was added ethyl
4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol,
Preparation #X.1). The reaction was shaken for about 90 min at
about 50.degree. C. under about 30 psi of hydrogen. After removal
of the hydrogen source and introduction of a nitrogen atmosphere,
the resulting mixture was filtered through a pad of Celite.RTM. and
the filtrate was coned under reduced pressure to give ethyl
4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow
syrup: .sup.1H NMR (CDCl.sub.3) .delta. 4.03-3.88 (m, 2H), 3.17 (m,
1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m,
1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m,
2H), 0.78-0.69 (m, 3H).
TABLE-US-00037 TABLE Y.1 Examples prepared using General Procedure
Y R.sub.t min (Table 1, m/z ESI+ Dibenzyl amine Product Ex #
Method) (M + H).sup.+ trans-1-(4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclohexyl)-N,N- dibenzylmethanamine
(prepared using S from methyl 4- (aminomethyl)cyclohexanecarboxy-
late [prepared as described in Molecules 2008, 13, 1111-1119] and
benzyl bromide, Z with NaOH, R, S with Example #3 Step E, E with
TFA, KKKK with PFPAA, D with NaOH) ##STR00661## Y.1.x 1.27 (a)
270
[1508] General Procedure Z: Basic Hydrolysis of an Ester to a
Carboxylic Acid
[1509] To a flask containing an ester (preferably 1 equiv) either
neat or in an organic solvent (such as 1,4-dioxane, MeOH, or
THF/MeOH, preferably 1,4-dioxane) is added an aqueous base (such as
aqueous NaOH or LiOH, 1-10 equiv, preferably 2-6 equiv). The
mixture is stirred at about 0-100.degree. C. (preferably ambient
temperature) for about 1-48 h (preferably about 4-8 h). The
reaction mixture is then acidified by the addition of a suitable
aqueous acid (such as aqueous HCl). The layers are separated and
the aqueous layer is optionally extracted with additional organic
solvent (such as EtOAc or DCM, preferably DCM). The organic layer
or layers are optionally dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, filtered, and concd to dryness under reduced pressure
to give crude target compound. Alternatively, the reaction mixture
is concd under reduced pressure to give crude target compound as a
carboxylate salt.
Illustration of General Procedure Z
Preparation #Z.1*:
(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic
acid
##STR00662##
[1511] To a flask containing (1S,2R,4S)-ethyl
4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (11.1
g, 38.4 mmol, prepared using K from Preparation #Y.1,
cyclopropanesulfonyl chloride and TEA, AA [Table 2, Method 1,
R.sub.t=9.5 min, or =negative]) was added aqueous NaOH (1 N, 210
mL, 210 mmol). After stirring at ambient temperature for about 8 h,
the reaction was acidified to about pH 1 using 6 N aqueous HCl and
extracted with DCM (3.times.150 mL). The combined organic layers
were washed with brine, dried over anhydrous MgSO.sub.4, filtered,
and concd under reduced pressure to give
(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic
acid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table
1, Method a) R.sub.t=1.71 min; MS m/z: 260 (M-H).sup.-.
[1512] General Procedure AA: Chiral Preparative HPLC
Purification
[1513] Chiral purification is performed using Varian 218 LC pumps,
a Varian CVM 500 with switching valves and heaters for automatic
solvent, column and temperature control and a Varian 701 Fraction
collector. Detection methods include a Varian 210 variable
wavelength detector, an inline polarimeter (PDR-chiral advanced
laser polarimeter, model ALP2002) used to measure qualitative
optical rotation (+/-) and an evaporative light scattering detector
(ELSD) (a PS-ELS 2100 (Polymer Laboratories)) using a 100:1 split
flow. ELSD settings are as follows: evaporator: 46.degree. C.,
nebulizer: 24.degree. C. and gas flow: 1.1 SLM. The absolute
stereochemistry of the purified compounds was assigned arbitrarily
and is drawn as such. Compounds of the invention where the absolute
stereochemistry has been determined by the use of a commercially
available enantiomerically pure starting material, or a
stereochemically defined intermediate, or X-ray diffraction are
denoted by an asterisk after the example number.
Illustration of General Procedure AA
Examples #AA.1.1 and AA.1.2
3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromet-
hyl)piperidin-1-yl)-3-oxopropanenitrile and
3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluorome-
thyl)piperidin-1-yl)-3-oxopropanenitrile
##STR00663##
[1515] A mixture of
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperi-
din-1-yl)-3-oxopropanenitrile (0.067 g, 0.18 mmol, prepared using O
from 4-(trifluoromethyl)nicotinic acid, N, H with Example #5, Step
C, HATU and DIEA, Q with Lawesson's reagent and mercury (II)
trifluoroacetate, D with NaOH, F, H with 2-cyanoacetic acid, HATU,
and DIEA) was dissolved in DMSO:MeOH (2:1, 3 mL). The mixture was
separated using Varian 218 LC pumps, a Varian CVM 500 with
switching valves and heaters for automatic solvent, column and
temperature control and a Varian 701 Fraction collector using
Method 4 (Table 2) to give 3-((3R,4R)-3-(6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxop-
ropanenitrile (R.sub.t=12.2 min, or =positive) (0.0284 g, 15%)
[AA.1.1] and 3-((3S,4S)-3-(6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-(trifluoromethyl)piperidin-1-yl)-3-oxop-
ropanenitrile (R.sub.t=5.3 min, or =negative) (0.0282 g, 15%)
[AA.1.2]: LC/MS (Table 1, Method b) R.sub.t=1.55 min; MS m/z: 377
(M+H).sup.+.
TABLE-US-00038 TABLE AA.1 Examples prepared using General Procedure
AA Stereoisomers R.sub.t min m/z ESI+ [Chiral Separation Method]
Structure Ex. # (method) (M + H).sup.+
4-((1R,3R)-3-(6H-imidazo[1,5-a] pyrrolo[2,3-e]pyrazin-1-yl)
cyclopentylamino)benzonitrile and 4-
((1R,3S)-3-(6H-imidazo[1,5-a]pyrrolo
[2,3-e]pyrazin-1-yl)cyclopentylamino) benzonitrile (prepared using
H from Example #5, Step C and (1R,3R)-3-(tert-
butoxycarbonylamino)cyclopentane carboxylic acid [Acros], HATU and
DIEA; Q with Lawesson's reagent and mercury (II) trifluoroacetate;
E with HCl; PP from 4-cyanophenylboronic acid; D with NaOH) [Table
2, Method 18, R.sub.t = 14.5 min, or = ND] ##STR00664## AA.1.3*
1.84 (b) 343 N-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-
(cyclopentyl)cyclopropanesulfonamide (prepared using A from Example
#1, Step D and Preparation #Z.1 with HATU and TEA, B with TEA, D
with NaOH) [Table 2, Method 2, R.sub.t = 10.4 min, or = negative]
##STR00665## AA.1.4* 1.76 (a) 375 N-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-
cyclopentyl)cyclopropanesulfonamide (prepared using A from Example
#1, Step D and Preparation #Z.1 with HATU and TEA, B with TEA, D
with NaOH) [Table 2, Method 2, R.sub.t = 11.3 min, or = positive]
##STR00666## AA.1.5* 1.86 (a) 375 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)piperidin-1-yl)(3,3-
difluoroazetidin-1-yl)methananone (prepared using J from Example
#3, Step G and 3,3-difluoroazetidine hydrochloride with CDI) [Table
2, Method 12, R.sub.t = 11.4 min, or = positive] ##STR00667##
AA.1.6* 1.58 (b) 361 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)piperidin-1-yl)(3,3- difluoroazetidin-1-yl)methanone
(prepared using J from Example #3, Step G and 3,3-difluoroazetidine
hydrochloride with CDI) [Table 2, Method 12, R.sub.t = 7.4 min, or
= negative] ##STR00668## AA.1.7* 1.58 (b) 361
(3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)piperidin-1-yl)(3,3-
difluoropyrrolidin-1-yl)methanone (prepared using J from Example
#3, Step G and 3,3-difluoropyrrolidine hydrochloride with CDI)
[Table 2, Method 8, R.sub.t = 11.5 min, or = positive] ##STR00669##
AA.1.8* 1.64 (b) 375 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)piperidin-1-yl)(4,4-
difluoropiperidin-1-yl)methanone (prepared using J from Example #3,
Step G and 4,4-difluoropiperidine hydrochloride with CDI) [Table 2,
Method 13, R.sub.t = 15.6 min, or = positive] ##STR00670## AA.1.9*
1.72 (b) 389 (3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)piperidin-1-yl)((R)-2-
(trifluoromethyl)pyrrolidin-1- yl)methanone (prepared using J from
Example #3, Step G and (R)-2- (trifluoromethyl)pyrrolidine with
CDI) [Table 2, Method 9, R.sub.t = 10.4 min, or = positive]
##STR00671## AA.1.10* 1.87 (b) 407 2-(-3-(6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1-yl)-4- methylpiperidin-1-yl)thiazole-5-
carbonitrile (prepared using L from Example #5, Step J and 2-
chlorothiazole-5-carbonitrile [ArkPharm]) [Table 2, Method 15,
R.sub.t = 13.4 min, or = positive] ##STR00672## AA.1.11* 1.89 (b)
364 1-((R)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)piperidine-1- carbonyl)pyrrolidine-3-carbonitrile (prepared
using J from Example #6, Step H and pyrrolidine-3- carbonitrile
[Tyger] with CDI) [Table 2, Method 14, R.sub.t = 16.9 min, or =
positive] ##STR00673## AA.1.12* 1.41 (b) 364 N-(3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-3,3,3-
trifluoropropane-1-sulfonamide (prepared using K from Preparation
#53 and 3,3,3- trifluoropropylsulfonyl chloride [Matrix]) [Table 2,
Method 9, R.sub.t = 14.3 min, or = positive] ##STR00674## AA.1.13
1.79 (a) 416 N-(3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-
methylcyclopentyl)-3,3,3- trifluoropropane-1-sulfonamide (prepared
using K from Preparation #53 and 3,3,3- trifluoropropylsulfonyl
chloride [Matrix]) [Table 2, Method 9, R.sub.t = 12.4 min, or =
positive] ##STR00675## AA.1.14 1.79 (a) 416 N-(3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-yl)-4- methylcyclopentyl)-3,3,3-
trifluoropropane-1-sulfonamide (prepared using K from Preparation
#51 and 3,3,3- trifluoropropylsulfonyl chloride [Matrix]) [Table 2,
Method 9, R.sub.t = 11.9 min, or = negative] ##STR00676## AA.1.15
1.79 (a) 416 5-(3-(3H-imidazo[1,2-
a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-
2-carbonitrile (prepared using L from Preparation #53 and 2-chloro-
5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R.sub.t = 18.6 min,
or = negative] ##STR00677## AA.1.16 1.69 (a) 359
5-(3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-
methylcyclopentylamino)pyrazine- 2-carbonitrile (prepared using L
from Preparation #51 and 2-chloro- 5-cyanopyrazine [ArkPharm])
[Table 2, Method 8, R.sub.t = 14.8 min, or = positive] ##STR00678##
AA.1.17 1.69 (a) 359 5-(3-(3H-imidazo[1,2-
a]pyrrolo[2,3,-e]pyrazin-8-yl)-4- methylcyclopentylamino)pyrazine-
2-carbonitrile (prepared using L from Preparation #53 and 2-chloro-
5-cyanopyrazine [ArkPharm]) [Table 2, Method 8, R.sub.t = 11.5 min,
or = positive] ##STR00679## AA.1.18 1.69 (a) 359
5-(3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-
methylcyclopentylamino)pyrazine- 2-carbonitrile (prepared using L
from Preparation #51 and 2-chloro- 5-cyanopyrazine [ArkPharm])
[Table 2, Method 8, R.sub.t = 9.5 min, or = negative] ##STR00680##
AA.1.19 1.69 (a) 359 6-(3-(3H-imidazo[1,2-a]pyrrolo
[2,3-e]pyrazin-8-yl)piperidin-1- yl)niotinonitrile (prepared using
L from Example #3, Step G and 2- chloro-5-cyanopyridine) [Table 2,
Method 7, R.sub.t = 14.9 min, or = positive] ##STR00681## AA.1.20*
1.81 (a) 344 6-(3-(3H-imidazo[1,2-a]pyrrolo
[2,3,-e]pyrazin-8-yl)piperidin-1- yl)nicotinonitrile (prepared
using L from Example #3, Step G and 2- chloro-5-cyanopyridine)
[Table 2, Method 7, R.sub.t = 11.9 min, or = negative] ##STR00682##
AA.1.21* 1.81 (a) 344 2-(3-(3H-imidazo[1,2-
a]pyrrolo[2,3,-e]pyrazin-8- yl)piperidin-1-yl)thiazole-5-
carbonitrile (prepared using L from Example #3, Step and
2-chloro-5- cyanothiazole [ArkPharm]) [Table 2, Method 5, R.sub.t =
12.5 min, or = positive] ##STR00683## AA.1.22* 1.74 (a) 350
2-(3-(3H-imidazo[1,2- a]pyrrolo[2,3,-e]pyrazin-8-
yl)piperidin-1-yl)thiazole-5- carbonitrile (prepared using L from
Example #3, Step G and 2-chloro-5- cyanothiazole [ArkPharm]) [Table
2, Method 5, R.sub.t = 9.4 min, or = negative] ##STR00684##
AA.1.23* 1.74 (a) 350 N-(3-ethyl-4-(3H-imidazo[1,2-a]
pyrrolo[2,3-e]pyrazin-8-yl) cyclopentyl)cyclopropane- sulfonamide
(prepared using TT from Preparation #X.1 with HCl, R with
trimethylsilyl diazomethane, S with Example #3, Step E, E with 4 N
HCl in 1,4-dioxane, T using Lawesson's reagent, D with NaOH, Y with
Pd(OH).sub.2 on C, and K from cyclopropylsulfonyl chloride) [Table
2, Method 6, R.sub.t = 8.2 min, or = negative] ##STR00685## AA.1.24
1.64 (a) 374 N-(3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)cyclopropanesulfonamide
(prepared using TT from Preparation #X.1 with HCl, R with
trimethylsilyl diazomethane, S with Example #3, Step E, E with 4N
HCl in 1,4-dioxane, T using Lawesson's reagent, D with NaOH, Y with
Pd(OH).sub.2 on C, and K from cyclopropylsulfonyl chloride) [Table
2, Method 6, R.sub.t = 13.0 min, or = positive] ##STR00686##
AA.1.25 1.64 (a) 374 1-(3-(3H-imidazo[1,2-a]pyrrolo
[2,3,-e]pyrazin-8-yl)piperidine-1-
carbonyl)cyclopropanecarbonitrile (prepared using H from Example
#3, Step G and 1-cyano-1- cyclopropane-carboxylic acid) [Table 2,
Method 5, R.sub.t =7.3 min, or = negative] ##STR00687## AA.1.26*
1.46 (a) 335 3-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)-4-methylpiperidin- 1-yl)-3-oxopropanenitrile
(prepared using N from Example #5, Step D with
N-(benzyloxycarbonyloxy) succinimide, R with trimethylsilyl
diazomethane, S with Example #3, Step E, E with 4N HCl in 1,4-
dioxane, T using Lawesson's reagent, D with NaOH, Y with Pd/C, and
H from cyanoacetic acid, EDC, and DIEA) [Table 2, Method 4, R.sub.t
= 15.9 min, or = negative] ##STR00688## AA.1.27 1.36 (a) 323
4-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)-benzonitrile (prepared using H from 4-
hydroxybenzonitrile and Preparation #FF.1, D with Na.sub.2CO.sub.3)
[Table 2, Method 17, R.sub.t 20.8 min, or = positive] ##STR00689##
AA.1.28 2.12 (b) 373 6-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)-nicotinonitrile (prepared using II from 6-
hydroxynicotino-nitrile and Preparation #FF.1, D with
Na.sub.2CO.sub.3) [Table 2, Method 18, R.sub.t 14.6 min, or =
negative] ##STR00690## AA.1.29 2.07 (b) 374
6-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)-nicotinonitrile (prepared using II from 6-
hydroxynicotino-nitrile and Preparation #FF.1, D with
Na.sub.2CO.sub.3) [Table 2, Method 18, R.sub.t 16.9 min, or =
positive] ##STR00691## AA.1.30 2.04 (b) 374 1-(2-ethyl-4-(4-
methoxybenzyloxy)cyclopentyl)- 6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine (prepared using Z from Preparation
#EE.1, A from Example #1, Step D, HATU, and TFA, B with DIEA, D
with Na.sub.2CO.sub.3) [Table 2, Method 19, R.sub.t 17.1 min, or =
negative] ##STR00692## AA.1.31 2.23 (b) 392
1-(2-ethyl-4-(4-methoxybenzyloxy) cyclopentyl)-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine (prepared using Z from Preparation
#EE.1, A from Example #1, Step D, HATU, and TEA, B with DIEA, D
with Na.sub.2CO.sub.3) [Table 2, Method 19, R.sub.t 19.1 min, or =
positive] ##STR00693## AA.1.32 2.22 (b) 392
5-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)pyrazine-2- carbonitrile (Preparation #LL.1)
[Table 2, Method 20, R.sub.t 8.1 min, or = negative] ##STR00694##
AA.1.33 2.04 (b) 375 5-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)pyrazine-2-
carbonitrile (Preparation #LL.1) [Table 2, Method 20, R.sub.t 13.9
min, or = positive] ##STR00695## AA.1.34 2.04 (b) 375
6-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)nicotino-nitrile carbonitrile (prepared using II
from 6-hydroxynicotinonitrile and Preparation #FF.1, D with
Na.sub.2CO.sub.3) [Table 2, Method 21, R.sub.t 10.9 min, or =
negative] ##STR00696## AA.1.35 2.03 (b) 374
6-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)nicotino-nitrile carbonitrile (prepared using II
from 6-hydroxynicotinonitrile and Preparation #FF.1, D with
Na.sub.2CO.sub.3) [Table 2, Method 21, R.sub.t 7.4 min, or =
positive] ##STR00697## AA.1.36 2.02 (b) 374
5-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)pyrazine-2- carbonitrile (prepared using LL from
Preparation #JJ.1) [Table 2, Method 22, R.sub.t 15.5 min, or =
negative] ##STR00698## AA.1.37 1.99 (b) 375
5-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)pyrazine-2- carbonitrile (prepared using LL from
Preparation #JJ.1) [Table 2, Method 22, R.sub.t 16.4 min, or =
positive] ##STR00699## AA.1.38 1.97 (b) 375 N-(1-(6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)pyrrolidin-3-
yl)cyclopropanesulfonamide (Example #15) [Table 2, Method 16,
R.sub.t = 15.3 min, or = negative] ##STR00700## AA.1.39 1.42 (a)
347 N-(1-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)pyrrolidin-3- yl)cyclopropanesulfonamide (Example #15) [Table 2,
Method 16, R.sub.t = 12.5 min, or = positive] ##STR00701## AA.1.40
1.42 (a) 347 5-((cis-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)methoxy)-pyrazine- 2-carbonitrile (prepared using P
from Preparation #11 with LAH, JJ with 2-chloro-5-cyanopyrazine
[ArkPharm], TT with HCl, A from Example #1, Step D, HATU and TEA, B
with TEA, D with Na.sub.2CO.sub.3) [Table 2, Method 11, R.sub.t =
7.5 min, or = ND] ##STR00702## AA.1.41 1.99 (a) 389
5-((cis-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)methoxy)-pyrazine- 2-carbonitrile (prepared using P
from Preparation #11 with LAH, JJ with 2-chloro-5-cyanopyrazine
[ArkPharm], TT with HCl, A from Example #1, Step D, HATU and TEA, B
with TEA, D with Na.sub.2CO.sub.3) [Table 2, Method 11, R.sub.t =
16.1 min, or = ND] ##STR00703## AA.1.42 1.99 (a) 389
N-(cis-4-ethyl-3-fluoro-3-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamide (prepared
using Z from Preparation #7 with NaOH, A from Example #1, Step D,
HATU and TEA, B with TEA, D with Na.sub.2CO.sub.3) [Table 3, Method
10, R.sub.t = 18.3 min, or = negative] ##STR00704## AA.1.43 1.71
(a) 393 N-(cis-4-ethyl-3-fluoro-3-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamide (prepared
using Z from Preparation #7 with NaOH, A from Example #1, Step D,
HATU and TEA, B with TEA, D with Na.sub.2CO.sub.3) [Table 2, Method
10, R.sub.t = 14.9
min, or = positive] ##STR00705## AA.1.44 1.74 (a) 393
N-(cis-4-ethyl-3-fluoro-3-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamide (prepared
using Z from Preparation #7 with NaOH, A from Example #1, Step D,
HATU and TEA, B with TEA, D with Na.sub.2CO.sub.3) [Table 2, Method
10, R.sub.t = 15.5 min, or = positive] ##STR00706## AA.1.45 1.73
(a) 393 N-(cis-4-ethyl-3-fluoro-3-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)cyclo- propanesulfonamide (prepared
using Z from Preparation #7 with NaOH, A from Example #1, Step D,
HATU and TEA, B with TEA, D with Na.sub.2CO.sub.3) [Table 2, Method
10, R.sub.t = 16.5 min, or = negative] ##STR00707## AA.1.46 1.75
(a) 393 1-(cis-4-((azetidin-1- ylsulfonyl)methyl)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using the conditions described in Example #1, Step K
substituting azetidine for diethylamine, Z with NaOH, A from
Example #1, Step D, HATU and TEA, B with TEA, D with NaOH) [Table
2, Method 27, R.sub.t = 14.3 min, racemic] ##STR00708## AA.1.47
1.70 (a) 389 1-(cis-4-((azetidin-1- ylsulfonyl)methyl)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using the conditions described in Example #1, Step K
substituting azetidine for diethylamine, Step, Z with NaOH, A from
Example #1, Step D, HATU and TEA, B with TEA, D with NaOH) [Table
2, Method 27, R.sub.t = 15.5 min, or = positive] ##STR00709##
AA.1.48 1.70 (a) 389 N-(3-(6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1-yl)-4- methylcyclopentyl)aniline
(prepared using TT from Preparation #8 with HCl, H from Example #5,
Step C, HATU and TEA, Q with Lawesson's reagent and mercury (II)
trifluoroacetate, D with NaOH) [Table 2, Method 25, R.sub.t = 8.0
min, or = negative] ##STR00710## AA.1.49 2.27 (a) 332
N-(3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-yl)-4-
methylcyclopentyl)aniline (prepared using TT from Preparation #8
with HCl, H from Example #5, Step C, HATU and TEA, Q with
Lawesson's reagent and mercury (II) trifluoroacetate, D with NaOH)
[Table 2, Method 25, R.sub.t = R.sub.t = 7.1 min, or = positive]
##STR00711## AA.1.50 2.24 (a) 332 N-(3-methyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)aniline (prepared
using TT from Preparation #8 with HCl, A from Example #1, Step D,
HATU and TEA, B with TEA, D with NaOH) [Table 2, Method 19, R.sub.t
= 17.1 min, or = negative] ##STR00712## AA.1.51 1.99 (a) 333
N-(3-methyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)aniline (prepared using TT from Preparation #8 with
HCl, A from Example #1, Step D, HATU and TEA, B with TEA, D with
NaOH) [Table 2, Method 19, R.sub.t = 18.7 min, or = positive]
##STR00713## AA.1.52 2.02 (a) 333 3-(cis-4-ethyl-3-(6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)piperidin-1-yl)-3- oxopropanenitrile
(prepared using W from Preparation #9 with Pd(OH).sub.2 on C, TT
with HCl, M, H from Example #5, Step C, HATU and DIEA, Q with
Lawesson's reagent and mercury (II) trifluoroacetate, D with NaOH,
E with HCl, H from cyanoacetic acid, EDC, and DIEA) [Table 2,
Method 26, R.sub.t = 8.9 min, or = negative] ##STR00714## AA.1.53
1.73 (a) 337 3-(cis-4-ethyl-3-(6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazin-1- yl)piperidin-1-yl)-3- oxopropanenitrile
(prepared using W from Preparation #9 with Pd(OH).sub.2) on C,TT
with HCl, M, H from Example #5, Step C, HATU and DIEA, Q with
Lawesson's reagent and mercury (II) trifluoroacetate, D with NaOH,
E with HCl, H from cyanoacetic acid, EDC, and DIEA) [Table 2,
Method 26, R.sub.t = 16.1 min, or = positive] ##STR00715## AA.1.54
1.73 (a) 337 1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-
b]pyridin-1(6H)-piperidine-1- carbonyl)cyclopropanecarbonitrile
(prepared using Y from Preparation #10 with Pd(OH).sub.2 on C, H
from 1- cyanocyclopropanecarboxylic acid, HATU, and DIEA) [Table 2,
Method 10, R.sub.t = 18.6 min, or = negative] ##STR00716## AA.1.55
1.81 (a) 335 1-(3-(pyrazolo[3,4-d]pyrrolo[2,3-
b]pyridin-1(6H)-yl)piperidine-1- carbonyl)cyclopropanecarbonitrile
(prepared using Y from Preparation #10 with Pd(OH).sub.2 on C, H
from 1- cyanocyclopropanecarboxylic acid, HATU, and DIEA) [Table 2,
Method 10, R.sub.t = 21.6 min, or = positive] ##STR00717## AA.1.56
1.83 (a) 335 1-(-2-ethyl-4-(2-(tetrahydro-2H-
pyran-4-yl)ethoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine prepared using FFF
from Example #22 Step D with 2- (tetrahydro-2H-pyran-4-
yl)acetaldehyde (Biofine), Z, A with Example #1, Step D, HATU, and
TEA, B with TEA, D with NaOH [Table 2, Method 33, R.sub.t = 11.2
min, or = negative] ##STR00718## AA.1.57 1.85 (a) 384
1-(-2-ethyl-4-(2-(tetrahydro-2H- pyran-4-yl)ethoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine prepared using FFF
from Example #22 Step D with 2- (tetrahydro-2H-pyran-4-
yl)acetaldehyde (Biofine), Z, A with Example #1, Step D, HATU, and
TEA, B with TEA, D with NaOH [Table 2, Method 33, R.sub.t = 5.2
min, or = negative] ##STR00719## AA.1.58 1.90 (a) 384
3-Ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentanone prepared using D with Preparation #25 and NaOH
[Table 2, Method 34, R.sub.t = 9.7 min, or = negative] ##STR00720##
AA.1.59 1.34 (a) 270 N-(((1S,3S)-3-(6H-imidazo[1,5-a]
pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl) methyl)cyclopropane
sulfonamide and N-(((1S,3R)-3-(6H-imidazo[1,5-a]
pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl) methyl)cyclopropane
sulfonamide (prepared using H from Example #5 Step C and
Preparation #M.1, HATU and DIEA; Q with Lawesson's reagent and
mercury (II) trifluoroacetate; K with cyclopropanesulfonyl chloride
[Matrix]; D with NaOH) [Table 2, Method 21, R.sub.t = 9.3 min,
##STR00721## AA.1.60* 1.67 (a) 360 or = ND]
N-(((1S,3S)-3-(6H-imidazo[1,5-a]
pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl) methyl)cyclopropane
sulfonamide and N-(((1S,3R)-3-(6H-imidazo[1,5-a]
pyrrolo[2,3-e]pyrazin-1-yl) cyclopentyl)methyl)cyclopropane
sulfonamide (prepared using H from Example #5 Step C and
Preparation #M.1, HATU and DIEA; Q with Lawesson's reagent and
mercury (II) trifluoroacetate; K with cyclopropanesulfonyl chloride
[Matrix]; D with NaOH) ##STR00722## AA.1.61* 1.70 (a) 360 [Table 2,
Method 21, R.sub.t = 11.6 min, or = ND]
N-(((1S,3R)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide and
N-(((1S,3S)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide
(prepared using H from Example #5 Step C and Preparation #M.1, HATU
and DIEA; Q with Lawesson's reagent and mercury (II)
trifluoroacetate; K with 3,3,3- ##STR00723## AA.1.62* 1.90 (a) 416
trifluoropropylsulfonyl chloride [Matrix]; D with NaOH) [Table 2,
Method 33, R.sub.t = 11.8 min, or = negative]
N-(((1S,3R)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide and
N-(((1S,3S)-3-(6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide
(prepared using H from Example #5 Step C and Preparation #M.1, HATU
and DIEA; Q with Lawesson's reagent and mercury (II)
trifluoroacetate; K with 3,3,3- ##STR00724## AA.1.63* 1.93 (a) 416
trifluoropropylsulfonyl chloride [Matrix]; D with NaOH) [Table 2,
Method 33, R.sub.t = 9 min, or = negative]
N-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)methyl)cyclopropane sulfonamide (prepared using K
with Preparation #21 Step C and cyclopropanesulfonyl chloride
[Matrix]; QQQ with TFA; A from Example #1 Step D, HATU and TEA; B
with TEA; D with NaOH) [Table 2, Method 5, R.sub.t = 5.8 min, or =
positive] ##STR00725## AA.1.64 1.61 (a) 389
N-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)methyl)cyclopropane sulfonamide (prepared using K
with Preparation #21 Step C and cyclopropanesulfonyl chloride
[Matrix]; QQQ with TFA; A from Example #1 Step D, HATU and TEA; B
with TEA; D with NaOH) [Table 2, Method 5, R.sub.t = 11.4 min, or =
negative] ##STR00726## AA.1.65 1.61 (a) 389
1-(2-ethyl-4-((tetrahydro-2H-pyran- 4-yl)methoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using FFF
from Example 22 Step D and tetrahydro-2H-pyran-4- carbaldehyde [J
& W PharmLab]; Z with NaOH; A from Example #1 Step D, HATU and
TEA; B with TEA; D with NaOH) [Table 2, Method 47, R.sub.t = 8.7
min, or = negative] ##STR00727## AA.1.66 1.83 (a) 370
1-(2-ethyl-4-((tetrahydro-2H-pyran- 4-yl)methoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using FFF
from Example #22 Step D and tetrahydro-2H-pyran-4- carbaldehyde [J
& W PharmLab]; Z with NaOH; A from Example #1 Step D, HATU and
TEA; B with TEA; D with NaOH) [Table 2, Method 47, R.sub.t = 13.8
min, or = negative] ##STR00728## AA.1.67 1.79 (a) 370
1-(2-ethyl-4-(tetrahydro-2H- thiopyran 1,1-dioxide-4-
yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using FFF from Example #22 Step D and dihydro-2H-
thiopyran-4(3H)-one; LLL with mCBPA; Z with NaOH; A from Example #1
Step D, HATU and TEA; B with DIEA; D with NaOH) [Table 2, Method
48, R.sub.t = 17.1 min, or = negative] ##STR00729## AA.1.68 1.67
(a) 404 1-(2-ethyl-4-(tetrahydro-2H- thiopyran 1,1-dioxide-4-
yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using FFF from Example #22 Step D and dihydro-2H-
thiopyran-4(3H)-one; LLL with mCPBA; Z with NaOH; A from Example #1
Step D, HATU and TEA; B with DIEA; D with NaOH) [Table 2, Method
48, R.sub.t = 11.6 min, or = negative] ##STR00730## AA.1.69 1.69
(a) 404 1-(2-ethyl-4-(tetrahydro-2H- thiopyran 1,1-dioxide-4-
yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example 22 Step C with 4-nitrobenzoic acid;
SS; VV; FFF with dihydro-2H- thiopyran-4(3H)-one; LLL with mCPBA; Z
with NaOH; A from Example #1 Step D, HATU and TEA; B with DIEA; D
with NaOH) [Table 2, Method 32, R.sub.t = 17.3 min, or = negative]
##STR00731## AA.1.70 1.66 (a) 404 1-(2-ethyl-4-
isopropoxycyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine (prepared using II from Example 22 Step C with 4-
nitrobenzoic acid; SS; VV; FFF with acetone; Z with NaOH; A from
Example #1 Step D, HATU and TEA; B with DIEA; D with NaOH) [Table
2, Method 28, R.sub.t = 7.1 min, or = negative] ##STR00732##
AA.1.71 1.85 (a) 314 N-((3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-
trifluoropropane-1-sulfonamide (prepared using X from Preparation
#22 Step C with dibenzylamine and NaBH(OAc).sub.3; TT with HCl; R
with trimethysilyl diazomethane, S with Example #3 Step E; E with
TFA; T using Lawesson's reagent; D with NaOH; KK; Y with
Pd(OH).sub.2 on C; K with 3,3,3-trifluoropropylsulfonyl chloride
[Matrix]; LL with NH.sub.4OH) [Table 2, Method 49 R.sub.t = 24.9
min then 50, R.sub.t = 8.6 min, or = negative] ##STR00733## AA.1.72
1.96 (a) 444 N-((3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)methyl)-3,3,3-
trifluoropropane-1- sulfonamide (prepared using X from Preparation
#22 Step C with dibenzylamine and NaBH(OAc).sub.3; TT with HCl; R
with trimethysilyl diazomethane; S with Example #3 Step E; E with
TFA; T using Lawesson's reagent; D with NaOH; KK; Y with
Pd(OH).sub.2 on C; K with 3,3,3-trifluoropropylsulfonyl chloride
[Matrix]; LL with NH.sub.4OH) [Table 2, Method 49 R.sub.t = 15 min
then 50 R.sub.t = 8.7 min, or = positive] ##STR00734## AA.1.73 1.96
(a) 444 N-((3-ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide
(prepared using X from Preparation #22 Step C with dibenzylamine
and NaBH(OAc).sub.3; TT with HCl; R with trimethylsilyl
diazomethane, S with Example #3 Step E; E with TFA; T using
Lawesson's reagent; D with NaOH; KK; Y with Pd(OH).sub.2 on C; K
with 3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with
NH.sub.4OH) [Table 2, Method 49 R.sub.t = 20.7 min then 50 R.sub.t
= 9.5 min, or = positive] ##STR00735## AA.1.74 1.96 (a) 444
N-((3-ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)methyl)-3,3,3- trifluoropropane-1-sulfonamide
(prepared using X from Preparation #22 Step C with dibenzylamine
and NaBH(OAc).sub.3; TT with HCl; R with trimethylsilyl
diazomethane, S with Example #3 Step E; E with TFA; T using
Lawesson's reagent; D with NaOH; KK; Y with Pd(OH).sub.2 on C; K
with 3,3,3-trifluoropropylsulfonyl chloride [Matrix]; LL with
NH.sub.4OH) [Table 2, Method 49 R.sub.t = 26.5 min then 50 R.sub.t
= 9 min, or = negative] ##STR00736## AA.1.75 1.97 (a) 444
N-(3-ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)-3,3,3- trifluoropropane-1-sulfonamide (prepared
using X from Example #22 Step B with dibenzylamine, TT with HCl, R
with trimethylsilyl diazomethane, S with Example #3 Step E, E with
TFA, T with Lawesson's reagent, D with NaOH, Y, K with
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix) and DIEA)
[Table 2, Method 31, R.sub.t = 16.9 min, or = positive]
##STR00737## AA.1.76 1.94 (a) 430 N-(3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)-3,3,3-
trifluoropropane-1-sulfonamide (prepared using X
from Example #22 Step B with dibenzylamine, TT with HCl, R with
trimethylsilyl diazomethane, S with Example #3 Step E, E with TFA,
T with Lawesson's reagent, D with NaOH, Y, K with
3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix) and DIEA)
[Table 2, Method 31, R.sub.t = 24 min, or = negative] ##STR00738##
AA.1.77 1.94 (a) 430 N-(3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)cyclopropanesulfonamide
(prepared using X from Example #22 Step B with dibenzylamine, TT
with HCl, R with trimethylsilyl diazomethane, S with Example #3
Step E, E with TFA, T with Lawesson's reagent, D with NaOH, Y, K
with cyclopropanesulfonyl chloride (Matrix) and DIEA) [Table 2,
Method 12, R.sub.t = 15 min, or = negative] ##STR00739## AA.1.78
1.73 (a) 374 N-(3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)-3,3-
difluoroazetidine-1-sulfonamide (prepared from prepared using X
from Example #22 Step B with dibenzylamine, TT with HCl, R with
trimethylsilyl diazomethane, S with Example #3 Step E, E with TFA,
T with Lawesson's reagent, D with NaOH, Y, ZZ, AAA with
3,3-difluoro- azetidine hydrochloride and TEA) [Table 2, Method 40,
R.sub.t = 15.8 min, ##STR00740## AA.1.79 1.84 (a) 425 or =
negative] 1-(4-(cyclopropylmethoxy)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using FFF from Example #22 Step D and
cyclopropanecarboxaldehyde, Z with NaOH, A with Example #1 Step D,
HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 38,
R.sub.t = 13.1 min, or = negative] ##STR00741## AA.1.80 1.90 (a)
326 N-3-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-4-
methylcyclopentyl)-2- hydroxyethylamino-1-sulfonamide (prepared
using D from Example #25 Step R with NaOH, LL) [Table 2, Method 32,
R.sub.t = 20.2 min, or = negative] ##STR00742## AA.1.81 1.21 379
N-3-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-4-
methylcyclopentyl)-2-methyl-2- hydroxypropylamino-1-sulfonamide
(prepared using AAA from Example #25 Step R and 2-methyl-2-
hydroxypropyl amine, D with NaOH, LL) [Table 2, Method 36, R.sub.t
= 12.4 min, or = negative] ##STR00743## AA.1.82 1.38 407
N-(3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-
methylcyclopentyl)morpholine-4- sulfonamide (prepared using AAA
from Example #25 Step R and morpholine, LL) [Table 2, Method 37,
R.sub.t = 16.4 min, or = negative] ##STR00744## AA.1.83 1.53 405
N-3-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-4-
methylcyclopentyl)-3-amino-1-N- methylazetidine-1-sulfonourea
(prepared using AAA from Example #25 Step R and 3-amino-1-N-methyl
azetidine, LL) [Table 2, Method 37, R.sub.t = 16.9 min, or =
negative] ##STR00745## AA.1.84 1.14 404 1-(8-ethyl-1,4-
dioxaspiro[4.4]nonan-7-yl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine (prepared using D from Preparation #25 Step D and NaOH)
[Table 2, Method 12, R.sub.t = 9.9 min, or = negative] ##STR00746##
AA.1.85 1.52 (a) 314 3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-
trifluoroethyl)cyclopentanamine (prepared using X from Preparation
#25 and 2,2,2-trifluoroethanamine, D with NaOH) [Table 2, Method
31, R.sub.t = 16.9 min, or = negative] ##STR00747## AA.1.86 1.62
(a) 353 1-(4-(3,3-difluoroazetidin-1-yl)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using X from Preparation #25 and 3,3-difluoroazetidine
hydrochloride [Matrix], D with NaOH) [Table 2, Method 21, R.sub.t =
9.4 min, or = negative] ##STR00748## AA.1.87 1.57 (a) 347
1-(4-(3,3-difluoropyrrolidin-1-yl)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using X from Preparation #25 and 3,3-difluoropyrrolidine
hydrochloride, D with NaOH) [Table 2, Method 20, R.sub.t = 9.5 min,
or = negative] ##STR00749## AA.1.88 1.60 (a) 361
1-(4-(4,4-dimethylcyclohexyloxy)-
2-ethylcyclopentyl)-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example
#22 Step with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with 4,4-
dimethylcyclohexanone, Z with NaOH, A with Example #1 Step D, HATU
and TEA, B with DIEA, D with NaOH) [Table 2, Method 41, R.sub.t =
10.5 min or = negative] ##STR00750## AA.1.89 2.45 (b) 382
1-(4-(cyclopropylmethoxy)-2- ethylcyclopentyl)-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example
#22 Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with
cyclopropanecarboxaldehyde, Z with NaOH, A with Example #1 Step D,
HATU and TEA, B with DIEA, D with NaOH) [Table 2, Method 42,
R.sub.t = 6.8 min, or = negative] ##STR00751## AA.1.90 1.89 (b) 326
1-(2-ethyl-4-(tetrahydro-2H-pyran- 4-yloxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using II
from Example #22 Step C with 4- nitrobenzoic acid, SS with NaOH,
VV, FFF with tetrahydro-4H-pyran- 4-one, Z with NaOH, A from
Example #1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table
2, Method 33, R.sub.t = 7.6 min, or = negative] ##STR00752##
AA.1.91 1.63 (b) 356 3-chloro-N-(3-ethyl-4-(3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)cyclopentyl)-4-
fluorobenzenesulfonamide (prepared using X from Example #22 Step B
with dibenzylamine, TT with HCl, R with trimethylsilyl
diazomethane, S with Example #3 Step E, E with TFA, T with
Lawesson's reagent, D with NaOH, Y, K with 3-chloro-4-
fluorobenzenesulfonyl chloride [Lancaster] and DIEA [Table 2,
Method 19, R.sub.t = 24.2 min, or = negative] ##STR00753## AA.1.92
2.11 (a) 462 4-(3-methyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyloxy)benzonitril
(prepared using P from Example #7, step G, EE with 4-methoxybenzyl-
2,2,2-trichloroacetimidate, Z with NaOH, , A with Example #1 Step
D, HATU, and TEA, B with DIEA, FF with 2,3-dichloro-5,6-dicyano-p-
benzoquinone, II with hydroxy- benzonitile, D with
Na.sub.2CO.sub.3) [Table 2, Method 17, R.sub.t = 25.7 min,
##STR00754## AA.1.93 1.94 (b) 430 or = positive]
4-(3-methyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)benzonitrile (prepared using P from Example #7,
step G, EE with 4-methoxybenzyl- 2,2,2-trichloroacetimidate, Z with
NaOH, A with Example #1 Step D, HATU, and TEA, B with DIEA, FF with
2,3-dichloro-5,6-dicyano-p- benzoquinone, II with hydroxy-
benzonitrile, D with Na.sub.2CO.sub.3) [Table 2, Method 17, R.sub.t
= 14.7 min, ##STR00755## AA.1.94 1.94 (b) 430 or = negative]
1-(2-ethyl-4-(5- (trifluoromethyl)pyridin-2-
yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from 5- (trifluoromethyl)pyridin-2-ol and
Preparation #FF.1, D with NaOH) [Table 2, Method 21, R.sub.t = 8
min, or = negative] ##STR00756## AA.1.95 2.33 (b) 417
1-(2-ethyl-4-(5- (trifluoromethyl)pyridin-2-
yloxy)cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from 5- (trifluoromethyl)pyridin-2-ol and
Preparation #FF.1, D with NaOH) [Table 2, Method 21, R.sub.t = 5.3
min, or = positive] ##STR00757## AA.1.96 2.33 (b) 417
5-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)pyrazine-2- carbonitrile (prepared using LL from
Preparation #JJ.1) [Table 2, Method 43, R.sub.t = 19.9 min, or =
negative] ##STR00758## AA.1.97 1.99 (b) 375
5-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)pyrazine-2- carbonitrile (prepared using LL from
Preparation #JJ.1) [Table 2, Method 43, R.sub.t = 18.3 min, or =
positive] ##STR00759## AA.1.98 2.01 (b) 375
3-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)methyl)benzo- nitrile (prepared using JJ from 3-
(bromomethyl)benzonitrile and Preparation #SS.1, LL with TFA and
ammonium hydroxide) [Table 2, Method 34, R.sub.t = 11.9 min, or =
negative] ##STR00760## AA.1.99 2.05 (b) 387
3-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)methyl)benzo- nitrile (prepared using JJ from 3-
(bromomethyl)benzonitrile and Preparation #SS.1, LL with TFA and
ammonium hydroxide) [Table 2, Method 34, R.sub.t = 15.1 min, or =
positive] ##STR00761## AA.1.100 2.05 (b) 387
4-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)methyl)benzo- nitrile (prepared using JJ from 4-
(bromomethyl)benzonitrile and Preparation #SS.1, LL with TFA and
ammonium hydroxide) [Table 2, Method 34, R.sub.t = 13.4 min, or =
negative] ##STR00762## AA.1.101 2.04 (b) 387
4-((3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)methyl)benzo- nitrile (prepared using JJ from 4-
(bromomethyl)benzonitrile and Preparation #SS.1, LL with TFA and
ammonium hydroxide) [Table 2, Method 34, R.sub.t = 16.9 min, or =
positive] ##STR00763## AA.1.102 2.04 (b) 387
4-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)-2- fluorobenzonitrile (prepared using II from
2-fluoro-4- hydroxybenzonitrile and Example #4 Step J, B with DIEA,
D with Na.sub.2CO.sub.3) [Table 2, Method 5, R.sub.t = 7.7 min, or
= negative] ##STR00764## AA.1.103 2.08 (b) 391
4-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)-3- fluorobenzonitrile (prepared using II from
3-fluoro-4- hydroxybenzonitrile and Example #4 Step J, B with DIEA,
D with Na.sub.2CO.sub.3) [Table 2, Method 44, R.sub.t = 12.5 min,
or = negative] ##STR00765## AA.1.104 2.12 (b) 391
3-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyloxy)benzonitrile (prepared using II from 3-
hydroxybenzonitrile and Example #4 Step J, B with DIEA, D with
Na.sub.2CO.sub.3) [Table 2, Method 33, R.sub.t = 12.1 min, or =
negative] ##STR00766## AA.1.105 2.09 (b) 373
3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentanol (prepared using II from benzoic acid and Example
#4 Step J, B with DIEA, D with Na.sub.2CO.sub.3) [Table 2, Method
45, R.sub.t = 9.1 min, or = negative] ##STR00767## AA.1.106 1.46
(b) 272 1-(2-ethyl-4-(3,3,3- trifluoropropoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using EE
from Preparation #UU.1 with 3,3,3- trifluoropropanol, Z with NaOH,
A from Example #1 Step D, HATU, and TEA, B with DIEA, D with NaOH)
[Table 2, Method 46, R.sub.t = 8.1 min] ##STR00768## AA.1.107 2.04
(b) 368 1-(2-ethyl-4-((tetrahyro-2H-pyran-
4-yl)methoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine (prepared using FFF from Example #22 Step D and
tetrahydro-2H-pyran-4- carbaldehyde [Pharmcore], Z with NaOH, A
from Example #1 Step D, HATU, and TEA, B with DIEA, D with NaOH)
[Table 2, Method 47, R.sub.t = 10 min, or = negative] ##STR00769##
AA.1.108 1.79 (b) 370 1-(2-ethyl-4-(2-
methoxyethoxy)cyclopentyl)-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine (prepared using FFF from Example #22 Step D and 2-
methoxyacetaldehyde [BBB Scientific], Z with NaOH, A from Example
#1 Step D, HATU, and TEA, B with DIEA, D with NaOH) [Table 2,
Method 44, R.sub.t = 11.7 min, or = negative] ##STR00770## AA.1.109
1.67 (b) 330 1-(2-ethyl-4-(2- methoxyethoxy)cyclopentyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine pyrazine (prepared
using FFF from Example #22 Step D and 2-methoxyacetaldehyde [BBB
Scientific], Z with NaOH, A from Example #1 Step D, HATU, and TEA,
B with DIEA, D with NaOH) [Table 2, Method 44, R.sub.t = 5.6 min,
or = negative] ##STR00771## AA.1.110 1.70 (b) 330
N-((1R,4R)-3,3-dimethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)cyclopropanesulfonamide and
N-((1S,4S)-3,3-dimethyl- 4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)cyclopropanesulfonamide (prepared as in
WO2009152133A1) [Table 2, Method 54, R.sub.t = 12.4 min, or =
negative] ##STR00772## AA.1.111 1.59 (b) 375
N-((1R,4R)-3,3-dimethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyl)cyclopropanesulfonamide and
N-((1S,4S)-3,3-dimethyl- 4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)cyclopropanesulfonamide (prepared as in
WO2009152133A1) [Table 2, Method 54, R.sub.t = 16.9 min, or =
positive] ##STR00773## AA.1.112 1.59 (b) 375
2-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)acetonitrile (prepared using III from Preparation
#25, Step E and diethyl cyanomethylphosphonate; BBBB; W.1) [Table
2, Method 33, R.sub.t = 9.6 min, or = negative] ##STR00774##
AA.1.113 1.58 (b) 295 2-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetonitrile
(prepared using III from Preparation #25, Step E and diethyl
cyanomethylphosphonate; BBBB; W.1) [Table 2, Method 33, R.sub.t =
11.8 min, or = negative] ##STR00775## AA.1.114 1.58 (a) 295
N-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)cyclopropanesulfonamide (prepared using D from
Preparation #25 and NaOH, KK, P with NaBH.sub.4, IIII, JJJJ with
NaN.sub.3, UUUU, K with cyclopropylsulfonyl chloride [Matrix], LL)
[Table 2, Method 56, R.sub.t = 12.2 min, or = negative]
##STR00776## AA.1.115 1.43 (a) 375 2-(3-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentylamino)oxetan-3-
yl)acetonitrile (prepared using D from
Preparation #25 and NaOH, KK, P with NaBH.sub.4, IIII, JJJJ with
NaN.sub.3, UUUU, YYY with 2-(oxetan- 3-ylidene)acetonitrile
[prepared as described in J. Med. Chem, 2010, 53(8) 3227-3246], LL)
[Table 2, Method 5, R.sub.t = 17.2 min, or = negative] ##STR00777##
AA.1.116 1.27 (a) 366 3-ethyl-1-methyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentanol (prepared using
ZZZ from Example #35, Step G and MeLi, LL) [Table 2, Method 33,
R.sub.t = 7.6 min, or = negative] ##STR00778## AA.1.117 1.59 (a)
286 3-(3-ethyl-4-(6-tosyl-6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyloxy)propanenitrile (prepared using YYY
from Example #22, Step C, acrylonitrile and DBU, Z with NaOH, A
with Example #1, Step D, B with SOCl.sub.2 and TEA, and D with
NaOH) [Table 2, Method 60, R.sub.t = 10.9 min, or = negative]
##STR00779## AA.1.118 1.70 (a) 325 3-(3-ethyl-4-(6-tosyl-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyloxy)propanenitrile (prepared using YYY from Example
#22, Step C, acrylonitrile and DBU, Z with NaOH, A with Example #1,
Step D, B with SOCl.sub.2 and TEA, and D with NaOH) [Table 2,
Method 60, R.sub.t = 15.0 min, or = negative] ##STR00780## AA.1.119
1.69 (a) 325 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (prepared
using W from Preparation #AAAA.1 and PdOH.sub.2 on C, and ZZZ with
CH.sub.3MgCl.sub.2) [Table 2, Method 40, R.sub.t = 6.0 min, or =
negative] ##STR00781## AA.1.120 1.75 (a) 328 Ethyl
2-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)acetate (prepared using W from Preparation #AAAA.1
and PdOH.sub.2 on C, and ZZZ with CH.sub.3MgCl.sub.2) [Table 2,
Method 40, R.sub.t = 10.3 min, or = negative] ##STR00782## AA.1.121
1.72 (a) 328 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (prepared
using W from Preparation #AAA.1 and PdOH.sub.2 on C, and ZZZ with
CH.sub.3MgCl.sub.2) [Table 2, Method 40, R.sub.t = 14.8 min, or =
negative] ##STR00783## AA.1.122 1.72 (a) 328 Ethyl
2-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)acetate (prepared using W from Preparation #AAA.1
and PdOH.sub.2 on C, and DDDD with (Z)-N'-
hydroxycyclopropanecarbox- imidamide [Tyger Scientific]) [Table 2,
Method 61, R.sub.t = 27.5 min, or = nd] ##STR00784## AA.1.123 1.95
(a) 378 Ethyl 2-(3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)acetate (prepared
using W from Preparation #AAAA.1 and PdOH.sub.2 on Carbon, and DDDD
with (Z)-N'- hydroxycyclopropane- carboximidamide [Tyger
Scientific]) [Table 2, Method 61, R.sub.t = 29.4 min, or = nd]
##STR00785## AA.1.124 1.95 (a) 378 Ethyl
2-(3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)cyclopentyl)acetae (prepared using W from Preparation #AAAA.1
and PdOH.sub.2 on C, and DDDD with (Z)-N'- hydroxycyclopropane-
carboximidamide [Tyger Scientific]) [Table 2, Method 61, R.sub.t =
32.8 min, or = nd] ##STR00786## AA.1.125 1.95 (a) 378
(cis)-N-(1-cyanocyclopropyl)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, step F, CDI and 1-
aminocyclopropanecarbonitrile.cndot. hydrochloride [Astatech], and
D with Na.sub.2CO.sub.3) [Table 2, Method 62, R.sub.t = 11.2 min,
or = negative] ##STR00787## AA.1.126 1.47 (a) 365
(cis)-N-(1-cyanocyclopropyl)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, step F, CDI and 1-
aminocyclopropanecarbonitrile.cndot. hydrochloride [Astatech], and
D with Na.sub.2CO.sub.3) [Table 2, Method 62, R.sub.t = 13.7 min,
or = positive] ##STR00788## AA.1.127 1.45 (a) 365
(cis)-N-cyclobutyl-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
carboxamide (prepared using J.1 from Example #36, step F, CDI and
cyclobutanamine, and D with NaOH) [Table 2, Method 34, R.sub.t =
8.6 min, or = positive] ##STR00789## AA.1.128 1.58 (a) 354
(cis)-N-cyclobutyl-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
carboxamide (prepared using J.1 from Example #36, step F, CDI and
cyclobutanamine, and D with with NaOH) [Table 2, Method 34, R.sub.t
= 11.2 min, or = negative] ##STR00790## AA.1.129 1.60 (a) 354
(cis)-3-ethyl-N-(3-methylisothiazol- 5-yl)-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and 3-
methylisothiazol-5-amine.cndot. hydrochloride, and D with NaOH)
[Table 2, Method 63, R.sub.t = 10.5 min, or = negative]
##STR00791## AA.1.130 1.56 (a) 397
(cis)-3-ethyl-N-(3-methylisothiazol- 5-yl)-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and 3-
methylisothiazol-5-amine.cndot. hydrochloride, and D with NaOH)
[Table 2, Method 63, R.sub.t = 13.4 min, or = positive]
##STR00792## AA.1.131 1.56 (a) 397 (cis)-N-(cyanomethyl)-3-ethyl-4-
(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)pyrrolidine-1-carboxamide (prepared using J.1 from Example #36,
Step F, CDI and 2- aminoacetonitrile, and D.2 with
Na.sub.2CO.sub.3) [Table 2, Method 64, R.sub.t = 11.0 min, or =
negative] ##STR00793## AA.1.132 1.42 (a) 339
(cis)-N-(cyanomethyl)-3-ethyl-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and 2-
aminoacetonitrile, and D.2 with Na.sub.2CO.sub.3) [Table 2, Method
64, R.sub.t = 13.3 min, or = positive] ##STR00794## AA.1.133 1.42
(a) 339 (cis)-3-ethyl-N-(oxazol-4-ylmethyl)- 4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and oxazol-4-
ylmethanamine.cndot.hydrochloride [J & W Pharmlab], and D with
NaOH) [Table 2, Method 65, R.sub.t = 10.6 min, or = negative]
##STR00795## AA.1.134 1.44 (a) 381
(cis)-3-ethyl-N-(oxazol-4-ylmethyl)- 4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and oxazol-4-
ylmethanamine.cndot.hydrochloride hydrochloride [J & W
Pharmlab], and D with NaOH) [Table 2, Method 65, R.sub.t = 11.8
min, or = positive] ##STR00796## AA.1.135 1.44 (a) 381
(cis)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)-N-(2,2,2- trifluoroethyl)pyrrolidine-1- carboxamide (prepared
using J.1 from Example #36, Step F, CDI and
2,2,2-trifluoroethanamine, and D with NaOH) [Table 2, Method 55,
R.sub.t = 14.5 min, or = negative] ##STR00797## AA.1.136 1.62 (a)
382 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-
trifluoroethyl)pyrrolidine-1- carboxamide (prepared using J.1 from
Example #36, Step F, CDI and 2,2,2-trifluoroethanamine, and D with
NaOH) [Table 2, Method 55, R.sub.t = 17.3 min, or = positive]
##STR00798## AA.1.137 1.62 (a) 382
(3,3-difluoroazetidin-1-yl)(cis)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)methanone
(prepared using D with Preparation #EEEE.1 and NaOH) [Table 2,
Method 64, R = 11.4 min, or = negative] ##STR00799## AA.1.138 1.65
(a) 376 (3,3-difluoroazetidin-1-yl)((cis)-3-
ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)pyrrolidin-1-yl)methanone (prepared using D with Preparation
#EEEE.1 and NaOH) [Table 2, Method 64, R.sub.t = 12.9 min, or =
positive] ##STR00800## AA.1.139 1.65 (a) 376
(cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
carboxamide (prepared using J.1 from Example #36, Step F, CDI and
oxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65,
R.sub.t = 7.1 min, or = racemic] ##STR00801## AA.1.140 1.34 (a) 356
(cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
carboxamide (prepared using J.1 from Example #36, Step F, CDI and
oxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65,
R.sub.t = 11.7 min, or = negative] ##STR00802## AA.1.141 1.43 (a)
356 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
carboxamide (prepared using J.1 from Example #36, Step F, CDI and
oxetan-3-amine [Synthonix], and D with NaOH) [Table 2, Method 65,
R.sub.t = 13.3 min, or = positive] ##STR00803## AA.1.142 1.42 (a)
356 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((R)-3-
hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example
#36, Step F, with (R)- pyrrolidin-3-ol, and D with NaOH) [Table 2,
Method 64, R.sub.t = 10.1 min, or = negative] ##STR00804## AA.1.143
1.44 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((R)-3-
hydroxypyrrolidin-1-yl)methananone (prepared using EEEE from
Example #36, Step F, (R)- pyrrolidin-3-ol, and D with NaOH) [Table
2, Method 64, R.sub.t = 11.8 min, or = positive] ##STR00805##
AA.1.144 1.42 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((S)-3-
hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example
#36, Step F, with (S)- pyrrolidin-3-ol, and D with NaOH) [Table 2,
Method 67, R.sub.t = 11.9 min, or = negative] ##STR00806## AA.1.145
1.40 (a) 370 ((cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidin-1-yl)((S)-3-
hydroxypyrrolidin-1-yl)methanone (prepared using EEEE from Example
#36, Step F, (S)-pyrrolidin- 3-ol, and D with NaOH) [Table 2,
Method 67, R.sub.t = 13.9 min, or = positive] ##STR00807## AA.1.146
1.42 (a) 370 (cis)-N-(cyclopropylmethyl)-3-ethyl-
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo
[4,3-a]pyrazin-1-yl)pyrrolidine-1- sulfonamide (prepared using ZZ
from cyclopropylmethanamine and TEA, AAA with Example #36, Step F,
and D with NaOH). [Table 2, Method 33, R.sub.t = 10.0 min, or =
positive] ##STR00808## AA.1.147 1.80 (a) 390
(cis)-N-(cyclopropylmethyl)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-sulfonamide
(prepared using ZZ from cyclopropylmethanamine and TEA, AAA with
Example #36, Step F, and D with NaOH). [Table 2, Method 33, R.sub.t
= 14.0 min, or = negative] ##STR00809## AA.1.148 1.78 (a) 390
(cis)-N-(2-cyclopropylethyl)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and 2-
cyclopropylethanamine [Oakwood], and D with NaOH). [Table 2, Method
33, R.sub.t = 6.8 min, or = positive] ##STR00810## AA.1.149 1.69
(a) 368 (cis)-N-(2-cyclopropylethyl)-3- ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1-carboxamide
(prepared using J.1 from Example #36, Step F, CDI and 2-
cyclopropylethanamine [Oakwood], and D with NaOH). [Table 2, Method
33, R.sub.t = 9.3 min, or = negative] ##STR00811## AA.1.150 1.70
(a) 368 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
sulfonamide (prepared using ZZ from oxetan-3-amine [Synthonix] and
TEA, AAA with Example #36, Step F, and D with NaOH). [Table 2,
Method 11, R.sub.t = 6.6 min, or = positive] ##STR00812## AA.1.151
1.58 (a) 392 (cis)-3-ethyl-N-(oxetan-3-yl)-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
sulfonamide (prepared using ZZ from oxetan-3-amine [Synthonix] and
TEA, AAA with Example #36, Step F, and D with NaOH). [Table 2,
Method 11, R.sub.t = 10.8 min, or = negative] ##STR00813## AA.1.152
1.58 (a) 392 (cis)-N-cyclobutyl-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
sulfonamide (prepared using ZZ from cyclobutanamine and TEA, AAA
with Example #36, Step F, and D with NaOH). [Table 2, Method 33,
R.sub.t = 9.5 min, or = positive] ##STR00814## AA.1.153 1.79 (a)
390 (cis)-N-cyclobutyl-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)pyrrolidine-1-
sulfonamide (prepared using ZZ from cyclobutanamine and TEA, AAA
with Example #36, Step F, and D with NaOH). [Table 2, Method 33,
R.sub.t = 12.7 min, or = negative] ##STR00815## AA.1.154 1.79 (a)
390 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)pyrrolidine-1- sulfonamide
(prepared using ZZ from 2-aminoacetonitrile and TEA, AAA with
Example #36, Step F, and D with NaOH). [Table 2, Method 68, R.sub.t
= 4.9 min, or = positive] ##STR00816## AA.1.155 1.48 (a) 336
(cis)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)pyrrolidine-1- sulfonamide (prepared using ZZ from
2-aminoacetonitrile and TEA, AAA with Example #36, Step F, and D
with NaOH). [Table 2, Method 68, R.sub.t = 10.4 min, or = negative]
##STR00817## AA.1.156 1.48 (a) 336 (cis)-3-ethyl-4-(6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-N-(2,2,2-
trifluoroethyl)pyrrolidine-1- sulfonamide (prepared using ZZ from
2,2,2-trifluoroethanamine and TEA, AAA with Example #36, Step F,
and D with NaOH). [Table 2, Method 66, R.sub.t = 12.9 min, or =
negative] ##STR00818## AA.1.157 1.85 (a) 418
(cis)-3-ethyl-4-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-
yl)-N-(2,2,2- trifluoroethyl)pyrrolidine-1- sulfonamide (prepared
using ZZ from 2,2,2-trifluoroethanamine and TEA, AAA with Example
#36, Step F, and D with NaOH). [Table 2, Method 66, R.sub.t = 15.8
min, or = positive] ##STR00819## AA.1.158 1.85 (a) 418
(cis)-3-ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-N-
(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide (prepared using
J.1 with Preparation #F.1.1 and 2,2,2- trifluoroethanamine, and D
with NaOH). [Table 2, Method 69, R.sub.t = 11.2 min, or = positive]
##STR00820## AA.1.159 1.52 (a) 381 (cis)-3-ethyl-4-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8-yl)-N-
(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide (prepared using
J.1 with Preparation #F.1.1 and 2,2,2- trifluoroethanamine, and D
with NaOH). [Table 2, Method 69, R.sub.t = 15.5 min, or = negative]
##STR00821## AA.1.160 1.52 (a) 381 1-((1,2,4)-4-(4,4-
difluorocyclohexyloxy)-2- ethylcyclopentyl)-6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine (prepared using II from Example
#22 Step C with 4-nitrobenzoic acid, SS with NaOH, VV, FFF with
4,4- difluorocyclohexanone [Small Molecule], Z with NaOH, A with
Example #1 Step D, HATU and TEA, B with DIEA, D with NaOH) [Table
2, Method 28, R.sub.t = 10.1 min, or = negative] ##STR00822##
AA.1.161 2.07 (b) 390 1-((1,2,4)-4-(4,4- difluorocyclohexyloxy)-2-
ethylcyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example #22 Step C with 4-nitrobenzoic
acid, SS with NaOH, VV, FFF with 4,4- difluorocyclohexanone [Small
Molecule], Z with NaOH, A with Example #1 Step D, HATU and TEA, B
with DIEA, D with NaOH) [Table 2, Method 28, R.sub.t = 15.1 min, or
= negative] ##STR00823## AA.1.162 2.05 (b) 390
1-((1,2,4)-2-ethyl-4-((1,4)-4- (trifluoromethyl)cyclohexyloxy)
cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example #22 Step C with 4-nitrobenzoic
acid, SS with NaOH, VV, FFF with 4- trifluoromethylcyclohexanone
[Matrix], Z with NaOH, A with Example #1 Step D, HATU and TEA, B
with DIEA, D with NaOH) [Table 2, Method 58, R.sub.t = 7.8 min, or
= negative] ##STR00824## AA.1.163 2.34 (b) 422
1-((1,2,4)-2-ethyl-4-((1,4)-4- (trifluoromethyl)cyclohexyloxy)
cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example #22 Step C with 4-nitrobenzoic
acid, SS with NaOH, VV, FFF with 4- trifluoromethylcyclohexanone
[Matrix], Z with NaOH, A with Example #1 Step D, HATU and TEA, B
with DIEA, D with NaOH) [Table 2, Method 51, R.sub.t = 14.6 min, or
= negative] ##STR00825## AA.1.164 2.22 (b) 422
1-((1,2,4)-2-ethyl-4-((1,4)-4- (trifluoromethyl)cyclohexyloxy)
cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example #22 Step C with 4-nitrobenzoic
acid, SS with NaOH, VV, FFF with 4- trifluoromethylcyclohexanone
[Matrix], Z with NaOH, A with Example #1 Step D, HATU and TEA, B
with DIEA, D with NaOH) [Table 2, Method 58, R.sub.t = 14.6 min, or
= negative] ##STR00826## AA.1.165 2.29 (b) 422
1-((1,2,4)-2-ethyl-4-((1,4)-4- (trifluoromethyl)cyclohexyloxy)
cyclopentyl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine
(prepared using II from Example #22 Step C with 4-nitrobenzoic
acid, SS with NaOH, VV, FFF with 4- trifluoromethylcyclohexanone
[Matrix], Z with NaOH, A with Example #1 Step D, HATU and TEA, B
with DIEA, D with NaOH) [Table 2, Method 51, R.sub.t = 15.8 min, or
= negative] ##STR00827## AA.1.166 2.22 (b) 422
(1,4)-4-((1,3,4)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1- yl)cyclopentyloxy)cyclohexane- carbonitrile (prepared
using II from Example #22 Step C with 4- nitrobenzoic acid, SS with
NaOH, VV, FFF with 4- oxocyclohexanecarbonitrile [Beta Pharma], Z
with NaOH, A with Example #1 Step D, HATU and TEA, B with DIEA, D
with NaOH) [Table 2, Method 57, R.sub.t = 14.3 min, or = negative]
##STR00828## AA.1.167 1.80 (b) 379 (1,4)-4-((1,3,4)-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyloxy)cyclohexane- carbonitrile (prepared using II from
Example #22 Step C with 4- nitrobenzoic acid, SS, with NaOH, VV,
FFF with 4- oxocyclohexanecarbonitrile [Beta Pharma], Z with NaOH,
A with Example #1 Step D, HATU and TEA, B with DIEA, D with NaOH)
[Table 2, Method 57, R.sub.t = 19.5 min, or = negative]
##STR00829## AA.1.168 1.80 (b) 379 (cis-3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclobutyl)methanamine (prepared from
Preparation #36 using N, R with trimethylsilyl diazomethane, S with
Example #3 Step E, E with TFA, KKKK with
2,2,3,3,3-pentafluoropropanoic anhydride, D with NaOH, F.1 with HBr
in AcOH) [Table 2, Method 71, R.sub.t = 29.8 min] ##STR00830##
AA.1.169 2.10 (r) 242 (trans-3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclobutyl)methanamine (prepared from
Preparation #36 using N, R with trimethylsilyl diazomethane, S with
Example #3 Step E, E with TFA, KKKK with
2,2,3,3,3-pentafluoropropanoic anhydride, D with NaOH, F.1 with HBr
in AcOH) [Table 2, Method 71, R.sub.t = 27.9 min] ##STR00831##
AA.1.170 2.10 (r) 242 N-((5-(3H-imidazo[1,2-a]pyrrolo
[2,3-e]pyrazin-8-yl)-4-methyltetra- hydrofuran-2-yl)methyl)-3,3,3-
trifluoropropane-1-sulfonamide (prepared using E with HCl from
Preparation #43, K with 3,3,3-trifluoro- propane-1-sulfonyl
chloride (Matrix), Z with NaOH, H with N,O-dimethyl- hydroxylamine,
hydrochloric acid, MMMM with methylmagnesium bromide, M.1, LLLL, S
from Example #3 Step E, E with TFA, KKKK with TFA & TFAA, D
with Na.sub.2CO.sub.3) ##STR00832## AA.171 1.72 (a) 432 [Table 2,
Method 51, R.sub.t = 46.2 min, or = positive]
N-((5-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-4-
methyltetrahydrofuran-2- yl)methyl)-3,3,3-trifluoropropane-
1-sulfonamide (prepared using E with HCl from Preparation #43, K
with 3,3,3-trifluoropropane-1- sulfonyl chloride (Matrix), Z with
NaOH, H with N,O- dimethylhydroxylamine, Hydrochloric Acid, MMMM
with methylmagnesium bromide, M.1, LLLL, S from Example #3
##STR00833## AA.172 1.72 (a) 432 Step E, E with TFA, KKKK with TFA
& TFAA, D with Na.sub.2CO.sub.3) [Table 2, Method 51, R.sub.t =
41.2 min, or = negative] 3-ethyl-1- (morpholinosulfonylmethyl)-4-
(6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)cyclopentanol
(prepared using NNNN with Preparation #41 and Example 35 Step G,
LL) [Table 2, Method 52, R.sub.t = 12 min, or = negative]
##STR00834## AA.173 1.63 (a) 435 3-ethyl-1-
(morpholinosulfonylmethyl)-4- (6H-pyrrolo[2,3-
e][1,2,4]triazolo[4,3-a]pyrazin- 1-yl)cyclopentanol (prepared using
NNNN with Preparation #41 and Example 35 Step G, LL) [Table 2,
Method 52, R.sub.t = 8.9 min, or = negative] ##STR00835## AA.174
1.60 (a) 435 3-ethyl-1- (morpholinosulfonylmethyl)-4-
(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-
1-yl)cyclopentanol (prepared using NNNN with Preparation #41 and
Example 35 Step G, LL) [Table 2, Method 53, R.sub.t = 18.7 min, or
= negative] ##STR00836## AA.175 1.56 (a) 435
8-(2-methyl-4-(tetrahydro-2H- pyran-4-yloxy)cyclopentyl)-3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (prepared using P from
Example #24 Step H, VV, FFF with dihydro-2H-pyran- 4(3H)-one, Z
with NaOH, R, S from Example #3 Step E, E with TFA, KKKK with
PFPAA, D with NaOH) [Table 2, Method 21, R.sub.t = 17.6 min, or =
negative] ##STR00837## AA.176 1.60 (a) 341
8-(2-methyl-4-(tetrahydro-2H- pyran-4-yloxy)cyclopentyl)-3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (prepared using P from
Example #24 Step H, VV, FFF with dihydro-2H-pyran- 4(3H)-one, Z
with NaOH, R, S from Example #3 Step E, E with TFA, KKKK with
PFPAA, D with NaOH) [Table 2, Method 21, R.sub.t = 5.1 min, or =
negative] ##STR00838## AA.177 1.65 (a) 341
8-(2-methyl-4-(tetrahydro-2H- pyran-4-yloxy)cyclopentyl)-3H-
imidazo[1,2-a]pyrrolo[2,3- e]pyrazine (prepared using P from
Example #24 Step H, II with 4-nitrobenzoic acid, SS, VV, FFF with
dihydro-2H- pyran-4(3H)-one, Z with NaOH, R, S from Example #3 Step
E, E with TFA, KKKK with PFPAA, D with NaOH) [Table 2, Method 28,
R.sub.t = 18.6 min, ##STR00839## AA.178 1.85 (a) 341 or = negative]
N-(3-methyl-4-(7-methyl-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using LLLL from
Preparation #M.1.1, S from Example #3 Step E, E with TFA, T with
Lawesson's Reagent, D with NaOH) [Table 2, Method 6, R.sub.t = 14.2
min, or = negative] ##STR00840## AA.179 1.66 (a) 374
N-(3-methyl-4-(7-methyl-3H- imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-
yl)cyclopentyl)cyclopropane- sulfonamide (prepared using LLLL from
Preparation #M.1.1, S from Example #3 Step E, E with TFA, T with
Lawesson's Reagent, D with NaOH) [Table 2, Method 6, R.sub.t = 9.3
min, or = positive] ##STR00841## AA.180 1.66 (a) 374
N,N-dibenzyl-3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentanamine (prepared using X from 3-
oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG with
Preparation #E.1.1, KKKK with PFPAA, D with NaOH, Y with
Pd(OH).sub.2) [Table 2, Method 59, R.sub.t = 10.5 min, or = ND]
##STR00842## AA.1.181 1.18 (b) 242 N,N-dibenzyl-3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X
from 3- oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF,
GGGGG with Preparation #E.1.1,, KKKK with PFPAA, D with NaOH, Y
with Pd(OH).sub.2) [Table 2, Method 59, R.sub.t = 12.0 min, or =
ND] ##STR00843## AA.1.182 1.17 (b) 242
N,N-dibenzyl-3-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentanamine (prepared using X from 3-
oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF, GGGGG with
Preparation #E.1.1, KKKK with PFPPA, D with NaOH, Y with
Pd(OH).sub.2) [Table 2, Method 59, R.sub.t = 13.5 min, or = ND]
##STR00844## AA.1.183 1.11 (b) 242 N,N-dibenzyl-3-(3H-imidazo[1,2-
a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine (prepared using X
from 3- oxocyclopentanecarboxylic acid and dibenzylamine, FFFFF,
GGGGG with Preparation #E.1.1, KKKK with PFPAA, D with NaOH, Y with
Pd(OH).sub.2) [Table 2, Method 59, R.sub.t = 17.1 min, or = ND]
##STR00845## AA.1.184 1.17 (b) 242 N-(2-cyclopropylethyl)-N-
((1S,3R,4S)-3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)oxetan- 3-amine (prepared using X from
Preparation #25 and oxetan-3-amine [Synthonix], X using 2-
cyclopropylacetaldehyde [Anichem], and D with NaOH [Table 2, Method
55, R.sub.t = 22.7 min, or = negative] ##STR00846## AA.1.185* 1.38
(a) 395 N-(cyclopropylmethyl)-N- ((1S,3R,4S)-3-ethyl-4-(6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)oxetan- 3-amine (prepared using X from
Preparation #25 and oxetan-3-amine [Synthonix], X using
cyclopropanecarbaldehyde, and D with NaOH [Table 2, Method 6,
R.sub.t = 15.9 min, or = negative] ##STR00847## AA.1.186* 1.21 (a)
381
[1516] General Procedure BB: Acidic Hydrolysis of an Acetyl
Protected Amine
[1517] To a solution of an N-acetamide (preferably 1 equiv) in an
organic solvent (such as 1,4-dioxane) is added an acid, such as 6 N
aqueous HCl (3-100 equiv, preferably 30-40 equiv). The reaction
mixture is heated at about 60-100.degree. C. (preferably about
90-100.degree. C.) for about 1-24 h (preferably about 16 h). The
reaction mixture is allowed to cool to ambient temperature before
it is partitioned between an organic solvent (such as EtOAc or DCM)
and aqueous base (such as NaHCO.sub.3, Na.sub.2CO.sub.3 or NaOH,
preferably NaHCO.sub.3) and the aqueous layer is optionally
extracted with additional organic solvent (such as EtOAc or DCM).
The organic layer is dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, filtered, and concd under reduced pressure.
Illustration of General Procedure BB
Preparation #BB.1*:
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine
##STR00848##
[1519] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)acetamide (6.0 g, 12.86 mmol, Example #8,
Step L) in 1,4-dioxane (78 mL) was added aqueous HCl (6 N, 75 mL,
450 mmol). The reaction mixture was heated at about 95.degree. C.
for about 16 h. The reaction was cooled to ambient temperature and
the solvent was removed under reduced pressure. The residue was
diluted with DCM (50 mL) and washed with saturated aqueous
NaHCO.sub.3 (100 mL). The aqueous portion was extracted with
additional DCM (3.times.50 mL) and the combined organic layers were
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-100%
DCM/MeOH/NH.sub.4OH (950:45:5) in DCM to give
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (3.05 g, 56%) as a tan solid: LC/MS
(Table 1, Method a) R.sub.t=1.85 min; MS m/z: 425 (M+H).sup.+.
[1520] General Procedure CC: Formation of a Sulfamoyl Chloride
[1521] A round bottom flask is charged with an amine or amine salt
(preferably 1 equiv) in an organic solvent (for example, DCM or
toluene or toluene/DCM). If an amine salt is used, a base such as
TEA or DIEA, preferably DIEA (1-10 equiv, preferably 2.5 equiv) is
added and the reaction is stirred for about 1-20 min, (preferably
about 5 min). The reaction mixture is then cooled to about
-50-20.degree. C., (preferably about -30.degree. C.) for about 1-10
min (preferably about 5 min). Sulfuryl chloride or a solution of
sulfuryl chloride (such as 1 M in DCM), preferably sulfuryl
chloride (1-10 equiv, preferably 3.5 equiv) is added dropwise to
the reaction mixture. The reaction mixture is stirred at about
-50-0.degree. C. (preferably about -30.degree. C.) for about 0.5-4
h (preferably about 1 h) then is allowed to warm to ambient
temperature and is stirred for about 1-24 h (preferably about 5 h).
The reaction is then diluted with an organic solvent (such as DCM,
EtOAc or toluene), and is washed with an aqueous solution of HCl
(such as 0.1-6 M, preferably 1 M). Optionally, the reaction is
poured over crushed ice and the layers are separated. The organic
extracts are optionally washed with water and/or brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or decanted, and
coned under reduced pressure.
Illustration of General Procedure CC
Preparation #CC.1: azetidine-1-sulfonyl chloride
##STR00849##
[1523] An oven dried flask is charged with azetidine hydrochloride
(2.00 g, 21.38 mmol), DIEA (5.60 mL, 32.10 mmol), and DCM (50 mL).
The reaction mixture was stirred for about 5 min at ambient
temperature and then cooled to about -30.degree. C. in a dry
ice/MeCN bath for about 5 min. Sulfuryl chloride (4.30 mL, 53.60
mmol, Acros) was added dropwise over about 5 min. The reaction
mixture was stirred at about -30.degree. C. for about 1 h, then at
ambient temperature for about 5 h. The reaction mixture was diluted
with aqueous HCl (1 N, 15 mL). The layers were separated and the
aqueous layer was extracted with DCM (10 mL). The combined organic
layers were washed with aqueous HCl (1 N, 10 mL) and brine (20 mL).
The organic layers were dried over anhydrous MgSO.sub.4, filtered,
and the solvent was removed under reduced pressure to give
azetidine-1-sulfonyl chloride (1.86 g, 56%): .sup.1H NMR
(CDCl.sub.3) .delta. 4.25-4.01 (m, 4H), 2.51-2.29 (m, 2H).
[1524] General Procedure DD: Formation of a Sulfonylurea
[1525] To a solution of an amine (preferably 1 equiv) and a base
such as TEA, DIEA, Na.sub.2CO.sub.3, or K.sub.2CO.sub.3 (1-20
equiv, preferably 2.5 equiv of TEA) in an organic solvent (such as
DMF, DMA, DCM, THF, or 1,4-dioxane, preferably DMF) at about
-10.degree. C. to ambient temperature (preferably about 0.degree.
C.) is added a sulfamoyl chloride (1-5 equiv, preferably 2.2
equiv). The reaction mixture is stirred for about 1-48 h
(preferably about 2-4 h) at ambient temperature. In cases where the
reaction does not proceed to completion as monitored by TLC, LC/MS,
or HPLC, additional sulfamoyl chloride is added portionwise (1-20
equiv in total, preferably 3 equiv per addition) to the reaction
mixture about every 12-72 h (preferably about every 24 h) and the
reaction mixture is stirred at ambient temperature until progress
of the reaction has halted as monitored by TLC, LC/MS, or HPLC. The
reaction mixture is concd to dryness under reduced pressure and/or
diluted with an organic solvent (such as EtOAc or DCM) and water.
The combined organic extracts are optionally washed with water
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, or decanted, and concd under reduced pressure.
Optionally, the reaction is diluted with water and the solid is
collected by vacuum filtration, washed with additional water, and
dried under vacuum.
Illustration of General Procedure DD
Preparation #DD.1*:
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)azetidine-1-sulfonamide
##STR00850##
[1527] A flask was charged with
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (0.200 g, 0.471 mmol, Example #8, Step M)
and DMF (4 mL). The solution was cooled to about 0.degree. C.
followed by the addition of TEA (0.16 mL, 1.2 mmol) and
azetidine-1-sulfonyl chloride (0.165 g, 1.06 mmol, Preparation
#CC.1). The reaction mixture was warmed to ambient temperature and
was stirred for about 2 h. The solvent was removed under reduced
pressure and DCM (10 mL) was added to the resulting residue. The
organic solution was washed with water and brine (5 mL each). The
combined organics were dried over anhydrous MgSO.sub.4, filtered,
and concd under reduced pressure to give a brown oil. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-70% EtOAc in DCM to afford
N--((S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)-cyclopentyl)azetidine-1-sulfonamide (0.20 g, 77%) as a
white solid: LC/MS (Table 1, Method a) R.sub.t=2.39 min; MS m/z:
544 (M+H).sup.+.
TABLE-US-00039 TABLE DD.1 Example prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) using
General Procedure DD R.sub.t min (Table 1, m/z ESI+ Sulfonyl
chloride Product Example # Method) (M + H).sup.+
pyrrolidine-1-sulfonyl chloride [ChemBridge-BB] ##STR00851##
DD.1.1* 1.79 (b) 389
TABLE-US-00040 TABLE DD.2 Example prepared from
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazine
hydrochloride (Example #6, Step H) using General Procedure DD
R.sub.t min (Table 1, m/z ESI+ Sulfonyl chloride Product Example #
Method) (M + H).sup.+ pyrrolidine-1-sulfonyl chloride
[ChemBridge-BB] ##STR00852## DD.2.1* 1.67 (b) 375
[1528] General Procedure EE: Ether Formation from a
Trichloroacetimidate Derivative
[1529] To an alcohol (preferably 1 equiv) in a mixture of organic
solvents such as DCM and cyclohexane (1:1 to 1:5, preferably 1:2)
at about -10-5.degree. C. (preferably about 0.degree. C.) is added
a 2,2,2-trichloroacetimidate derivative (1-3 equiv, preferably 1.6
equiv) followed by a slow addition of an acid such as
p-toluenesulfonic acid or trifluoromethanesulfonic acid (0.05-1
equiv, preferably 0.08-0.1 equiv). The reaction mixture is stirred
at about -10-5.degree. C. (preferably about 0.degree. C.) for about
5-60 min (preferably about 30 min). The ice bath is removed and the
reaction mixture is stirred at ambient temperature for about 2-24 h
(preferably about 16 h). The suspension is poured into ice water
and stirred for about 5-60 min (preferably about 30 min). The
suspension is either filtered while washing with an organic solvent
such as DCM or diluted with an organic solvent such as DCM. The
layers are separated and the aqueous layer is extracted with an
organic solvent such as DCM. The combined organic layers are washed
with water, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered and coned under reduced pressure.
Illustration of General Procedure EE
Preparation #EE.1: Ethyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate
##STR00853##
[1531] To a mixture of ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (37.78 g, 203 mmol,
Preparation #P.1) in DCM (100 mL) and cyclohexane (200 mL) at about
0.degree. C. was added 4-methoxybenzyl 2,2,2-trichloroacetimidate
(93.58 g, 331 mmol) followed by dropwise addition of
trifluoromethanesulfonic acid (1.6 mL, 18.0 mmol) over about 35
min. The reaction mixture was stirred at about 0.degree. C. for
about 30 min. The ice bath was removed and the reaction mixture was
stirred at ambient temperature for about 16 h. The suspension was
poured into ice-water (500 mL) and stirred for about 30 min. The
solid was removed by filtration while washing with DCM (100 mL).
The layers in the filtrate were separated and the aqueous layer was
extracted with DCM (3.times.200 mL). The combined organic layers
were washed with water (200 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The crude material was
purified using silica gel chromatography eluting with a gradient of
0-100% DCM:EtOAc (95:5) in DCM to give ethyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.80 g,
64%): LC/MS (Table 1, Method b) R.sub.t=2.90 min; MS m/z: 307
(M+H).sup.+.
[1532] General Procedure FF: Deprotection of a PMB Protected
Alcohol
[1533] To a PMB protected alcohol (preferably 1 equiv) in an
mixture of solvents such as DCM and water (1:1 to 7:1, preferably
5:1) is added 2,3-dichloro-5,6-dicyano-p-benzoquinone (1-2 equiv,
preferably 1.2 equiv). The reaction mixture is stirred at ambient
temperature for about 8-24 h (preferably about 16 h). The solid is
removed by filtration while washing with an organic solvent such as
DCM. The layers in the filtrate are separated and the organic layer
is washed with saturated aqueous NaHCO.sub.3 and brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure.
Illustration of General Procedure FF
Preparation #FF.1:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanol
##STR00854##
[1535] To
2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,-
3-e][1,2,4]triazolo[4,3-a]pyrazine (1.153 g, 2.11 mmol, prepared
using Z from Preparation #EE.1, A from Example #1, Step D, HATU,
and TEA, B with DIEA) in DCM (18 mL) and water (3.5 mL) was added
2,3-dichloro-5,6-dicyano-p-benzoquinone (0.576 g, 2.54 mmol). The
reaction mixture was stirred at ambient temperature for about 16 h.
The solid was removed by filtration while washing with DCM (150
mL). The organic layer was separated and washed with saturated
aqueous NaHCO.sub.3 (2.times.40 mL) and brine (40 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The residue was purified using silica gel chromatography (40 g)
eluting with a gradient of 30-100% EtOAc in DCM to give
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanol (0.672 g, 75%): LC/MS (Table 1, Method b) R.sub.t=2.09
min; MS m/z: 426 (M+H).sup.+.
[1536] General Procedure GG: Formation of a Lactone
[1537] To a .gamma.-alcohol carboxylic acid (preferably 1 equiv) in
an organic solvent such as DCM is added a base (such as TEA, 3-5
equiv, preferably 3 equiv) and BOP-Cl (1-2 equiv, preferably 1.2
equiv). The reaction mixture is stirred at ambient temperature for
about 1-5 h (preferably about 2 h). The reaction mixture is poured
into an organic solvent (preferably Et.sub.2O). The solid is
removed by filtration while washing with an organic solvent such as
Et.sub.2O. The filtrate is concd under reduced pressure.
Alternatively, the filtrate is washed with saturated aqueous
NaHCO.sub.3, 1 N aqueous citric acid, and brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure.
Illustration of General Procedure GG
Preparation #GG.1*:
(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one
##STR00855##
[1539] To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid
(0.943 g, 5.96 mmol, Example #4, Step H) in DCM (60 mL) was added
TEA (2.5 mL, 18 mmol) and BOP-Cl (1.82 g, 7.15 mmol). The reaction
mixture was stirred at ambient temperature for about 2 h then
poured into Et.sub.2O (350 mL). The solid was removed by filtration
while washing with Et.sub.2O (50 mL). The filtrate was concd under
reduced pressure to give a yellow oil which was dissolved in DCM (5
mL) and Et.sub.2O was added to give a solid. The supernatant was
decanted and the solid was washed with additional Et.sub.2O. The
combined organic extracts were concd under reduced pressure to give
(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about
15 mol % TEA (0.912 g, 99% crude): .sup.1H NMR (CDCl.sub.3) .delta.
4.85 (s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m,
1H), 1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
[1540] General Procedure HH: Opening of a Lactone with an Amine or
Hydrazine
[1541] To a lactone (preferably 1 equiv) in an organic solvent such
as 1,4-dioxane or DCM (preferably 1,4-dioxane) is added a hydrazine
(1-1.5 equiv, preferably 1 equiv). Alternatively, a lactone
(preferably 1 equiv) is added to a solution of an HCl salt of an
amine and DIEA (1-1.5 equiv, preferably 1 equiv) in an organic
solvent or mixture of solvents (such as 1,4-dioxane, DCM, or
DCM/DMF, preferably DCM). The reaction mixture is stirred at
ambient temperature or heated at about 40-100.degree. C.
(preferably about 80.degree. C. when 1,4-dioxane is used, reflux
when DCM is used) for about 1-24 h (preferably about 16 h). If
heating, the reaction mixture is cooled to ambient temperature. In
cases where the reaction does not proceed to completion as
monitored by TLC, LC/MS or HPLC, trimethylaluminum (1-8 equiv,
preferably 3 equiv) is added dropwise neat or in solution (such as
2 M in chlorobenzene, 2 M in heptane, or 2 M in toluene, preferably
2M in toluene) after the optional addition of an organic solvent
(such as 1,4-dioxane, DCM, or DMF, preferably 1,4-dioxane) and the
reaction mixture is stirred at ambient temperature for about
0.25-16 h (preferably about 0.5 h). Optionally, trimethylaluminum
neat or in solution as described above may be added from the onset
of the reaction. Aqueous HCl (1 N, 3-10 equiv, preferably 8 equiv)
is added dropwise and the reaction mixture is stirred for about
10-60 min (preferably about 30 min). The layers are separated and
the aqueous layer is extracted with an organic solvent such as
EtOAc or DCM (preferably EtOAc). The combined organic portions are
washed with water, saturated aqueous NaHCO.sub.3, brine and dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd
under reduced pressure.
Illustration of General Procedure HH
Preparation #HH.1*:
(1S,2R,4S)-2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cy-
clopentanecarbohydrazide
##STR00856##
[1543] To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835
g, 5.96 mmol, Preparation #GG.1) in 1,4-dioxane (12 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D,
1.81 g, 5.96 mmol). The reaction mixture was heated at about
80.degree. C. for about 16 h then cooled to ambient temperature.
1,4-Dioxane (25 mL) and trimethylaluminum (2 N in toluene, 9 mL, 18
mmol) were added sequentially. The reaction mixture was stirred at
ambient temperature for about 30 min. Aqueous HCl (1 N, 50 mL) was
added dropwise and the reaction mixture was stirred for about 30
min. The layers were separated. The aqueous portion was extracted
with EtOAc (2.times.100 mL). The combined organic extracts were
washed with water (10 mL), saturated aqueous NaHCO.sub.3 (15 mL),
brine (15 mL) and dried over anhydrous MgSO.sub.4, filtered, and
coned under reduced pressure. The residue was purified using silica
gel chromatography (40 g) eluting with 100% EtOAc to give
(1S,2R,4S)-2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-
-2-yl)cyclopentane-carbohydrazide (1.887 g, 53%): LC/MS (Table 1,
Method b) R.sub.t=2.05 min; MS m/z: 444 (M+H).sup.+.
TABLE-US-00041 TABLE HH.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-
a]pyrrolo[2,3-e]pyrazine hydrochloride (Example #5, Step J) using
General Procedure HH with DIEA R.sub.t min (Table 1, m/z ESI+
Lactose Product Example # Method) (M + H).sup.+
.beta.-propiolactone ##STR00857## HH.1.1* 1.02 (b) 328
[1544] General Procedure II: Mitsunobu Reaction of an Alcohol
[1545] To an alcohol (preferably 1 equiv) in an organic solvent
such as THF, benzene, toluene, or 1,4-dioxane (preferably THF) is
added a suitably acidic reactant (such as a carboxylic acid, a
phenol or a heteroaryl alcohol, 1-3 equiv, preferably 1.5 equiv),
followed by tri-n-butylphosphine, triphenylphosphine or polymer
bound triphenylphosphine (preferably polymer bound
triphenylphosphine, 1-3 equiv, preferably 1.5 equiv), and TEA (1-6
equiv, preferably 4.5 equiv). TMAD,
1,1'-(azodicarbonyl)dipiperidine, DIAD or DEAD (preferably DEAD,
1-3 equiv, preferably 1.5 equiv) is added dropwise. The reaction
mixture is stirred at ambient temperature for about 5-48 h
(preferably about 16 h). Alternatively, after about 0.1-24 h
(preferably about 1 h), additional phosphine reagent (0.2-2 equiv,
preferably 0.75 equiv) and TMAD, 1,1'-(azodicarbonyl)dipiperidine,
DIAD or DEAD (0.2-1 equiv, preferably 0.75 equiv) are added to
drive the reaction to completion. When polymer bound reagent is
used, the reaction mixture is filtered and washed with a mixture of
solvents such as DCM, EtOAc and MeOH (preferably DCM then MeOH).
The filtrate is concd under reduced pressure. When no polymer bound
reagent is used, the reaction mixture is diluted with an organic
solvent such as DCM or EtOAc and then washed with water, saturated
aqueous NaHCO.sub.3, brine and dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure II
Preparation #II.1*:
(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-AN-(5-tosyl-5H-pyrrolo[2,3-b]pyrazi-
n-2-yl)cyclopentanecarbohydrazide
##STR00858##
[1547] To
(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-
-2-yl)cyclopentane-carbohydrazide (0.885 g, 1.99 mmol, Example #4,
Step J) in THF (15 mL) was added 4-hydroxybenzonitrile (0.357 g,
2.99 mmol), triphenylphosphine (0.998 g, 2.99 mmol, polymer bound,
3 mmol/g), and TEA (1.3 mL, 9 mmol). DEAD (0.47 mL, 2.99 mmol) was
added dropwise. The reaction mixture was stirred for about 1 h then
additional triphenylphosphine (0.50 g, 1.50 mmol, polymer bound, 3
mmol/g) and DEAD (0.2 mL, 1.3 mmol) were added and the reaction
mixture was stirred at ambient temperature for about 16 h. The
solid was removed by filtration while washing with DCM (5.times.5
mL) then MeOH (4.times.5 mL). The filtrate was concd under reduced
pressure and the residue was purified using silica gel
chromatography (40 g) eluting with a gradient of 0-40% EtOAc in DCM
to give
(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazi-
n-2-yl)cyclopentanecarbohydrazide (0.958 g, 88%) as a yellow foam:
LC/MS (Table 1, Method b) R.sub.t=2.56 min; MS m/z: 545
(M+H).sup.+.
[1548] General Procedure JJ: Displacement of a Halide with an
Alcohol
[1549] To an alcohol (preferably 1 equiv) in an organic solvent
such as DMF, THF or 1,4-dioxane (preferably DMF) at about
0-25.degree. C. (preferably ambient temperature) is added NaH (60%
dispersion in mineral oil, 1-4 equiv, preferably 1.2 equiv) in
portions. After about 2-60 min (preferably about 5 min), a halide
(1-30 equiv, preferably 1.1 equiv) is added. The reaction mixture
is heated at about 60-80.degree. C. (preferably about 70.degree.
C.) for about 1-16 h (preferably about 2 h). After cooling to
ambient temperature, ice-water is added to the reaction mixture or
the reaction mixture is poured into ice water and then extracted
with an organic solvent such as DCM or EtOAc (preferably DCM). The
combined organic portions are concd under reduced pressure.
Alternatively, the combined organic portions are washed with water,
saturated aqueous NaHCO.sub.3, brine and dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure JJ
Preparation #JJ.1:
5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,-
4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile
##STR00859##
[1551] To
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.098 g, 0.24
mmol, prepared using FF from Preparation #KK.1) in DMF (1 mL) was
added NaH (0.012 g, 0.29 mmol, 60% dispersion in mineral oil)
portionwise. After about 5 min, 2-chloro-5-cyanopyrazine (0.039 g,
0.28 mmol, ArkPharm) was added. The reaction mixture was heated at
about 70.degree. C. for about 2 h. After cooling to ambient
temperature, ice water (2 mL) was added and the mixture was
extracted with DCM (3.times.5 mL). The organic layers were combined
and the solvents were removed under reduced pressure. The residue
was purifed using silica gel chromatography (12 g) eluting with a
gradient of 20-80% EtOAc in DCM to give
5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e[
]1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile-
(0.085 g, 69%): LC/MS (Table 1, Method b) R.sub.t=2.84 min; MS m/z:
505 (M+H).sup.+.
[1552] General Procedure KK: SEM-Protection
[1553] To a pyrrole derivative (preferably 1 equiv) in an organic
solvent (such as THF, 1,4-dioxane, or DMF, preferably 1,4-dioxane)
at about 0-40.degree. C. (preferably ambient temperature) is added
NaH (60% dispersion in mineral oil) (1-3 equiv, preferably 1.05
equiv) in portions. The reaction mixture is stirred for about 1-60
min (preferably about 30 min). SEM-Cl (1-3 equiv, preferably 1.5
equiv) is then added. After about 15 min-24 h (preferably about 30
min), the solvent is removed and the residue is partitioned between
an organic solvent such as EtOAc and water. The layers are
separated and the organic solvent is removed under reduced pressure
to give the target compound. Alternatively, the reaction mixture is
poured slowly into ice water with stirring to provide a suspension.
Solids may be collected by filtration and dried to provide the
target compound. Also, the filtrate may be partitioned between an
organic solvent (such as EtOAc or DCM) and an aqueous base (such as
saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2SO.sub.4, preferably saturated aqueous NaHCO.sub.3). The
organic portion is separated and concd under reduced pressure to
provide the target compound.
Illustration of General Procedure KK
Preparation #KK.1:
1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-((2-(trimethylsilyl)ethox-
y)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR00860##
[1555] To a suspension of
1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]-tr-
iazolo[4,3-a]pyrazine (0.323 g, 0.825 mmol, prepared using Z from
Preparation #EE.1, A from Example #1, Step D, HATU, and TEA, B with
DIEA, D with NaOH) in 1,4-dioxane (2.5 mL) was added NaH (0.035 g,
0.866 mmol, 60% dispersion in mineral oil) in portions. The
reaction mixture was stirred at ambient temperature for about 30
min. SEM-Cl (0.15 mL, 0.83 mmol) was added. After about 30 min, the
solvent was removed and the residue was partitioned between EtOAc
(12 mL) and water (2 mL). The organic layer was separated and concd
under reduced pressure. The residue was purified using silica gel
chromatography (40 g) eluting with a gradient of 0-60% EtOAc in DCM
to give
1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-((2-(trimethylsilyl)ethox-
y)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.372 g,
86%): LC/MS (Table 1, Method b) R.sub.t=2.96 min; MS m/z: 522
(M+H).sup.+.
[1556] General Procedure LL: SEM-Deprotection
[1557] To a solution of a N-SEM-protected compound (preferably 1
equiv) in an organic solvent (such as DMF, 1,4-dioxane, or DCM,
preferably DCM) is added TFA (5-70 equiv, preferably 50 equiv) and
the reaction mixture is stirred at about 0-40.degree. C.
(preferably ambient temperature) for about 1-20 h (preferably about
1-4 h). Additional TFA (5-20 equiv, preferably 10 equiv) may be
added. The resulting mixture is concd under reduced pressure and
the residue is dissolved in an organic solvent such as 1,4-dioxane,
MeOH or EtOH (preferably 1,4-dioxane). An aqueous base (such as
NaOH or NH.sub.4OH, preferably NH.sub.4OH, 30-200 equiv, preferably
120 equiv) is added and the reaction mixture is heated at about
30-100.degree. C. (preferably about 60.degree. C.) for about 30 min
-10 h (preferably about 30 min). The reaction mixture is cooled to
ambient temperature, water is added and the product is isolated by
filtration. Alternatively the mixture may be partitioned between an
organic solvent (such as EtOAc or DCM) and an aqueous base (such as
saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2SO.sub.4, preferably saturated aqueous NaHCO.sub.3). The
organic portion is separated and concd under reduced pressure to
provide the target compound. In some cases an intermediate
hydroxymethylsulfonamide may be isolated.
Illustration of General Procedure LL
Preparation #LL.1:
5-(-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entyloxy)pyrazine-2-carbonitrile
##STR00861##
[1559] To
5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,-
3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitr-
ile (0.097 g, 0.19 mmol, Preparation #JJ.1) in DCM (2.5 mL) was
added TFA (0.7 mL, 10 mmol). The reaction mixture was stirred at
ambient temperature for about 1.5 h. The solvents were removed
under reduced pressure and the residue was dissolved in 1,4-dioxane
(1.3 mL). Ammonium hydroxide (28-30% aqueous ammonia, 2.5 mL, 24
mmol) was added and the reaction mixture was heated at about
60.degree. C. for about 30 min then cooled to ambient temperature.
Water (4 mL) was added and the precipitate was collected by
filtration to give
5-(-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entyloxy)pyrazine-2-carbonitrile (0.0628 g, 87%): LC/MS (Table 1,
Method b) R.sub.t=1.99 min; MS m/z: 375 (M+H).sup.+.
TABLE-US-00042 TABLE LL.1 Examples prepared using General Procedure
LL R.sub.t min m/z (Table 1, ESI+ Silyl protected pyrrole Product
Ex # Method) (M + H).sup.+ N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-
((2-(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)-N-((2-
(trimethylsilyl)ethoxy)methyl)cyclopro- panesulfonamide
(Preparation #23) ##STR00862## LL.1.1* 1.71 (a) 389
N-((1S,3R,4S)-3-ethyl-4-(8-methyl-6-
((2-(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyl)-N-((2-
(trimethylsilyl)ethoxy)methyl)cyclopro- panesulfonamide
(Preparation #23) ##STR00863## LL.1.2* 1.96 (a) 419
N-((1S,3S,4R)-3-(8-cyano-6-((2- (trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)-4-
ethylcyclopentyl)cyclopropanesul- fonamide (Preparation #HHH.1)
##STR00864## LL.1.3* 1.64 (b) 400 1-((1S,2R,4R)-2-ethyl-4-(2,2,2-
trifluoroethylsulfonyl)cyclopentyl)-6-
((2-(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (Preparation #LLL.1)
##STR00865## LL.1.4 1.81 (a) 402
3-fluoro-N-((1S,3R,4S)-3-methyl-4-(3-
((2-(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)propane-1-sulfonamide (prepared using FFFFF from
Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D
with NaOH, KK, Y; K with 3-fluoropropane-1-sulfonyl chloride
[Hande]) ##STR00866## LL.1.5* 1.53 (b) 380
3,3-difluoro-N-((1S,3R,4S)-3-methyl-4-
(3-((2-(trimethylsilyl)ethoxy)methyl)-
3H-imidazo[1,2-a]pyrrolo[2,3-
e]pyrazin-8-yl)cyclopentyl)cyclobutane- 1-sulfonamide (prepared
using FFFFF with Preparation #33, GGGGG with Preparation #E.1.1,
KKKK with PFPAA, D with NaOH, KK, Y, K with Preparation #34 and
DIEA) ##STR00867## LL.1.6* 1.84 (a) 410
3,3,3-trifluoro-N-methyl-N-((1S,3R,4S)- 3-methyl-4-(3-((2-
(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)propane-1-sulfonamide (prepared using FFFFF with
Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D
with NaOH, KK, Y, K with 3,3,3-trifluoropropane-1- sulfonyl
chloride (Matrix), S with iodomethane) ##STR00868## LL.1.7* 2.04
429 N-((1S,3R,4S)-3-methyl-4-(3-((2-
(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)azetidine-1-sulfonamide (prepared using FFFFF with
Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D
with NaOH, KK, Y, ZZ, AAA with azetidine) ##STR00869## LL.1.8* 1.53
375 3-fluoro-N-((1S,3R,4S)-3-methyl-4-(3-
((2-(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)azetidine-1-sulfonamide (prepared using FFFFF with
Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D
with NaOH, KK, Y, ZZ, AAA with 3- fluoroazetidine hydrochloride
[Parkway]) ##STR00870## LL.1.9* 1.73 393
2-cyano-N-((1S,3R,4S)-3-methyl-4-(3-
((2-(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentyl)acetamide
(prepared using FFFFF with Preparation #33, GGGGG with Preparation
#E.1.1, KKKK with PFPAA, D with NaOH, KK, Y, H with cyanoacetic
acid) ##STR00871## LL.1.10* 1.61 323
1-((1S,2R,4R)-4-(1H-pyrazol-1-yloxy)- 2-ethylcyclopentyl)-6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared from
Example # 35, Step H, using IIII and JJJJ with N- hydroxypyrazole
(prepared according to Journal of the Chemical Society, Perkin
Transactions 1: Organic and Bio- Organic Chemistry (1995), (3),
243- 7). ##STR00872## LL.1.11 1.87 338 (1R,3R,4S)-3-ethyl-4-(6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentanecarbonitrile (prepared from Example #35,
step H, using IIII and JJJJ with sodium cyanide) ##STR00873##
LL.1.12 1.75 281 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-
pyrazol-1-yl)-2-ethylcyclopentyl)-6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using JJJJ
from Example #35 step I, with sodium hydride and
5-cyclopropyl-1H-pyrazole (ChemBridge)) ##STR00874## LL.1.13 1.98
362 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-
pyrazol-1-yl)-2-ethylcyclopentyl)-6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared from
Example #35 step I, using JJJJ with sodium hydride and
5-cyclopropyl-1H-pyrazole (ChemBridge)) ##STR00875## LL.1.14 2.02
362 3-(-3-ethyl-4-(6-((2- (trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyloxy)methyl)- 5-methylisoxazole
(Preparation #HHHH.1) ##STR00876## LL.1.15 1.71 (b) 367
4-(2-(3-ethyl-4-(6-((2- (trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-
yl)cyclopentyloxy)ethyl)morpholine (prepared using HHHH from
Example #35, step H and 4-(2- chloroethyl)morpholine [Beta Pharma]
with KOH) ##STR00877## LL.1.16 1.16 (b) 385
1-(4-(2,2-difluoroethoxy)-2- ethylcyclopentyl)-6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using HHHH
from Example #35 step H and 2-bromo-1,1- difluoroethane [Lancaster]
with KOH) ##STR00878## LL.1.17 1.78 (b) 336
1-(4-(2,2-difluoroethoxy)-2- ethylcyclopentyl)-6-((2-
(trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine (prepared using HHHH
from Example #35, step H and 2-bromo-1,1- difluoroethane
[Lancaster] with KOH) ##STR00879## LL.1.18 1.62 (b) 314
1-(3-ethyl-4-(6-((2- (trimethylsilyl)ethoxy)methyl)-6H-
pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazin-1-yl)cyclopentyloxy)-2- methylpropan-2-ol (prepared using
HHHH from Example #35, step H and 1-chloro-2-methyl-2-propanol with
KOH) ##STR00880## LL.1.19 1.61 (b) 344
4-(3-((2-(trimethylsilyl)ethoxy)methyl)-
3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)piperidine-1-
carboximidamide (prepared using R from
1-(benzyloxycarbonyl)piperidine- 4-carboxylic acid (Matrix), S with
Example #3 Step E, E with TFA, KKKK with PFPAA, D with NaOH, KK,
DDDDD, EEEEE) ##STR00881## LL.1.20 2.04 (r) 284
8-cyclohexyl-1-methyl-3-((2- (trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (prepared using GGG with 8-
cyclohexyl-3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazine
(WO2009152133A1), KK, VVV with 2,4,6-trimethyl-1,3,5,2,4,6-
trioxatriborinane) ##STR00882## LL.1.21 2.21 (a) 255 t-butyl
2-oxo-2-(4-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H- imidazo[1,2-a
]pyrrolo[2,3-e]pyrazin-8- yl)piperidin-1-yl)ethylcarbamate
(prepared using R from 1- (benzyloxycarbonyl)piperidine-4-
carboxylic acid (Matrix), S from Example #3 Step E, E with TFA,
KKKK with PFPAA, D with NaOH, KK, DDDDD, H from 2-(t-
butoxycarbonylamino)acetic acid) ##STR00883## LL.1.22 2.84 (r) 299
(1S,3R,4S)-3-methyl-4-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- yl)cyclopentanamine
(prepared using X from Example #24 Step H and dibenzyl amine,
FFFFF, GGGGG from Preparation #E.1.1, KKKK with PFPAA, D with NaOH,
KK, Y) ##STR00884## LL.1.23 1.39 (a) 256
2-(3-((1S,3R,4S)-3-methyl-4-(3-((2-
(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentylamino)oxetan-3- yl)acetonitrile (Preparation YYY.1)
##STR00885## LL.1.24 1.49 (a) 351
N-(2-cyclopropylethyl)-N-((1S,3R,4S)-3- methyl-4-(3-((2-
(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)oxetan-3-amine (prepared using using X from Example
#24 Step H and dibenzyl amine, FFFFF, GGGGG from Preparation
#E.1.1), KKKK with PFPAA, D with NaOH, KK, Y, X with oxetan-3-one
[PharmaBlock], X with 2- cyclopropylacetaldehyde [Anichem])
##STR00886## LL.1.25 1.55 (a) 380
N-(cyclopropylmethyl)-N-((1S,3R,4S)-3- methyl-4-(3-((2-
(trimethylsilyl)ethoxy)methyl)-3H-
imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
yl)cyclopentyl)oxetan-3-amine (prepared using using X from Example
#24 Step H and dibenzyl amine, FFFFF, GGGGG from Preparation
#E.1.1), KKKK with PFPAA, D with NaOH, KK, Y, X with oxetan-3-one
[PharmaBlock], X with cyclopropanecarbaldehyde) ##STR00887##
LL.1.26 1.40 (a) 366
[1560] General Procedure LL.1: SEM-Deprotection
[1561] A N-SEM-protected compound is dissolved or suspended in an
organic solvent (such as DMF, 1,4-dioxane, THF, MeOH, or DCM,
preferably DCM). TFA, camphorsulfonic acid, or HCl, preferably TFA
(5-70 equiv, preferably 50 equiv) may be added and the reaction
mixture is stirred at about 0-40.degree. C. (preferably ambient
temperature) for about 1-20 h (preferably about 1-4 h). Optionally,
additional TFA (5-20 equiv, preferably 10 equiv) may be added. The
resulting mixture is concentrated under reduced pressure.
Alternatively, the solution or suspension of SEM-protected material
may be treated with a fluoride source such as TBAF or LiBF.sub.4,
preferably TBAF (1-20 equiv, preferably 6 equiv). Optionally, a
base such as aqueous NaOH, ethylenediamine, or aqueous NH.sub.4OH
(1-200 equiv, preferably ethylenediamine, 2 equiv) may be added.
The reaction mixture is heated at about 30-100.degree. C.
(preferably about 60.degree. C.) for about 30 min -72 h (preferably
about 24 h). The reaction mixture is cooled to ambient temperature.
Optionally the volatiles are removed under reduced pressure. The
reaction mixture is worked up using one of the following methods.
Method 1: The residue is dissolved in an organic solvent such as
1,4-dioxane, MeOH or EtOH (preferably 1,4-dioxane). A base such as
aqueous NaOH, ethylenediamine, or aqueous NH.sub.4OH (preferably
aqueous NH.sub.4OH, 1-200 equiv, preferably 120 equiv) is added and
the reaction mixture is heated at about 30-100.degree. C.
(preferably about 60.degree. C.) for about 5 min-10 h (preferably
about 30 min). The reaction mixture is cooled to ambient
temperature, water is added and the product is isolated by
filtration. Method 2: The mixture is partitioned between an organic
solvent (such as EtOAc or DCM) and an aqueous base (such as
saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2SO.sub.4, preferably saturated aqueous NaHCO.sub.3). The
organic portion is separated and concentrated under reduced
pressure to provide the target compound. Method 3: Optionally,
water, aqueous NaHCO.sub.3, or aqueous NH.sub.4Cl (preferably
water) is added. The product may be isolated by filtration or the
mixture may be extracted with an organic solvent (such as EtOAc or
DCM). The organics are dried over Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concentrated under reduced pressure to provide the
target compound. In some cases an intermediate
hydroxymethylsulfonamide may be isolated.
Illustration of General Procedure LL.1
Preparation #LL.1.1: tert-butyl
(trans-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)c-
yclohexyl)methylcarbamate
##STR00888##
[1563] Ethylenediamine (0.011 mL, 0.16 mmol) was added to a
solution of tert-butyl
(trans-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]tr-
iazolo[4,3-a]pyrazine-8-carboxamido)cyclohexyl)methylcarbamate
(0.043 g, 0.079 mmol, prepared using Z from Preparation #AAAAA.1
and KOH, H with tert-butyl trans-4-aminocyclohexylmethylcarbamate
[AMRI], HATU, and TEA) in THF (1 mL). TBAF (1.0 M solution in THF,
0.470 mL, 0.470 mmol) was added in one portion. The mixture was
heated at about 60.degree. C. After about 24 h, the solution was
allowed to cool to ambient temperature and stirred for about 40 h.
The volatiles were removed under reduced pressure. The residue was
slurried in water (10 mL) and extracted with EtOAc (4.times.20 mL).
The combined organic portions were washed with brine (10 mL), dried
over Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
eluting with a gradient of 2-10% MeOH/DCM to give tert-butyl
(trans-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carboxamido)
cyclohexyl)methylcarbamate (0.0094 g, 29%): LC/MS (Table 1, Method
n) R.sub.t=0.55 min; MS m/z: 414 (M+H).sup.+.
[1564] General Procedure MM: Halogenation of an Imidazole
[1565] To a solution of an imidazole (preferably 1 equiv) in an
organic solvent (such as DCM, MeOH or THF, preferably THF) is added
a halogenating reagent (such as bromine, pyridinium hydrobromide
perbromide, NCS, NBS, or NIS) (0.9-1.1 equiv, preferably 1 equiv).
The reaction is stirred at about -20-150.degree. C. (preferably
about 0-60.degree. C.) for about 10 min-48 h (preferably about 30
min). The reaction mixture is then partitioned between an organic
solvent (such as EtOAc, DCM or 1,4-dioxane, preferably EtOAc) and
an aqueous base (such as saturated aqueous NaHCO.sub.3 or saturated
aqueous Na.sub.2CO.sub.3, preferably saturated aqueous
NaHCO.sub.3). The aqueous layer is optionally extracted with
additional organic solvent (such as EtOAc or DCM). The combined
organic layers may optionally be washed with brine and concd in
vacuo or dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4 and
then decanted or filtered prior to concentrating under reduced
pressure to give the tareagent, and mercury(II)acetate) in THF (10
mL) at about 0.degree. C. was added a solution of NBS (0.12 g,
0.672 mmol) in THF (2 mL). After about 30 min, the reaction mixture
was diluted with EtOAc (20 mL) and saturated aqueous NaHCO.sub.3
(20 mL). The organic layer was separated, concd in vacuo, and
purified by chromatography on silica gel (40 g) eluting with
EtOAc:DCM:heptane (1:1:2) to provide
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazine (0.27 g 83%) as a tan solid: LC/MS
(Table 1, Method a) R.sub.t=3.12 min; MS m/z 473, 475 (1:1)
(M+H).sup.+.
Preparation #MM.1:
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
##STR00889##
[1567] To a solution of
1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27
g, 0.67 mmol, prepared using Q from Preparation #13, Lawesson's
reagent, and mercury(II)acetate) in THF (10 mL) at about 0.degree.
C. was added a solution of NBS (0.12 g, 0.672 mmol) in THF (2 mL).
After about 30 min, the reaction mixture was diluted with EtOAc (20
mL) and saturated aqueous NaHCO.sub.3 (20 mL). The organic layer
was separated, concd in vacuo, and purified by chromatography on
silica gel (40 g) eluting with EtOAc:DCM:heptane (1:1:2) to provide
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
(0.27 g 83%) as a tan solid: LC/MS (Table 1, Method a) R.sub.t=3.12
min; MS m/z 473, 475 (1:1) (M+H).sup.+.
[1568] General Procedure NN: Formation of an Amide from a
Carboxylic Acid and an Amine with Loss of a Sulfonamide Protecting
Group
[1569] To mixture of a 1-substituted
6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine with a
pendant amino group (preferably 1 equiv) and a carboxylic acid (1-2
equiv, preferably 1.5 equiv) in a solvent (such as DMF or THF,
preferably DMF) is added a coupling agent such as EDC.HCl or HATU
(1.0-2.0 equiv, preferably 1.2 equiv) with an organic base (such as
TEA or DIEA, 1-5 equiv, preferably 2 equiv). If EDC.HCl is used as
the coupling reagent, HOBT (1-3 equiv, preferably 1.2 equiv) is
added. After about 1-72 h (preferably about 18 h) at about
20-60.degree. C. (preferably ambient temperature), water is added
and the aqueous layer is extracted with an organic solvent such as
EtOAc or DCM. The combined organic layers are dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or decanted, and concd
under reduced pressure. Intermediates and final compounds prepared
via this General Procedure can be optionally purified using one or
more of the Purification Methods described above.
Illustration of General Procedure NN
Example #NN.1.1
N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobu-
tyl)methyl)-2-cyanoacetamide
##STR00890##
[1571] To a solution of
(1-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)--
cyclobutyl)methanamine (0.225 g, 0.548 mmol) (prepared using A from
Example #1, Step D,
2-(1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid [prepared as
described WO9921824A1], EDC.HCl, B with TEA, E with 4.0 M HCl in
1,4-dioxane) in DMF (10 mL) was added cyanoacetic acid (0.070 g,
0.822 mmol), HOBt (0.101 g, 0.658 mmol), EDC.HCl (0.126 g, 0.658
mmol) and DIEA (0.190 mL, 1.096 mmol) to give a brown solution. The
mixture was stirred at ambient temperature for about 18 h. Water
(20 mL) was added and the mixture was extracted with EtOAc
(3.times.25 mL). The combined organic layers were dried over
anhydrous MgSO.sub.4, filtered, and coned in vacuo. The crude
material was purified by flash chromatography on silica gel eluting
with a gradient of 0-10% MeOH in DCM to give
N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclob-
utyl)methyl)-2-cyanoacetamide as an off-white solid (0.030 g, 17%):
LC/MS (Table 1, Method a) R.sub.t=1.48 min; MS m/z: 324
(M+H).sup.+.
TABLE-US-00043 TABLE NN.1 Examples prepared using General Procedure
NN with cyanoacetic acid R.sub.t min m/z (Table ESI+ 1, Me- (M +
Amine Product Ex. # thod) H).sup.+ 1-((6-tosyl-6H- pyrrolo[2,3-e]
[1,2,4]triazolo [4,3-a]pyrazin- 1-yl)methyl) cyclo- butanamine
(prepared using A from Example #l, Step D and 2-(1-(tert- butoxy-
##STR00891## NN.1.2 1.40 (a) 310 carbonylamino) cyclobutyl) acetic
acid [prepared as described in [i Eur. J. Med. Chem, [l 1999, 34,
363] EDC.cndot.HCl, B with TEA, E with HCl)
[1572] General Procedure OO: Cyclization with POCl.sub.3
[1573] To a solution of a urea, an amide, or a hydrazide (1-3
equiv, preferably 2 equiv) neat or in an organic solvent (for
example, 1,4-dioxane) is added POCl.sub.3 (10-200 equiv, preferably
100 equiv). The mixture is heated at about 25-100.degree. C.
(preferably about 60.degree. C.) for about 1-16 h (preferably about
1-3 h). The reaction mixture is cooled to ambient temperature and
ice is added. Following dissolution, the pH of the mixture is
adjusted to about 7 with a base such as aqueous NaOH. If the
product precipitates from the reaction mixture it can be collected
by filtration. Alternatively the product can be extracted into an
organic solvent (such as EtOAc or DCM) and the organic layers may
be optionally washed with aqueous base (such as saturated aqueous
NaHCO.sub.3) and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, then decanted or filtered prior to concentrating under
reduced pressure.
Preparation #OO.1:
N-((3S,5R)-5-methyl-1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-y-
l)pyrrolidin-3-yl)cyclopropanesulfonamide
##STR00892##
[1575] A flask was charged with
(2R,4S)-4-(cyclopropanesulfonamido)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b-
]pyrazin-2-yl)methyl)pyrrolidine-1-carboxamide (0.11 g, 0.207 mmol,
prepared using E from Preparation #14 and J from Example #5 Step C
and CDI) and POCl.sub.3 (1.9 mL, 21 mmol). The reaction mixture was
heated to about 60.degree. C. resulting in a homogeneous mixture.
After about 2 h, the reaction mixture was cooled to ambient
temperature and crushed ice was added. After the ice had melted, 2
N aqueous NaOH was added until a pH of about 7 was obtained. The
resulting precipitate was collected by filtration and dried in
vacuo to provide N-((3S,5R)-5-methyl-1-(6-tosyl-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide
(0.10 g, 94%) as a tan solid: LC/MS (Table 1, Method a)
R.sub.t=2.14 min; MS m/z: 515 (M+H).sup.+.
[1576] General Procedure OO.1: Cyclization with POCl.sub.3
[1577] To a urea, an amide, or a hydrazide, neat or in an organic
solvent (such as 1,4-dioxane, DCE, or toluene), is added POCl.sub.3
(3-200 equiv, preferably 100 equiv). The mixture is heated at about
25-110.degree. C. (preferably about 100.degree. C.) for about 1-16
h (preferably about 1-3 h). The reaction mixture is allowed to cool
to ambient temperature. The reaction mixture may be added to ice or
ice may be added. Alternatively, the volatiles may be removed under
reduced pressure. Optionally, DCM is added followed by slow
addition of MeOH and then the mixture is concentrated under reduced
pressure. An aqueous layer such as water or aqueous HCl is added
and an organic solvent such as 1,4-dioxane may be added and the
solution may be warmed to about 30-110.degree. C. (preferably about
100.degree. C.) for about 0.5-6 h (preferably about 3 h). Following
concentration under reduced pressure, the pH of the mixture may be
adjusted with a base such as aqueous NaOH or NaHCO.sub.3
(preferably to about pH 7) and an organic solvent such as EtOAc or
DCM is added. The product may be collected by filtration or
extracted into an organic solvent (such as EtOAc or DCM). The
organic layers may be optionally washed with aqueous base (such as
saturated aqueous NaHCO.sub.3) and/or brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, and then decanted or filtered prior
to concentrating under reduced pressure.
Preparation #OO.1.1:
3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine
##STR00893##
[1579] To 2-(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylamino)acetamide
(0.845 g, 2.45 mmol, prepared using E from Preparation #S.1.1 and
HCl) under nitrogen was added POCl.sub.3 (5.0 mL, 54 mmol). After
about 15 min, a reflux condenser was attached and the mixture was
warmed to about 100.degree. C. After about 2 h, the solution was
allowed to cool to ambient temperature. The mixture was concd under
reduced pressure. The residue was slurried in DCM (10 mL) and
slowly treated with MeOH (10 mL). The reaction mixture was stirred
for about 5 min then concd under reduced pressure. The residue was
dissolved in MeOH (20 mL) and then concentrated under reduced
pressure. The residue was dissolved in 1,4-dioxane (5 mL) and 2N
aqueous HCl (5 mL). The solution was warmed to about 100.degree. C.
for about 3 h. The solution was allowed to cool to ambient
temperature and the volatiles were removed under reduced pressure.
The aqueous mixture was slurried in saturated aqueous
NaHCO.sub.3/water (1:1, 100 mL) and DCM (50 mL). The solid was
collected by filtration, rinsed with water and DCM, and dried to
afford 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine
(0.343 g, 43%): LC/MS (Table 1, Method n) R.sub.t=0.56 min; MS m/z:
328 (M+H).sup.+.
[1580] General Procedure PP: Reaction of an Amine with an Aryl
Boronic Acid
[1581] To a solution of a boronic acid (preferably 1-3 equiv) in an
organic solvent (such as DCM or MeCN) is added an organic base,
such as DIEA (1-5 equiv, preferably 1 equiv), an inorganic catalyst
(such as copper (II) acetate monohydrate (0.1 to 0.5 equiv,
preferably 0.25 equiv), an amine (preferably 1 equiv) and a drying
reagent (such as 4 .ANG. molecular sieves). The reaction mixture is
purged with oxygen (1-5 times, preferably 3 times) and heated at
about 20-60.degree. C. (preferably about 40-50.degree. C.) for
about 1-24 h (preferably about 18 h) under an atmosphere of oxygen.
If the reaction does not reach completion, additional inorganic
catalyst (such as copper (II) acetate monohydrate (0.1 to 0.5
equiv, preferably 0.25 equiv) may be added. The reaction mixture is
allowed to cool to ambient temperature before it is concd under
reduced pressure
Illustration of General Procedure PP
Preparation #PP.1*:
3-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentylamino)benzonitrile
##STR00894##
[1583] To a solution of 3-cyanophenylboronic acid (0.143 g, 0.974
mmol) in DCM (4 mL) was added copper (II) acetate monohydrate
(0.013 g, 0.122 mmol) and 4 .ANG. molecular sieves. The reaction
mixture was purged 3 times with oxygen. A solution of
(1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]-triazolo[4,3-a]py-
razin-1-yl)cyclopentanamine (0.20 g, 0.48 mmol, Preparation #19.2)
and DIEA (0.085 mL, 0.487 mmol) in MeCN (1 mL) was added and the
reaction mixture was heated at about 45.degree. C. for about 18 h.
Additional copper (II) acetate monohydrate (0.013 g, 0.122 mmol)
was added and the reaction mixture was stirred for about 4 h. The
reaction mixture was filtered through a pad of Celite.RTM. and
concd under reduced pressure. The crude material was purified by
silica gel chromatography eluting with a gradient of 0-60% EtOAc in
DCM to give
3-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]-
pyrazin-1-yl)cyclopentylamino)benzonitrile (0.16 g, 48%) as a dark
brown solid: LC/MS (Table 1, Method c) R.sub.t=1.54 min; MS m/z:
512 (M+H).sup.+.
[1584] General Procedure QQ: Formation of a Urea from an Amine and
an Isocyanate
[1585] To a flask containing an amine or an amine salt (1 equiv) in
an organic solvent (such as THF, DCM, or MeCN, preferably DCM) is
optionally added a base (such as DIEA or TEA, preferably DIEA, 1-3
equiv, preferably 1 equiv) and the reaction mixture is stirred at
ambient temperature for about 0-30 min (preferably about 5 min). An
isocyanate (1-5 equiv, preferably 1 equiv) is added and the mixture
is stirred at about 10-60.degree. C. (preferably ambient
temperature) for about 1-24 h (preferably about 18 h). The organic
solvent is optionally removed under reduced pressure unless MeCN is
used in which case the solvent is preferably removed under reduced
pressure. The crude material can be partitioned between an organic
solvent (such as EtOAc or DCM) and water, an aqueous base (such as
saturated aqueous NaHCO.sub.3) or brine. The layers are separated
and the aqueous layer is optionally washed with an organic solvent
(such as EtOAc or DCM). The combined organic extracts are dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd
under reduced pressure to give the target compound.
Illustration of General Procedure QQ
Example #QQ.1.1*
(3R,4R)--N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin--
1-yl)-4-methylpiperidine-1-carboxamide
##STR00895##
[1587] A round bottom flask was charged with
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (0.05 g, 0.17 mmol, Example #5 Step J) and DIEA
(0.03 mL, 0.17 mmol) in DCM (1.6 mL). The reaction mixture was
stirred for about 5 min at ambient temperature then
2,4-difluoro-1-isocyanatobenzene (0.02 mL, 0.17 mmol) was added and
the reaction mixture was stirred at ambient temperature for about
18 h. The reaction mixture was diluted with DCM (5 mL) and washed
with water (2 mL). The aqueous layer was back extracted with DCM (2
mL). The combined organic layers were dried over anhydrous
MgSO.sub.4, filtered, and coned under reduced pressure. The
material was purified by RP-HPLC (Table 1, Method e) to afford
(3R,4R)--N-(2,
4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methy-
lpiperidine-1-carboxamide (0.014 g, 20%): LC/MS (Table 1, Method j)
R.sub.t=1.77 min; MS m/z 411 (M+H).sup.+.
TABLE-US-00044 TABLE QQ.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (Example #5 Step J) using General Procedure QQ
R.sub.t min (Table 1, m/z ESI+ Isocyanate Product Example # Method)
(M + H).sup.+ 2-(4- isocyanatophenyl) acetonitrile ##STR00896##
QQ.1.2* 1.69 (b) 414 3-isocyanato- benzonitrile ##STR00897##
QQ.1.3* 1.76 (b) 400 4-isocyanato- benzonitrile ##STR00898##
QQ.1.4* 1.74 (b) 400
[1588] General Procedure RR: Formation of a Urea from an Amine, a
Heteroaryl Amine and Phenyl Chloroformate
[1589] To a flask containing a heteroaryl amine (1-6 equiv,
preferably 2.1 equiv) in an organic solvent or mixture of solvents
(such as THF/MeCN, THF, DCM, or MeCN, preferably MeCN), a base such
as pyridine, DIEA or TEA, preferably TEA (1-6 equiv, preferably 2
equiv) and DMAP (0.1-0.6 equiv, preferably 0.2 equiv) is added
phenyl chloroformate (1-6 equiv, preferably 2.0 equiv) at about
-5-25.degree. C. (preferably about 0.degree. C.). The reaction
mixture is warmed to ambient temperature and stirred for about 1-4
h (preferably about 3 h). The organic solvent is optionally removed
under reduced pressure. The crude material can be partitioned
between an organic solvent such as EtOAc, DCM or Et.sub.2O
(preferably Et.sub.2O) and water or brine. The layers are separated
and the organic layer is optionally washed with water or brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd under reduced pressure to give the crude carbamate. The crude
carbamate is dissolved in an organic solvent such as MeCN, THF or
DMF (preferably MeCN) and added to a solution of amine or amine
salt (1-2 equiv, preferably 1 equiv), and a base such as pyridine,
TEA or DIEA (preferably DIEA, 1-2 equiv, preferably 1 equiv) in an
organic solvent such as MeCN, THF or DMF (preferably MeCN) and
stirred at about 25-80.degree. C. (preferably about 70.degree. C.)
for about 0.5-48 h (preferably about 2-18 h). The solvent is
optionally removed under reduced pressure. The crude material can
be partitioned between an organic solvent (such as EtOAc or DCM)
and water, an aqueous base (such as aqueous NaHCO.sub.3) or brine.
The layers are separated and the organic layer is optionally washed
with water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd under reduced pressure to give the target
compound.
Illustration of General Procedure RR
Example #RR.1.1*
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrimi-
din-4-yl)piperidine-1-carboxamide
##STR00899##
[1591] To solution of 4-aminopyrimidine (0.04 g, 0.43 mmol), TEA
(0.07 mL, 0.47 mmol) and DMAP (0.006 g, 0.05 mmol), in MeCN (1 mL)
at about 0.degree. C. was added phenyl chloroformate (0.05 mL, 0.41
mmol). The reaction mixture was warmed to ambient temperature and
stirred for about 3 h. To the reaction mixture was added water (2
mL) and Et.sub.2O (5 mL). The organic layer was separated, washed
with water (2 mL), dried over anhydrous MgSO.sub.4, filtered, and
concd under reduced pressure to provide the crude carbamate. The
carbamate was dissolved in MeCN (1 mL) and to it was added a
solution of
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (0.06 g, 0.21 mmol, Example #5 Step J) and DIEA
(0.04 mL, 0.21 mmol) in MeCN (1 mL). The reaction mixture was
heated to about 70.degree. C. for about 2 h. The solvent was
removed under reduced pressure. The crude residue was dissolved in
DCM (5 mL) and washed with water (2 mL), brine (3 mL), dried over
anhydrous MgSO.sub.4, filtered, and coned under reduced pressure.
The crude material was purified by RP-HPLC (Table 1, Method e) to
give
(3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methyl-N-(pyrim-
idin-4-yl)piperidine-1-carboxamide (0.007 g, 9%): LC/MS (Table 1,
Method b) R.sub.t=1.40 min; MS m/z 377 (M+H).sup.+.
TABLE-US-00045 TABLE RR.1 Examples prepared from
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo
[2,3-e]pyrazine hydrochloride (Example #5 Step J) using General
Procedure RR Hetero- R.sub.t min aryl (Table 1, m/z ESI+ amine
Product Example # Method) (M + H).sup.+ pyrimidin-2- amine
##STR00900## RR.1.2* 1.29 (b) 377 pyridin-2-amine ##STR00901##
RR.1.3* 1.95 (b) 376 pyrazin-2-amine ##STR00902## RR.1.4* 1.41 (b)
377
[1592] General Procedure SS: Hydrolysis of an Ester to an
Alcohol
[1593] A solution of an ester (preferably 1 equiv) in an organic
solvent such as THF, MeOH, or EtOH (preferably MeOH) is added to a
base in an organic solvent (such as NaOH in MeOH) or aqueous base
(such as Na.sub.2CO.sub.3 or NaOH) (1-20 equiv, preferably 2-10
equiv). The reaction mixture is stirred at ambient temperature for
about 1-16 h (preferably about 3 h). The mixture is partitioned
between an organic solvent (such as EtOAc or DCM) and an aqueous
base (such as saturated aqueous NaHCO.sub.3 or saturated aqueous
Na.sub.2CO.sub.3, preferably saturated aqueous NaHCO.sub.3). The
organic layer is separated, dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, filtered, and concd under reduced pressure to
provide the target compound.
Illustration of General Procedure SS
Preparation #SS.1:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanol
##STR00903##
[1595] To a solution of NaOH (0.088 g, 2.20 mmol) in MeOH (8 mL)
was added a solution of
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (0.158 g, 0.312
mmol, prepared using KK from Preparation #20.2) in MeOH (2 mL). The
reaction mixture was stirred at ambient temperature for about 3 h.
The solvent was removed under reduced pressure and DCM (150 mL) was
added. The organic layer was washed with water (5 mL), saturated
aqueous NaHCO.sub.3 (15 mL), brine (15 mL), and dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.123 g, 98%) as clear
oil: LC/MS (Table 1, Method b) R.sub.t=2.34 min; MS m/z: 402
(M+H).sup.+.
[1596] General Procedure TT: Acid-Mediated Conversion of an Ester
to a Carboxylic Acid
[1597] To a solution of an ester (preferably 1 equiv) in an organic
solvent such as 1,4-dioxane or THF (preferably 1,4-dioxane) is
added HCl (0.5-12 N, preferably 1-6 N aqueous; 5-100 equiv,
preferably 10-20 equiv). The reaction is heated at about
30-120.degree. C. (preferably about 60.degree. C.) for about 12-120
h (preferably about 36-72 h). In any case where an additional acid
labile group is present (for example, a Boc group) this group may
also be cleaved during the reaction. The reaction mixture is concd
under reduced pressure and the pH is adjusted to about 8 with an
aqueous inorganic base such as NaHCO.sub.3 or Na.sub.2CO.sub.3
(preferably saturated aqueous NaHCO.sub.3) and the aqueous phase is
extracted with an organic solvent such as DCM or EtOAc (preferably
EtOAc). The organic extract is optionally washed with brine, dried
over a drying agent such as anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4 (preferably anhydrous MgSO.sub.4) and concd under
reduced pressure to yield the target compound.
Illustration of General Procedure TT
Preparation #TT.1: 4-(dibenzylamino)-2-methylcyclopentanecarboxylic
acid
##STR00904##
[1599] Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
(3.65 g, 10.38 mmol, Example #7, step H) was dissolved in HCl (6 N
aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture
was heated at about 60.degree. C. for about 72 h. The solvents were
removed under reduced pressure and the residue was neutralized by
the addition of saturated aqueous NaHCO.sub.3 (40 mL) and extracted
with EtOAc (50 mL). The organic phase was washed with brine (40
mL), dried over anhydrous MgSO.sub.4 and concd under reduced
pressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarboxylic
acid (3.3 g, 98%) as a white amorphous solid: LC/MS (Table 1,
Method a) R.sub.t=1.66 min; MS m/z 324 (M+H).sup.+.
[1600] General Procedure UU: Formation of
2,2,2-trichloroacetimidate
[1601] To a mixture of an alcohol (preferably 1 equiv) in an
organic solvent (such as Et.sub.2O, heptane or DCM, preferably DCM)
at about -20.degree. C. to 30.degree. C. (preferably about
0.degree. C.) is added an aqueous base (such as aqueous sodium
hydroxide or potassium hydroxide, preferably aqueous potassium
hydroxide, 1-20 equiv, preferably 10 equiv). A catalytic amount of
phase transfer reagent (preferably tetrabutylammonium hydrogen
sulfate, 0.01-0.5 equiv, preferably 0.1 equiv) is added followed by
2,2,2-trichloroacetonitrile (1-10 equiv, preferably 5 equiv). The
reaction mixture is allowed to warm to ambient temperature and
stirred at about 15-60.degree. C. (preferably ambient temperature)
for about 5-48 h (preferably about 14 h). The layers are separated
and the aqueous layer is extracted with an organic solvent (such as
Et.sub.2O, EtOAc or DCM, preferably DCM). The combined organic
layers are washed with water, an aqueous base (such as saturated
aqueous Na.sub.2CO.sub.3 or NaHCO.sub.3) or brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure. Alternatively, an organic base (such as DBU) may
be used as the base for this reaction. In this case, to a mixture
of an alcohol (preferably 1 equiv) in an organic solvent (such as
Et.sub.2O, heptane or DCM, preferably DCM) at about -20.degree. C.
to 30.degree. C. (preferably about 0.degree. C.) is added
2,2,2-trichloroacetonitrile (1-10 equiv, preferably 5 equiv),
followed by an organic base preferably DBU (0.2-1 equiv, preferably
about 0.4 equiv). The reaction mixture is stirred at about
-20-30.degree. C. (preferably about 0.degree. C.) for about 0.5-10
h (preferably about 1 h) then concd.
Illustration of General Procedure UU
Preparation #UU.1: ethyl
2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate
##STR00905##
[1603] To ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (3.52 g,
18.9 mmol, Preparation #P.1) in DCM (21 mL) at about 0.degree. C.
was added aqueous potassium hydroxide (50%, 21 mL, 189 mmol),
tetrabutylammonium hydrogen sulfate (0.64 g, 1.891 mmol) and
2,2,2-trichloroacetonitrile (9.5 mL, 95 mmol). The reaction mixture
was allowed to warm to ambient temperature and stirred at ambient
temperature for about 14 h. The layers were separated and the
aqueous layer was extracted with DCM (4.times.60 mL). The combined
organic layers were washed with water (2.times.50 mL), brine (60
mL), dried over anhydrous MgSO.sub.4, filtered and concd under
reduced pressure. The material was purified by silica gel
chromatography eluting with a gradient of 15-50% EtOAc in heptane
to afford ethyl
2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate
(2.80 g, 45%) as a colorless oil: LC/MS (Table 1, Method b)
R.sub.t=2.91 min; MS m/z: 330 (M+H).sup.+.
[1604] General Procedure W: TBDMS-Protection of an Alcohol
[1605] To a mixture of an alcohol (preferably 1 equiv) in an
organic solvent (preferably DMF) is added TBDMS-Cl (1-5 equiv,
preferably 1.2 equiv) and imidazole (1-10 equiv, preferably 2.5
equiv). The reaction mixture is stirred at about 10-60.degree. C.
(preferably ambient temperature) for about 1-24 h (preferably about
3 h). An organic solvent is added (such as heptane, hexane or
pentane, preferably heptane). The layers are separated and the
bottom layer (DMF layer) is extracted with an organic solvent (such
as pentane, hexane or heptane, preferably heptane). The combined
extracts are washed with water, an aqueous base (such as saturated
aqueous NaHCO.sub.3) or brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure W
Preparation #VV.1: Ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
##STR00906##
[1607] To a solution of ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (4.97 g, 26.7 mmol,
prepared using II from Preparation #P.1, SS with NaOH)) in DMF (9
mL) was added TBDMS-Cl (4.83 g, 32.1 mmol) and imidazole (4.55 g,
66.8 mmol). The reaction mixture was stirred at ambient temperature
for about 3 h. Heptane (30 mL) was added. The layers were separated
and the bottom layer (DMF layer) was extracted with heptane
(3.times.30 mL). The combined organic extracts were washed with
water (2.times.30 mL), brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. The material
was purified by silica gel chromatography eluting with a gradient
of 0-15% EtOAc in heptane to afford ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (5.16
g, 64%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.45 (m, 1H), 4.11 (m, 2H), 3.08 (m, 1H), 2.34 (m, 1H),
2.18 (m, 1H), 1.75 (m, 2H), 1.57 (m, 1H), 1.41 (m, 1H), 1.25 (m,
3H), 1.10 (m, 1H), 0.90 (m, 3H), 0.87 (s, 9H), 0.03 (s, 6H).
[1608] General Procedure WW: Formation of a Ketal
[1609] To a solution of a ketone (preferably 1 equiv), an organic
solvent (such as DCM, DCE, or toluene, preferably DCM), a diol such
as ethylene glycol (1-3 equiv, preferably 2 equiv), and an acid
such as p-toluenesulfonic acid monohydrate (0.1-0.5 equiv,
preferably 0.2 equiv) is optionally added a dehydrating agent such
as triethylorthoformate or trimethylorthoformate (preferably
triethylorthoformate, 1-4 equiv, preferably 1.5 equiv) The reaction
mixture is stirred at rt to about 110.degree. C. (preferably rt in
the presence of a dehydrating agent such as triethylorthoformate or
preferably about 110.degree. C. in the absence of a dehydrating
agent) for about 16-96 h (preferably about 24 h). If heated, the
reaction mixture is cooled to rt. The reaction mixture is worked up
using one of the following methods. Method 1: Water is added to the
reaction mixture, the layers are separated, and the organic
solution is optionally washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, then decanted or filtered prior to
concentrating under reduced pressure. Method 2: The reaction
mixture is concd under reduced pressure and purified directly.
Illustration of General Procedure WW
Preparation #WW.1: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR00907##
[1611] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22,
Step B) in DCM (22 mL). To the flask were added ethylene glycol
(0.91 mL, 16 mmol), triethylorthoformate (2.0 mL, 12 mmol), and
p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The reaction
mixture was stirred at rt for about 24 h. The solution was concd
under reduced pressure to give a brown oil that was dissolved in
minimal EtOAc and purified by silica gel chromatography (Silicycle
25 g column) eluting with a gradient of 0-50% EtOAc in heptane to
give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (1.6 g, 83%) as a
light yellow oil: LC/MS (Table 1, Method c) MS m/z 229 (M+H);
.sup.1H NMR (CDCl.sub.3) .delta. 4.14 (q, 2H), 3.90 (m, 4 H), 2.99
(q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H), 2.05-1.99 (m, 1H),
1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m, 1H), 1.31-1.24
(m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).
[1612] General Procedure XX: Palladium Catalyzed Coupling of a
Hydrazone
[1613] To a mixture of a substituted
5-chloro-4-(hydrazonomethyl)-1H-pyrrolo[2,3-b]pyridine (1 equiv) in
an organic solvent (preferably NMP) is added a base (such as
K.sub.2CO.sub.3 or sodium tert-butoxide, preferably sodium
tert-butoxide [1-4 equiv, preferably 2.5 equiv]) a palladium
catalyst (preferably palladium acetate [0.01-0.2 equiv, preferably
0.1 equiv]) and a ligand (preferably
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphi-
ne [0.01-0.2 equiv, preferably 0.1 equiv]). The reaction mixture is
heated thermally or in a microwave (preferably in a microwave) at
about 100-165.degree. C. (preferably 150.degree. C. for about 10
min-6 h (preferably about 2 h)). The reaction mixture is filtered
through a pad of Celite.RTM. washing with an organic solvent (such
as EtOAc or DCM, preferably EtOAc) and concd under reduced pressure
to remove wash solvent. The crude material is optionally
resubmitted to the reaction conditions. Then the crude material is
partitioned between an organic solvent (such as EtOAc or DCM,
preferably EtOAc) and water and the aqueous phase is extracted with
an organic solvent (such as EtOAc or DCM, preferably EtOAc), washed
with water and/or brine, dried over anhydrous MgSO.sub.4, filtered
and concd under reduced pressure.
Illustration of General Procedure XX
Preparation #XX.1: tert-butyl
benzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2-
.2.2]octan-1-yl)carbamate
##STR00908##
[1615] A microwave reaction vial was charged with tert-butyl
benzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo-
[2.2.2]octan-1-yl)carbamate (0.700 g, 1.38 mmol, Example #29 Step
G) and NMP (11 mL). Sodium tert-butoxide (0.331 g, 3.44 mmol),
palladium acetate (0.031 g, 0.138 mmol) and
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphi-
ne (0.076 g, 0.138 mmol) were each added sequentially. The reaction
mixture was heated in a Biotage microwave at about 150.degree. C.
for about 2 h (250 psi maximum pressure, 1 min ramp, 150 max
watts). The reaction mixture was filtered through a pad of
Celite.RTM. washing with EtOAc (about 15 mL), and the EtOAc was
removed under reduced pressure. The remaining material was
transferred to a microwave vial and sodium tert-butoxide (0.331 g,
3.44 mmol), palladium acetate (0.031 g, 0.138 mmol) and
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]-ethyl-di-tert-b-
utylphosphine (0.076 g, 0.138 mmol) were added. The reaction
mixture was heated in a Biotage microwave at about 160.degree. C.
for about 2 h (250 psi maximum pressure, 1 min ramp, 150 max
watts). The reaction mixture was through a pad of Celite.RTM.
washing with EtOAc (about 20 mL). Water (15 mL) was added and the
layers were separated. The aqueous layer was extracted with EtOAc
(2.times.10 mL) and the combined organics were washed with water
(3.times.10 mL) and brine (5.times.15 mL), dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. The
remaining dark residue was purified by silica gel chromatography
eluting with a gradient of 10-100% EtOAc in heptane to give
tert-butyl
benzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicyclo[2-
.2.2]octan-1-yl)carbamate with 0.5 eq EtOAc as an excipient (0.281
g, 39.5%) as a light brown solid.: LC/MS (Table 1, Method b)
R.sub.t=2.57 min; MS m/z: 472 (M+H).sup.+.
[1616] General Procedure YY: Michael Addition of an Amine, Amine
Salt or Heterocycle to an .alpha.,.beta.-Unsaturated
Sulfonamide
[1617] To a mixture of an .alpha.,.beta.-unsaturated sulfonamide
(1-3 equiv, preferably 1.0 equiv) and an amine, amine salt or
heterocycle (1-10 equiv, preferably 4 equiv) in an organic solvent
or mixture of solvents (such as THF, n-PrOH, water, EtOH, THF/PrOH,
THF/EtOH, preferably n-PrOH) is optionally added a base (such as
DIEA or TEA 0-25 equiv, preferably DIEA 10-20 equiv). The mixture
is stirred at about 25-100.degree. C. (preferably about
60-80.degree. C.) for about 2-72 h (preferably about 18-20 h). In
cases where the reaction does not proceed to completion as
monitored by LC/MS, HPLC, and/or TLC; additional amine, amine salt
or heterocycle (1-10 equiv, preferably 2 equiv) and/or a cosolvent
(such as EtOH) may be added. The reaction is continued at about
25-100.degree. C. (preferably about 80.degree. C.) for about 1-24 h
(preferably about 1-2 h). In cases where there is a base-labile
protecting group present (for example, a tosyl), the compound may
be deprotected. The reaction mixture is allowed to reach ambient
temperature and the organic solvent is optionally removed under
reduced pressure. The crude material can be partitioned between an
organic solvent (such as EtOAc or DCM) and water, an aqueous base
(such as saturated aqueous NaHCO.sub.3) or brine. The layers are
separated and the organic layer is optionally washed with water, an
aqueous base (such as saturated aqueous NaHCO.sub.3) or brine,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd under reduced pressure to give the target compound.
Illustration of General Procedure YY
Example #YY.1.1*
2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2-
,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide
##STR00909##
[1619] A mixture of
N--((S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)ethenesulfonamide (0.065 g, 0.13 mmol,
prepared using K.1 from Example #8 Step M and
2-chloroethanesulfonyl chloride with TEA), DIEA (0.30 mL, 1.7 mmol)
and 1H-pyrazole-4-carbonitrile (0.047 g, 0.51 mmol, American Custom
Chemicals Corp) in n-PrOH (2.0 mL) was stirred for about 2 h at
about 60.degree. C. then at about 80.degree. C. for about 18 h. The
reaction mixture was cooled to ambient temperature and concd under
reduced pressure. The crude residue was dissolved in DCM (10 mL),
washed with saturated NaHCO.sub.3 (5 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-5% MeOH in DCM to give
2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide
(0.024 g, 42%): LC/MS (Table 1, Method b) R.sub.t=1.63 min; MS m/z:
454 (M+H).sup.+.
TABLE-US-00046 TABLE YY.1 Examples prepared from
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-(1H-
1,2,4-triazol-1-yl)ethanesulfonamide (prepared using K.1 from
Example #8 Step M and 2-chloroethanesulfonyl chloride with TEA)
using General Procedure YY (Table 1, Me- thod) m/z R.sub.t min ESI+
(me- (M + Amine Structure Ex. # thod) H).sup.+ 1H- 1,2,4- tria-
zole ##STR00910## YY.1.2* 1.41 (b) 430
[1620] General Procedure ZZ: Formation of an Oxazolidinone
Sulfonourea
[1621] To a mixture of an amine or an amine salt (1 equiv) and
2-chloroethyl chlorosulfonylcarbamate (prepared as detailed in
Bioorg. Med. Chem. Lett., 2006 16, 3367-3370)(1-3 equiv, preferably
1 equiv) in an organic solvent (preferably DCM) is added a base
(such as DIEA or TEA, preferably TEA [2-5 equiv, preferably 3
equiv]) and optionally DMAP (1-3 equiv, preferably 1 equiv) and
stirred at ambient temperature for about 10 min-6 h (preferably
about 1 h). The solvent is removed under reduced pressure. In cases
where DMAP is used, the crude material can be partitioned between
an organic solvent (such as EtOAc or DCM) and water or brine, dried
over anhydrous MgSO.sub.4, filtered and concd under reduced
pressure.
Illustration of General Procedure ZZ
Preparation #ZZ.1*:
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide
##STR00911##
[1623] To a mixture of 2-chloroethyl chlorosulfonylcarbamate
(prepared as detailed in Bioorg. Med. Chem. Lett., 2006 16,
3367-3370; 0.052 g, 0.236 mmol) and
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)cyclopentanamine (0.100 g, 0.236 mmol, Example
#8 Step M) in DCM (2.4 mL) was added TEA (0.098 mL, 0.71 mmol) and
the reaction mixture was stirred at ambient temperature for about 1
h. The reaction mixture was concd under reduced pressure to give
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.098 g,
65%) as a light brown solid: LC/MS (Table 1, Method a) R.sub.t=2.18
min; MS m/z 574 (M+H).sup.+.
[1624] General Procedure AAA: Formation of a Sulfonylurea from an
Oxazolidinone Sulfonourea
[1625] To a solution of an oxazolidinone (preferably 1 equiv) in an
organic solvent (preferably MeCN) is added an amine or a
hydrochloride salt of an amine (1-2 equiv, preferably 1.5 equiv)
and an organic base, such as TEA or DIEA (1-4 equiv, preferably 2
equiv). The reaction is irradiated in the microwave at about
100-150.degree. C. (preferably 120.degree. C.) for about 0.5-1 h
(preferably 0.5 h). The reaction mixture is cooled to ambient
temperature and is optionally concd under reduced pressure to give
a residue. The reaction mixture or residue is optionally
partitioned between an organic solvent (such as DCM or EtOAc,
preferably EtOAc), water, an aqueous solution (such as saturated
aqueous NaHCO.sub.3 or saturated aqueous ammonium chloride
(preferably saturated aqueous ammonium chloride) or brine. The
layers are separated and the organic layer is dried over anhydrous
Na.sub.2SO.sub.4 or MgSO4, filtered, and concd under reduced
pressure to give a sulfonylurea.
Illustration of General Procedure AAA
Preparation #AAA.1*:
(R)--N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyr-
azin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide
##STR00912##
[1627] To a solution of
N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin--
1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.200 g, 0.261
mmol, prepared from
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(WO2009152133) and
(1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid
[prepared from ethyl 4-amino-2-methylcyclopentanecarboxylate
(WO2009152133) using G, AA, and Z] using H, OO, BB, and ZZ) and
(R)-2-trifluoromethylpyrrolidine (0.055 g, 0.392 mmol) in MeCN (1.4
mL) was added TEA (0.073 mL, 0.523 mmol). The reaction was
irradiated in a CEM microwave at about 120.degree. C. for about 0.5
h. The reaction mixture was cooled to ambient temperature and concd
under reduced pressure to afford a residue. The crude material was
purified by silica gel chromatography eluting with a gradient of
0-70% EtOAc in DCM to afford
(R)--N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidin-
e-1-sulfonamide (0.12 g, 75%, 72% purity) as an off-white solid:
LC/MS (Table 1, Method a) R.sub.t=2.79 min; MS m/z: 611
(M+H).sup.+.
[1628] General Procedure BBB: Reduction of a Nitro Group
[1629] To a solution of a nitro-containing compound (preferably 1
equiv) in an organic solvent (preferably EtOH) is added tin (II)
chloride dihydrate (1-3 equiv, preferably 1 equiv) and the reaction
is stirred at about 25-80.degree. C. (preferably at about
75.degree. C.) for about 0.5-24 h (preferably about 1-2 h).
Optionally, additional portions of tin (II) chloride dihydrate (1-5
equiv, preferably 2 equiv) can be added to the reaction mixture and
heating can be continued for about 0.5-24 h (preferably about 5-14
h). The reaction mixture is concd under reduced pressure. The crude
mixture may be diluted with an organic solvent (for example, EtOAc
or DCM) and aqueous base (such as 1 N NaOH or saturated aqueous
NaHCO.sub.3). The layers are separated and the aqueous layer is
extracted with an organic solvent (such as EtOAc and/or DCM). The
combined organic layers are optionally washed with brine, dried
over anhydrous MgSO.sub.4, filtered and concd under reduced
pressure.
Illustration of General Procedure BBB
Preparation #BBB.1:
N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine
##STR00913##
[1631] To a mixture of
N-cyclohexyl-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine
(0.111 g, 0.268 mmol, prepared using K.1 from Example #21 Step D
with 4-methylbenzene-1-sulfonyl chloride, L with cyclohexylamine)
in EtOH (2.5 mL) was added tin (II) chloride dihydrate (0.060 g,
0.268 mmol). The reaction mixture was heated at about 75.degree. C.
for about 75 min. Tin (II) chloride dihydrate (0.030 g, 0.134 mmol)
was added and the reaction mixture was heated at about 75.degree.
C. for about 5 h. Additional tin (II) chloride dihydrate (0.060 g,
0.268 mmol) was added and the reaction mixture was heated at about
75.degree. C. for about 14 h. The solvent was removed under reduced
pressure. The residue was diluted with EtOAc (25 mL) and washed
with saturated aqueous NaHCO.sub.3 (25 mL) and brine (25 mL). The
organic portion was separated. The aqueous portion was extracted
with EtOAc (3.times.25 mL). The organic extracts were combined,
dried over MgSO.sub.4, filtered, and concd under reduced pressure
to give
N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.081
g, 79%) as a brown oil: LC/MS (Table 1, Method n) R.sub.t=0.82 min;
MS m/z 385 (M+H).sup.+.
[1632] General Procedure CCC: Formation of an Amide
[1633] To a mixture of an amine or amine salt (1 equiv) in an
organic solvent (for example, DCM or THF, preferably DCM) at about
0-25.degree. C. (preferably 0.degree. C.) is added and organic base
(TEA or DIEPA, preferably TEA) (neat or as a solution in an organic
solvent (preferably DCM)), 1-3 equiv (preferably 1 equiv) and an
acylating agent (for example, an anhydride or an acid chloride)
(preferably an anhydride) (neat or as a solution in an organic
solvent (preferably DCM)), 1-3 equiv (preferably 1 equiv). The
reaction mixture is stirred at ambient temperature for about 5
min-6 h (preferably about 10 min). The reaction mixture is
optionally washed with saturated aqueous NaHCO.sub.3, water, or
brine, dried over MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure CCC
Preparation #CCC.1:
N-(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,2,2-trifl-
uoroacetamide
##STR00914##
[1635] To a 0.degree. C. solution of
N-4-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine
(Preparation #BBB.1, 0.080 g, 0.208 mmol) in DCM (2.0 mL) was added
TEA (2 M in DCM, 0.104 mL, 0.208 mmol) and TFAA (2 M in DCM, 0.104
mL, 0.208 mmol). The reaction mixture was stirred for about 10 min.
The reaction mixture was washed with saturated aqueous NaHCO.sub.3
(2 mL) and water (2 mL), dried over anhydrous MgSO.sub.4, filtered
and concd under reduced pressure to give
N-(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,2,2--
trifluoroacetamide with 40 mol % dichloromethane as an excipient
(0.089 g, 83%, 90% purity) as a brown solid: LC/MS (Table 1, Method
n) R.sub.t=0.88 min; MS m/z 481 (M+H).sup.+.
[1636] General Procedure DDD: Cyclization to Form a Fused
Imidazole
[1637] To a solution of a diamine (preferably 1 equiv) in an
organic solvent such as DMF, DCM, 1,4-dioxane, or MeOH (preferably
MeOH) is added the corresponding cyclization reagent such as TMOF
(1-10 equiv, preferably 1-2 equiv.). (A catalytic amount of acid,
such as TsOH (0.005-0.5 equiv, preferably 0.01 equiv) is optionally
added to the reaction mixture when TMOF is used). Alternatively, a
solution of an ortho-substituted amidoaminoaryl or heteroaryl
compound (preferably 1 equiv) is cyclized in an organic solvent
such as DMF or THF using a dehydrating agent such as TPP,
POCl.sub.3 or HCl (5-100 equiv, preferably 10 equiv of TPP). The
reaction mixture is heated at about 25-120.degree. C. (preferably
about 65.degree. C.) for about 1-24 h (preferably about 12-16 h),
cooled to ambient temperature and optionally concd under reduced
pressure to give a residue. The residue is partitioned between an
organic solvent (such as DCM or EtOAc, preferably EtOAc), water, an
aqueous base (such as saturated aqueous NaHCO.sub.3) and/or brine.
The layers are separated and the organic layer is optionally washed
with water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd under reduced pressure.
Illustration of General Procedure DDD
Preparation #DDD.1:
N-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclope-
ntyl)cyclopropanesulfonamide
##STR00915##
[1639] To a solution of
N-(3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopen-
tyl)cyclopropanesulfonamide (0.095 g, 75% purity, 0.142 mmol,
prepared using L from Preparation #27 and Preparation #000.1 with
DIEA, K.1 with TsCl and NaH, and BBB) and TMOF (0.016 mL, 0.147
mmol) in MeOH (3.09 mL) was added toluene-4-sulfonic acid hydrate
(0.0003 g, 0.0015 mmol). The reaction was heated at about
65.degree. C. for about 14 h. The reaction was cooled to ambient
temperature and concd under reduced pressure to give a crude solid.
The solid was dissolved in EtOAc (10 mL) and was washed with
saturated aqueous NaHCO.sub.3 (5 mL), water (5 mL), and brine (5
mL). The organic portion was separated and dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to afford
N-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1
(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.075 g, 99%) as a
yellow solid: LC/MS (Table 1, Method a) R.sub.t=2.15 min; MS m/z:
514 (M+H).sup.+.
[1640] General Procedure EEE: Formation of a Sulfonyl Chloride
[1641] To a solution of a sulfonic acid or the potassium salt of a
sulfonate (preferably 1 equiv) in thionyl chloride (2-30 equiv,
preferably 20-25 equiv) is added DMF (0.01-0.10 equiv, preferably
0.09 equiv). The reaction is heated at about 50-100.degree. C.
(preferably about 80.degree. C.) for about 8-24 h (preferably about
12-16 h). The reaction mixture is cooled to 0-25.degree. C.
(preferably about 0.degree. C.) and is diluted with water. The
reaction mixture is partitioned between an organic solvent (such as
DCM or EtOAc) and water or brine. The layers are separated and the
organic layer is optionally washed with water and/or brine, dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd
under reduced.
Illustration of General Procedure EEE
Preparation #EEE.1: 1-ethylcyclopropane-1-sulfonyl chloride
##STR00916##
[1643] To a mixture of potassium 1-ethylcyclopropane-1-sulfonate
(0.420 g, 2.23 mmol, Preparation #JJJ.1) in thionyl chloride (3.58
mL, 49.1 mmol) was added DMF (0.016 mL, 0.20 mmol). The reaction
was heated at about 80.degree. C. for about 16 h. The reaction was
cooled to 0.degree. C. before the slow addition of water (10 mL).
The reaction mixture was diluted with DCM (20 mL). The layers were
separated and the aqueous portion was extracted with DCM
(3.times.10 mL). The combined organic layers were separated, dried
over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure to afford crude 1-ethylcyclopropane-1-sulfonyl chloride
(0.52 g, 83% yield, 60% purity) as an orange oil: 1H NMR (400 MHz,
DMSO) .delta. 2.09 (q, J=7.4, 2H), 1.62-1.60 (m, 2H), 1.45-1.39 (m,
2H), 0.91 (t, J=7.5, 3H).
[1644] General Procedure FFF: Generation of an Ether Under
Reductive Conditions
[1645] To a solution of a TBDMS ether (1.0 equiv) in MeCN at
ambient temperature is added triethyl silane (1-2 equiv preferably
1.5 equiv), and bismuth (III) bromide (0.05-0.2 equiv, preferably
0.06 equiv). The reaction is stirred at about 25-60.degree. C.
(preferably about 25.degree. C.) for about 0.5-5 min (preferably
1-3 min). To the reaction mixture is added an aldehyde or ketone
(1-6 equiv, preferably 1.5 equiv) that can be optionally dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4. In cases where the
reaction does not proceed to completion as monitored by TLC,
additional triethyl silane (1-2 equiv preferably 1.5 equiv) and/or
bismuth (III) bromide (0.05-0.2 equiv, preferably 0.06 equiv)
and/or aldehyde or ketone (1-6 equiv, preferably 1.5 equiv) can be
added. The reaction is continued at about 25-60.degree. C.
(preferably about 25.degree. C.) for about 15 min-24 h (preferably
about 1 h). The reaction is worked up using one of the following
methods. Method 1: The reaction mixture is filtered through a pad
of Celite.RTM.. The pad of Celite.RTM. can be rinsed with
additional organic solvent (preferably heptane or MeCN) and the
filtrate is concd under reduced pressure. Method 2: The reaction
mixture is filtered through an Acrodisc.RTM. and the filtrate is
concd under reduced pressure.
Illustration of General Procedure FFF
Preparation #FFF.1: ethyl
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate
##STR00917##
[1647] To a solution of ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
(0.200 g, 0.666 mmol, Example #22Step D) in MeCN (4.5 mL) was added
triethylsilane (0.160 mL, 1.00 mmol) and bismuth(III) bromide
(0.020 g, 0.045 mmol). The reaction mixture was stirred at ambient
temperature for about 1 min followed by dropwise addition of
dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol). The reaction
mixture was stirred at ambient temperature for about 15 min. The
reaction was filtered through an Acrodisc.RTM. and the solvent was
removed under reduced pressure. The crude material was purified by
silica gel chromatography using a gradient of 10-100% EtOAc in
heptane to give ethyl
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate
(0.253 g, 94%) as a colorless oil; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.13 (q, J=7.1, 2H), 4.05-3.98 (m, 1H),
3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m, 2H), 2.80 (q,
J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H),
1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2,
1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).
[1648] General Procedure GGG: Iodination of a Pyrrole Based
Heterocycle
[1649] To a pyrrole based heterocycle (preferably 1 equiv) in an
organic solvent such as DMF is added a base such as KOH (1-10
equiv, preferably 3 equiv) at about 0.degree. C. to 40.degree. C.
(preferably at ambient temperature) and the mixture is stirred for
about 2-45 min (preferably about 5 min). Iodine (0.95-1.2 equiv,
preferably 1.0 equiv) is added in small portions and the mixture is
stirred for 10-100 min. (preferably about 30 min). The mixture is
added drop-wise into saturated aqueous ammonium chloride (10 mL for
every 1 mL of DMF used) and the target compound is collected by
filtration, washed with additional water and dried.
Illustration of General Procedure GGG
Preparation #GGG.1:
N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR00918##
[1651] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)cyclopropanesulfonamide (0.396 g, 1.06 mmol,
prepared as detailed in WO2009152133) in DMF (20 mL) was added KOH
(0.190 g, 3.38 mmol). The mixture was stirred at rt for 5 min.
Iodine (0.268 g, 1.058 mmol) was added in small portions and the
reaction mixture was stirred at rt for 30 min. The mixture was
added dropwise into a saturated aqueous ammonium chloride (200 mL).
The precipitate was collected by filtration, washed with water, and
dried to give
N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.494 g, 93%) as an
off-white solid: LC/MS (Table 1, Method a) R.sub.t=1.83 min; MS m/z
501 (M+H).sup.+.
[1652] General Procedure GGG.1: Iodination, Chlorination or
Bromination of a Pyrrole Based Heterocycle
[1653] To a pyrrole based heterocycle (preferably 1 equiv) in an
organic solvent such as DMF, THF, MeCN, MeOH, AcOH, CHCl.sub.3, or
DCM (preferably DMF) is optionally added a base such as TEA, NaOAc,
K.sub.2CO.sub.3, or KOH (1-10 equiv) at about 0-40.degree. C.
(preferably at 0.degree. C.) and the mixture is stirred for about
2-45 min (preferably about 5 min). A halogen source such as
I.sub.2, Br.sub.2, NBS, pyridinium tribromide, NCS, or NIS
(0.95-1.2 equiv, preferably 1.0 equiv) is added portionwise,
dropwise neat, or as a solution in a solvent such as DMF. If
cooling the ice bath is removed and the mixture is stirred for
about 0.1-2 h (preferably about 40 min) at rt. Optionally, a
reagent such as sodium thiosulfate or sodium bisulfite as a
solution in water may be added or the reaction mixture is added to
the solution and the reaction mixture stirred for about 5-60 min
(preferably about 30 min). The mixture may be diluted with or added
into water or saturated aqueous NH.sub.4Cl (preferably using 10 mL
of water per 1 mL of DMF). The target compound may be collected by
filtration or extracted using an organic solvent such as EtOAc or
DCM, dried over Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated under reduced pressure.
Illustration of General Procedure GGG.1
Preparation #GGG.1.1:
8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR00919##
[1655] A solution of
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.500 g, 3.14
mmol, prepared using D from Preparation #BBBBB.1 and NaOH) and DMF
(16 mL) under nitrogen was cooled to about 0.degree. C. The mixture
was stirred for about 5 min. N-Iodosuccinimide (0.707 g, 3.14 mmol)
was added. After about 40 min, 5% aq. sodium thiosulfate (10 mL)
was added. The cold bath was removed. After stirring for about 30
min, water (15 mL) was added. The solid was collected by
filtration. The filter cake was washed with water (2.times.5 mL).
The aqueous layer was extracted with EtOAc (4.times.50 mL). The
combined organics were dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The residue was slurried in
water (10 mL) and then filtered, rinsing with water (2.times.1 mL).
The solid was dried in vacuo to afford a brown solid (0.689 g)
containing an approximate 4:1 ratio of mono- to di-iodinated
material. 8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.506 g, 57%): LC/MS (Table 1, Method n) R.sub.t=0.39 min; MS m/z
286 (M+H).sup.+.
[1656] General Procedure HHH: Cyanation of a Heterocycle
[1657] To a solution of a heteroaryl halide (preferably 1 equiv) in
an organic solvent (such as 1,4-dioxane, NMP or DMF, preferably
DMF) is added potassium cyanide (1-4 equiv, preferably 2.5 equiv),
copper(I) iodide (1-4 equiv, preferably 2.5 equiv),
tetrakis(triphenylphosphine) palladium(0) (0.01-0.05 equiv,
preferably 0.01 equiv) and 18-crown-6 (0.01-1.0 equiv, preferably
0.06-0.07 equiv). The reaction is heated at about 25-120.degree. C.
(preferably about 110.degree. C.) for about 0.5-10 h (preferably
about 4 h). The reaction is cooled to rt and the organic solvent is
optionally removed under reduced pressure. The crude material can
be partitioned between an organic solvent (such as EtOAc or DCM)
and water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
or brine. The layers are separated and the aqueous layer is
optionally washed with an organic solvent (such as EtOAc or DCM).
The combined organic extracts are dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure HHH
Preparation #HHH.1*:
N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[-
2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanes-
ulfonamide
##STR00920##
[1659] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-p-
yrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesu-
lfonamide (0.1 g, 0.16 mmol, prepared using KK from Preparation
#GGG.1) in DMF (1.2 mL) was added potassium cyanide (0.03 g, 0.40
mmol), copper(I) iodide (0.076 g, 0.40 mmol),
tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) and
18-crown-6 (0.003 g, 0.01 mmol). The reaction mixture was stirred
at about 110.degree. C. for about 4 h and cooled to ambient
temperature. The solvent was removed under reduced pressure. The
residue was partitioned between EtOAc (15 mL) and water (8 mL). The
aqueous layer was further extracted with EtOAc (15 mL). The
combined organic layers were dried with MgSO.sub.4, filtered, and
concd under reduced pressure to give
N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[-
2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanes-
ulfonamide (0.069 g, 82%): LC/MS (Table 1, Method b) R.sub.t=2.50
min; MS m/z: 530 (M+H).sup.+.
[1660] General Procedure III: Horner-Wadsworth-Emmons Reaction of a
Ketone
[1661] To a flask charged with a base (preferably NaH) (1-5 equiv,
preferably 1.2 equiv) in an organic solvent (preferably THF) at
about 0-50.degree. C. (preferably rt) is added a
beta-ketophosphonate (1-5 equiv, preferably 1.25 equiv). After the
evolution of hydrogen gas has ceased a solution of a ketone
(preferably 1 equiv) in an organic solvent (preferably THF) is
added. After about 1-20 h (preferably about 4 h) the reaction
mixture is partitioned between an organic solvent (such as DCM or
EtOAc, preferably EtOAc) and an aqueous phase such as saturated
aqueous NaHCO.sub.3. The organic layer is separated and optionally
washed with brine, dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, filtered, and concd under reduced pressure.
Illustration of General Procedure III
Preparation #III.1: (E)-ethyl
2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylidene)acetate
##STR00921##
[1663] To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was
added ethyl 2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at
rt. After about 30 min, a solution of
(3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)cyclopentanone (0.300 g, 0.708 mmol, Preparation #25) in THF
(1 mL) was added. After about 4 h, EtOAc (20 mL) and saturated
aqueous NaHCO.sub.3 (20 mL) were added. The organic layer was
separated, concd in vacuo, and purified by chromatography on silica
gel (40 g) eluting with EtOAc/heptane/DCM (2:1:1) to provide
(E)-ethyl
2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylidene)acetate (0.260 g, 74%). LC/MS (Table 1,
Method a) R.sub.t=2.54 min; MS m/z: 494 (M+H).sup.+.
[1664] General Procedure JJJ: Formation of a Potassium
Sulfonate
[1665] To a solution of a sulfonate (preferably 1 equiv) in an
organic solvent (preferably 1,4-dioxane) and water is added
potassium thiocyanate (1-3 equiv, preferably 1 equiv). The reaction
is heated at about 80-100.degree. C. (preferably about 100.degree.
C.) for about 5-24 h (preferably about 16 h). The reaction mixture
is cooled to ambient temperature and is concd under reduced
pressure.
Illustration of General Procedure JJJ
Preparation #JJJ.1: potassium 1-ethylcyclopropane-1-sulfonate
##STR00922##
[1667] To a solution of butyl 1-ethylcyclopropane-1-sulfonate (0.46
g, 2.23 mmol prepared from Preparation #6 Step A and ethyl iodide
using KKK) in 1,4-dioxane (2.79 mL) and water (2.79 mL) was added
potassium thiocyanate (0.12 mL, 2.23 mmol). The reaction is heated
to about 100.degree. C. for about 16 h. The reaction mixture was
cooled to ambient temperature and was concd under reduced pressure
to afford potassium 1-ethylcyclopropane-1-sulfonate (0.42 g, 100%)
as a white crystalline solid: 1H NMR (400 MHz, DMSO) .delta.
1.70-1.58 (m, 2H), 0.89 (t, J=7.5, 3H), 0.80 (q, J=3.8, 2H), 0.32
(q, J=3.8, 2H).
[1668] General Procedure KKK: Alkylation of a Sulfonate
[1669] To a solution of a sulfonate (preferably 1 equiv) in an
organic solvent (preferably THF), cooled to about -78-0.degree. C.
(preferably -78.degree. C.) is added an organic base such as
n-BuLi, KHMDS, or LDA (preferably n-BuLi) (1-3 equiv, preferably 1
equiv) and an alkylating reagent such as iodomethane, iodoethane,
or trifluoroethyl iodide (1-5 equiv, preferably 1.2 equiv). The
reaction is stirred at about -78-25.degree. C. (preferably
-78.degree. C.) for about 1-24 h (preferably 2 h). Optionally, the
reaction is warmed to ambient temperature and stirred for about
1-24 h (preferably 2 h). The reaction mixture is quenched by the
addition of saturated aqueous ammonium chloride. The reaction
mixture is partitioned between an organic solvent (such as DCM or
EtOAc) and water or brine. The layers are separated and the organic
layer is optionally washed with water and/or brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under
reduced pressure.
Illustration of General Procedure KKK
Preparation #KKK.1: butyl 1-methylcyclopropane-1-sulfonate
##STR00923##
[1671] To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4
mmol, Preparation #6 Step A) in THF (8 mL) at about -78.degree. C.
was added n-BuLi (1.6 M in hexanes, 5.26 mL, 8.42 mmol) and
iodomethane (0.684 mL, 10.9 mmol) simultaneously. The resulting
mixture was stirred at about -78.degree. C. for about 2 h and then
at ambient temperature for about 2 h. The reaction was quenched by
the addition of saturated aqueous NH.sub.4Cl (7 mL) and the layers
were separated. The aqueous layer was extracted with EtOAc (15 mL)
and the combined organic extracts were dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The residue
was purified by silica gel column chromatography eluting with 5 to
25% EtOAc in heptanes to yield butyl
1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a colorless oil. H
NMR (DMSO-d.sub.6) .delta. 4.17 (t, 2H), 1.62 (m, 2H), 1.43 (s,
3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m, 2H), 0.88 (t, 3H).
[1672] General Procedure LLL: Oxidation of a Thioether to a
Sulfone
[1673] To a solution of a thioether (preferably 1 equiv) in an
organic solvent (preferably DCM) is added an oxidant (such as
m-CPBA, oxone, preferably m-CPBA) (1-4 equiv, preferably 2 equiv).
The reaction is stirred at ambient temperature for about 0.25-24 h
(preferably about 0.5 h). The reaction mixture is optionally
filtered, washed with additional DCM, and the filtrate is concd
under reduced pressure. The reaction mixture is optionally quenched
with the addition of an aqueous base (such as saturated aqueous
NaHCO.sub.3) and partitioned between an organic solvent (such as
DCM or EtOAc, preferably DCM). The layers are separated and
optionally washed with water and/or brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure to give a sulfone.
Illustration of General Procedure LLL
Preparation #LLL.1:
1-(2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethyls-
ilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR00924##
[1675] To a mixture of
1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl-
)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.100 g, 0.200 mmol, Preparation #MMM.1) in DCM (0.667 mL) was
added m-CPBA (0.090 g, 0.400 mmol). The reaction stirred at ambient
temperature for about 0.5 h. The reaction mixture was quenched by
the addition of saturated aqueous NaHCO.sub.3 (5 mL). The aqueous
portion was extracted with DCM (2.times.10 mL). The combined
organic layers were separated, dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
0-60% EtOAc in DCM to afford
1-2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethylsi-
lyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.095 g, 89%, 93% purity) as a clear oil: LC/MS (Table 1, Method
a) R.sub.t=2.63 min; MS m/z: 532 (M+H).sup.+.
[1676] General Procedure MMM: Mitsunobu Reaction Using a Thiol
[1677] To a solution of an azodicarboxylate such as DIAD, DEAD, or
TMAD (preferably DIAD) (1-2 equiv, preferably 1.2 equiv) in an
organic solvent (preferably THF) is added a phosphine reagent such
as PPh.sub.3 or P(n-Bu).sub.3 (preferably P(n-Bu).sub.3) (1-2
equiv, preferably 1.2 equiv), an alcohol (preferably 1 equiv), TEA
(1-2 equiv, preferably 1.2 equiv) and a thiol (1-1.5 equiv,
preferably 1.2 equiv). The reaction is stirred at ambient
temperature for about 1-24 h (preferably 16 h). The reaction
mixture is optionally concd under reduced pressure to give a
residue. The reaction mixture or residue is partitioned between an
organic solvent (such as DCM or EtOAc, preferably EtOAc) and water,
an aqueous base (such as saturated aqueous NaHCO.sub.3) or brine.
The layers are separated and the organic layer is optionally washed
with water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd under reduced pressure to give a thioether.
Illustration of General Procedure MMM
[1678] Preparation #MMM.1:
1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl-
)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR00925##
[1679] An oven-dried flask was charged with DIAD (0.177 mL, 0.896
mmol) and THF (3.74 mL). The reaction flask was cooled to 0.degree.
C. before the addition of P(n-Bu).sub.3 (0.221 mL, 0.896 mmol),
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.300 g, 0.747 mmol,
prepared from Preparation #20 using KK and SS), TEA (0.125 mL,
0.896 mmol) and 2,2,2-trifluoroethanthiol (0.080 mL, 0.896 mmol).
The reaction was stirred at ambient temperature for about 16 h. The
reaction mixture was partitioned between water (10 mL) and EtOAc
(10 mL). The aqueous layer was extracted with EtOAc (3.times.10
mL). The combined organic layers were dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to afford a
crude oil. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-60% EtOAc in DCM to
afford
1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimeth-
ylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.165 g, 44%) as an orange solid: LC/MS (Table 1, Method a) R=3.02
min; MS m/z: 500 (M+H).sup.+.
[1680] General Procedure NNN: Curtius Rearrangement to Form an
Isocyanate
[1681] To a solution of a carboxylic acid (preferably 1 equiv) in
an organic solvent such as t-BuOH or toluene (preferably t-BuOH) is
added DPPA (1-3 equiv, preferably 1-1.1 equiv) and an organic base
such as TEA (2-4 equiv, 2.2 equiv). The reaction is stirred at
about 25-110.degree. C. (preferably about 70.degree. C. for t-BuOH
and 110.degree. C. for toluene) for about 0.5-16 h (preferably
about 2 h). The reaction mixture is cooled to ambient temperature
and is optionally concd under reduced pressure to give a residue.
The reaction mixture or residue is optionally partitioned between
an organic solvent (such as DCM or EtOAc) and water, an aqueous
base (such as saturated aqueous NaHCO.sub.3) or brine. The layers
are separated and the organic layer is dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure NNN
Preparation #NNN.1:
N-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide
##STR00926##
[1683] To a solution of
4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid
(4.10 g, 16.58 mmol, prepared from Example #24 Step I using Y, K,
and Z) and DPPA (3.58 mL, 16.58 mmol) in t-BuOH (55 mL) was added
TEA (5.0 mL, 36.5 mmol). The reaction was heated to about
70.degree. C. for about 2 h then cooled to ambient temperature and
concd under reduced pressure to afford a crude residue. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-10% MeOH in DCM to afford
N-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide (3.25
g, 80%) as a white solid: LC/MS (Table 1, Method n) R.sub.t=0.49
min; MS m/z: 245 (M+H).sup.+.
[1684] General Procedure OOO: Hydrolysis of an Isocyanate
[1685] To a mixture of an isocyanate (preferably 1 equiv) in an
organic solvent (preferably THF) is added an aqueous base or acid
(such as aqueous NaOH, LiOH, or HCl) (10-50 equiv, preferably 20
equiv). The reaction is heated at about 30-100.degree. C. for about
5-36 h (preferably about 50.degree. C. for about 16 h). The
reaction is cooled to ambient temperature and the reaction mixture
is partitioned between an organic solvent (such as DCM or EtOAc)
and water, an aqueous base (such as saturated aqueous NaHCO.sub.3)
or brine. The layers are separated and the organic layer is
optionally washed with water and or brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd under reduced
pressure.
Illustration of General Procedure OOO
Preparation #OOO.1:
N-(3-amino-4-methylcyclopentyl)cyclopropanesulfonamide
##STR00927##
[1687] To a mixture of
N-(3-isocyanato-4-methylcyclopentyl)cyclopropanesulfonamide (1.00
g, 4.09 mmol, Preparation #NNN.1) in THF (2.0 mL) was added aqueous
LiOH (4 N, 20.5 mL, 82 mmol). The reaction was heated to about
50.degree. C. for about 16 h, cooled to ambient temperature and
partitioned between water (5 mL) and EtOAc (10 mL). The organic
portion was separated and the aqueous portion was extracted with
DCM (3.times.20 mL). The combined organic extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give crude N-(3-amino-4-methylcyclopentyl)cyclopropanesulfonamide
(0.66 g, 74%) as a white solid: LC/MS (Table 1, Method n)
R.sub.t=0.020 min; MS m/z: 219 (M+H).sup.+.
[1688] General Procedure PPP: Formation of an Oxime Ether from a
Ketone
[1689] To a solution of a ketone (preferably 1 equiv) in an organic
solvent (preferably EtOH) is added an O-alkyl hydroxylamine (1-10
equiv, preferably about 1 equiv). If the O-alkyl hydroxylamine is a
hydrochloride salt, an organic base is added such as TEA or DIEA
(preferably TEA, 1-5 equiv, preferably about 1.5 equiv). The
reaction mixture is stirred at ambient temperature for about 12-24
h (preferably about 18 h). In cases where the reaction does not
proceed to completion as monitored by TLC, LC/MS, or HPLC,
additional O-alkyl hydroxylamine may be added (1-10 equiv,
preferably about 1 equiv). The reaction is stirred at ambient
temperature for about 1-24 h (preferably about 5 h). The solvent is
removed under reduced pressure.
Illustration of General Procedure PPP
Example #PPP.1.1
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyc-
lopentanone O-cyclopropylmethyl oxime
##STR00928##
[1691] To a solution of
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone (0.05 g, 0.19 mmol, Example #AA.1.59) in EtOH (1 mL)
was added TEA (0.04 mL, 0.28 mmol) and
O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19
mmol, Huhu Technologies). The reaction mixture was stirred for
about 18 h at ambient temperature. Additional
O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19
mmol, Huhu Technologies) was added. The reaction was stirred at
ambient temperature for about 5 h. The solvent was removed under
reduced pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 1-10% MeOH in DCM to
afford
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone O-cyclopropylmethyl oxime (0.051 g, 80%): LC/MS (Table
1, Method a) R.sub.t=1.94 min; MS m/z: 339 (M+H).sup.+.
TABLE-US-00047 TABLE PPP.1 Examples prepared using PPP and
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo
[4,3-a]pyrazin-1-yl)cyclopentanone (Example #AA.1.59) R.sub.t min
(Table 1 m/z ESI+ Hydroxylamine Structure Ex. # method) (M +
H).sup.+ O-(2- (methylsulfonyl) ethyl)hydroxyl- amine (Huhu
Technologies) ##STR00929## PPP.1.2 1.63 (a) 391 O-(cyclobutyl-
methyl)hydroxyl- amine (Huhu Technologies) ##STR00930## PPP.1.3
2.15-2.12 (a) 353 O-(tetrahydro- 2H-pyran-4- yl)hydroxyl- amine
(Huhu Technologies) ##STR00931## PPP.1.4 1.72 (a) 369
[1692] General Procedure QQQ: Acid-Mediated Conversion of a t-Butyl
Ester to a Carboxylic Acid with TFA
[1693] To a t-butyl ester (preferably 1 equiv) is added TFA (10-400
equiv, preferably 200-250 equiv). The reaction is maintained at
about -20-60.degree. C. (preferably about 25.degree. C.) for about
0.5-16 h (preferably about 1 h). In any case where an additional
acid labile group is present (for example, a Boc group) this group
may also be cleaved during the reaction. The reaction mixture is
concd under reduced pressure. The resulting residue can be used
without further purification or dissolved in an organic solvent
such as DCM or EtOAc (preferably DCM) and is washed with an aqueous
inorganic base such as NaHCO.sub.3 or Na.sub.2CO.sub.3 (preferably
saturated aqueous NaHCO.sub.3). The organic layer is optionally
washed with brine, dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, and concd under reduced pressure to yield the
target compound.
Illustration of General Procedure QQQ
Preparation #QQQ.1:
4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylic
acid
##STR00932##
[1695] tert-Butyl
4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylate
(0.080 g, 0.241 mmol, prepared using K from Preparation #21 and
cyclopropylsulfonyl chloride) in TFA (4 mL, 51.9 mmol) was stirred
at about 25.degree. C. for about 1 h. The organic solvent was
removed under reduced pressure to yield crude
4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylic
acid (0.066 g, 100%): LC/MS (Table 1, Method b) R.sub.t=1.81 min;
MS m/z: 276 (M+H).sup.+.
[1696] General Procedure RRR: Reduction of an Alkyne to an
Alkene
[1697] To a flask charged with a hydrogenation catalyst (preferably
Lindlar catalyst) (0.001 to 1 equiv, preferably 0.01 equiv) is
added a solvent (preferably THF) and an additive to prevent
over-reduction (such as pyridine or quinoline, preferably pyridine)
in a ratio of 5:1 to 20:1 (preferably 10:1) followed by an alkyne
(1 equiv). The reaction mixture is sparged with hydrogen for about
5-30 min (preferably about 10 min) and an atmosphere of hydrogen is
maintained via balloon. After about 1-40 h (preferably about 15 h)
the reaction mixture is filtered, diluted with an organic solvent
(preferably Et.sub.2O) and washed with saturated aqueous
CuSO.sub.4, followed by water. The organic layer is separated,
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd under reduced pressure.
Illustration of General Procedure RRR
Preparation #RRR.1: (Z)-ethyl pent-2-enoate
##STR00933##
[1699] To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF
(100 mL) and pyridine (10.00 mL) was added ethyl pent-2-ynoate
(5.22 mL, 39.6 mmol). The reaction mixture was sparged with
hydrogen for about 10 min and an atmosphere of hydrogen was
maintained via balloon. After about 15 h the reaction mixture was
filtered through a pad of Celite.RTM., diluted with Et.sub.2O (30
mL) and washed with saturated aqueous CuSO.sub.4 (40 mL), followed
by water (40 mL). The organic layer was separated, dried over
anhydrous MgSO.sub.4, filtered, and concd in vacuo to provide crude
(Z)-ethylpent-2-enoate (5 g, 98%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.05 (t, 3H), 1.28 (t, 3H), 2.65 (m, 2H), 4.18 (q, 2H),
5.72 (m, 1H), 6.21 (m, 1H).
[1700] General Procedure SSS: 1,3-Dipolar Cycloaddition to Form a
Pyrrolidine
[1701] To a solution of a 1,3-dipole precursor (0.5-3 equiv,
preferably 1 equiv) and a dipolarophile (0.5-3 equiv, preferably 1
equiv) in an organic solvent (preferably DCM) at about 0-45.degree.
C. (preferably rt) is added an acid (preferably TFA) (0.001-1
equiv, preferably 0.01 equiv). After about 1-60 h (preferably about
48 h) the mixture is concd in vacuo to provide the crude
cyclo-adduct.
Illustration of General Procedure SSS
Preparation #SSS.1: cis-ethyl
1-benzyl-4-ethylpyrrolidine-3-carboxylate
##STR00934##
[1703] To a solution of
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL,
39.0 mmol,) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol,
Preparation #RRR.1) in DCM (50 mL) was added TFA (0.030 mL, 0.390
mmol) at rt. After about 2 d, the reaction mixture was concd in
vacuo to provide crude cis-ethyl
1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil.
LC/MS (Table 1, Method a) R.sub.t=0.51 min; MS m/z: 262
(M+H).sup.+.
[1704] General Procedure TTT: Hydrogenation of an Azide to an
Amine
[1705] To an azide (preferably 1 equiv) in EtOH, MeOH, EtOAc or THF
(preferably EtOH), a catalyst such as 20 wt % palladium hydroxide
on carbon or 10% wt palladium on carbon (preferably palladium
hydroxide on carbon, 0.05-0.5 eq., preferably 0.15 equiv) is added
and the mixture is stirred at ambient temperature under atmospheric
pressure of hydrogen for 1-24 h, preferably about 2 h. The catalyst
is removed by filtration through a pad of Celite.RTM. and the
filtrate is concd under reduced pressure to yield the desired
product.
Illustration of General Procedure TTT
Preparation #TTT.1:
(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-
-3-amine
##STR00935##
[1707] To the solution of
8-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e-
]pyrazine (0.136 g, 0.459 mmol, prepared using S from Example #3
Step E and tert-butyl bromoacetate, E with HCl, H with
(2R,4S)-4-azido-2-methylpyrrolidine (prepared from
(2R,4S)-tert-butyl 4-azido-2-methylpyrrolidine-1-carboxylate as
detailed in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P.
B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem.
1988, 31, 1598-1611, then E with HCl), 00, D with NaOH) in EtOH (15
mL), 20% palladium hydroxide on carbon (0.05 g, 0.071 mmol) was
added and the reaction mixture was stirred under atmospheric
pressure of hydrogen for 2 h. The catalyst was removed by
filtration through a pad of Celite.RTM. and the solvent was removed
under reduced pressure to yield
(3S,5R)-5-ethyl-1-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidin-
-3-amine (0.11 g, 89%) as an off-white amorphous solid. LC/MS
(Table 1, Method a) R.sub.t=1.00 min; MS m/z 271 (M+H).sup.+.
[1708] General Procedure UUU: Reaction of an Aryl or Heteroaryl
Halide with a Boronic Acid or Boronate Ester Followed by Tosyl
Deprotection
[1709] To a mixture of an aryl halide (preferably 1 equiv), a
boronic acid or boronate ester (1-1.75 equiv, preferably 1.1
equiv), and an inorganic base (for example, potassium fluoride,
sodium carbonate or cesium carbonate, preferably cesium carbonate
(2-16 equiv, preferably 2.5 equiv) in a solvent (for example THF,
DME, DMF, 1,4-dioxane, DME/water, 1,4-dioxane/water,
toluene/EtOH/water, 1,4-dioxane/EtOH/water, water; preferably
1,4-dioxane/EtOH/water) is added a palladium catalyst (for example
tris(benzylideneacetone)dipalladium(0),
tetrakis(triphenylphosphine)palladium(0),
bis(acetato)triphenylphosphinepalladium(II), polymer-bound
FibreCat.TM. 1032,
(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex
with DCM, or dichlorobis(triphenylphosphine)palladium(II);
preferably dichlorobis(triphenylphosphine)palladium(II) (0.01-0.20
equiv, preferably 0.1 equiv)). The reaction mixture is heated at
about 40-120.degree. C. (preferably about 60.degree. C.) for about
1-24 h (preferably about 6 h) thermally, or at about
100-200.degree. C. (preferably about 120.degree. C. for about 5-60
min (preferably about 20 min) in a microwave (preferably 5 min ramp
time, 300 Watts max power, 250 psi max pressure). The reaction
mixture is allowed to cool to ambient temperature and is worked up
using one of the following methods. Method 1. For reactions
containing water, the reaction mixture may be diluted with an
organic solvent (such as DCM or EtOAc). The layers are separated,
the organic solution is optionally washed with water and/or brine,
dried over anhydrous MgSO.sub.4 or Na.sub.2SO.sub.4, filtered, and
the solvent is removed under reduced pressure to give the
intermediate. Method 2. The reaction mixture is coned under reduced
pressure and optionally purified using one or more of the
Purification Methods described above to give the intermediate. To
the intermediate are added an organic solvent (such as 1,4-dioxane,
MeOH, or THF/MeOH, preferably 1,4-dioxane) and an aqueous base
(such as aqueous Na.sub.2CO.sub.3 or aqueous NaOH, 1-30 equiv,
preferably 2-3 equiv for aqueous NaOH, preferably 15-20 equiv for
aqueous Na.sub.2CO.sub.3). The mixture is stirred at about
25-100.degree. C. (preferably about 60.degree. C.) for about 1-72 h
(preferably about 1-16 h) thermally or at about 80-200.degree. C.
(preferably about 100.degree. C.) for about 10-60 min (preferably
about 15 min) in a microwave (preferably 5 min ramp time, 300 Watts
max power, 250 psi max pressure). In cases where the reaction does
not proceed to completion as monitored by TLC, LC/MS, or HPLC,
additional aqueous base (such as aqueous Na.sub.2CO.sub.3, 10-20
equiv, preferably 10 equiv or aqueous NaOH, 1-5 equiv, preferably
1-2 equiv) and/or a cosolvent (such as EtOH) are added. The
reaction is continued at about 25-100.degree. C. (preferably about
60.degree. C.) for about 0.25-3 h (preferably about 1-2 h)
thermally or at about 80-100.degree. C. (preferably about
100.degree. C.) for about 10-60 min (preferably about 15 min) in a
microwave. In any case where an additional base labile group is
present (for example, an ester or a cyano group), this group may
also be hydrolyzed. The reaction is worked up using one of the
following methods. Method 1. The organic solvent is optionally
removed under reduced pressure and the aqueous solution is
neutralized with the addition of a suitable aqueous acid (such as
aqueous HCl). A suitable organic solvent (such as EtOAc or DCM) and
water are added, the layers are separated, and the organic solution
is dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered,
and concd to dryness under reduced pressure to give the target
compound. Method 2. The organic solvent is optionally removed under
reduced pressure, a suitable organic solvent (such as EtOAc or DCM)
and water are added, the layers are separated, and the organic
solution is dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd to dryness under reduced pressure to give the
target compound. Method 3. The reaction mixture is concd under
reduced pressure and directly purified by one of the subsequent
methods to give the target compound.
Illustration of General Procedure UUU
Example #UUU.1
1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]p-
yrazine
##STR00936##
[1711] A microwave vial was charged with
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
(0.050 g, 0.11 mmol, Preparation #MM.1),
4-(methylsulfonyl)phenylboronic acid (0.023 g, 0.12 mmol, Acros),
cesium carbonate (0.086 g, 0.26 mmol),
dichlorobis(triphenylphosphine)palladium(II) (0.0066 g, 0.0000094
mmol), and 1,4-dioxane (0.42 mL), EtOH (0.42 mL), and water (0.21
mL). The vial was capped and the mixture was heated to about
120.degree. C. for about 20 min (5 min ramp time, 300 Watts max
power, 250 psi max pressure) in a microwave. The reaction mixture
was concd under reduced pressure to give a solid that was dissolved
in 1,4-dioxane (1.0 mL) and transferred to a microwave vial.
Aqueous 2 N NaOH (0.11 mL, 0.21 mmol) was added and the vial was
capped. The solution was heated to about 100.degree. C. for about
15 min in a microwave (300 W max power, 250 psi max pressure, 5 min
ramp time). DCM (10 mL) and saturated aqueous NH.sub.4Cl (5 mL)
were added to the reaction solution. The layers were separated and
the aqueous solution was extracted with additional DCM (5 mL). The
combined extracts were dried over anhydrous MgSO.sub.4, filtered,
and concentrated to dryness under reduced pressure to give a light
brown solid. Upon addition of DCM (1 mL), a yellow precipitate
formed that was collected by vacuum filtration and dried overnight
on a Buchner funnel to give
1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazine (0.017 g, 41%): LC/MS (Table 1, Method
a) R.sub.t=2.39 min; MS m/z: 395 (M+H).sup.+.
TABLE-US-00048 TABLE UUU.1 Examples prepared from
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo
[1,5-a]pyrrolo[2,3-e]pyrazine (Preparation #MM.1) using General
Procedure UUU Boronic R.sub.t min m/z acid or Exam- (Table ESI+
boronate ple 1, Me- (M + ester Product # thod) H).sup.+ N-(4-
(4,4,5,5- tetra- methyl- 1,3,2- dioxa- boro- lan- 2-yl) phenyl) me-
thane- ##STR00937## UUU.1.1 2.25 (a) 410 sulfona- mide
[1712] General Procedure VVV: Reaction of an Aryl or Heteroaryl
Halide with a Boronic Acid or Boronate Ester
[1713] To a mixture of an aryl halide (preferably 1 equiv), a
boronic acid or boronate ester (1-1.75 equiv, preferably 1.1
equiv), and an inorganic base (for example, potassium fluoride,
sodium carbonate or cesium carbonate, preferably cesium carbonate)
(1.1-16 equiv, preferably 2 equiv) in a solvent (for example THF,
DME, DMF, 1,4-dioxane, DME/water, 1,4-dioxane/water,
toluene/EtOH/water, 1,4-dioxane/EtOH/water or water; preferably
1,4-dioxane) is added a palladium catalyst (for example
tris(benzylideneacetone)dipalladium(0),
tetrakis(triphenylphosphine)palladium(0),
bis(acetato)triphenylphosphinepalladium(II), polymer-bound
FibreCat.TM. 1032,
(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex
with DCM, or dichlorobis(triphenylphosphine)palladium(II);
preferably tris(benzylideneacetone)dipalladium(0), 0.01-0.20 equiv,
preferably 0.1 equiv) and a ligand (for example
tricyclohexylphosphine, tri-t-butyl-phosphane; preferably
tricyclohexylphosphine (0.01-1.0 equiv, preferably 0.16 equiv)) is
added optionally. The reaction mixture is heated at about
40-120.degree. C. (preferably about 85.degree. C.) for about 1-24 h
(preferably about 2 h) thermally, or at about 100-200.degree. C.
(preferably about 120.degree. C.) for about 5-60 min (preferably
about 20 min) in a microwave (preferably 5 min ramp time, 300 Watts
max power, 250 psi max pressure). The reaction mixture is allowed
to cool to ambient temperature and is worked up using one of the
following methods. Method 1. For reactions containing water, the
reaction mixture may be diluted with an organic solvent (such as
DCM or EtOAc). The layers are separated, the organic solution is
optionally washed with water and/or brine, dried over anhydrous
MgSO.sub.4 or Na.sub.2SO.sub.4, filtered, and the solvent is
removed under reduced pressure to give the desired compound. Method
2. The reaction mixture is concd under reduced pressure and
optionally purified using one or more of the Purification Methods
described above to give the desired compound. Method 3. The
catalyst is removed by filtration and the filtrate is concentrated
under reduced pressure.
Illustration of General Procedure VVV
Preparation #VVV.1:
8-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-
-a]pyrrolo[2,3-e]pyrazine
##STR00938##
[1715] To the solution of
8-cyclohexyl-1-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a-
]pyrrolo[2,3-e]pyrazine (0.100 g, 0.201 mmol, prepared using GGG
with 8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
[WO2009152133A1], KK) in 1,4-dioxane (1 mL) was added cesium
carbonate (0.131 g, 0.403 mmol), tricyclohexylphosphine (20 wt %
solution in toluene, 0.045 g, 0.032 mmol), Pd.sub.2(dba).sub.3
(0.018 g, 0.020 mmol) and trimethylborate (0.033 g, 0.262 mmol).
The mixture was degassed and heated at about 85.degree. C. for
about 2 h. The catalyst was filtered off. The filtrate was
concentrated and purified by RP-HPLC (Table 1, Method s) to give
8-cyclohexyl-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-
-a]pyrrolo[2,3-e]pyrazine (0.032 g, 41%) as a clear oil: LC/MS
(Table 1, Method b) R.sub.t=3.41 min; MS m/z: 385 (M+H).sup.+.
[1716] General Procedure WWW: Formation of a Carbamate
[1717] To an amine (2-10 equiv, preferably 5 equiv) and DMAP (0-5
equiv, preferably 2 equiv) in an organic solvent (such as THF or
1,4-dioxane, preferably 1,4-dioxane) at about -20.degree. C. to
80.degree. C. (preferably about 40.degree. C.) is added a carbonate
or a solution of a carbonate (preferably 1 equiv) in an organic
solvent (such as THF or 1,4 dioxane, preferably 1,4-dioxane). After
about 1-16 h (preferably about 2 h), the reaction mixture is either
concd under reduced pressure or optionally diluted with an organic
solvent (such as Et.sub.2O, EtOAc or DCM, preferably EtOAc), washed
with water and an aqueous base (such as saturated aqueous
Na.sub.2CO.sub.3 or NaHCO.sub.3 and brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and coned under reduced
pressure.
Illustration of General Procedure WWW
Preparation #WWW.1:
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl phenylcarbamate
##STR00939##
[1719] To aniline (0.063 g, 0.677 mmol) and DMAP (0.033 g, 0.271
mmol) in 1,4-dioxane (1 mL) at about 40.degree. C. was added a
solution of
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.080 g, 0.135 mmol,
prepared from Example #42Step N) in 1,4-dioxane (1 mL). After about
2 h, the solvent was removed and the residue was purified by silica
gel chromatography (12 g) eluting with 0-40% EtOAc in DCM to give
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl phenylcarbamate (0.0468 g, 63%): LC/MS (Table
1, Method b) R.sub.t=2.58 min; MS m/z: 545 (M+H).sup.+.
[1720] General Procedure XXX: Urea Formation with Loss of
Protecting Group
[1721] To a solution or slurry of an amine or amine salt (1-3
equiv, preferably 1-2 equiv) in an organic solvent such as DCM,
THF, or DMF (preferably THF) at about 20-80.degree. C. (preferably
about 20.degree. C.) is optionally added an organic base, such as
TEA, DIEA, pyridine (preferably DIEA) (1-10 equiv, preferably 1-5
equiv) followed by CDI (1-5 equiv, preferably 1 equiv). After about
0.5-24 h (preferably about 1-3 h), a second amine or amine salt
(1-10 equiv, preferably 1-3 equiv) is added neat or as a solution
or slurry in an organic solvent such as DCM, THF, or DMF
(preferably THF). The reaction is held at about 20-80.degree. C.
for about 2-24 h (preferably about 16 h). If the reaction is not
complete, the reaction may be heated at about 40-80.degree. C.
(preferably 55.degree. C.). In addition, additional amine or amine
salt (1-50 equiv, preferably 20 equiv), and/or DMAP (1-10 equiv,
preferably 1 equiv) may be added. The reaction is held at about
20-80.degree. C. for about 24-96 h (preferably 72 h). This may be
repeated if the reaction is not complete by TLC, LC/MS, or HPLC.
The reaction mixture is cooled to ambient temperature. The reaction
mixture is optionally partitioned between an organic solvent (such
as EtOAc or DCM) and an aqueous base (such as saturated aqueous
NaHCO.sub.3 or saturated aqueous Na.sub.2CO.sub.3, preferably
saturated aqueous NaHCO.sub.3). Alternatively, the reaction mixture
is concd under reduced pressure and the residue is partitioned as
above. In either case, the aqueous layer is then optionally
extracted with additional organic solvent such as EtOAc or DCM. The
combined organic layers may optionally be washed with brine and
concd in vacuo or dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4 and then decanted or filtered prior to concentrating
under reduced pressure. Optionally, the reaction mixture is concd
under reduced pressure and the residue is directly purified.
Illustration of General Procedure XXX
Preparation #XXX.1:
(cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(-
(tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxamide
##STR00940##
[1723] To a solution of
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazine.hydrochloride (0.075 g, 0.168 mmol, Example #36,
step F) in THF (1.00 mL) was added DIEA (0.150 mL, 0.861 mmol) and
CDI (0.027 g, 0.168 mmol). After about 1 h,
4-aminomethyltetrahydropyran (0.020 g, 0.17 mmol, Acros) was added
and the reaction mixture was stirred at ambient temperature for
about 16 h. The reaction mixture was heated at about 55.degree. C.
for about 24 h. DMAP (0.021 g, 0.168 mmol) was added and continued
stirring at about 55.degree. C. for about 48 h.
4-aminomethyltetrahydropyran (0.400 g, 3.47 mmol, Acros) was added
and continued stirring at about 55.degree. C. for about 24 h. The
solvent was removed under reduced pressure. The crude material was
purified by RP-HPLC (Table 1, Method m) to afford
(cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(-
(tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxamide (0.007
g, 10%) as product: LC/MS (Table 1, Method a) R.sub.t=1.32 min; MS
m/z: 398 (M+H).sup.+.
TABLE-US-00049 TABLE XXX.1 Urea formation with loss of protecting
group (prepared from Example #36, step F) using General Procedure
XXX R.sub.t min m/z Starting (Table ESI+ material 1, Me- (M + amine
Product Ex # thod) H).sup.+ cyclo- propyl- methana- mine
##STR00941## XXX.1 1.62 (a) 354
[1724] General Procedure YYY: Michael Addition
[1725] To a mixture of a nucleophile (such as an amine or an
alcohol, preferably 1 equiv) and a Michael acceptor (0.5-30 equiv,
preferably 2-5 equiv) optionally in an organic solvent (such as
DMF, EtOH or MeCN, preferably DMF) is optionally added an organic
base (such as TEA, DIEA, or DBU, preferably DBU, 1-5 equiv,
preferably 1-2 equiv). The reaction mixture is heated at about
20-120.degree. C. (preferably about 80.degree. C.) for about 2-60 h
(preferably about 12-16 h). Optionally additional Michael acceptor
(0.5-30 equiv, preferably 2-5 equiv) is added followed by optional
addition of an organic base (such as TEA, DIEA, or DBU, preferably
DBU, 1-5 equiv, preferably 1-2 equiv) and the reaction mixture is
heated at about 20-120.degree. C. (preferably about 80.degree. C.)
for about 2-60 h (preferably about 2-5 h). In cases where the
reaction does not proceed to completion as monitored by TLC, LC/MS,
or HPLC, the reaction mixture is resubjected to the previously
described conditions. The reaction mixture is then cooled to
ambient temperature. Optionally, DCM is added and the suspension is
filtered. The reaction mixture or the optional filtrate is
concentrated under reduced pressure.
Illustration of General Procedure YYY
Preparation #YYY.1:
2-(3-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methyl-
cyclopentylamino)oxetan-3-yl)acetonitrile
##STR00942##
[1727] To a solution of
(1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,-
2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.605 g, 1.569
mmol, prepared using FFFFF from Preparation #33, GGGGG with
Preparation #E.1.1, KKKK with PFPAA, D with NaOH, KK, Y) in DMF (6
mL) was added 2-(oxetan-3-ylidene)acetonitrile (0.298 g, 3.14 mmol,
J. Med. Chem. 2010, 53(8), 3227) and the reaction mixture was
heated at about 80.degree. C. for about 15 h.
2-(Oxetan-3-ylidene)acetonitrile (0.149 g, 1.569 mmol) was added
and the reaction mixture was heated at about 80.degree. C. for
about 3.5 h. The reaction mixture was cooled to ambient
temperature, concentrated in vacuo and the residue was purified by
silica gel chromatography eluting with 0% to 10% MeOH in DCM. A
second purification by silica gel chromatography eluting with 50%
to 100% EtOAc in heptane followed by 10% MeOH in DCM yielded
2-(3-((1S,3S,4R)-3-(3H-imidazo[1,
2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acet-
onitrile (0.262 g, 33%) as a sticky brown solid: LC/MS (Table 1,
Method n) R.sub.t=0.75 min; MS m/z 481 (M+H).sup.+.
[1728] General Procedure ZZZ: Grignard or Alkyl Lithium Addition to
a Carbonyl-Containing Compound
[1729] A solution of a carbonyl-containing compound (preferably 1
equiv) in an organic solvent (such as THF, 1,4-dioxane, Et.sub.2O,
preferably THF) was cooled to about -78.degree. C.-50.degree. C.
(preferably about 0.degree. C.) followed by the optional addition
of an additive such as lithium chloride (1-10 equiv, preferably 4
equiv) in an organic solvent (such as THF or Et.sub.2O, preferably
THF). To the reaction solution is added a solution of a Grignard
reagent or alkyl lithium in an organic solvent (such as THF or
Et.sub.2O, preferably Et.sub.2O) and the resulting mixture is
stirred at about -78.degree. C.-50.degree. C. for about 15 min-2 h
(preferably about 0.degree. C. for about 20 min) and then is
optionally warmed to ambient temperature and stirred for about 2-16
h (preferably about 4 h). In cases where the reaction did not
proceed to completion, an additional portion or portions of a
solution of a Grignard reagent or alkyl lithium in an organic
solvent (such as THF or Et.sub.2O, preferably Et.sub.2O) was added
to drive the reaction to completion. The reaction mixture is then
optionally cooled to about -78.degree. C.-0.degree. C. (preferably
about -78.degree. C.) and is quenched with the addition of a
saturated aqueous solution of NH.sub.4Cl. The mixture is optionally
stirred for about 5-30 min (preferably about 5 min) followed by the
addition of an organic solvent (such as EtOAc or DCM). The layers
are separated and the organic solution is dried over anhydrous
MgSO.sub.4, filtered, and concentrated under reduced pressure.
Illustration of General Procedure ZZZ
Example #ZZZ.1
1-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1--
yl)cyclopentyl)-2-methylpropan-2-ol
##STR00943##
[1731] To a solution of ethyl
2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate (0.166 g, 0.486 mmol, Example #38, Step H)
in THF (4 mL) at about 0.degree. C. was added lithium chloride in
THF (0.5 M, 3.9 mL) followed by methylmagnesium bromide in
Et.sub.2O (3.0 M, 0.65 mL). After about 20 min the reaction mixture
was allowed to warm to rt. After about 4 h the reaction mixture was
cooled to about -78.degree. C. and saturated aqueous NH.sub.4Cl
(about 5 mL) was added. After about 5 min the reaction mixture was
allowed to warm to rt and EtOAc (about 10 mL) was added. The layers
were separated and the organic solution was dried over anhydrous
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
crude material was purified by silica gel chromatography eluting
with EtOAc/MeOH to provide
1-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)-2-methylpropan-2-ol (0.118 g, 74%) as a foam:
LC/MS (Table 1, Method a) R.sub.t=1.64 min; MS m/z 328
(M+H).sup.+.
TABLE-US-00050 TABLE ZZZ.1 Examples prepared using General
Procedure ZZZ with methylmagnesium bromide R.sub.t min (Table 1,
m/z ESI+ Ester Product Ex # Method) (M + H).sup.+ ethyl
2-((1S,3R,4R)- 3-ethyl-4-(6H- pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]
pyrazin-1-yl) cyclopentyl) acetate (prepared from Preparation
#BBBB.l*, using W.1, from Preparation #BBBB.l, AA, Table 2, method
3) ##STR00944## ZZZ.1.1* 1.63 (a) 328 ethyl 2-((1R,3R,4S)-
3-ethyl-4-(3- (trifluoromethyl)- 6H-imidazo[1,5-a] pyrrolo[2,3-e]
pyrazin-1-yl) cyclopentyl)acetate (Example #BBBB.1.1*) ##STR00945##
ZZZ.1.2* 2.33 (a) 395
[1732] General Procedure AAAA: Deprotection of a Sulfonamide with
DBU
[1733] To a flask containing a sulfonamide, for example, a
sulfonyl-protected pyrrole, (preferably 1 equiv) in an organic
solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, MeCN, preferably
MeCN) is added DBU (1-30 equiv, preferably 5-6 equiv). The mixture
is stirred at about 20-100.degree. C. (preferably about rt) for
about 1-72 h (preferably about 24 h). In cases where the reaction
does not proceed to completion as monitored by TLC, LC/MS, or HPLC
the reaction is heated at about 30-100.degree. C. (preferably about
45.degree. C.) for about 1-48 h (preferably about 12-24 h). In
cases where the reaction does not proceed to completion as
monitored by TLC, LC/MS, or HPLC, additional DBU (1-20 equiv,
preferably 1 equiv) is added. This may be repeated if the reaction
is not complete by TLC, LC/MS, or HPLC. The reaction is cooled to
rt and worked up using one of the following methods. Method 1. The
organic solvent is optionally removed under reduced pressure, a
suitable organic solvent (such as EtOAc or DCM) and water or brine
are added, the layers are separated, and the organic solution is
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concd to dryness under reduced pressure to give the target
compound. Method 2. The reaction mixture is concd under reduced
pressure and directly purified by one of the subsequent
methods.
Illustration of General Procedure AAAA
Preparation #AAAA.1: (E/Z)-ethyl
2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentylidene)acetate
##STR00946##
[1735] To a solution of (E/Z)-ethyl
2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylidene)acetate (2.00 g, 4.05 mmol, Preparation
#III.1) in MeCN (20 mL) was added DBU (3.70 mL, 24.51 mmol). The
reaction mixture was stirred at rt for about 16 h. The reaction
mixture was heated at about 45.degree. C. for about 24 h. DBU (1.00
mL, 6.63 mmol) was added and continued heating at about 45.degree.
C. for about 24 h. Additional DBU (1.00 mL, 6.63 mmol) was added
and continued heating at about 45.degree. C. for about 24 h. The
reaction mixture was cooled to rt and the solvent was removed under
reduced pressure. The crude material was purified via flash
chromatography on silica gel eluting with a gradient of 0-10% MeOH
in DCM to afford (E/Z)-ethyl
2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentylidene)acetate (0.70 g, 51%) as a brown foam: LC/MS
(Table 1, Method b) R.sub.t=1.90-1.95 min; MS m/z: 340
(M+H).sup.+.
[1736] General Procedure BBBB: Deprotection of a Sulfonamide with
TBAF
[1737] To a solution of a sulfonamide (preferably 1 equiv) in an
organic solvent (preferably THF) at about -30 to 65.degree. C.
(preferably 0.degree. C.) is added TBAF (1-10 equiv, preferably 3
equiv). Additional TBAF (1-10 equiv, preferably 3 equiv) can be
added to drive the reaction to completion. Once the reaction has
preceded to an acceptable level the reaction mixture is partitioned
between an organic solvent (such as DCM or EtOAc, preferably EtOAc)
and an aqueous phase (such as water or brine). The organic layer is
separated and optionally washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, and/or filtered prior to
concentrating under reduced pressure.
Illustration of General Procedure BBBB
Preparation #BBBB.1*: Ethyl
2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentylidene)acetate
##STR00947##
[1739] To a solution of ethyl
2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentylidene)acetate (1.9 g, 3.85 mmol, Preparation
#III.1) in THF (30 mL) at about 0.degree. C. was added a solution
of TBAF (11.55 mL, 11.55 mmol, 1M in THF). After about 30 min
additional TBAF (7.70 mL, 7.70 mmol, 1M in THF) was added. After
about 1 h EtOAc and brine were added to the reaction mixture. The
organic layer was separated, coned in vacuo and purified by
chromatography on silica gel eluting with EtOAc to provide ethyl
2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentylidene)acetate (1.3 g, 100%) as a mixture of
stereoisomers. LC/MS (Table 1, Method a) R.sub.t=1.86 and 1.90
min.; MS m/z: 340 (M+H).sup.+.
TABLE-US-00051 TABLE BBBB.1 Examples prepared using General
Procedure BBBB R.sub.t min Example (Table 1, m/z ESI+ Sulfonamide
Product # Method) (M + H).sup.+ ethyl 2-((1R,3R,4S)-
3-ethyl-4-(6-tosyl-3- (trifluoromethyl)-6H- imidazo[1,5-a]
pyrrolo[2,3-e] pyrazin-1-yl) cyclopentyl)acetate (prepared using H
with Preparation #32 Preparation #31 HATU, and DIEA, and OO)
##STR00948## BBBB.1.1 2.62 (a) 409 N-((1S,3R,4S)-3-
ethyl-4-(6-tosyl- 3-(2,2,2- trifluoroethyl)-6H- imidazo[1,5-a]
pyrrolo[2,3-e] pyrazin-1-yl) cyclopentyl)cyclo- propane-
sulfonamide (prepared using H with Preparation #30 and Preparation
#Z.1, and OO) ##STR00949## BBBB.1.X 2.04 (a) 456
[1740] General Procedure CCCC: Deprotection of a Sulfonamide with
KCN
[1741] To a flask containing a sulfonamide, for example, a
sulfonyl-protected pyrrole, (preferably 1 equiv) in an organic
solvent (such as 1,4-dioxane, MeOH, or THF, preferably MeOH) is
added KCN (1-3 equiv, preferably 2.2 equiv) as a solution in an
organic solvent (such as 1,4-dioxane, MeOH, or THF, preferably
MeOH) or as a solid. The mixture is stirred at ambient temperature
for about 1-18 h (preferably about 16 h). The organic solvent is
optionally removed under reduced pressure and a suitable organic
solvent (such as EtOAc or DCM) and water are added. The layers are
separated and the organic solution is dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered or decanted, and coned to
dryness under reduced pressure and directly purified by one of the
subsequent methods.
Illustration of General Procedure CCCC
Preparation #CCCC.1:
3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopenty-
l benzoate
##STR00950##
[1743] To a mixture of
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentyl benzoate (5.00 g, 7.84 mmol, prepared using II from
Example #4 Step J with benzoic acid and B) in MeOH (16 mL) was
added a solution of potassium cyanide (0.74 mL, 17 mmol) in MeOH
(16 mL). The reaction was stirred at ambient temperature for about
16 h. The reaction mixture was concd under reduced pressure to
afford a residue. The residue was partitioned between water (20 mL)
and DCM (20 mL). The layers were separated and the aqueous layer
was extracted with DCM (3.times.10 mL). The extract was then washed
with saturated aqueous NaHCO.sub.3, dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to afford a
crude oil. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to
3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopenty-
l benzoate (2.30 g, 78%) as a solid. LC/MS (Table 1, Method a)
R.sub.t=2.08 min; MS m/z: 376 (M+H).sup.+.
TABLE-US-00052 TABLE CCCC.1 Examples prepared using General
Procedure D with KCN R.sub.t min m/z (Table 1, ESI+ Sulfonamide
Product Ex # Method) (M + H).sup.+ N-((1S,3R,4S)-3-
ethyl-4-(6-tosyl- 6H-pyrrolo[2,3-e] [1,2,4]triazolo[4,3-a]
pyrazin-1-yl) cyclopentyl)-N-((5- methylisoxazol-3-yl)
methyl)oxetan-3- amine (prepared using X from Example #8 Step M
with oxetan-3-one [PharmaBlock], and X with 5- methylisoxazole-3-
carbaldehyde) ##STR00951## CCCC.1.1* 1.57 (a) 422
[1744] General Procedure DDDD: Formation of an Oxadiazole
[1745] To a solution of a carboxylic ester (preferably 1 equiv) in
an organic solvent (such as DMF, NMP, THF, MeOH/toluene, p-Dioxane,
or MeOH, preferably MeOH/toluene) is added a base (such as
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3, 2-10 equiv, preferably 2-4
equiv) and an acetimidamide (1-20 equiv, preferably 4-10 equiv).
The reaction mixture is heated at about 100-160.degree. C.
(preferably about 130.degree. C.) for about 15 min to 2 h
(preferably about 45 min) under microwave irradiation. In cases
where the reaction does not proceed to completion as monitored by
TLC, LC/MS, or HPLC, additional acetimidamide (1-20 equiv,
preferably 3-10 equiv) and/or base (such as K.sub.2CO.sub.3 or
Cs.sub.2CO.sub.3, 2-10 equiv, preferably 2-4 equiv) may be added.
The reaction mixture is heated at about 100-160.degree. C.
(preferably about 130-140.degree. C.) for about 15 min to 2 h
(preferably about 45 min) under microwave irradiation. The
additional heating with or without addition of acetimidamide and/or
base is optionally repeated. Alternatively, a solution of an
acetimidamide (1-20 equiv, preferably 4-10 equiv) in an organic
solvent (such as THF or p-dioxane, preferably THF) is added a base
(such as NaH, 1-5 equiv, preferably 3 equiv). After about 0.5-2 h
(preferably about 0.5 h), a carboxylic ester (preferably 1 equiv)
is added. After about 0.25-3 h (preferably about 0.25 h), the
reaction mixture is heated at about 40-120.degree. C. (preferably
about 70.degree. C.) for about 1-48 h (preferably about 4 h). If
the reaction is heated the reaction mixture is cooled to ambient
temperature. The reaction is worked up using one of the following
methods. Method 1. The organic solvent is optionally removed under
reduced pressure, a suitable organic solvent (such as EtOAc or DCM)
and water, brine or saturated NH.sub.4Cl are added, the layers are
separated. The organic solution is washed with water, brine or
saturated NH.sub.4Cl and the organic solution is dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concd to
dryness under reduced pressure to give the target compound. Method
2. The reaction mixture is concd under reduced pressure and
directly purified.
Illustration of General Procedure DDDD
Preparation #DDDD.1:
(5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol
##STR00952##
[1747] To a solution of ethyl
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate (0.195 g, 0.571 mmol, Example #38, Step H)
in toluene (1.00 mL) and MeOH (1.000 mL) were added
(Z)--N',2-dihydroxyacetimidamide (0.515 g, 5.71 mmol, Tyger) and
K.sub.2CO.sub.3 (0.195 g, 1.41 mmol). The reaction was heated in a
CEM microwave at about 130.degree. C. twice at about 45 min each
(250 psi maximum pressure, 1 min ramp, 300 max watts).
(Z)--N',2-dihydroxyacetimidamide (0.200 g, 2.22 mmol, Tyger) was
added and the reaction mixture was heated in a CEM microwave at
about 140.degree. C. for about 45 min (250 psi maximum pressure, 1
min ramp, 300 max watts). (Z)--N',2-dihydroxyacetimidamide (0.200
g, 2.22 mmol, Tyger) and K.sub.2CO.sub.3 (0.100 g, 0.725 mmol) were
added, and the reaction mixture was heated in a CEM microwave at
about 140.degree. C. for about 45 min (250 psi maximum pressure, 1
min ramp, 300 max watts). The solvent was removed under reduced
pressure. The residue was dissolved with water (20 mL) and EtOAc
(50 mL). The aqueous layer was extracted with EtOAc (5.times.50
mL). The combined organic layers were dried over anhydrous
MgSO.sub.4, filtered, and concd to give a yellow residue. The crude
material was purified via flash chromatography on silica gel
eluting with a gradient of 0-10% MeOH in EtOAc to afford
(5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol (0.042 g,
20%) as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.67 min;
MS m/z: 368 (M+H).sup.+.
TABLE-US-00053 TABLE DDDD.1 Examples prepared using General
Procedure DDDD with (Z)-N'-hydroxy-methoxyacetimidamide R.sub.t min
(Table 1, m/z ESI+ Ester Product Ex # Method) (M + H).sup.+ ethyl
2- ((1R,3R,4S)- 3-ethyl-4-(6- tosyl-3-(trifluoro- methyl)-6H-
imidazo[1,5-a] pyrrolo[2,3-e] pyrazin-1-yl) cyclopentyl)acetate
(Example # BBBB.1.1*) ##STR00953## DDDD.1.1* 2.41 (a) 449
[1748] General Procedure EEEE: Formation of a Urea Using
Phosgene
[1749] To a solution of phosgene (1-1.5 equiv, preferably 1.2
equiv, 20% solution in toluene) in an organic solution (such as
DCM), under an inert atmosphere at about 0.degree. C. is added
solution or slurry of an amine or amine salt (preferably 1 equiv)
in an organic solvent (such as DCM, THF, or 1,4-dioxane, preferably
DCM) and an organic base (such as TEA, DIEA, pyridine, 1-10 equiv,
preferably 5 equiv, preferably TEA). After about 0.5-24 h
(preferably about 40 min) at about 0.degree. C., a second amine or
amine salt (1-10 equiv, preferably 1-3 equiv) is added neat or as a
solution or slurry in an organic solvent (such as DCM, THF, or DMF,
preferably DCM) and an organic base (such as TEA, DIEA, pyridine,
1-10 equiv, preferably 5 equiv, preferably TEA). The reaction
mixture is stirred at about 0.degree. C. for 0.5-24 h (preferably
45 min). An aqueous base (such as aqueous NH.sub.4OH or saturated
aqueous Na.sub.2CO.sub.3) is added with the optional addition of an
organic solvent such as EtOAc or DCM. The aqueous layer is then
optionally extracted with additional organic solvent (such as EtOAc
or DCM). The combined organic layers may optionally be washed with
water or brine and coned in vacuo or dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4 and then decanted or filtered prior
to concentrating under reduced pressure to give the target
compound.
Illustration of General Procedure EEEE
Preparation #EEEE.1:
(3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone
##STR00954##
[1751] To a solution of phosgene (0.400 mL, 0.761 mmol, 20% in
toluene) in DCM (1.5 mL) under a balloon of N.sub.2 at about
0.degree. C. were added a solution of
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazine (0.250 g, 0.609 mmol, Example #36, step F) in DCM
(5.0 mL) and TEA (0.430 mL, 3.08 mmol). After about 40 min, at
about 0.degree. C., a solution of
3,3-difluoroazetidine.hydrochloride (0.095 g, 0.731 mmol, Matrix)
and TEA (0.430 mL, 3.08 mmol) in DCM (5.0 mL) were added dropwise
and stirred at about 0.degree. C. for about 45 min. Saturated
aqueous sodium bicarbonate (2 mL) was added and the layers were
separated. The aqueous layer was extracted with DCM (2.times.30
mL). The combined organic layers were washed with water (25 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd to give a
brown residue. The crude material was purified via flash
chromatography on silica gel eluting with a gradient of 0-10% MeOH
in DCM to afford
(3,3-difluoroazetidin-1-yl)((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1-yl)methanone (0.208 g,
65%) as a brown residue: LC/MS (Table 1, Method a) R.sub.t=2.17
min; MS m/z: 530 (M+H).sup.+.
[1752] General Procedure FFFF: Formation of an Amide from an
Ester
[1753] To a pressure reactor charged with an ester (preferably 1
equiv) is added a solution of ammonia in a protic solvent (such as
ethanol, methanol or water, preferably methanol). The reactor is
sealed and the temperature is maintained at about ambient
temperature to about 200.degree. C. (preferably about 85.degree.
C.). After about 1 to 10 days (preferably about 2 days) the
reaction mixture is cooled to rt and the reaction mixture is concd
in vacuo to provide the crude amide.
Illustration of General Procedure FFFF
Example #FFFF.1
4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopen-
tyl)butanamide
##STR00955##
[1755] Ethyl
4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)butanoate (0.080 g, 0.217 mmol, prepared using III from
Preparation #25 and (E)-ethyl 4-(diethoxyphosphoryl)but-2-enoate,
W) and ammonia (7 N in MeOH, 6.2 mL, 43.3 mmol). The reaction
vessel was sealed and heated to about 85.degree. C. After about 2
days the tube was cooled to rt and the reaction mixture was concd
in vacuo to provide
4-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)butanamide (0.074 g, 100%) as a solid which was used
without further purification: LC/MS (Table 1, Method c)
R.sub.t=0.50 min.; MS m/z: 341 (M+H).sup.+.
[1756] General Procedure GGGG: Formation of a Nitrile from a
Primary Amide
[1757] To solution of a primary amide (preferably 1 equiv) in an
organic solvent (such as DCM, THF, DCE, preferably DCM) is added a
dehydrating reagent (such as TFAA or SOCl.sub.2, preferably TFAA)
(1-20 equiv, preferably 10 equiv). After about 1-20 h (preferably
about 4 h) at 10 to 60.degree. C. (preferably ambient temperature)
the reaction mixture is concd in vacuo.
Illustration of General Procedure GGGG
Example #GGGG.1
4-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1--
yl)cyclopentyl)butanenitrile and
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)butanenitrile
##STR00956##
[1759] To a solution of
4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)butanamide (0.090 g, 0.264 mmol, Example #FFFF.1) in DCM (3
mL) was added TFAA (0.373 mL, 2.64 mmol). After about 4 h at
ambient temperature the reaction mixture was concd in vacuo and
purified by chiral preparative HPLC (Table 2, Method 33) to provide
4-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)butanenitrile (0.013 g, 15%) (rt=16.1 min, or =neg)
LC/MS (Table 1, Method a) R.sub.t=1.79 min; MS m/z: 323 (M+H).sup.+
and
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)butanenitrile (0.010 g, 12%) (rt=13.7 min, or =neg)
LC/MS (Table 1, Method a) R.sub.t=1.79 min; MS m/z: 323 (M+H).sup.+
as solids.
[1760] General Procedure HHHH: O-alkylation with KOH or NaOH and
TBAB
[1761] To an alcohol (preferably 1 equiv) is added an aqueous base
(such as 50% w/v KOH or 50% w/v NaOH, 1-60 equiv, preferably 11-24
equiv) and a solvent (such as 1,4-dioxane or THF, preferably
1,4-dioxane) and the reaction mixture is heated to about
45-100.degree. C. (preferably about 70.degree. C.). To the reaction
mixture is added an alkyl halide or mesylate (1-30 equiv,
preferably 8-16 equiv), and TBAB (0.05-2 equiv, preferably 0.08-1.6
equiv) and stirred for about 8-48 h (preferably about 24 h).
Alternatively, the order of addition may be reversed. In cases
where the reaction does not proceed to completion as monitored by
TLC, LC/MS, or HPLC, the reaction may be re-subjected to heating at
about 25-100.degree. C. (preferably about 70.degree. C.) for about
2-48 h (preferably about 8-24 h) with the optional addition of more
base (such as 50% w/w aqueous KOH or 50% w/w aqueous NaOH, 1-60
equiv, preferably 11-24 equiv), solvent (such as 1,4-dioxane or THF
preferably 1,4-dioxane), alkyl halide or mesylate (1-30 equiv,
preferably 8-16 equiv), and/or TBAB (0.05-2 equiv, preferably
0.08-1.5 equiv). This process is repeated until the reaction
proceeds no further. After cooling to ambient temperature, the
reaction is worked up using one of the following methods. Method 1:
An organic solvent such as EtOAc or DCM is added with the optional
addition of water or brine and the layers are separated. The
aqueous layer is then optionally extracted with additional organic
solvent such as EtOAc or DCM. The combined organic layers are
optionally washed with brine or water, dried over anhydrous
MgSO.sub.4 or Na.sub.2SO.sub.4, filtered or decanted, and coned
under reduced pressure. Method 2: A reaction mixture containing a
precipitate may be filtered. To the filtrate is added an organic
solvent such as EtOAc or DCM with the optional addition of water or
brine and the layers are separated. The aqueous layer is then
optionally extracted with additional organic solvent such as EtOAc
or DCM. The combined organic layers are optionally washed with
brine or water, dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, filtered or decanted, and coned under reduced
pressure.
Illustration of General Procedure HHHH
Preparation #HHHH.1:
3-(((1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)-5-methyli-
soxazole
##STR00957##
[1763] A mixture of
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.072 g, 0.179 mmol,
Example #35, Step H), KOH aqueous (50% w/v 0.118 g, 2.10 mmol) and
1,4-dioxane (0.1 mL) was heated to about 70.degree. C. To the
reaction mixture was added 3-(bromomethyl)-5-methylisoxazole (0.063
g, 0.359 mmol, Maybridge) and TBAB (0.004 g, 0.01 mmol) and the
reaction mixture was stirred for about 24 h. To the reaction
mixture was added 3-(bromomethyl)-5-methylisoxazole (0.063 g, 0.36
mmol, Maybridge) and aqueous KOH (50% w/v 0.118 g, 2.10 mmol) and
stirring was continued for about 24 h. The reaction was cooled to
ambient temperature and EtOAc (10 mL) and water (5 mL) were added.
The layers were separated and the aqueous layer was extracted with
EtOAc (10 mL). The combined organic layers were dried over
anhydrous MgSO.sub.4, filtered, and coned under reduced pressure.
The crude material was purified by silica gel chromatography
eluting with a gradient of 0-5% MeOH in DCM to give
3-(((1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)-5-methyli-
soxazole (0.064 g, 72%): LC/MS (Table 1, Method b) R.sub.t=2.58
min; MS m/z: 497 (M+H).sup.+.
[1764] General Procedure IIII: Formation of a Mesylate
[1765] To a solution of an alcohol (preferably 1 equiv) in an
organic solvent such as DCM an organic base such as TEA or Hunig's
base (1-4 equiv, preferably 2 equiv) is added at about 0-40.degree.
C. (preferably room temperature) followed by a dropwise addition at
this temperature of mesyl chloride (1-2 equiv preferably 1.1
equiv). In cases where the reaction mixture is cooled to below rt,
it is stirred at this temperature for about 1-3 h (preferably about
2 h) and then optionally warmed up to ambient temperature while
stirring overnight. The product could be worked up by one of the
following methods. 1) The reaction mixture is concentrated. 2) The
reaction mixture is washed with saturated aqueous NaHCO.sub.3 and
brine, dried over anhydrous MgSO.sub.4, filtered, and
concentrated.
Illustration of General Procedure IIII
Preparation #IIII.1:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate
##STR00958##
[1767] Mesyl chloride (0.067 mL, 0.866 mmol) was added dropwise to
a solution of
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.316 g, 0.787 mmol,
Example #35 Step H) and TEA (0.219 mL, 1.57 mmol) in DCM (8 mL),
and the reaction mixture was stirred at rt overnight. The solvent
was removed under reduced pressure and the residue purified by
silica gel column chromatography (0 to 60% EtOAc in DCM) to yield
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.29 g,
77%) as a white amorphous solid: LC/MS (Table 1, Method a)
R.sub.t=2.53 min; MS m/z 480 (M+H).sup.+.
[1768] General Procedure JJJJ: Displacement of an Alkyl Mesylate,
Tosylate, or Halide with a Nucleophile
[1769] A round bottom flask is charged with an alkyl mesylate,
tosylate, or halide (preferably 1 equiv) and an organic solvent
such as DMF, DMA, NMP or DMSO (preferably DMF). To the reaction
flask is added the sodium or potassium salt (preferably the sodium
salt) of the nucleophile such as, but not limited to, an azide,
cyanide, thioacetate, pyrazole and triazole (1-10 equiv, preferably
5.0 equiv) in portions. When the nucleophile is not already the
sodium or potassium salt, a base such as 60% NaH in mineral oil
(1-10 equiv, preferably an equimolar amount to the nucleophile
used) is added. The mixture is stirred at about 10-100.degree. C.
(preferably ambient temperature) for about 1-24 h (preferably about
20 h). If the reaction does not go to completion as monitored by
HPLC, LC/MS, or TLC, additional nucleophile and/or base is used
(5-300% of the original amount used, preferably 10%) may be added
and the reaction is continued for about 0.5-24 h (preferably about
2 h). The reaction is partitioned between an organic solvent such
as EtOAc or DCM (preferably EtOAc) and water. The layers are
separated and the organic solution is dried over anhydrous
MgSO.sub.4 or Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure to provide the target compound.
Illustration of General Procedure JJJJ
Preparation #JJJJ.1:
1-((1S,2R,4R)-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)me-
thyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR00959##
[1771] A round bottom flask was charged with
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.83 g,
1.7 mmol, Preparation #IIII.1) and DMF (7.0 mL). To the reaction
flask was added sodium azide (0.56 g, 8.6 mmol). The mixture was
stirred at ambient temperature for about 20 h. Another portion of
sodium azide (0.056 g, 0.86 mmol) was added and the reaction was
stirred for about 2 h. The reaction was partitioned between EtOAc
(20 mL) and water (20 mL). The layers were separated and the
organic solution was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give
1-(-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-p-
yrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.65 g, 88%) as a
brown oil: LC/MS (Table 1, Method b) R.sub.t=2.85 min; MS m/z: 427
(M+H).sup.+.
[1772] General Procedure KKKK: Cyclization of a Ketone Using TFAA
or PFPAA
[1773] To a ketone (preferably 1 equiv) optionally dissolved in an
organic solvent such as acetonitrile or DCM (preferably
acetonitrile) is added TFA/TFAA (2-100 equiv/10-60 equiv,
preferably 2 equiv/10 equiv) or PFPAA (2-30 equiv, preferably 10
equiv) or 2,2,3,3,3-pentafluoropropanoic acid/PFPAA (1-10
equiv/5-50 equiv, preferably 2 equiv/10 equiv) at about 0.degree.
C. to 50.degree. C. (preferably ambient temperature). The reaction
is warmed and stirred at about 0.degree. C. to about 80.degree. C.
(preferably about 60.degree. C.) for about 0.5-48 h (preferably
about 2-4 h). Additional TFAA or PFPAA (2-10 equiv) can be added to
complete the reaction. MeOH is optionally added to quench the
reaction. The reaction mixture is concentrated under reduced
pressure. Alternatively, the crude mixture may be optionally
concentrated before partitioning between an aqueous solution of an
inorganic base (for example aqueous NaHCO.sub.3 or K.sub.2CO.sub.3)
and an organic solvent (for example EtOAc or DCM). The layers are
separated and the aqueous layer is extracted further with organic
solvent (such as EtOAc and/or DCM). The combined organic layers are
optionally washed with brine, dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, filtered, and concentrated to dryness under
reduced pressure.
Illustration of General Procedure KKKK
Preparation #KKKK.1:
3-Tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H-imidazo[1,2-a]pyrrolo[2-
,3-e]pyrazine
##STR00960##
[1775] To a solution of
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)-1-(2-tosyl-2-azaspiro[3.3]-
heptan-6-yl)ethanone (0.631 g, 1.089 mmol, prepared using R with
2-tosyl-2-azaspiro[3.3]heptane-6-carboxylic acid [prepared as
described in J. Org Chem, 2010, 75, 5941] and trimethylsilyl
diazomethane, S with Example #3 Step E, E with TFA) in MeCN (5 mL)
was added PFPAA (2.15 mL, 10.9 mmol). The mixture was heated at
about 60.degree. C. for about 2 h. The reaction mixture was
partitioned between DCM (30 mL) and saturated aqueous NaHCO.sub.3
(50 mL). The layers were separated and the aqueous layer was
extracted further with DCM (2.times.30 mL). The combined organic
layers were dried over anhydrous MgSO.sub.4, filtered, and
concentrated to dryness under reduced pressure. The crude material
was purified using silica gel flash chromatography eluting with a
gradient of 50-100% EtOAc in heptane to give
3-tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H-imidazo[1,2-a]pyrrolo[2-
,3-e]pyrazine (0.467 g, 76%) as a white solid: LC/MS (Table 1,
Method b) R.sub.t=2.53 min; MS m/z 562 (M+H).sup.+.
[1776] General Procedure LLLL: Formation of a Bromoketone from a
Ketone or an Aldehyde
[1777] To a ketone or an aldehyde (preferably 1 equiv) in an
organic solvent (DCM or DCE, preferably DCM) at about -20 to
20.degree. C. (preferably about 0.degree. C.), an organic base such
as TEA or DIEA (preferably DIEA, 1-20 equiv, preferably 5-10 equiv)
is added, followed by addition of trimethylsilyl
trifluoromethanesulfonate (1-8 equiv, preferably 4.5 equiv). The
reaction is stirred at the same temperature for about 0.5 to 6 h
(preferably about 1 h). A suitable organic solvent (such as EtOAc
or DCM) is optionally added. An aqueous solution (such as saturated
aqeuous NaHCO.sub.3 or water) is added. The layers are separated,
the aqueous layer is optionally extracted with additional organic
solvent (such as EtOAc or DCM) and the organic layer or combined
organic layers are dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, filtered, and concd under reduced pressure to give a
TMS-protected enol intermediate. The intermediate is dissolved in
an organic solvent (DCM or DCE, preferably DCM) at about -20 to
60.degree. C. (preferably rt) and an inorganic base such as
NaHCO.sub.3 or Na.sub.2CO.sub.3 (preferably NaHCO.sub.3, 1-20
equiv, preferably 4 equiv) and NBS (1-3 equiv, preferably 1 equiv)
are added. The reaction is stirred at the same temperature for
about 1-48 h (preferably about 18 h). A suitable organic solvent
(such as EtOAc or DCM) and an aqueous solution (such as saturated
aqueous NaHCO.sub.3 or water) are added, the layers are separated,
and the organic solution is dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, filtered, and concd under reduced pressure.
Illustration of General Procedure LLLL
Preparation #LLLL.1:
t-butyl-(cis-5-(2-bromoacetyl)-4-methyltetrahydrofuran-2-yl)methyl(3,3,3--
trifluoropropylsulfonyl)carbamate
##STR00961##
[1779] To a solution of t-butyl
(cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl(3,3,3-trifluoropropylsu-
lfonyl)carbamate (0.54 g, 1.3 mmol, prepared using M.1 from
Preparation #MMMM.1) in DCM (5 mL) at about 0.degree. C. was added
DIEA (2.03 mL, 11.6 mmol) and trimethylsilyl
trifluoromethanesulfonate (1.06 mL, 5.82 mmol). The reaction was
stirred at about 0.degree. C. for about 1 h. Saturated aqueous
NaHCO.sub.3 (10 mL) was added and the layers were separated. The
aqueous layer was extracted with DCM (2.times.10 mL). The combined
organic extracts were dried over anhydrous MgSO.sub.4, filtered,
and concd under reduced pressure. The residue was dissolved in DCM
(5 mL) and NaHCO.sub.3 (0.435 g, 5.17 mmol) and NBS (0.230 g, 1.294
mmol) were added. The reaction was stirred at ambient temperature
for about 18 h. The reaction mixture was partitioned between water
(30 mL) and DCM (30 mL). The aqueous layer was extracted with DCM
(2.times.30 mL). The combined organic extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The product was purified by silica gel chromatography eluting with
a gradient of 0-30% EtOAc in heptane to give
t-butyl-(cis-5-(2-bromoacetyl)-4-methyltetrahydrofuran-2-yl)methyl(3,
3,3-trifluoropropylsulfonyl)carbamate (0.472 g, 73%) as a yellow
solid: LC/MS (Table 1, Method b) R.sub.t=2.76 min; MS m/z: 494, 496
(M-H).sup.-.
[1780] General Procedure MMMM: Formation of a Ketone from a Weinreb
Amide
[1781] To a Weinreb amide (preferably 1 equiv) in an organic
solvent (for example DCM, MeCN, 1,4-dioxane or THF, preferably THF)
is added a Grignard or an alkyl lithium reagent (1-10.0 equiv,
preferably 6 equiv) at about -30 to 40.degree. C. (preferably about
-10.degree. C.). The reaction mixture is stirred at about -30 to
40.degree. C. (preferably about -10.degree. C.) for about 1-24 h
(preferably about 5 h). The reaction mixture is quenched with an
aqueous acid (such as aqueous HCl) and then water, partitioned
between an organic solvent (such as Et.sub.2O, EtOAc or DCM) and
water. The layers are separated and the aqueous layer is extracted
with additional organic solvent and the combined organic layers may
be optionally washed with brine. The organic layer is optionally
dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, and then
decanted or filtered prior to concentrating under reduced
pressure.
Illustration of General Procedure MMMM
Preparation #MMMM.1:
N-((cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl)-3,3,3-trifluoroprop-
ane-1-sulfonamide
##STR00962##
[1783] To a solution of
cis-N-methoxy-N,3-dimethyl-5-((3,3,3-trifluoropropylsulfonamido)methyl)te-
trahydrofuran-2-carboxamide (0.70 g, 1.9 mmol, prepared using E
from Preparation #43 with HCl, K with
3,3,3-trifluoropropane-1-sulfonyl chloride (Matrix), Z with NaOH, H
with N,O-dimethylhydroxylamine hydrochloric acid) in THF (5 mL) was
added methylmagnesium bromide (3 N in Et.sub.2O, 3.86 mL, 11.6
mmol) dropwise at about -10.degree. C. The reaction mixture was
stirred at about -10.degree. C. for about 5 h. Aqueous HCl (1 N,
9.66 mL, 9.66 mmol) was added to quench the reaction. The reaction
mixture was partitioned between water (10 mL) and DCM (20 mL). The
layers were separated and the aqueous layer was extracted with DCM
(2.times.20 mL). The combined organic extracts were concd under
reduced pressure. The product was purified by silica gel
chromatography eluting with a gradient of 0-100% EtOAc in heptane
to give
N-((cis-5-acetyl-4-methyltetrahydrofuran-2-yl)methyl)-3,3,3-trifluoroprop-
ane-1-sulfonamide (0.57 g, 93%) as a clear oil: LC/MS (Table 1,
Method b) R.sub.t=2.02 min; MS m/z: 318 (M+H).sup.+.
[1784] General Procedure NNNN: Formation of (3-Hydroxysulfonamide
from a Ketone
[1785] To an optionally substituted methyl sulfonamide (1-8 equiv,
preferably 1.5 equiv) in an organic solvent (DCM or THF, preferably
THF) at about -20 to 20.degree. C. (preferably about 0.degree. C.),
an alkyl lithium reagent (for example n-BuLi, t-BuLi or LDA
(preferably n-BuLi, 1-20 equiv, preferably 1-2 equiv) is added. The
reaction is stirred at about -20 to 20.degree. C. (preferably about
0.degree. C.) for about 0.5-72 h (preferably about 1 h). The
resulting solution is added dropwise to a solution of ketone
(preferably 1.0 equiv) in an organic solvent (DCM or THF,
preferably THF) at about -20 to 20.degree. C. (preferably about
0-5.degree. C.). The reaction is stirred at about -20 to 20.degree.
C. (preferably about 0-5.degree. C.) for about 1-72 h (preferably
about 48 h). A suitable organic solvent (such as EtOAc or DCM) and
an aqueous solution (such as saturated aqueous NaHCO.sub.3 or
water) are added, the layers are separated, and the organic
solution is dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concd under reduced pressure.
Illustration of General Procedure NNNN
Preparation #NNNN.1:
3-Ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)
ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entanol
##STR00963##
[1787] To a solution of 4-(methylsulfonyl)morpholine (0.217 g,
1.314 mmol, Preparation #41) in THF (4 mL) at about 0.degree. C.
was added n-BuLi (2.5 M in hexanes, 0.53 mL, 1.3 mmol). The
reaction mixture was stirred at about 0.degree. C. for about 1 h.
The resulting solution was added dropwise to a solution of
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo)[2,3-e][1,2,4]-
triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.350 g, 0.876 mmol,
Example #35 Step G) in THF (4 mL) at about 0.degree. C. The
reaction mixture was maintained at about 4.degree. C. in a
refrigerator for about 48 h. The reaction mixture was partitioned
between water (5 mL) and DCM (5 mL) The layers were separated and
the aqueous solution was extracted with DCM (2.times.5 mL). The
combined organic extracts were concd under reduced pressure. The
product was purified by silica gel chromatography eluting with a
gradient of 0-2% MeOH/DCM, then by RP-HPLC (Table 1, Method 1) to
give
3-ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy-
)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol
(0.17 g, 34%) as a yellow oil: LC/MS (Table 1, Method b)
R.sub.t=2.32 & 2.42 min; MS m/z: 565 (M+H).sup.+.
[1788] General Procedure OOOO: Formation of a Carbonate
[1789] To an alcohol (preferably 1 equiv) in an organic solvent
(preferably pyridine) at about -20.degree. C. to 80.degree. C.
(preferably ambient temperature) is added DMAP (0.1-5 equiv,
preferably 0.3 equiv) and a chloroformate (1-10 equiv, preferably 2
equiv). The reaction mixture is stirred at about -20.degree. C. to
80.degree. C. (preferably ambient temperature) for about 1-16 h
(preferably about 1 h). The reaction mixture is either concd under
reduced pressure or optionally filtered, diluted with an organic
solvent (preferably EtOAc), washed with water and an aqueous base
(such as saturated aqueous Na.sub.2CO.sub.3 or NaHCO.sub.3) or
saturated brine, dried over anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4, filtered, and coned under reduced pressure.
Illustration of General Procedure OOOO
Preparation #OOOO.1:
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate
##STR00964##
[1791] To a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanol (1.20 g, 2.82 mmol, Example #41, Step N) in
pyridine (10 mL) was added DMAP (0.103 g, 0.846 mmol) and
4-nitrophenyl chloroformate (0.853 g, 4.23 mmol). The resulting
mixture was stirred at ambient temperature for about 1 h. The
reaction mixture was concentrated and purified using silica gel
chromatography eluting with 0-30% EtOAc in DCM to give a scalemic
mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.72 g. 43%): LC/MS
(Table 1, Method b) R.sub.t=2.64 min; MS m/z: 591 (M+H).sup.+.
[1792] General Procedure PPPP: Formation of a Carbamate Followed by
Sulfonamide Hydrolysis
[1793] To a carbonate (preferably 1 equiv) in an organic solvent
(preferably 1,4-dioxane) at about -20 to 60.degree. C. (preferably
at ambient temperature) is added an amine (2-10 equiv, preferably 5
equiv) and optionally DMAP (0-5 equiv, preferably 0 equiv). After
about 1-16 h (preferably about 1 h), aqueous sodium hydroxide (1-2
N, preferably 1 N; 1-10 eq, preferably 4 equiv) is added. The
reaction mixture is stirred at about 25-100.degree. C. (preferably
about 60.degree. C.) for about 10 min-5 h (preferably about 30 min)
and, if the reaction was heated, cooled to ambient temperature. The
reaction mixture is either concd under reduced pressure or the
layers are separated and the aqueous layer is extracted with an
organic solvent (preferably DCM). The combined organic extracts are
washed with water, an aqueous base (such as saturated aqueous
Na.sub.2CO.sub.3 or NaHCO.sub.3), or saturated brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and then concd
under reduced pressure.
Preparation #PPPP.1:
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl cyclopropylcarbamate
##STR00965##
[1795] To a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (Example #41 Step O,
0.211 g, 0.357 mmol) in 1,4-dioxane (1.5 mL) was added
cyclopropylamine (0.102 g, 1.79 mmol). After about 1 h, 1N aqueous
sodium hydroxide (1.5 mL, 1.5 mmol) was added and the reaction
mixture was heated at about 60.degree. C. for about 30 min then
cooled to ambient temperature. The layers were separated and the
aqueous layer was extracted with DCM (3.times.5 mL). The combined
organic layers were coned under reduced pressure. The residue was
purified by silica gel chromatography eluting with 0-10% MeOH in
EtOAc to give
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl cyclopropylcarbamate (0.085 g, 67%): LC/MS (Table 1,
Method b) R.sub.t=1.73 min; MS m/z: 355 (M+H).sup.+.
TABLE-US-00054 TABLE PPPP.1 Examples prepared from a scalemic
mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl
4-nitrophenyl carbonate (Example #41 Step O) R.sub.t min (Table 2,
m/z ESI+ Amine Product Example # Method) (M + H).sup.+
3,3-difluoro- azetidine hydrochloride [Matrix] ##STR00966##
PPPP.1.1 1.94 (b) 391 2-amino- acetonitrile ##STR00967## PPPP.1.2
1.64 (b) 354 dimethylamine ##STR00968## PPPP.1.3 1.75 (b) 343
oxetan-3- amine ##STR00969## PPPP.1.4 1.54 (b) 371 cyclo-
butanamine ##STR00970## PPPP.1.5 1.89 (b) 369 2-amino- acetonitrile
##STR00971## PPPP.1.6 1.42 (b) 372 piperidin-4-ol ##STR00972##
PPPP.1.7 1.39 (b) 399 2,2,2- trifluoro- ethanamine ##STR00973##
PPPP.1.8 1.80 (b) 397
TABLE-US-00055 TABLE PPPP.2 Examples prepared from a scalemic
mixture enriched in (1S,3R,4S)-3-ethyl-
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl
cyclobutylcarbamate (Example #42 Step N) R.sub.t min (Table 2, m/z
ESI+ Amines Product Example # Method) (M + H).sup.+ dimethylamine
##STR00974## PPPP.2.1 1.66 (b) 343 cyclo- butanamine ##STR00975##
PPPP.2.2 1.17 (c) 369 piperidin-4-ol ##STR00976## PPPP.2.3 1.63 (b)
399 2-amino- acetonitrile ##STR00977## PPPP.2.4 1.67 (b) 354 cyclo-
propanamine ##STR00978## PPPP.2.5 1.75 (b) 355 2,2,2- trifluoro-
ethanamine ##STR00979## PPPP.2.6 1.90 (b) 397 3,3-difluoro-
azetidine hydrochloride [Matrix] ##STR00980## PPPP.2.7 1.91 (b) 391
piperidine-4- carbonitrile ##STR00981## PPPP.2.8 1.81 (b) 408
azetidine-3- carbonitrile hydrochloride [Astatech] ##STR00982##
PPPP.2.9 1.76 (b) 380 phenyl- methanamine ##STR00983## PPPP.2.10
2.01 (b) 405 oxetan-3- amine ##STR00984## PPPP.2.11 1.62 (b) 371
1-amino- cyclopropane- carbonitrile hydrochloride [Astatech]
##STR00985## PPPP.2.12 1.77 (b) 380 3-methyl- oxetan-3- amine
[Synthonix] ##STR00986## PPPP.2.13 1.69 (b) 385 (R)- pyrrolidin-3-
ol ##STR00987## PPPP.2.14 1.62 (b) 385 (S)- pyrrolidin-3- ol
##STR00988## PPPP.2.15 1.61 (b) 385 4-fluoro- piperidine
hydrochloride ##STR00989## PPPP.2.16 1.92 (b) 401 2,2-difluoro-
ethanamine [Matrix] ##STR00990## PPPP.2.17 1.82 (b) 379 piperidine
##STR00991## PPPP.2.18 1.41 (v) 383 3-fluoro- azetidine
hydrochloride [Acesys] ##STR00992## PPPP.2.19 1.81 (b) 373
1-methyl- cyclo- butanamine [Matrix] ##STR00993## PPPP.2.20 1.98
(b) 383 1-(amino- methyl)cyclo- propanol [ChemPacific] ##STR00994##
PPPP.2.21 1.72 (b) 385 N-methyl- oxetan-3- amine [Synthonix]
##STR00995## PPPP.2.22 1.68 (b) 385 (3-methyl- oxetan-3-yl)
methanamine [Synthonix] ##STR00996## PPPP.2.23 1.68 (b) 399
2-methyl- propan-2- amine ##STR00997## PPPP.2.24 0.81 (u) 371
2,2-dimethyl- propan-1- amine ##STR00998## PPPP.2.25 0.84 (u) 385
2-methoxy- ethanamine ##STR00999## PPPP.2.26 0.66 (u) 373 (3,5-bis
(trifluoro- methyl) phenyl) methanamine ##STR01000## PPPP.2.27 0.96
(u) 541 N1,N1,N2- trimethyl- ethane-1,2- diamine ##STR01001##
PPPP.2.28 0.56 (u) 400 N1,N1,N3- trimethyl- propane-1,3- diamine
##STR01002## PPPP.2.29 0.59 (u) 414 N-benzyl- propan-2- amine
##STR01003## PPPP.2.30 0.92 (u) 447 (R)- piperidin-3-ol
##STR01004## PPPP.2.31 0.70 (u) 399 1-methyl- piperazine
##STR01005## PPPP.2.32 0.53 (u) 398 1-(piperazin- 1-yl) ethanone
##STR01006## PPPP.2.33 0.66 (u) 426 1-(2-fluoro- phenyl) piperazine
##STR01007## PPPP.2.34 0.89 (u) 478 pyridin-2- yl- methanamine
##STR01008## PPPP.2.35 0.54 (u) 406 pyridin-3- yl- methanamine
##STR01009## PPPP.2.36 0.54 (u) 406 pyridin-4- yl- methanamine
##STR01010## PPPP.2.37 0.54 (u) 406 2-methyl- propan-1- amine
##STR01011## PPPP.2.38 0.80 (u) 371 (S)-(tetra- hydrofuran- 2-yl)
methanamine ##STR01012## PPPP.2.39 0.71 (u) 399 (R)-(tetra-
hydrofuran- 2-yl) methanamine ##STR01013## PPPP.2.40 0.71 (u) 399
3-(cyclo- propylamino) propane- nitrile ##STR01014## PPPP.2.41 0.72
(u) 408 diisobutyl- amine ##STR01015## PPPP.2.42 0.97 (u) 427
azetidine ##STR01016## PPPP.2.43 0.72 (u) 355 2-methoxy- N-methyl-
ethanamine ##STR01017## PPPP.2.44 0.72 (u) 387 morpholine
##STR01018## PPPP.2.45 0.70 (u) 385 thio- morpholine ##STR01019##
PPPP.2.46 0.78 (u) 401 N1,N1- dimethyl- ethane-1,2- diamine
##STR01020## PPPP.2.47 0.53 (u) 386 N1,N1- dimethyl- propane-1,3-
diamine ##STR01021## PPPP.2.48 0.54 (u) 400 2-(pyrrolidin- 1-yl)
ethanamine ##STR01022## PPPP.2.49 0.55 (u) 412 3-(pyrrolidin-
1-yl)propan- 1-amine ##STR01023## PPPP.2.50 0.56 (u) 426
2-(piperidin- 1-yl) ethanamine ##STR01024## PPPP.2.51 0.57 (u) 426
3-(piperidin- 1-yl)propan- 1-amine ##STR01025## PPPP.2.52 0.58 (u)
440 2-morpholino- ethanamine ##STR01026## PPPP.2.53 0.54 (u) 428
3-morpholino- propan-1- amine ##STR01027## PPPP.2.54 0.55 (u)
442
[1796] General Procedure QQQQ: Oxidation of an Alkyl Thioacetate to
an Alkyl Sulfonic Acid
[1797] To a mixture of the alkyl thioacetate (preferably 1 equiv)
and formic acid (30-100 equiv, preferably 36 equiv) and aqueous
H.sub.2O.sub.2 (.about.30%, 3-10 equiv, preferably 5 equiv) are
added dropwise. The reaction is stirred at ambient temperature for
about 1-8 h (preferably about 2 h). The reaction is quenched with
saturated aqueous Na.sub.2S.sub.2O.sub.3 and is extracted with an
organic solvent such as DCM. The organic extract is concd under
reduced pressure. The resulting residue is optionally partitioned
between an organic solvent such as EtOAc and brine. The aqueous
extract is concd under reduced pressure and the resulting residue
is optionally triturated in an organic solvent or mixture of
organic solvents such as MeOH, DCM or MeOH/DCM (preferably
MeOH/DCM) and filtered. The filtrate is concd under reduced
pressure and optionally purified.
Illustration of General Procedure QQQQ
Preparation #QQQQ.1:
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentane-1-sulfonic acid
##STR01028##
[1799] To a mixture of
S-(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyl ethanethioate (0.28 g, 0.58 mmol, prepared
using P from Preparation #25, Step E and DIBAL-H; IIII, and JJJJ
with potassium thioacetate) and formic acid (0.80 mL, 20.8 mmol)
was added aqueous H.sub.2O.sub.2 (.about.30%, 0.30 mL, 2.9 mmol)
dropwise. The reaction was stirred at ambient temperature for about
2 h. The reaction was quenched with saturated aqueous
Na.sub.2S.sub.2O.sub.3 (25 mL) and extracted with DCM (2.times.25
mL). The combined extracts were coned under reduced pressure. The
resulting residue was partitioned between EtOAc and brine (25 mL
each). The aqueous extract was coned under reduced pressure. The
resulting residue was partially dissolved in MeOH/DCM (1:1, 50 mL),
filtered and coned under reduced pressure. The resulting residue
was purified by RP-HPLC (Table 1, Method y) to give
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentane-1-sulfonic acid (0.058 g, 20%) as an
off-white solid: LC/MS (Table 1, Method b) R.sub.t=1.60 min; MS
m/z: 490 (M+H).sup.+.
[1800] General Procedure RRRR: Cyclization of a Diamine with
Cyanogen Bromide
[1801] To a mixture of a substituted diamine (1 equiv) in an
organic solvent (for example, MeOH or EtOH, preferably MeOH) is
added cyanogen bromide or cyanogen bromide in MeCN (1-10 equiv,
preferably 8.0 equiv). The mixture is stirred at ambient
temperature for about 1-24 h (preferably about 16 h) and the
solvent is removed under reduced pressure.
Illustration of General Procedure RRRR
Preparation #RRRR.1*:
N-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1
(6H)-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide
##STR01029##
[1803] To a solution of
N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-et-
hylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.301 mmol,
Example #23 Step I) in MeOH (3.0 mL) was added cyanogen bromide (5
M in MeCN, 0.482 mL, 2.41 mmol) dropwise. The reaction was stirred
at ambient temperature for about 16 h. The solvent was removed
under reduced pressure and the residue was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to give
N-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)-4-ethylcyclopentyl)cyclopropane-sulfonamide (0.11 g, 67%) as a
brown solid.: LC/MS (Table 1, Method a) R.sub.t=2.00 min; MS m/z:
543 (M+H).sup.+.
[1804] General Procedure SSSS: Cyclization of a Diamine with
NaNO.sub.2
[1805] A mixture of a diamine (preferably 1 equiv) and an acidic
aqueous solution (such as 6 M HCl in water) is cooled to about
0.degree. C. Then an aqueous solution of NaNO.sub.2 (1-5 equiv,
preferably 1-2 equiv) is added and the reaction is maintained at
about 0.degree. C. for about 1-6 h (preferably about 2-3 h) and
then warmed slowly to rt or is allowed to warm slowly to rt
immediately following the addition. After about 1-18 h (preferably
about 12-16 h), the reaction is filtered, while washing with water,
to collect the solid.
Illustration of General Procedure SSSS
Preparation #SSSS.1*:
N-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyrid-
in-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide
##STR01030##
[1807] A mixture of
N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-et-
hylcyclopentyl)cyclopropanesulfonamide (0.15 g, 0.23 mmol, Example
#23 Step I) and aqueous HCl (6 N, 1.0 mL, 6.00 mmol) was cooled to
about 0.degree. C. A solution of NaNO.sub.2 (0.022 g, 0.32 mmol) in
water (0.2 mL) was added and the reaction was stirred at about
0.degree. C. After about 3 h, the reaction was warmed to rt. After
about 15.5 h, the reaction was filtered to collect the yellow solid
by vacuum filtration, while washing with water (10 mL). The crude
solid was purified by silica gel chromatography eluting with 0-20%
EtOAc in DCM to give
N-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,
3]triazolo[4,5-d]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide
(0.088 g, 74%): LC/MS (Table 1, Method a) R.sub.t=2.44 min; MS m/z:
529 (M+H).sup.+.
[1808] General Procedure TTTT: Formation of a Squaramide
[1809] A mixture of a 3-amino-4-methoxycyclobut-3-ene-1,2-dione
(preferably 1 equiv), an amine (1-5 equiv, preferably 2 equiv), an
organic base such as DIEA or TEA (1-10 equiv, preferably 5-6 equiv
of DIEA), and a suitable organic solvent such as MeOH or DCE
(preferably MeOH) was heated at about 40 to 65.degree. C.
(preferably about 50.degree. C.). After about 1-24 h (preferably
about 12-18 h), the reaction is filtered, while washing with water,
to collect the solid.
Illustration of General Procedure TTTT
Preparation #TTTT.1*:
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-
-1,2-dione
##STR01031##
[1811] A mixture of
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione
(0.090 g, 0.17 mmol, Preparation #29),
3,3,3-trifluoropropan-1-amine hydrochloride (0.050 g, 0.337 mmol,
Fluorochem Limited), DIEA (0.18 mL, 1.0 mmol) and MeOH (1.2 mL) was
heated at about 50.degree. C. After about 18 h, the reaction was
cooled to rt. The solid was collected via vacuum filtration, while
washing with MeOH (about 3-5 mL), and then dried in a vacuum oven
at about 60.degree. C. to give
3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)-4-(3,
3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione (0.083 g, 79%) as
an off-white solid: LC/MS (Table 1, Method a) R.sub.t=2.27 min; MS
m/z: 616 (M+H).sup.+.
[1812] General Procedure UUUU: Reduction of an Azide to an
Amine
[1813] To a solution of an azide (preferably 1 equiv) in a suitable
organic solvent (such as THF or 1,4-dioxane, preferably THF) and
water is added triphenylphosphine (1-2 equiv, preferably 1.2
equiv). The reaction mixture is stirred at about room temperature
-80.degree. C. (preferably about 45.degree. C.) for about 1-24 h
(preferably about 7 h). If heated, the reaction mixture is cooled
to room temperature. The reaction mixture is worked up using one of
the following methods. Method 1. The reaction mixture is diluted in
an organic solvent (such as DCM or EtOAc) and water is added. The
layers are separated and the organic solution is optionally washed
with water and/or brine, dried over anhydrous MgSO.sub.4 or
Na.sub.2SO.sub.4, filtered, and the solvent is removed under
reduced pressure. Method 2. The reaction mixture is concentrated
under reduced pressure.
Illustration of General Procedure UUUU
Preparation #UUUU.1:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanamine
##STR01032##
[1815] A round bottom flask was charged with
1-(-4-azido-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-p-
yrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.650 g, 1.52 NN-mmol,
prepared using D from Preparation #25 with NaOH, KK, P with
NaBH.sub.4, IIII, JJJJ with NaN.sub.3), THF (8.0 mL), and water
(1.6 mL). To the flask was added triphenylphosphine (0.480 g, 1.83
mmol). The reaction mixture was heated to about 45.degree. C. for
about 7 h. The reaction mixture was cooled to room temperature and
EtOAc (20 mL) and water (15 mL) were added. The layers were
separated and the organic solution was dried over anhydrous
MgSO.sub.4, filtered, and concentrated under reduced pressure to
give an oil that solidified upon standing. The crude material was
purified via flash silica gel chromatography eluting with a
gradient of 1-10% DCM/MeOH/DEA (900:90:10) in DCM. The product
containing fractions were combined and concentrated under reduced
pressure to give an oil that was then dried on a vacuum pump
overnight to give
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanamine as a tacky oil (0.49 g,
80%): LC/MS (Table 1, Method b) R.sub.t=1.85 min; MS m/z 401
(M+H).sup.+.
[1816] General Procedure VVVV: Formation of a Ketone from a
Heteroaryl Halide
[1817] To a solution of a heteroaryl halide (preferably 1 equiv) in
an organic solvent (for example THF) at about -100.degree. C. to
0.degree. C. (preferably about -78.degree. C.) is added an alkyl
lithium base (1-2 equiv) (preferably sec-butyllithium, 1.3 equiv)
drop-wise. The reaction mixture is stirred at about -100.degree. C.
to 0.degree. C. (preferably about -78.degree. C.) for about 15 min
to 5 h (preferably about 1 h). A solution of an acylating agent
(such as an acid chloride, Weinreb amide or acylimidazole for
example, preferably an acid chloride, 1-3 equiv, preferably 1.5
equiv). The reaction mixture is allowed to reach ambient
temperature and water is added. The layers are separated and the
aqueous layer is then extracted with an organic solvent such as DCM
or EtOAc. The combined organic layers are then washed with water
and/or brine, dried over anhydrous MgSO.sub.4 or NaSO.sub.4,
filtered and concentrated under reduced pressure.
Illustration of General Procedure VVVV
Preparation #VVVV.1: tert-butyl
4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxo-
ethyl)piperidine-1-carboxylate
##STR01033##
[1819] To a solution of
5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.338 g,
1.09 mmol, Adesis) in THF (5.5 mL) at about -78.degree. C. was
added sec-butyllithium (1.015 mL, 1.421 mmol) drop-wise. The
reaction mixture was stirred at about -78.degree. C. for about 1 h
then a suspension of tert-butyl
4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (0.429 g, 1.64
mmol, Preparation #WWWW.1) in THF (2 mL) was added. The reaction
mixture was stirred at about -78.degree. C. for about 1 h then
allowed to reach ambient temperature. Water (5 mL) was added and
the product was extracted into DCM (3.times.10 mL). The combined
organic extracts were washed with brine and dried over anhydrous
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
crude material was purified by silica gel chromatography eluting
with 0-30% EtOAc in heptane to afford tert-butyl
4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxo-
ethyl)piperidine-1-carboxylate (0.147 g, 25%) as a colorless oil:
LC/MS (Table 1, Method r) R.sub.t=3.97 min; MS m/z: 534/536
(M+H).sup.+
[1820] General Procedure WWWW: Formation of an Acid Chloride
[1821] To a solution of a carboxylic acid (preferably 1 equiv) in
an organic solvent (for example DCM or DCE, preferably DCM) is
added oxalyl chloride (1-5 equiv, preferably 1-2 equiv) and
N,N-dimethylformamide (0.05-0.5 equiv, preferably 0.1 equiv). The
reaction mixture is stirred at about 0 to 50.degree. C. (preferably
ambient temperature) for about 30 min to 15 h (preferably 3 h). The
solvent is removed under reduced pressure and the residue is in the
next step without further purification.
Illustration of General Procedure WWW
Preparation #WWWW.1: tert-butyl
4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate
##STR01034##
[1823] To a solution of
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (3.84 g, 15.78
mmol) (prepared using M from ethyl 2-(piperidin-4-yl)acetate
(Oakwood), Z) in DCM (79 mL) at ambient temperature were added
oxalyl chloride (1.658 mL, 18.94 mmol) and DMF (0.115 g, 1.58
mmol). The reaction mixture was stirred at ambient temperature for
about 3 h. The solvent was removed under reduced pressure to afford
tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (4.13 g,
100%) as a light yellow solid. The product was used in the next
step without further purification.
[1824] General Procedure XXXX: Formation of a Hydrazone
[1825] To a mixture of a ketone (preferably 1 equiv) in an organic
solvent (preferably EtOH) are added a hydrazine (5-100 equiv,
preferably 45-55 equiv) and acetic acid (1-10 equiv, preferably 4-6
equiv). The reaction mixture is stirred at ambient temperature to
reflux (preferably at reflux) for about 1-24 h (preferably about 16
h). The solvent is removed under reduced pressure and the crude
material is taken up in an organic solvent (such as DCM) and dried
over anhydrous MgSO.sub.4 or NaSO.sub.4. The solvent is removed
under reduced pressure.
Illustration of General Procedure XXXX
Preparation #XXXX.1: tert-butyl
4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-
-1-carboxylate
##STR01035##
[1827] To a suspension of tert-butyl
4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxo-
ethyl)piperidine-1-carboxylate (1.00 g, 1.87 mmol) in EtOH (6.4 mL)
were added anhydrous hydrazine (2.94 mL, 94.0 mmol) and AcOH (0.536
mL, 9.36 mmol). The reaction mixture was stirred at reflux for
about 16 h. The solvent was removed under reduced pressure and the
crude material was taken up in DCM and dried over anhydrous
MgSO.sub.4. The solvent was removed and DCM (3 mL) was added. The
solid was removed by filtration and the filtrate was purified by
silica gel chromatography eluting with 0-10% MeOH in DCM to afford
tert-butyl
4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-
-1-carboxylate (0.324 g, 44%) as a white solid consisting of a 1/1
mixture of E/Z isomers: LC/MS (Table 1, Method r) R.sub.t=1.46 and
1.53 min; MS m/z: 392/394 and 392/394 (M+H).sup.+.
[1828] General Procedure YYYY: Cyclization with an
.alpha.-haloaldehyde
[1829] To an .alpha.-haloaldehyde (1-20 equiv, preferably 1.5
equiv) and a protected 2-amino-5H-pyrrolo[2,3-b]pyrazine
(preferably 1 equiv) is optionally added an organic solvent such a
DCE, DMF, 1,4-dioxane, EtOH, n-butanol, or toluene (preferably
n-butanol or 1,4-dioxane) with or without an acid catalyst such as
TsOH or sulfuric acid (0.05-0.2 equiv). The reaction mixture is
stirred at about room temperature -150.degree. C. (preferably about
90.degree. C.) for about 30 min-72 h (preferably about 48 h).
Optionally the reaction mixture can be subjected to microwave
heating at about 100-150.degree. C. (preferably about 130.degree.
C.) for about 30 min-15 h (preferably about 9 h). In cases where
the reaction does not proceed to completion as monitored by TLC,
LC/MS, or HPLC, the reaction may be re-subjected to heating at
about 25-100.degree. C. (preferably about 70.degree. C.) for about
2-48 h (preferably about 8-24 h) with the optional addition of. In
cases where the reaction does not proceed to completion as
monitored by TLC, LC/MS, or HPLC, an additional portion or portions
of an .alpha.-haloaldehyde (1-20 equiv, preferably 2.5 equiv) in an
organic solvent such as 1,4-dioxane can be added and the reaction
continued at about rt-150.degree. C. (preferably about 125.degree.
C.). The volatiles are removed under reduced pressure. Optionally
the crude mixture is diluted with water, aqueous NH.sub.4Cl, or
aqueous NaHCO.sub.3. The product may be isolated by filtration or
an organic solvent (for example, EtOAc or DCM) may be added. The
layers are separated and the aqueous layer may be extracted further
with an organic solvent (such as EtOAc and/or DCM). The combined
organic layers are optionally washed with additional aqueous
solutions such as aqueous NH.sub.4Cl, aqueous NaHCO.sub.3, water,
and/or brine, dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4,
filtered, and concentrated to dryness under reduced pressure.
Illustration of General Procedure YYYY
Preparation #YYYY.1: ethyl
3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate
##STR01036##
[1831] A solution of ethyl 2-chloro-3-oxopropanoate (1.60 g, 7.65
mmol, prepared as described in US2009005359A1) and 1,4-dioxane
(10.0 mL) was added to 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine
(1.45 g, 5.03 mmol, Preparation #E.1.1) under nitrogen. Anhydrous
butan-1-ol (30.0 mL) was added, a reflux condenser was attached,
and the system was sealed. After about 30 min, the mixture was
warmed to about 80.degree. C. The solution was allowed to cool to
ambient temperature. A solution of ethyl 2-chloro-3-oxopropanoate
(2.78 g, 13.3 mmol) and 1,4-dioxane (5 mL) was added. After about
30 min, the reaction mixture was warmed to about 80.degree. C.
After about 30 min, the mixture was warmed to about 125.degree. C.
After about 48 h, the brown solution was allowed to cool to ambient
temperature. The volatiles were removed under reduced pressure. The
residue was purified by silica gel chromatography eluting with a
gradient of 5-50% EtOAc in heptane to give ethyl
3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate (1.16
g, 60%): LC/MS (Table 1, Method b) R.sub.t=2.52 min; MS m/z 385
(M+H).sup.+.
[1832] General Procedure ZZZZ: Cyclization with SOCl.sub.2
[1833] To the amide, urea, hydrazide, or ketone (preferably 1
equiv), neat or as a solution in an organic solvent such as
1,4-dioxane, DCE, or toluene (preferably 1,4-dioxane), optionally
with a buffering co-solvent such as pyridine or TEA (preferably
TEA) is added dropwise SOCl.sub.2 (1.3-200 equiv, preferably 3
equiv) either neat or as a solution in an organic solvent such as
1,4-dioxane, DCE, or toluene. Optionally, the reaction vessel is
cooled to about -10 to 25.degree. C. (preferably about 0.degree.
C.) during the addition. Alternatively, the order of addition may
be reversed. The reaction mixture is warmed to about 30 to
100.degree. C. (preferably about 80.degree. C.) for about 0.5 to 24
h (preferably about 2 h). The reaction mixture is allowed to cool
to ambient temperature. The volatiles are optionally removed under
reduced pressure and an organic solvent such as DCM, 1,4-dioxane,
or EtOAc (preferably EtOAc) is added. The organic layer is washed
with an aqueous solution such as aqueous HCl, aqueous NaOH, aqueous
NaHCO.sub.3, aqueous NH.sub.4Cl, aqueous Na.sub.2CO.sub.3, or water
(preferably aqueous Na.sub.2CO.sub.3), with optional cooling, and
the product is isolated using one or more of the Purification
Methods described above. Optionally, subsequent removal of
protecting groups can be performed using General Procedures listed
above.
Preparation #ZZZZ.1: tert-butyl
(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyc-
lohexyl)methylcarbamate
##STR01037##
[1835] Thionyl chloride (0.030 mL, 0.41 mmol) was added dropwise to
a solution of tert-butyl
(trans-4-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)et-
hyl)cyclohexyl)methylcarbamate (0.127 g, 0.228 mmol, prepared using
M from trans-(4-aminomethylcyclohexyl)acetic acid hydrochloride
[AstaTech], H from Example #1, Step D, HATU, TEA), TEA (0.160 mL,
1.15 mmol), and 1,4-dioxane (2.3 mL) under nitrogen. A reflux
condenser was attached and the reaction mixture was warmed to about
80.degree. C. After about 2 h, the solution was cooled to ambient
temperature and aqueous Na.sub.2CO.sub.3 (2 M, 3.4 mL, 6.8 mmol)
was added and the biphasic mixture was warmed to about 80.degree.
C. After about 2 h, aqueous NaOH (2 M, 0.570 mL, 1.14 mmol) was
added due to slow rate of deprotection. After about 17 h, the
mixture was allowed to cool to ambient temperature. The reaction
solution was diluted with water (5 mL) and then extracted with
EtOAc (2.times.10 mL). The combined organics were dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography eluting with a gradient of 2-8% MeOH in DCM to give
tert-butyl
(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyc-
lohexyl)methylcarbamate (0.0565 g, 63%): LC/MS (Table 1, Method a)
R.sub.t=1.85 min; MS m/z: 385 (M+H).sup.+.
[1836] General Procedure AAAAA: Formation of a Carboxylic Acid or
Ester from an Aryl Halide
[1837] An aryl or heteroaryl halide (preferably 1 equiv) is
dissolved or suspended in an organic solvent such as DMF,
1,4-dioxane, THF, Et.sub.2O, or toluene (preferably DMF or THF).
The halide may be transmetallated using a base such a n-, t-, or
sec-butyllithium (1-3 equiv) or a Grignard reagent such as
isopropyl magnesium bromide (1-3 equiv) and then trapped with
CO.sub.2 to afford the carboxylic acid following an acidic workup.
Alternatively, the solution of the aryl or heteroaryl halide may be
treated with a base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, or
TEA (1-10 equiv, preferably TEA, 2 equiv). Optionally, MeOH, (1-200
equiv, preferably 50 equiv) is added. A palladium source such a
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-CH.sub.2Cl.s-
ub.2 adduct,
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),
bis(triphenylphosphine)dichloropalladium, or
tetrakis(triphenylphosphinepalladium(0) (0.02-1 equiv, preferably
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-CH.sub.2Cl.s-
ub.2 adduct, 0.1 equiv) is added. The mixture is placed under a CO
atmosphere and then warmed to about 40-120.degree. C. (preferably
about 100.degree. C.) for about 0.5-24 h (preferably about 4.5 h).
The reaction is optionally quenched using sodium methoxide or
aqueous NaOH (1-100 equiv) and an organic solvent (for example,
EtOAc or DCM) is added. The layers are separated and the aqueous
layer may be extracted further with an organic solvent (such as
EtOAc and/or DCM). The combined organic layers are optionally
washed with additional aqueous solutions such as brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated to dryness under reduced pressure.
Illustration of General Procedure AAAAA
Preparation #AAAAA.1: methyl
6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazine-8-carboxylate
##STR01038##
[1839] To a solution of
8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triaz-
olo[4,3-a]pyrazine (0.050 g, 0.12 mmol, prepared using KK from
Preparation #GGG.1.1 and NaH), TEA (0.034 mL, 0.24 mmol), MeOH
(0.25 mL, 6.2 mmol), and DMF (0.6 mL) purged with nitrogen was
added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(0.0098 g, 0.012 mmol). The mixture was purged with CO and a
balloon of CO was attached to the reaction vessel. The mixture was
warmed to about 100.degree. C. After about 4.5 h, the solution was
allowed to cool to ambient temperature. Water (5 mL) was added and
the mixture was extracted with EtOAc (2.times.10 mL). The combined
organics were dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
25-75% EtOAc/heptane over 30 min to afford methyl
6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triaz-
olo[4,3-a]pyrazine-8-carboxylate (0.0311 g, 74%): LC/MS (Table 1,
Method n) R.sub.t=0.74 min; MS m/z: 348 (M+H).sup.+.
[1840] General Procedure BBBBB: Cyclization with an Orthoester
[1841] To an orthoester (1-20 equiv, preferably 10 equiv) and a
protected 2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (preferably 1
equiv) is optionally added an organic solvent such a DCE, DMF,
1,4-dioxane, or toluene (preferably DMF) with or without an acid
catalyst such as TsOH or TFA (0.05-0.2 equiv). The mixture may be
left at ambient temperature or warmed at about 30-100.degree. C.
(preferably about 100.degree. C.) for about 0.5-24 h (preferably
about 17 h). The volatiles may be removed under reduced pressure.
Optionally, the crude mixture may be diluted with water, aqueous
NH.sub.4Cl, or aqueous NaHCO.sub.3. The product may be isolated by
filtration and an organic solvent (for example, EtOAc or DCM) may
be added. Alternatively, an organic solvent may be added directly
to the aqueous mixture. The layers are separated and the aqueous
layer may be extracted further with an organic solvent (such as
EtOAc and/or DCM). The combined organic layers are optionally
washed with additional aqueous solutions such as aqueous
NH.sub.4Cl, aqueous NaHCO.sub.3, water, and/or brine, dried over
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and
concentrated to dryness under reduced pressure.
Illustration of General Procedure BBBBB
Preparation #BBBBB.1:
6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01039##
[1843] Triethyl orthoformate (76.0 mL, 456 mmol) was added to a
mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (13.8 g,
45.4 mmol, Example #1, Step D) and DMF (45 mL) under nitrogen. A
reflux condenser was attached and the mixture was warmed to about
100.degree. C. After about 17 h, the solution was allowed to cool
to ambient temperature. The volatiles were removed under reduced
pressure. The residue was slurried in water (100 mL) and then
filtered, rinsing with water. The aqueous phase was extracted with
EtOAc (200 mL). The organics were dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated. The material was
combined with the precipitate and then purified by silica gel
chromatography eluting with a gradient of 0-5% MeOH in DCM to give
6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (10.4 g,
73%): LC/MS (Table 1, Method n) R.sub.t=0.59 min; MS m/z 314
(M+H).sup.+.
[1844] General Procedure CCCCC: Stille Coupling of an Aryl or
Heteroaryl Halide
[1845] To a degassed solution of a aryl, heteroaryl, or vinyl
stannane (preferably 1.3 equiv) and an aryl, heteroaryl or alkeneyl
halide (preferably 1 equiv) in an organic solvent such as DMF,
1,4-dioxane, or toluene (preferably DMF) may be added a base such
as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, or TEA (1-10 equiv).
Optionally, additives such as LiCl (1-10 equiv, preferably 3
equiv), CsF (1-10 equiv, preferably 1.5 equiv), and/or CuI
(0.05-0.5 equiv, preferably 0.2 equiv) may be added. A palladium(0)
source such a tetrakis(triphenylphosphine)palladium(0),
bis(dibenzylideneacetone)palladium or a palladium(II) source such
as bis(triphenylphosphine)palladium(II) chloride or palladium
acetate is added (0.01-0.2 equiv, preferably
tetrakis(triphenylphosphine)palladium(0), preferably 0.1 equiv).
The mixture is warmed at about 40 to 150.degree. C. (preferably
about 80.degree. C.) either thermally or using a microwave for
about 0.5 to 72 h (preferably about 4 h). The solution is cooled to
rt and volatiles may be removed under reduced pressure and the
crude mixture diluted with water, aqueous NH.sub.4Cl, aqueous
NaHCO.sub.3 and an organic solvent such as EtOAc or DCM. If a solid
was present, the resulting reaction mixture was filtered to remove
it. The resulting layers of the filtrate are separated and the
aqueous layer may be extracted with additional organic solvent. The
combined organic layers are optionally washed with additional
aqueous solutions such as brine, then dried over anhydrous
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and concentrated to
dryness under reduced pressure.
Illustration of General Procedure CCCCC
Preparation #CCCCC.1:
8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazine
##STR01040##
[1847] A vial containing
8-bromo-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.030 g, 0.076 mmol, prepared using D from Preparation #BBBBB.1
and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH),
2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.054 g,
0.12 mmol, Preparation #39), LiCl (0.010 g, 0.24 mmol), CuI (0.003
g, 0.02 mmol), CsF (0.017 g, 0.12 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol)
under nitrogen was evacuated and then back-filled with nitrogen.
1,4-Dioxane (0.5 mL) was added and nitrogen was bubbled through the
mixture for about 30 min. The reaction vessel was sealed and the
mixture was warmed to about 80.degree. C. After about 4 h, the
mixture was allowed to cool to ambient temperature. The mixture was
diluted with water (5 mL) and EtOAc (5 mL) and then filtered
through a syringe filter. The layers were separated and the aqueous
phase was extracted with EtOAc (5 mL). The combined organics were
concentrated under reduced pressure. The residue was purified by
silica gel chromatography eluting with a gradient of 0-10% MeOH in
DCM over min to afford
8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,-
2,4]triazolo[4,3-a]pyrazine (0.026 g, 69%): LC/MS (Table 1, Method
n) R.sub.t=0.56 min; MS m/z 490 (M+H).sup.+.
[1848] General Procedure DDDDD: Deprotection of a Cbz-Protected
Amine Using a Silane
[1849] A solution of Cbz-protected amine (preferably 1 equiv) and a
silane (for example triethylsilane, t-BuMe.sub.2SiH (preferably
triethylsilane, 10-500 equiv, preferably 100 equiv)) is added an
organic base such as TEA or DIEA (preferably TEA, 0.1-10 equiv,
preferably 0.2 equiv), and a palladium catalyst (for example
palladium (II) chloride, palladium (II) acetate,
tris(benzylideneacetone)dipalladium(0),
bis(acetato)triphenylphosphinepalladium(II), or
dichlorobis(triphenylphosphine)palladium(II); preferably palladium
(II) chloride, 0.01-0.20 equiv, preferably 0.1 equiv). The reaction
is heated at about 40 to 180.degree. C. (preferably about
120.degree. C.) for about 1 to 48 h (preferably about 8 h). The
catalyst is removed by filtration and the filtrate is concentrated
under reduced pressure. The reaction mixture is optionally worked
up by adding a suitable organic solvent (such as EtOAc or DCM) and
water. The layers are separated, and the organic solution is dried
over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and coned
under reduced pressure to give the target compound.
Illustration of General Procedure DDDDD
Preparation #DDDDD.1:
8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]-
pyrrolo[2,3-e]pyrazine
##STR01041##
[1851] A solution of benzyl
4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]py-
razin-8-yl)piperidine-1-carboxylate (0.580 g, 1.15 mmol, prepared
using R from 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid
(Matrix), S from Example #3 Step E, E with TFA, KKKK with PFPAA, D
with NaOH, KK), TEA (0.03 mL, 0.229 mmol), palladium (II) chloride
(0.020 g, 0.115 mmol) in triethylsilane (18.3 mL, 115 mmol) was
heated at about 120.degree. C. for about 8 h. The catalyst was
removed by filtration and the filtrate was concentrated under
reduced pressure. The product was purified by silica gel
chromatography eluting with a gradient of 0-10% (90:9:1)
(MeOH/DCM/DEA) in DCM to give
8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]-
pyrrolo[2,3-e]pyrazine (0.234 g, 55%) as a brown oil: LC/MS (Table
1, Method b) R.sub.t=1.93 min; MS m/z: 372 (M+H).sup.+.
[1852] General Procedure EEEEE: Formation of a Guanidine
[1853] To an amine (preferably 1 equiv) in an organic solvent (for
example DMF, MeCN, 1,4-dioxane or THF, preferably DMF) is added an
aqueous base (for example aqueous Na.sub.2CO.sub.3, NaOH,
K.sub.2CO.sub.3 or NaHCO.sub.3; (preferably Na.sub.2CO.sub.3, 2-20
equiv, preferably 2-10 equiv)) or an organic base such as TEA or
DIEA (preferably DIEA, 1-5 equiv, preferably 4 equiv) and addition
of 1H-pyrazole-1-carboximidamide hydrochloride (1-10.0 equiv,
preferably 3 equiv). The reaction is stirred at about 10-40.degree.
C. (preferably rt) for about 2-90 h (preferably about 72 h) and
worked up using one of the following methods. Method 1: An organic
solvent (such as Et.sub.2O, EtOAc or DCM) and water are added and
the layers are separated. The aqueous layer is extracted with
additional organic solvent and the combined organic layers may be
optionally washed with brine, dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, and then decanted or filtered prior to concentrating
under reduced pressure. Method 2: The reaction mixture is directly
purified.
Illustration of General Procedure EEEEE
Preparation #EEEEE.1:
4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]py-
razin-8-yl)piperidine-1-carboximidamide
##STR01042##
[1855] A solution of
8-(piperidin-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]-
pyrrolo[2,3-e]pyrazine (0.100 g, 0.269 mmol, Preparation #DDDDD.1),
1H-pyrazole-1-carboximidamid, hydrochloride (0.118 g, 0.807 mmol)
and DIEA (0.188 mL, 1.08 mmol) in DMF (2 mL) was stirred at rt for
about 72 h. The reaction mixture was purified by RP-HPLC (Table 1,
Method 1) to give
4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-
-e]pyrazin-8-yl)piperidine-1-carboximidamide (0.037 g, 33%) as a
brown oil: LC/MS (Table 1, Method b) R.sub.t=1.82 min; MS m/z: 414
(M+H).sup.+.
[1856] General Procedure FFFFF: Formation of a Sulfoxonium
Ylide
[1857] To a suspension of a carboxylic acid (preferably 1 equiv) in
an organic solvent (such as THF, 2-methyl tetrahydrofuran, or MTBE,
preferably THF) is added an organic base such as Hunig's base or
TEA (preferably TEA) (1.2-3.5 equiv, preferably 3.5 equiv) and
activating agent such as DCC or HATU (preferably HATU) (1-1.5
equiv, preferably 1.01 equiv). The reaction is stirred at 10 to
40.degree. C. preferably ambient temperature for about 1-20 h
(preferably about 1-2 h). In a separate flask, trimethylsulfoxonium
chloride (1.25-5 equiv, preferably 3 equiv) is added to a
suspension of a base such as sodium tert-butoxide or potassium
tert-butoxide (3-5 equiv, preferably 3.15 equiv) in an organic
solvent (such as THF, 2-methyl tetrahydrofuran, or MTBE, preferably
THF). The reaction is stirred at about 60 to 70.degree. C.
(preferably 65.degree. C.) for about 2-4 h (preferably about 3 h).
The suspension is cooled to about -5 to 5.degree. C. and the above
activated ester solution is added dropwise over about 20-60 min.
The reaction mixture is stirred at about -5 to 5.degree. C. for
about 1-20 h (preferably about 1-2 h). The reaction mixture is
quenched with water dropwise at about 0 to 40.degree. C.
(preferably ambient temperature) over about 2-50 min and stirred
for about 0.2-20 h (preferably about 18 h at ambient temperature.
The reaction may be concentrated under reduced pressure to remove
volatiles and then partitioned between an organic solvent (such as
EtOAc) and water. The aqueous layer can be optionally extracted
with additional organic solvent such as EtOAc. The combined organic
layer is washed with water, dried over anhydrous Na.sub.2SO.sub.4
or MgSO.sub.4, filtered, concentrated under reduced pressure to
give the target compound.
Illustration of General Procedure FFFFF
Preparation #FFFFF.1:
2-(4-(Dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide
##STR01043##
[1859] To a 250 mL flask, 4-(dibenzylamino)cyclohexanecarboxylic
acid (5.6 g, 17.3 mmol), HATU (6.75 g, 17.4 mmol) and TEA (8.45 mL,
60.6 mmol) in THF (60 mL) were added to give a white suspension.
The reaction mixture was stirred at ambient temperature for about 1
h. To a 500 mL flask, trimethylsulfoxonium chloride (6.82 g, 51.9
mmol) and potassium tert-butoxide (6.44 g, 54.5 mmol) in THF (60
mL) were added to give another white suspension. The reaction
mixture was stirred at about 65.degree. C. for about 3 h. The
reaction mixture was cooled to about 5.degree. C. The above
activated ester solution was added dropwise over about 50 min. The
reaction mixture was stirred at about 0-5.degree. C. for about 90
min. The reaction mixture was quenched by the addition of water
(120 mL) dropwise at about 0-5.degree. C. over about 25 min. The
reaction mixture was stirred at about 0-5.degree. C. for about 30
min, then at ambient temperature for about 18 h. The mixture was
concd under reduced pressure to give a white suspension. The
suspension was partitioned between EtOAc (300 mL) and water (200
mL). The aqueous layer was extracted with EtOAc (2.times.100 mL).
The combined organic layer was washed with water (50 mL) and brine
(3.times.40 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concd under reduced pressure. The residue was
dissolved in hot MeOH (100 mL) and concd under reduced pressure.
The oil was dissolved in hot MeOH (60 mL) and concd to give a white
solid. The solid was dissolved in MeOH (36 mL) and water (12 mL) at
about 55.degree. C. The solution was cooled to ambient temperature,
then to about 5.degree. C. Additional 3:1 MeOH/water (40 mL) was
added to the suspension. The suspension was filtered, washed with
1:1 MeOH/water (20 mL) then with heptane (20 mL). The collected wet
cake was dried in a heated vacuum oven at about 60.degree. C. for
about 72 h to
2-(4-(dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide
(5.44 g, 79%) as white solid: LC/MS (Table 1, Method a)
R.sub.t=1.42, 1.45 min; MS m/z 398 (M+H).sup.+.
[1860] General Procedure GGGGG: Reaction of a Sulfoxonium Ylide
with an Amine
[1861] To a mixture of sulfoxonium ylide (preferably 1 equiv) and
an amine (0.7-2 equiv, preferably 1.2 equiv) is added a catalyst
(such as [Ir(COD)Cl].sub.2, [(COD)Ir(OMe)].sub.2, (COD)Ir(acac),
Ir(COD).sub.2BF.sub.4, Ir(COD).sub.2BArF, Rh.sub.2(OAc).sub.2,
Rh.sub.2(TFA).sub.4, [Ru(cym)Cl.sub.2]2,
RuCl.sub.2(PPh.sub.3).sub.3, RuCl.sub.2(DMSO).sub.4, preferably
[Ir(COD)Cl].sub.2 (0.01-0.1 equiv, preferably 0.04 equiv)). A
degassed organic solvent (such as DCM, DCE, MeCN, THF, 2-methyl
tetrahydrofuran, CHCl.sub.3, toluene, or DMF, preferably DCE) is
added. The reaction is purged with N.sub.2 for about 10-20 min and
stirred at about 20-90.degree. C. (preferably about 70.degree. C.)
for about 1-96 h (preferably about 3-6 h). Optionally, additional
catalyst (preferably [Ir(COD)Cl].sub.2 equiv) may be added to the
reaction mixture in cases where the reaction does not proceed to
completion as monitored by TLC, LC/MS, or HPLC. Once the reaction
has proceeded to an acceptable level, the reaction mixture can be
concd in vacuo to provide the product.
Illustration of General Procedure GGGGG
Preparation #GGGGG.1:
1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-1H-pyrrolo[2,3-b]pyrazin-2-yla-
mino)ethanone
##STR01044##
[1863] To a 100 mL 2-neck round-bottomed flask,
2-(4-(dibenzylamino)cyclohexyl)-dimethylsulfoxonium-2-oxo-ethylide
(5.4 g, 13.6 mmol, Preparation #FFFFF.1),
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (4.7 g, 16.3 mmol,
Preparation #E.1.1), and [Ir(COD)Cl].sub.2 (0.365 g, 0.543 mmol,
Alfa Aesar) were added. The reaction vessel was purged with N.sub.2
for about 10 min. To the reaction vessel, degassed DCE (25 mL) was
added via syringe. The reaction mixture was purged with N.sub.2 for
about 10 min and stirred under an atmosphere of N.sub.2 at about
70.degree. C. for about 3 h. The reaction mixture was allowed to
cool to ambient temperature. The solvent was removed under reduced
pressure. The residue was purified by silica gel flash
chromatography eluting with a gradient of 5-70% EtOAc in heptane to
yield
1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yla-
mino)ethanone (5.8 g, 65%) as glassy solid: LC/MS (Table 1, Method
a)R.sub.t=3.24 and 3.26 min; MS m/z 608 (M+H).sup.+.
Example #1
[1864] Example #1.1:
N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide, [1865] Example
#1.2:
N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide, [1866] Example
#1.3:
N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide, [1867] Example
#1.4:
N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide, [1868] Example
#1.5:
N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide, and [1869] Example
#1.6:
N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide,
##STR01045##
[1869] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01046##
[1871] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01047##
[1873] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01048##
[1875] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min and cooled to ambient
temperature. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0
g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol),
and NaOt-Bu (12.28 g, 128 mmol) were added. After an additional
vacuum/nitrogen purge, the reaction was heated at about 80.degree.
C. After about 50 min, the reaction mixture was cooled to ambient
temperature and filtered through a pad of silica gel (6 cm in
height.times.6 cm in diameter), topped with Celite.RTM. (1 cm in
height.times.6 cm in diameter), while washing with EtOAc
(3.times.150 mL). Water (300 mL) was added to the filtrate and the
organic layer was separated. The aqueous layer was extracted with
additional EtOAc (3.times.200 mL). The combined organic extracts
were washed with saturated aqueous NH.sub.4Cl, saturated aqueous
NaHCO.sub.3, and brine (400 mL each), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to give a
dark brown oil (45 g). The brown oil was dissolved in DCM (250 mL),
silica gel (200 g) was added, and the mixture was concd under
reduced pressure. The resulting silica mixture was purified using
silica gel chromatography eluting with a gradient of 25-65% EtOAc
in heptane to give a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01049##
[1877] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR01050##
[1879] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. and ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep internal temperature below about 10.degree. C.
The resulting mixture was stirred at ambient temperature for about
0.5 h to give a clear yellow solution, and methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, coned under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01051##
[1881] A 5 liter round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL,
4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The
reaction was heated at reflux for about 6 h then cooled to ambient
temperature and added dropwise to NaHCO.sub.3 (8% aqueous, 3.5 L).
The resulting biphasic mixture was extracted with MTBE (2.times.1.5
L). The combined organic layers were washed with brine (1 L), dried
over anhydrous MgSO.sub.4 and concd under reduced pressure to give
191 g of crude material that was purified by vacuum distillation
(97-99.degree. C., 0.600 mm Hg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H NMR
(CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m,
1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
Step G: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR01052##
[1883] A round bottom flask was charged with 10 wt % Pd/C (10 g,
9.4 mmol). The flask was cooled to about 0.degree. C. and EtOAc
(400 mL) was added under a nitrogen atmosphere. The cooling bath
was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8
g, 263 mmol) was added. Hydrogen gas was bubbled through the
mixture for about 5 min and the mixture was then stirred under a
hydrogen atmosphere for about 48 h. The hydrogen source was removed
and the mixture was bubbled with nitrogen for about 5 min and was
filtered through a pad of Celite.RTM.. The filter cake was rinsed
with EtOAc (400 mL). The filtrate was concd under reduced pressure
to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1
mixture cis:trans) (48.0 g, 99%) as a yellow liquid: .sup.1H NMR
(CDCl.sub.3) .delta. 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m,
1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H),
1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).
Step H: ethyl 2-ethyl-4-methylenecyclopentanecarboxylate
##STR01053##
[1885] A solution of KOt-Bu (3.65 g, 32.6 mmol) and
methyltriphenylphosphonium bromide (11.6 g, 32.6 mmol) in THF (69.5
mL) was cooled to about -10.degree. C. A solution of ethyl
2-ethyl-4-oxocyclopentanecarboxylate (4.00 g, 21.7 mmol) in THF
(17.4 mL) was added dropwise while the temperature was kept at
about 0.degree. C. The reaction mixture was allowed to warm to
ambient temperature and stirred for about 16 h. The insoluble
material was removed by filtration. The filtrate was concd under
reduced pressure. The resulting material was purified by silica gel
(120 g) chromatography eluting with a gradient of 0-20% EtOAc in
heptane to provide ethyl 2-ethyl-4-methylenecyclopentanecarboxylate
(2.55 g, 64%) as a colorless liquid: .sup.1H NMR (d-DMSO) .delta.
4.88-4.78 (m, 2H), 4.16-3.96 (m, 2H), 2.66-2.31 (m, 4H), 2.24-1.82
(m, 2H), 1.50 (m, 1H), 1.35-1.22 (m, 1H), 1.18 (t, 3H), 0.85 (m,
3H).
Step I: ethyl 2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate
##STR01054##
[1887] Ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (0.720 g,
3.95 mmol), triphenylsilanethiol (1.329 g, 4.54 mmol) and
2,2'-azobis(2-methylpropionitrile) (0.195 g, 1.185 mmol) in toluene
(3.95 mL) was heated at reflux for about 6 h. The reaction mixture
was cooled to ambient temperature and then concd under reduced
pressure. The material was purified by silica gel (40 g)
chromatography eluting with a gradient of 0-10% EtOAc in heptane to
give a colorless oil. The resulting oil was dissolved in DCM (4 mL)
and TFA (1.52 mL, 19.7 mmol) was added. After stirring at ambient
temperature for about 1 h, the solvent was removed under reduced
pressure. The material was purified by silica gel (40 g)
chromatography eluting with a gradient of 0-15% EtOAc in heptane to
provide ethyl 2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate
(0.620 g, 72%) as a colorless oil: .sup.1H NMR (DMSO-d.sub.6)
.delta. 4.13-4.01 (m, 2H), 2.50-2.30 (m, 3H), 2.24 (m, 1H),
2.15-1.87 (m, 3H), 1.66-1.54 (m, 1H), 1.50-1.37 (m, 2H), 1.31-1.23
(m, 2H), 1.17 (t, 3H), 0.83 (m, 3H).
Step J: (3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic
acid
##STR01055##
[1889] To a stirred solution of ethyl
2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate (2.50 g, 11.6
mmol) in DCM (50.7 mL) was added dropwise ethaneperoxoic acid (7.29
mL, 34.7 mmol) at about 0.degree. C. The reaction mixture was
warmed to ambient temperature and stirred for about 16 h.
[1890] The solution was coned under reduced pressure to yield crude
(3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid (3.18
g, 104%) as a dark brown oil: LC/MS (Table 1, Method b)
R.sub.t=1.39 min; MS m/z: 265 (M+H).sup.+.
Step K: ethyl
4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate
##STR01056##
[1892] A solution of
(3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid (3.18
g, 12.03 mmol) in DCM (10 mL) and DMF (10 mL) was cooled to about
0.degree. C. Oxalyl chloride (24.1 mL, 48.1 mmol) was added
dropwise while the temperature was kept at about 0.degree. C. After
the addition was complete, the reaction mixture was warmed to
ambient temperature and stirred for about 1 h. The solvent was
removed under reduced pressure. The residue was dissolved in DMF
(10 mL) and then added dropwise to a solution of TEA (2.51 mL,
18.03 mmol) and diethylamine (0.937 mL, 9.02 mmol) in DMF (10 mL)
at about 0.degree. C. The reaction mixture was stirred at ambient
temperature for about 16 h. The solvent was removed under reduced
pressure. The material was purified by silica gel (120 g)
chromatography eluting with a gradient of 10-60% EtOAc in heptane
to provide ethyl
4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate
(0.570 g, 30%) as a yellow oil: LC/MS (Table 1, Method b)
R.sub.t=2.60 min; MS m/z: 320 (M+H).sup.+.
Step L: 4-N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic
acid
##STR01057##
[1894] A mixture of ethyl
4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate
(0.570 g, 1.784 mmol) in NaOH (1 N aqueous, 10 mL, 10 mmol) was
stirred at ambient temperature for about 72 h. The mixture was
partitioned with DCM (10 mL). The aqueous phase was acidified to
about pH=4 by addition of 6 N aqueous HCl. The solution was
partitioned with DCM (10 mL). The aqueous phase was washed with DCM
(2.times.10 mL). The organic layers were combined, dried over
anhydrous MgSO.sub.4, and concd under reduced pressure to give
4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid
(0.375 g, 72%) as yellow oil: LC/MS (Table 1, Method b)
R.sub.t=1.95 min; MS m/z: 292 (M+H).sup.+.
Step M:
N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl-
)hydrazinecarbonyl)cyclopentyl)methanesulfonamide
##STR01058##
[1896] To a suspension of
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-e][1,2,3-b]pyrazine (0.390 g,
1.287 mmol, Example #1 Step D),
4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid
(0.375 g, 1.287 mmol), and HATU (0.538 g, 1.416 mmol) in DCM (6.4
mL) was added TEA (0.538 mL, 3.86 mmol). The reaction mixture was
stirred at ambient temperature for about 1 h. The reaction mixture
was partitioned between water (50 mL) and DCM (50 mL). The aqueous
layer was extracted with DCM (2.times.50 mL). The organic layers
were combined and concd under reduced pressure. The material was
purified by silica gel (120 g) chromatography eluting with a
gradient of 20-100% EtOAc in DCM to provide
N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydraz-
inecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 98%) as a
brown solid: LC/MS (Table 1, Method b) R.sub.t=2.39 min; MS m/z:
577 (M+H).sup.+.
Step N:
N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)methanesulfonamide
##STR01059##
[1898] To a mixture of
N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydraz-
inecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 1.27 mmol) and
TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7 mL) was added
SOCl.sub.2 (0.185 mL, 2.53 mmol). The reaction mixture was heated
at about 80.degree. C. for about 2 h. The reaction mixture was
cooled to ambient temperature and partitioned between saturated
aqueous NaHCO.sub.3 (30 mL) and DCM (30 mL). The aqueous layer was
washed with DCM (2.times.30 mL). The organic layers were combined,
concd under reduced pressure, and purified by silica gel (80 g)
chromatography eluting with a gradient of 0-60% MeOH in DCM to give
a brown solid. The resulting solid was suspended in
Na.sub.2CO.sub.3 (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane
(2 mL). The reaction mixture was heated at about 60.degree. C. for
about 16 h. The reaction mixture was cooled to ambient temperature
and purified by RP-HPLC (Table 1, Method d) to afford
N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methanesulfonamide (0.300 g, 58%) as a tan solid:
LC/MS (Table 1, Method b) R.sub.t=1.89 min; MS m/z: 405
(M+H).sup.+. The solid was further purified by using General
Procedure AA to give
N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27,
R.sub.t=11.8 min, or =negative) (0.021 g, 7%) [Example #1.1];
N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27,
R.sub.t=11.1 min, or =positive) (0.018 g, 6%) [Example #1.2];
N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][,
2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide
(Table 2, Method 27, R.sub.t=10.7 min, or =positive) (0.018 g, 6%)
[Example #1.3];
N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 28,
R.sub.t=20.1 min, or =negative) (0.031 g, 11%) [Example #1.4];
N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27,
R=12.8 min, or =positive) (0.002 g, 1%) [Example #1.5]; and
N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27,
R.sub.t=12.8 min, or =positive) (0.001 g, 1%) [Example #1.6].
Example #2*
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopen-
tyl)aniline
##STR01060##
[1899] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01061##
[1901] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01062##
[1903] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01063##
[1905] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01064##
[1907] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: tert-butyl
(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyc-
lopentylcarbamate
##STR01065##
[1909] To
(1R,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid
(2.25 g, 9.81 mmol, Acros) in DCM (98 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.98 g, 9.81 mmol),
HATU (3.73 g, 9.81 mmol) and TEA (5.5 mL, 39 mmol). The reaction
mixture was stirred at ambient temperature for about 4 h then
diluted with DCM (300 mL). The reaction mixture was washed with
water (2.times.80 mL), saturated aqueous NaHCO.sub.3 (80 mL), dried
over anhydrous MgSO.sub.4, filtered, and coned under reduced
pressure. The residue was purified using silica gel chromatography
(220 g) eluting with a gradient of 50-100% EtOAc in DCM give
tert-butyl
(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyc-
lopentylcarbamate (5.03 g, 100%) as a brown solid: LC/MS (Table 1,
Method b) R.sub.t=2.18 min; MS m/z: 513 (M-H).sup.-
Step F:
(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentanamine
##STR01066##
[1911] To tert-butyl
(1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyc-
lopentylcarbamate (5.03 g, 9.78 mmol) in 1,4-dioxane (103 mL) was
added DIEA (7.2 mL, 41 mmol) and SOCl.sub.2 (2.3 mL, 31 mmol). The
reaction mixture was heated at about 80.degree. C. for about 1 h.
The solvent was removed under reduced pressure and the residue was
purified using silica gel chromatography (330 g) eluting with a
gradient of 0-20% MeOH in DCM to give
(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)cyclopentanamine (2.65 g, 68%): LC/MS (Table 1, Method b)
R.sub.t=1.55 min; MS m/z: 397 (M+H).sup.+.
Step G:
N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyraz-
in-1-yl)cyclopentyl)aniline
##STR01067##
[1913] A 100 mL round bottom flask was sequentially charged with
phenylboronic acid (0.123 g, 1.01 mmol), diacetoxycopper
monohydrate (0.010 g, 0.05 mmol), powdered 4{acute over (.ANG.)}
molecular sieves (0.375 g) and DCM (4 mL). The reaction mixture was
stirred for about 10 min then a suspension of
(1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanamine (0.20 g, 0.50 mmol) in DCM (2 mL) and MeCN (2 mL)
was added. The flask was fitted with an oxygen balloon. The flask
was purged with oxygen and then heated at about 40.degree. C. for
about 18 h. Additional diacetoxycopper monohydrate (0.010 g, 0.05
mmol) was added and the reaction mixture was heated at about
45.degree. C. under an atmosphere of oxygen for about 3 days. DCM
(50 mL) was added and the reaction mixture was filtered through a
pad of Celite.RTM. while washing with DCM (20 mL). The filtrate was
coned under reduced pressure and the residue was purified using
silica gel chromatography (20 g) eluting with a gradient of 30-80%
EtOAc in DCM to give
N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl)aniline (0.106 g, 45%): LC/MS (Table 1, Method b)
R.sub.t=2.39 min; MS m/z: 473 (M+H).sup.+.
Step H:
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-
cyclopentyl)aniline
##STR01068##
[1915] To
N-((1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentyl)aniline (0.106 g, 0.224 mmol) in 1,4-dioxane
(1 mL) was added NaOH (1 N aqueous, 1.12 mL, 1.12 mmol). The
reaction mixture was heated at about 60.degree. C. for about 1 h.
AcOH (0.5 mL) was added and the crude reaction mixture was purified
by RP-HPLC (Table 1, Method j) to give
N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclope-
ntyl)aniline (0.053 g, 74%) as a light yellow solid: LC/MS (Table
1, Method b) R.sub.t=1.84 min; MS m/z: 319 (M+H).sup.+.
Example #3*
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-di-
fluorocyclobutyl)methanone
##STR01069##
[1916] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01070##
[1918] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01071##
[1920] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate
##STR01072##
[1922] CO was bubbled into an orange solution of
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF
(2.50 L) within a 5 L round bottom flask for about 2 min.
Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2
mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were
added and the flask was fitted with a balloon of CO. The mixture
was heated at about 95.degree. C. under an atmosphere of CO (1
atmosphere). After stirring overnight, the reaction mixture was
cooled to ambient temperature overnight and poured into ice water
(3.2 L). The mixture was stirred for about 10 min and the
precipitate was collected by filtration, while washing with water,
and dried for 1 h. The crude material was dissolved in DCM,
separated from residual water, dried over anhydrous MgSO.sub.4,
filtered, added silica gel, and coned under reduced pressure to
prepare for chromatography. The crude material was purified by
silica gel column chromatography eluting with 0-5% MeOH in DCM to
yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5
mol % DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table
1, Method a) R.sub.t=2.35 min; MS m/z 332 (M+H).sup.+.
Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid
##STR01073##
[1924] HCl (6 N aqueous, 714 mL) was added to a yellow solution of
methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g,
53.6 mmol) in 1,4-dioxane (715 mL) within a 2 L round bottom flask,
and the mixture was heated at about 60.degree. C. for about 16 h.
The reaction mixture was cooled to ambient temperature. The organic
solvent was removed under reduced pressure and the precipitate was
collected, washed with water, and dried to yield
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%)
as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.63 min; MS
m/z 316 (M-H).sup.-.
Step E: tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
##STR01074##
[1926] In a 500 mL round bottom flask,
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3
mmol), diphenylphosphoryl azide (9.78 mL, 45.3 mmol) and TEA (13.9
mL, 100 mmol) in t-BuOH (200 mL) were added to give an orange
suspension. The mixture was heated at about 70.degree. C. for about
16 h, cooled to ambient temperature and the insoluble material was
removed by filtration. The solvent was removed under reduced
pressure and the crude material was purified by silica gel column
chromatography eluting with 25-60% EtOAc in heptane to yield
tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g,
54%) as an off-white solid: LC/MS (Table 1, Method a) R.sub.t=2.79
min; MS m/z 389 (M+H).sup.+.
Step F: (R)-1-(benzyloxycarbonyl)piperidine-3-carboxylic acid
##STR01075##
[1928] A mixture of (R)-piperidine-3-carboxylic acid (3.0 g, 23
mmol), benzyl 2,5-dioxopyrrolidin-1-yl carbonate (5.79 g, 23.2
mmol) and Na.sub.2CO.sub.3 (6.15 g, 58.1 mmol) was stirred in water
and 1,4-dioxane (1:1, 200 mL) at ambient temperature for about 96
h. The organic solvent was removed under reduced pressure. The
aqueous layer was acidified with 1 N aqueous HCl and extracted with
EtOAc (2.times.100 mL). The organic phase was washed with brine
(150 mL), dried over anhydrous MgSO.sub.4 and coned under reduced
pressure to yield crude
(R)-1-(benzyloxycarbonyl)-piperidine-3-carboxylic acid (11.6 g,
191%) as a white solid: LC/MS (Table 1, Method a) R.sub.t=1.80 min;
MS m/z 264 (M+H).sup.+.
Step G:
(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide and
(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide
##STR01076##
[1930] Oxalyl chloride (8.41 mL, 96 mmol) was added to a solution
of (R)-1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (11.5 g,
43.7 mmol, Ex#3, step F) in DCM (120 mL) followed by a dropwise
addition of DMF (0.5 mL, 6.55 mmol). The resulting mixture was
stirred at ambient temperature for about 14 h. The solvent was
removed under reduced pressure to yield a crude acid chloride (Ex#3
G1) as a yellow semi-solid, which was dissolved in THF and MeCN
(1:1, 160 mL) and added to trimethylsilyldiazomethane (2 M in
Et.sub.2O, 78 mL, 155 mmol) in THF and MeCN (1:1, 160 mL) at about
0.degree. C. The reaction mixture was stirred at about 0.degree. C.
for about 2 h after the completion of the addition. The reaction
mixture was then quenched by a dropwise addition of HBr (48%
aqueous, 40 mL, 354 mmol). The organic solvents were removed under
reduced pressure and the residue dissolved in EtOAc (100 mL). The
organic phase was washed with saturated aqueous NaHCO.sub.3 (100
mL), and brine (25 mL), dried over anhydrous MgSO.sub.4, filtered,
and coned under reduced pressure. The residue was purified by
silica gel chromatography eluting with 5 to 45% EtOAc in heptane to
yield the crude benzyl 3-(2-bromoacetyl)piperidine-1-carboxylate
(Ex#3 G2) as a colorless oil. To a mixture of NaH (60% dispersion
in mineral oil, 0.55 g, 14 mmol) in DMF (20 mL) was added dropwise
a solution of tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (Ex#3 step F) (5.00
g, 12.9 mmol) in DMF (20 mL) at about 0.degree. C. The reaction
mixture was stirred at this temperature for about 30 min and was
then added dropwise to a solution of crude benzyl
3-(2-bromoacetyl)piperidine-1-carboxylate (Ex#3 G2) (5.26 g, 15.5
mmol) in DMF (40 mL) at about 0.degree. C. The mixture was stirred
for about 3 h while warming to ambient temperature. The solvent was
removed under reduced pressure and the residue partitioned between
saturated aqueous NH.sub.4Cl and EtOAc (70 mL each). The organic
phase was further washed with brine (60 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to yield
crude Boc-protected aminomethylketone (Ex#3 G3) as a yellow oil
that was used in the next step without further purification. The
oil was dissolved in HCl (4 N in 1,4-dioxane, 40 mL) and the
solution was stirred at ambient temperature for about 2 h. The
solvent was removed under reduced pressure and the residue
partitioned between saturated aqueous NaHCO.sub.3 and DCM (200 mL
each). The organic phase was washed with brine (150 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
yield crude aminomethylketone (Ex#3 G4) as a brown amorphous solid.
It was dissolved in 1,4-dioxane (100 mL) and Lawesson's reagent
(1.94 g, 4.80 mmol) was added. The reaction mixture was heated at
about 60.degree. C. for about 2 h. NaOH (2 N aqueous, 3 mL) was
added and heating was continued at about 90.degree. C. for about 4
h. The organic solvent was removed under reduced pressure and
saturated aqueous NH.sub.4Cl (120 mL) was added. The aqueous phase
was extracted with DCM (2.times.100 mL) and the combined organic
extracts were dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure. The crude material was purified by silica
gel column chromatography eluting with 0-10% MeOH in DCM to yield
crude imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (Ex#3 G5) as a yellow
amorphous solid. It was suspended in HBr (33% in AcOH, 10 mL). The
resulting mixture was stirred for about 10 min and then was diluted
with EtOAc (80 mL). The precipitate was collected by filtration and
exhaustively washed with EtOAc to yield
(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide and
(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide [er=80:20](2.61 g, 62.9% overall) as a yellow solid:
LC/MS (Table 1, Method a) R.sub.t=0.63 min; MS m/z 242 (M+H);
chiral analytical LC (Table 1, Method 29) R.sub.t=17.75 min, or
=negative and R.sub.t=20.33 min, or =positive.
Step H:
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl-
)(3,3-difluorocyclobutyl)methanone
##STR01077##
[1932] To a solution of
(R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide and
(S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine
hydrobromide [er=80:20](0.30 g, 0.93 mmol), DIEA (0.52 mL, 3.0
mmol) and 3,3-difluorocyclobutanecarboxylic acid (0.35 g, 3.1 mmol,
Waterstone) in DMF (4 mL) was added EDC.HCl (0.21 g, 1.1 mmol). The
reaction was stirred at about 25.degree. C. for about 4 h. The
reaction was partitioned with aqueous Na.sub.2CO.sub.3 (2 M, 25 mL)
and DCM (25 mL). The organic layer was separated, dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concd in vacuo. The
resulting residue was purified on silica gel (12 g) using 0-5% MeOH
in DCM followed by purification using General Procedure AA (Table
2, Method 23, R.sub.t=16.4 min, or =positive) to give
(R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-d-
ifluorocyclobutyl)-methanone (0.10 g, 30%): LC/MS (Table 1, Method
b) R.sub.t=1.85 min; MS m/z: 360 (M+H).sup.+.
Example #4*
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1--
yl)cyclopentyloxy)benzonitrile
##STR01078##
[1933] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01079##
[1935] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was concd under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01080##
[1937] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01081##
[1939] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01082##
[1941] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR01083##
[1943] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. and ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep the internal temperature below about 10.degree.
C. The resulting mixture was stirred at ambient temperature for
about 0.5 h to give a clear yellow solution, and methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, concd under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01084##
[1945] A 5 L round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL,
4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The
reaction was heated at reflux for about 6 h then cooled to ambient
temperature and added dropwise to NaHCO.sub.3 (8% aqueous, 3.5 L).
The resulting biphasic mixture was extracted with MTBE (2.times.1.5
L). The combined organic layers were washed with brine (1 L), dried
over anhydrous MgSO.sub.4 and concd under reduced pressure to give
191 g of crude material that was purified by vacuum distillation
(97-99.degree. C., 0.600 mm Hg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H NMR
(CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m,
1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
Step G: (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate
##STR01085##
[1947] A mixture of copper (I) chloride (0.136 g, 1.37 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.854 g, 1.37
mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was
stirred at ambient temperature for about 15 min then cooled to
about 5.degree. C. and polymethylhydrosiloxane (12 mL, 55 mmol) was
added. The reaction mixture was stirred for about 40 min at about
5.degree. C. then cooled to about -12.degree. C. A solution of
ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol)
and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one
portion and the reaction mixture was stirred for about 16 h at
about -12.degree. C. The reaction mixture was quenched by the
addition of MeOH (50 mL). The solvents were removed under reduced
pressure. The residue was dissolved in MeOH (35 mL) and filtered
through a pad of Celite.RTM.. The filtrate was concd under reduced
pressure and the residue was triturated with EtOAc (100 mL) and
filtered. The filtrate was concd under reduced pressure and the
residue was purified using silica gel chromatography (280 g)
eluting with a gradient of 0-10% EtOAc in heptane to give
(1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g,
22%): 1H NMR (CDCl.sub.3) .delta. 4.30 (m, 1H), 4.24-4.08 (m, 2H),
2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H),
2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94
(t, J=7.4 Hz, 3H).
Step H: (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid
##STR01086##
[1949] NaOH (1 N aqueous, 12 mL, 12 mmol) was added to
(1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g,
5.96 mmol). The reaction mixture was stirred at ambient temperature
for about 3 days and then extracted with Et.sub.2O (3.times.25 mL).
The Et.sub.2O extracts were discarded and the aqueous portion was
cooled to about 0.degree. C. HCl (5 N aqueous) was slowly added to
bring the pH to about 2. The resulting aqueous suspension was
extracted with EtOAc (3.times.40 mL). The combined organic layers
were washed with brine (2.times.80 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to give
(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g,
100%) as clear oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.36 (tdd,
J=2.6, 4.9, 7.4, 1H), 2.95 (td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7,
14.1, 1H), 2.16-1.94 (m, 3H), 1.65-1.49 (m, 1H), 1.49-1.32 (m, 2H),
0.96 (q, J=7.4, 3H).
Step I: (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one
##STR01087##
[1951] To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid
(0.943 g, 5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol)
and BOP-Cl (1.821 g, 7.15 mmol). The reaction mixture was stirred
at ambient temperature for about 2 h then poured into Et.sub.2O
(350 mL). The solid was removed by filtration while washing with
Et.sub.2O (50 mL). The filtrate was concd under reduced pressure to
give a yellow oil which was dissolved in DCM (5 mL) and Et.sub.2O
was added to give a solid. The supernatant was decanted and the
solid was washed with additional Et.sub.2O. The combined organic
extracts were concd under reduced pressure to give crude
(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about
15 mol % TEA (0.912 g, 99%): .sup.1H NMR (CDCl.sub.3) .delta. 4.85
(s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H),
1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Step J:
(1S,2R,4S)-2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin--
2-yl)cyclopentanecarbohydrazide
##STR01088##
[1953] To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835
g, 5.96 mmol) in 1,4-dioxane (12 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g,
5.96 mmol). The reaction mixture was heated at about 80.degree. C.
for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25
mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were
added sequentially. The reaction mixture was stirred at ambient
temperature for about 30 min then HCl (1 N aqueous, 50 mL) was
added dropwise and the reaction mixture was stirred for about 30
min. The layers were separated and the aqueous portion was
extracted with EtOAc (2.times.100 mL). The combined organic
extracts were washed with water (10 mL), saturated aqueous
NaHCO.sub.3 (15 mL), brine (15 mL) and dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The residue
was purified using silica gel chromatography (40 g) eluting with
100% EtOAc to give
(1S,2R,4S)-2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-
-2-yl)cyclopentanecarbohydrazide (1.887 g, 71%): LC/MS (Table 1,
Method b) R.sub.t=2.05 min; MS m/z: 444 (M+H).sup.+.
Step K:
(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b-
]pyrazin-2-yl)cyclopentanecarbohydrazide
##STR01089##
[1955] To
(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-
-2-yl)cyclopentanecarbo-hydrazide (0.885 g, 1.99 mmol) in THF (15
mL) was added 4-hydroxybenzonitrile (0.357 g, 2.99 mmol),
triphenylphosphine (0.998 g, 2.99 mmol, polymer bound, 3 mmol/g),
and TEA (1.3 mL, 9 mmol). DEAD (0.47 mL, 2.99 mmol) was added
dropwise. The reaction mixture was stirred for about 1 h then
additional triphenylphosphine (0.50 g, 1.5 mmol, polymer bound, 3
mmol/g) and DEAD (0.2 mL, 1.3 mmol) were added and the reaction
mixture was stirred at ambient temperature for about 16 h. The
solid was removed by filtration while washing with DCM (5.times.5
mL) then MeOH (4.times.5 mL). The filtrate was coned under reduced
pressure and the residue was purified using silica gel
chromatography (40 g) eluting with a gradient of 0-40% EtOAc in DCM
to give
(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazi-
n-2-yl)cyclopentanecarbohydrazide (0.958 g, 88%) as a yellow foam:
LC/MS (Table 1, Method b) R.sub.t=2.56 min; MS m/z: 545
(M+H).sup.+.
Step L:
4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile
##STR01090##
[1957] To
(1S,2R,4R)-4-(4-cyanophenoxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3--
b]pyrazin-2-yl)cyclopentanecarbohydrazide (0.958 g, 1.76 mmol) in
1,4-dioxane (18 mL) was added DIEA (1.2 mL, 7.0 mmol) and thionyl
chloride (0.4 mL, 5.3 mmol). The reaction mixture was heated at
about 80.degree. C. for about 2 h. The solvent was removed under
reduced pressure and the residue was purified using silica gel
chromatography (80 g) eluting with a gradient of 20-80% EtOAc in
DCM to give
4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyloxy)benzonitrile (0.620 g, 67%): LC/MS
(Table 1, Method b) R.sub.t=2.65 min; MS m/z: 527 (M+H).sup.+.
Step M:
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyloxy)benzonitrile
##STR01091##
[1959] To
4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazol-
o[4,3-a]pyrazin-1-yl)cyclo-pentyloxy)benzonitrile (0.826 g, 1.57
mmol) in 1,4-dioxane (16 mL) was added Na.sub.2CO.sub.3 (2 N
aqueous solution, 16 mL, 31 mmol). The reaction mixture was heated
at about 80.degree. C. for about 16 h. The layers were separated
and the aqueous portion was extracted with EtOAc (3.times.40 mL).
The combined organic layers were washed with saturated aqueous
NaHCO.sub.3 (2.times.30 mL), brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and coned under reduced pressure. The residue
was purified by using General Procedure AA (Table 2, Method 17,
R.sub.t=19.2 min, or =negative) to give
4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyloxy)benzonitrile (0.298 g, 51%): LC/MS (Table 1,
Method b) R.sub.t=2.07 min; MS m/z: 373 (M+H).sup.+.
Example #5*
N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperi-
din-1-yl)(pyrrolidin-1-yl)methylene)cyanamide
##STR01092##
[1960] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01093##
[1962] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01094##
[1964] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine
hydrochloride
##STR01095##
[1966] A 5 L reactor was charged with
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (98.8 g, 281 mmol), zinc
dust (3.50 g, 53.3 mmol), palladium(II) trifluoroacetate (4.0 g, 12
mmol), and racemic-2-(di-t-butylphosphino)-1,1'-binapthyl (9.8 g,
24.7 mmol). The flask was equipped with a powder addition device
into which zinc cyanide (10.0 g, 157 mmol) was placed to be added
at a later step. The vessel was purged with argon for no longer
than about 30 min and then argon sparged DMA (2 L) was added to the
reactor. The mixture was stirred and heated to about 50.degree. C.
while maintaining an argon atmosphere. The resulting dark brown
solution was further heated to about 95.degree. C. while adding the
zinc cyanide, from the powder addition device, portionwise over
about 15 min. Upon reaching about 95.degree. C., the brown mixture
was stirred for about an additional 16 h. The reaction mixture was
cooled to ambient temperature, resulting in the precipitation of
salts. The mixture was filtered through a Buchner funnel containing
filter-aid and the filter cake was washed with DMA (20 mL). A
solution of the crude product in DMA was added to cold
(<10.degree. C.) water (16 L) and stirred for about 30 min. The
resulting suspension was filtered and the filter cake was rinsed
again with water (1 L). The resulting wet cake was dried in a
vacuum oven at about 50.degree. C. The crude solid was dissolved in
DCM (1.5 L) and further dried over anhydrous MgSO.sub.4. After
filtration, the solution was passed through a pad of silica (140
g), using DCM as the eluent until only predominantly impurities
were detected eluting off the pad. The solvent was removed under
reduced pressure and the crude solid was triturated with MeOH/DCM
(4:1, 10 volumes of solvent per gram of crude solid) at ambient
temperature for about 5 h. The solid was filtered and washed with
MeOH (300 mL). The product was dried in a vacuum oven to provide
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as a
white solid: .sup.1H NMR (CDCl.sub.3) 8.67 (s, 1H), 8.21 (d, J=4.2
Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d,
J=4.2 Hz, 1H), 2.42 (s, 3H). A 2-L 316-stainless steel pressure
reactor was charged with 5 wt % Pd/C (15.4 g of 63.6 wt % water wet
material, 5.6 g dry basis, 2.6 mmol Johnson Matthey A503032-5),
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol),
THF (1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL,
369 mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,
pressurized, and maintained at 40 psi with hydrogen supplied from a
high pressure reservoir. The mixture was vigorously agitated at
about 25.degree. C. After about 5 h the reactor was vented and
purged with nitrogen to remove most of the dissolved hydrogen, and
the reaction mixture was filtered to remove the catalyst. The
reactor and catalyst cake were rinsed with THF: water (1:1,
2.times.40 mL). The combined filtrate and rinses were concd and
EtOH (500 mL) was added then removed under reduced pressure. After
two further azeotropes using EtOH (2.times.500 mL), the crude
residue was concd under reduced pressure to give a residue (76 g)
that was suspended in EtOH (550 mL) and stirred at ambient
temperature for about 4 h. The solid was collected by filtration
and washed with cold EtOH (50 mL). The wet cake was dried in a
vacuum oven to provide
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(51.2 g, 82%) as a white solid: LC/MS (Table 1, Method a)
R.sub.t=1.44 min; MS m/z: 303 (M+H).sup.+.
Step D: 4-methylpiperidine-3-carboxylic acid hydrochloride
##STR01096##
[1968] AcOH (380 mL) was added to 4-methylnicotinic acid
hydrochloride (50.5 g, 291 mmol, Maybridge) and PtO.sub.2 (5.05 g,
22.2 mmol, Johnson Matthey) in a 600 mL stainless steel reactor.
The mixture was stirred under 220 psi of hydrogen at ambient
temperature for about 14 hr. The supernatant solution was filtered
through a nylon membrane and rinsed with enough AcOH until only the
catalyst remained. The filtrate was concd under reduced pressure to
give a clear oil that solidified upon cooling to ambient
temperature to give crude 4-methylpiperidine-3-carboxylic acid with
AcOH as an excipient (88.94 g, 170% crude): LC/MS (Table 1, Method
b) Rt=0.44 min; MS m/z: 144 (M+H).sup.+.
Step E: (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate
(2S,3S)-2,3-dihydroxysuccinate
##STR01097##
[1970] Crude racemic 4-methylpiperidine-3-carboxylic acid
hydrochloride (.about.70% chemical purity, approximately 15:1
cis:trans) in AcOH (2:1, 300 g) was dissolved in EtOH (1500 mL) and
sparged with HCl (gas) for about 15 min. The reaction mixture was
fitted with a balloon to allow for expansion then heated to about
85.degree. C. After about 48 h, the reaction mixture was cooled to
ambient temperature and concd in vacuo to provide a thick syrup
containing racemic ethyl 4-methylpiperidine-3-carboxylic acid
hydrochloride (260 g). To this ester was added CHCl.sub.3 (1000 mL)
followed by saturated aqueous NaHCO.sub.3 (500 mL) and NH.sub.4OH
(15% aqueous, 500 mL). The organic layer was separated and the
aqueous layer was further extracted with CHCl.sub.3 (1000 mL). The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and then concd in vacuo to provide crude ethyl
4-methylpiperidine-3-carboxylate (200 g) as an oil. To a slurry of
(2S,3S)-2,3-dihydroxysuccinic acid (150 g, 1001 mmol) in MeOH (200
mL) was added a solution of crude ethyl
4-methylpiperidine-3-carboxylate (200 g, 1168 mmol) in EtOAc (3000
mL). The mixture was stirred rapidly for about 3 h and the
resulting solids were collected by filtration to provide the
(2S,3S)-2,3-dihydroxysuccinate salt as a white solid (245 g)
(approximately 15:1 cis:trans, er=48:52 for cis stereoisomers). The
solids were dissolved in MeOH (1000 mL) and EtOAc (3000 mL) was
slowly added until solids began to form. After about 30 min, the
solids were collected by filtration and partially dried in vacuo to
provide a stereo-enriched mixture containing (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate as
a white solid (145 g) (approximately 15:1 cis:trans, er=60:40 for
(3R,4R):(3S,4S) enantiomers). The above solids were dissolved in
MeOH (1000 mL) and divided into four lots. Each lot (250 mL) was
diluted with MeOH (500 mL) and EtOAc (3000 mL) was slowly added to
the solution until solids formed. After about 4-15 h, the solids
were collected by filtration and dried in vacuo to provide multiple
lots of partially resolved (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate,
these were combined and dissolved in MeOH (1000 mL) and EtOAc (4000
mL) was slowly added. After stirring for about 1 h the solids were
collected by filtration to provide (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate
(4.5 g) (approximately 15:1 cis:trans, er=98:2 for (3R,4R):(3S,4S)
enantiomers), chiral analytical LC (Table 2, Method 30) minor
isomer R.sub.t=12.2 min; MS m/z: 343
(M+(2S,3S)-2,3-dihydroxysuccinate+Na); major isomer R.sub.t=10.6
min; MS m/z: 343 (M+(2S,3S)-2,3-dihydroxysuccinate+Na).sup.+
Step F:
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid
##STR01098##
[1972] To a flask charged with (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate
(36.9 g, 115 mmol) was added a solution of HCl (6 N aqueous, 191
mL). The reaction mixture was heated to about 60.degree. C. After
about 2 h, the reaction mixture was heated to about 90.degree. C.
After about 4 h the reaction mixture was cooled to ambient
temperature and concd in vacuo. To the residue was added
NaHCO.sub.3 (122 g, 1148 mmol) and di-tert-butyl dicarbonate (37.6
g, 172 mmol) followed by a mixture of 1,4-dioxane (500 mL) and
water (500 mL). After about 2 h, Et.sub.2O (500 mL) and water (500
mL) were added to the reaction mixture. The pH was adjusted to
about 4 with 1 N aqueous HCl. The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concd in vacuo
to provide a white solid. The solid was slurried in heptane and
filtered to provide
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid (25 g, 89%) as a white solid: LC/MS (Table 1, Method b)
R.sub.t=1.90 min; MS m/z: 244 (M+H).sup.+.
Step G: (3R,4R)-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperi-
dine-1-carboxylate
##STR01099##
[1974] To a slurry of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(34.0 g, 100 mmol, Example #5, Step C),
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700
mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at
ambient temperature for about 45 min. The reaction was washed with
saturated aqueous NaHCO.sub.3 (300 mL). The organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, filtered then
concd in vacuo. The resulting residue was purified by
chromatography on silica gel (330 g) using 33-100% EtOAc in heptane
to give
(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)met-
hylcarbamoyl)piperidine-1-carboxylate (53 g, 100%) as a pale-yellow
foam: LC/MS (Table 1, Method b) R.sub.t=2.40 min; MS m/z: 528
(M+H).sup.+. Step H: (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate
##STR01100##
[1975] A mixture of
(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)met-
hyl-carbamoyl)-piperidine-1-carboxylate (53 g, 100 mmol) and
Lawesson's reagent (22.4 g, 55.2 mmol) in 1,4-dioxane (500 mL) was
heated at about 80.degree. C. for about 1 h. The reaction was
allowed to cool to ambient temperature and then was partitioned
between EtOAc (1000 mL) and saturated aqueous NaHCO.sub.3 (700 mL).
The organic layer was washed with additional saturated aqueous
NaHCO.sub.3 (700 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered then concd in vacuo. The resulting residue was dissolved
in 1,4-dioxane (500 mL) then mercury (II) trifluoroacetate (54.0 g,
127 mmol) was added. The reaction was stirred at about 25.degree.
C. for about 1 h. The reaction was partitioned with saturated
aqueous Na.sub.2S.sub.2O.sub.3 (500 mL)/water (500 mL) with DCM
(1000 mL). The layers were filtered through Celite.RTM. and the
Celite.RTM. pad was washed with DCM (500 mL). The combined layers
were separated then the organic layer was washed with saturated
aqueous NaHCO.sub.3 (800 mL). The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and then concd in
vacuo. The resulting residue was purified on silica gel (330 g)
using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate (40.5 g, 79%) as a yellow foam: LC/MS (Table 1,
Method b) R.sub.t=2.62 min; MS m/z: 510 (M+H).sup.+.
Step I:
(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-
-4-methylpiperidine-1-carboxylate
##STR01101##
[1977] To a solution of (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate (40 g, 78 mmol) in 1,4-dioxane (160 mL) was added
NaOH (1 N aqueous, 157 mL). The mixture was heated at about
60.degree. C. for about 1 h. The mixture was allowed to cool to
ambient temperature. The mixture was partitioned with HCl (4 N
aqueous, 50 mL) and extracted with DCM (2.times.300 mL). The
combined organic extracts were washed with brine (400 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered then concd in vacuo. The
product was purified on silica gel (330 g) using 1-5% MeOH in DCM
to give (3R,4R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (30 g, 99%): LC/MS (Table 1, Method b) R.sub.t=2.00 min; MS
m/z: 356 (M+H).sup.+.
Step J:
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]-
pyrazine hydrochloride
##STR01102##
[1979] To a solution of (3R,4R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (27.9 g, 78 mmol) in 1,4-dioxane (400 mL) was added HCl (4
N in 1,4-dioxane, 58.9 mL, 235 mmol). The resulting suspension was
heated at about 60.degree. C. for about 1 h. The reaction was
allowed to cool to ambient temperature and then was filtered,
washed with 1,4-dioxane (100 mL) followed by Et.sub.2O (100 mL), to
give
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (20.6 g, 89%) as a tan solid: LC/MS (Table 1,
Method b) R.sub.t=1.27 min; MS m/z: 256 (M+H).sup.+.
Step K:
N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-meth-
ylpiperidin-1-yl)(pyrrolidin-1-yl)methylene)cyanamide
##STR01103##
[1981] To a solution of diphenyl cyanocarbonimidate (0.163 g, 0.685
mmol) and DIEA (0.239 mL, 1.371 mmol) in MeCN (5 mL) was added
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (0.20 g, 0.68 mmol). The reaction was heated at
about 80.degree. C. for about 2 h. The reaction mixture was concd
in vacuo. The residue was dissolved in pyrrolidine (1.0 mL, 12
mmol) and transferred to a sealed microwave vessel. The reaction
was heated at about 120.degree. C. for about 30 min in a CEM
microwave. The reaction mixture was concd in vacuo and purified by
RP-HPLC (Table 1, Method i) to give
N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiper-
idin-1-yl)(pyrrolidin-1-yl)-methylene)cyanamide (0.030 g, 11%):
LC/MS (Table 1, Method b) R.sub.t=1.62 min; m/z: 377
(M+H).sup.+
Example #6*
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-di-
fluoropiperidin-1-yl)methanone
##STR01104##
[1982] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01105##
[1984] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+. Step B:
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01106##
[1985] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine
hydrochloride
##STR01107##
[1987] A 5 L reactor was charged with
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (98.8 g, 281 mmol), zinc
dust (3.50 g, 53.3 mmol), palladium(II) trifluoroacetate (4.0 g, 12
mmol), and racemic-2-(di-t-butylphosphino)-1,1'-binapthyl (9.8 g,
24.7 mmol). The flask was equipped with a powder addition device
into which zinc cyanide (10.0 g, 157 mmol) was placed to be added
later. The vessel was purged with argon for no longer than about 30
min and then argon sparged DMA (2 L) was added to the reactor. The
mixture was stirred and heated to about 50.degree. C. while
maintaining an argon atmosphere. The resulting dark brown solution
was further heated to about 95.degree. C. while adding the zinc
cyanide, from the powder addition device, portionwise over about 15
min. Upon reaching about 95.degree. C., the brown mixture was
stirred for about an additional 16 h. The reaction mixture was
cooled to ambient temperature, resulting in the precipitation of
salts. The mixture was filtered through a Buchner funnel containing
filter-aid and the filter cake was washed with DMA (20 mL). A
solution of the crude product in DMA was added to cold
(<10.degree. C.) water (16 L) and stirred for about 30 min. The
resulting suspension was filtered and the filter cake was rinsed
again with water (1 L). The resulting wet cake was dried in a
vacuum oven at about 50.degree. C. The crude solid was dissolved in
DCM (1.5 L) and further dried over anhydrous MgSO.sub.4. After
filtration, the solution was passed through a pad of silica (140
g), washing with additional solvent until only predominantly
impurities were detected eluting off the pad. The solvent was
removed under reduced pressure and the crude solid was triturated
with MeOH/DCM (4:1, 10 volumes of solvent per gram of crude solid)
at ambient temperature for about 5 h. The solid was filtered and
washed with MeOH (300 mL). The product was dried in a vacuum oven
to provide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8
g, 70%) as a white solid: .sup.1H NMR (CDCl.sub.3) 8.67 (s, 1H),
8.21 (d, J=4.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz,
2H), 6.89 (d, J=4.2 Hz, 1H), 2.42 (s, 3H). A 2-L 316-stainless
steel pressure reactor was charged with 5 wt % Pd/C (15.4 g of 63.6
wt % water wet material, 5.6 g dry basis, 2.6 mmol, Johnson Matthey
A503032-5), 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g,
184 mmol), THF (1.1 L), deionized water (165 mL), HCl (37 wt %
aqueous, 30 mL, 369 mmol) and quinoline (1.1 mL, 9.0 mmol). The
vessel was purged, pressurized, and maintained at 40 psi with
hydrogen supplied from a high pressure reservoir. The mixture was
vigorously agitated at about 25.degree. C. After about 5 h the
reactor was vented and purged with nitrogen to remove most of the
dissolved hydrogen, and the reaction mixture was filtered to remove
the catalyst. The reactor and catalyst cake were rinsed with
THF:water (1:1, 2.times.40 mL). The combined filtrate and rinses
were concd and EtOH (500 mL) was added. After two additional
solvent switches with EtOH (2.times.500 mL), the crude residue was
concd under reduced pressure to give a residue (76 g) that was
suspended in EtOH (550 mL) and stirred at ambient temperature for
about 4 h. The solid was collected by filtration and washed with
cold EtOH (50 mL). The wet cake was dried in a vacuum oven to
provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine
hydrochloride (51.2 g, 82%) as a white solid: LC/MS (Table 1,
Method a) R.sub.t=1.44 min; MS m/z: 303 (M+H).sup.+.
Step D: (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-c-
arboxylate
##STR01108##
[1989] To a solution of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (5
g, 14.7 mmol) in DCM (78 mL) was added DIEA (7.7 mL, 44.3 mmol) and
stirred at ambient temperature for about 10 min followed by the
addition of (R)--N-Boc-piperidine-3-carboxylic acid (3.38 g, 14.7
mmol, CNH-Technologies) and HATU (5.61 g, 14.7 mmol). The mixture
was stirred for about 1 h at ambient temperature and to it was
added water (30 mL) and the layers were separated. The organic
layer was washed with saturated aqueous NaHCO.sub.3 (30 mL) and
brine (30 mL), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure. The crude material was purified by silica
gel chromatography eluting with a gradient of 0-5% MeOH in DCM to
afford crude (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-ca-
rboxylate (7.58 g, 94%): LC/MS (Table 1, Method b) R.sub.t=2.30
min; MS m/z: 514 (M+H).sup.+.
Step E: (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-
-1-carboxylate
##STR01109##
[1991] To a solution of (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-c-
arboxylate (7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added
Lawesson's reagent (3.37 g, 8.32 mmol) and the reaction mixture was
heated to about 60.degree. C. for about 2 h then cooled to ambient
temperature and concd under reduced pressure. The crude residue was
dissolved with EtOAc (40 mL) and washed with saturated aqueous
NaHCO.sub.3, (3.times.40 mL), brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine--
1-carboxylate (5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method
b) R.sub.t=2.60 min; MS m/z: 530 (M+H).sup.+.
Step F: (R)-tert-butyl
3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbo-
xylate
##STR01110##
[1993] To a solution of (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-
-1-carboxylate (5.61 g, 10.3 mmol) in 1,4-dioxane (96 mL) was added
mercury (II) trifluoroacetate (4.38 g, 10.3 mmol) and the reaction
mixture was stirred at ambient temperature for about 2 h then
filtered through a pad of Celite.RTM.. The Celite.RTM. pad was
rinsed with EtOAc (50 mL) and the filtrate was concd under reduced
pressure. The crude residue was dissolved in EtOAc (40 mL) and the
organic phase was washed with saturated aqueous NaHCO.sub.3
(2.times.40 mL), brine (30 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
0-5% MeOH in DCM to afford (R)-tert-butyl 3-(6-tosyl-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (4.4 g,
87%): LC/MS (Table 1, Method b) R.sub.t=2.49 min; MS m/z: 496
(M+H).sup.+.
Step G: (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
##STR01111##
[1995] To a solution of (R)-tert-butyl
3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbo-
xylate (4.44 g, 8.96 mmol) in 1,4-dioxane (54 mL) was added NaOH (2
N aqueous, 8.9 mL, 18 mmol), and the resulting mixture was heated
at about 60.degree. C. for about 3 h. The reaction was cooled to
ambient temperature and EtOAc (30 mL) and saturated aqueous
NH.sub.4Cl (20 mL) were added. The organic layer was separated and
the aqueous layer was further extracted with EtOAc (40 mL). The
combined organic layers were washed with brine (40 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The material was purified by silica gel chromatography eluting with
a gradient of 0-10% MeOH in DCM to afford (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
(2.80 g, 92%): LC/MS (Table 1, Method b) R.sub.t=1.85 min; MS m/z:
342 (M+H).sup.+.
Step H:
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride
##STR01112##
[1997] A round bottom flask was charged with (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
(2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in
1,4-dioxane, 6.2 mL, 24.6 mmol). The reaction mixture was heated at
about 60.degree. C. for about 18 h. The reaction mixture was cooled
to ambient temperature, Et.sub.2O (40 mL) was added and the mixture
was stirred for about 15 min. The solid was collected by vacuum
filtration and washed with Et.sub.2O (50 mL) then dried in a vacuum
oven at about 60.degree. C. to afford
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride as an off-white solid (2.4 g, 94%): LC/MS (Table 1,
Method b) R.sub.t=0.81 min; MS m/z 242 (M+H).sup.+.
Step I:
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl-
)(4,4-difluoropiperidin-1-yl)methanone
##STR01113##
[1999] To a solution of
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (0.24 g, 0.76 mmol) in pyridine (7.2 mL) was added
CDI (0.14 g, 0.87 mmol) and the reaction mixture was stirred at
about 50.degree. C. for about 2 h. Additional CDI (0.02 g, 0.14
mmol) was added and the reaction mixture was stirred for about 1 h.
To the reaction mixture was added 4,4-difluoropiperidine
hydrochloride (0.12 g, 0.76 mmol). The reaction mixture was heated
to about 55.degree. C. for about 1 h, cooled to ambient
temperature, and stirred for about 2 d. The solvent was removed
under reduced pressure and the crude residue dissolved with DCM (5
mL) and washed with water (2 mL). The aqueous layer was back
extracted with DCM (2 mL). The combined organic extracts were
washed with brine (3 mL), dried over anhydrous MgSO.sub.4,
filtered, and coned under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
0-5% MeOH in DCM to afford
(R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-d-
ifluoropiperidin-1-ylmethanone (0.146 g, 49%) as an off white
solid: LC/MS (Table 1, Method b) R.sub.t=1.70 min; MS m/z: 389
(M+H).sup.+.
Example #7
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentyl)-3,3,3-trifluoropropane-1-sulfonamide
##STR01114##
[2000] Step A:
5-Bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01115##
[2002] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01116##
[2004] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-Butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
##STR01117##
[2006] 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl carbamate (14.9 g, 128 mmol), 325 mesh potassium
carbonate (35.3 g, 256 mmol), palladium acetate (0.19 g, 0.85 mmol)
and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos)
(0.99 g, 1.70 mmol) were charged to a three-neck, 1 L cylindrical
reactor equipped with an over head stirrer, thermocouple and a
reflux condenser. The solids were purged with argon for not less
than 120 min. 2-methyl-butanol (240 mL) and 1,4-dioxane (60 mL)
were charged to a separate 500 mL round bottom flask and purged
with argon for not less than 60 min. The solvent mixture was
transferred to the 1 L flask using a cannula under a positive
pressure of argon, the temperature was raised to about 95.degree.
C. and the reaction mixture was stirred for about 3 h under a
positive pressure of argon. The reaction mixture was cooled to
about 40.degree. C., THF (100 mL) was added and filtered through a
2 inch pad of celite. The reaction mixture was split into 2 equal
batches (about 200 mL) and each of the batches were purified
separately. Each batch was diluted with THF (250 mL) and was
transferred to a 1 L cylindrical flask equipped with a magnetic
stir bar. A solution of L-cysteine (0.76 g), potassium bicarbonate
(1.52 g) and sodium chloride (0.76 g) in water (250 mL) was added
to the above flask and was allowed to stir for about 2-4 h. The
aqueous layer was separated. Formation of a rag layer was observed
that was kept with the organic layer. The organic layer was washed
with saturated sodium chloride solution (100 mL) and the aqueous
layer was separated. Charcoal (0.76 g) was added to the flask,
stirred for about 2-4 h, filtered through a 2 inch pad of celite,
rinsed with THF (30 mL) and concentrated in vacuo at about
60.degree. C. to obtain an oil/solid slurry. A mixture of
isopropanol (50 mL) and heptanes (15 mL) were added to the
oil/solid slurry and concentrated in vacuo to obtain light yellow
colored solid. Isopropanol (90 mL) was added to the solid, heated
to about 60.degree. C. and mixed for about 1 h. The mixture was
allowed to cool to room temperature with stirring, solids were
filtered off, rinsed with heptane (40 mL) and dried overnight in a
vacuum oven at about 50.degree. C. The 2 batches were combined to
obtain tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
(12.87 g), as a light yellow colored solid. .sup.1H NMR (400 MHz,
DMSO) .delta. 10.11 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=4.1 Hz, 1H),
7.99-7.92 (m, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.83 (d, J=4.1 Hz, 1H),
2.32 (s, 3H), 1.46 (s, 9H).
Step D: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine
##STR01118##
[2008] tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
(14.0 g, 36.0 mmol) and tetrahydrofuran (28 mL) were charged to a
500 mL round bottom flask containing a magnetic stir bar.
Phosphoric acid (10 equiv, 85%, 20.8 ml, 360 mmol) was added over
about 5 minutes via needle and syringe. Upon addition, effervescing
occurred and solids formed. The resultant slurry was heated to
about 65.degree. C. (bath temperature); upon reaching temperature
all solids dissolved. After about 1 hr, there was no starting
material present. The hot reaction mixture was diluted with
tetrahydrofuran (115 mL); then the solution was allowed to cool to
room temperature. A solution of potassium phosphate tribasic (35.3
g, 360 mmol) in water (145 mL) was prepared and added to the
mixture over about 20 minutes with vigorous stirring. The biphasic
mixture was transferred to a separatory funnel using THF and water.
The layers were separated and the organic layer was transferred to
a 500 mL round bottom flask. Water (100 mL) was added to the flask
and the organics are removed under reduced pressure. This resulted
in a suspension of solids in water, which was allowed to slurry for
about 30 minutes. The solids were isolated by vacuum filtration and
placed in a vacuum oven to dry (oven temperature about 50.degree.
C.) for about 16 hours. 5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine
was isolated as an off white solid (10.1 g, 97%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 7.88-7.84 (m, 3H), 7.64 (s, 1H), 7.39
(d, J=8.4, 2H), 6.55 (d, J=4.0, 1H), 6.31 (s, 2H), 2.33 (s, 3H)
Step E: Sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
##STR01119##
[2010] In a 12 L round bottom flask, NaH (60% dispersion in mineral
oil, 159 g, 3985 mmol) was added in portions to stirred anhydrous
THF (4004 mL) to give a gray suspension. The mixture was cooled to
about 5.degree. C. in an ice/salt bath before ethyl acetoacetate
(506 mL, 3985 mmol, Alfa Aesar) in anhydrous THF (200 mL) was added
dropwise via an addition funnel over about 1 h during which time
the temperature gradually increased to about 18.degree. C. After
the addition was complete, the reaction was stirred at ambient
temperature for about 1 h and then a solution of methyl
4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF
(200 mL) was added dropwise via an addition funnel over about 1 h.
The resulting mixture was stirred at ambient temperature for about
2 h and then heated at about 50.degree. C. for about 16 h. The
reaction mixture was coned in vacuo. The orange solid was cooled to
about 5.degree. C. and an ice/water mixture (2 L) was added. The
suspension was mixed by rotating on the rotovap without vacuum for
about 30 min. The solid was collected by filtration and washed with
ice-cold water (750 mL). Once most of the solvent (about 90%) had
been removed, the wet solid was triturated with MeCN (750 mL),
stirred for about 30 min and then the solid was collected by
filtration while washing with Et.sub.2O (2.times.500 mL). The solid
was dried in air for about 16 h and then in vacuo at about
55.degree. C. to give sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 98%): .sup.1H NMR (DMSO-d.sub.6) .delta. 3.95 (q, J=7.1 Hz,
2H), 3.48 (s, 3H), 2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H),
1.15 (t, J=7.1 Hz, 3H).
Step F: Ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate
##STR01120##
[2012] In a 5 L round bottom flask, sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392
mL, 6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL)
were heated at reflux for about 6 h. The reaction mixture was
allowed to cool to ambient temperature for about 16 h. The reaction
mixture was then poured into a 12 L flask and diluted with water (3
L). Solid NaHCO.sub.3 (450 g, 5.3 mol) was added cautiously
portionwise with stirring over about 1 h. After an additional about
30 min of stirring, the basic aqueous phase was separated and
further extracted with Et.sub.2O (4.times.400 mL). The combined
organic layers were washed with water (4.times.500 mL) and
saturated brine (500 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure to yield a yellow oil
that was purified by vacuum distillation (about 92-94.degree. C. at
about 0.4 mmHg) to give ethyl
2-methyl-4-oxocyclopent-2-enecarboxylate (229 g, 69%) as a yellow
oil: .sup.1H NMR (CDCl.sub.3) .delta. 6.04-6.01 (m, 1H), 4.26-4.17
(m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s, 3H),
1.32-1.27 (t, J=7.1 Hz, 3H).
Step G: Ethyl 2-methyl-4-oxocyclopentanecarboxylate
##STR01121##
[2014] EtOAc (580 mL) was added to a round bottom flask charged
with 10 wt % Pd/C (7.6 g, 7.1 mmol) at about 0.degree. C., under a
nitrogen atmosphere. The cooling bath was removed and ethyl
2-methyl-4-oxocyclopent-2-enecarboxylate (60.0 g, 357 mmol) was
added. Hydrogen gas was bubbled through the mixture for about 5 min
and the mixture was then stirred under a hydrogen atmosphere (1
atmosphere) for about 48 h. The hydrogen source was removed and the
mixture was bubbled with nitrogen for about 5 min and was filtered
through a pad of Celite.RTM.. The filter cake was rinsed with EtOAc
(500 mL). The filtrate was concd under reduced pressure to give
ethyl 2-methyl-4-oxocyclopentanecarboxylate (59.9 g, 99%) as a
yellow liquid: .sup.1H NMR (CDCl.sub.3) .delta. 4.23-4.14 (m, 2H),
3.18 (ddd, J=5.6, 6.8, 8.1 Hz, 1H), 2.73-2.65 (m, 1H), 2.60 (ddd,
J=1.7, 5.5, 18.7 Hz, 1H), 2.42-2.29 (m, 2H), 2.15 (ddd, J=1.7, 7.9,
18.3 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H).
Step H: Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
##STR01122##
[2016] A round bottom flask was charged with ethyl
2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE
(180 mL). The solution was cooled to about 0.degree. C. and AcOH
(5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were
added dropwise, resulting in formation of a thick suspension. The
reaction mixture was warmed to about 10.degree. C. and sodium
triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise and
the reaction mixture was stirred at ambient temperature for about
20 h. The reaction mixture was slowly poured into stirred saturated
aqueous NaHCO.sub.3 (300 mL) and was stirred for about 20 min. The
layers were separated and the aqueous phase was extracted with DCM
(3.times.100 mL). The combined organic extracts were washed with
brine (2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4, and
concd under reduced pressure. The crude yellow oil was purified via
flash column chromatography eluting with a gradient of 0-30% EtOAc
in heptane to give ethyl
4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as
a colorless oil: .sup.1H NMR (pyridine-d.sub.5) .delta. 7.53 (dd,
J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06
(m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H),
3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m,
1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5
Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Step I: 4-(Dibenzylamino)-2-methylcyclopentanecarboxylic acid
##STR01123##
[2018] Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
(3.65 g, 10.38 mmol) was dissolved in a mixture of HCl (6 N
aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture
was heated at about 60.degree. C. for about 72 h. The organic
solvent was removed under reduced pressure. The aqueous phase was
neutralized by the addition of saturated aqueous NaHCO.sub.3 (40
mL) and extracted with EtOAc (50 mL). The organic phase was washed
with brine (40 mL), dried over anhydrous MgSO.sub.4 and coned under
reduced pressure to yield
4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%)
as a white amorphous solid: LC/MS (Table 1, Method a) R.sub.t=1.66
min; MS m/z 324 (M+H).sup.+.
Step J:
2-(2-Methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-ox-
o-ethylide
##STR01124##
[2020] Trimethylsulfoxonium chloride (26.1 g, 198 mmol), THF (202
ml), and potassium tert-butoxide (23.35 g, 202 mmol) were added to
a 500 mL jacketed flask under a nitrogen blanket. The suspension
was stirred for about 2 hours at about 65.degree. C. before being
cooled to about 0.degree. C. In a separate flask,
(1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
(21.4 g, 66.2 mmol) was dissolved in THF (134 ml). HATU (31.4 g, 83
mmol) and triethylamine (11.53 ml, 83 mmol) were added and the
solution and mixed for about 4 h. With the sulfur ylide suspension
maintained between about 0 and -5.degree. C., the activated ester
solution was filtered and then added dropwise over about 3 h to the
ylide suspension. The resultant bright yellow suspension was
stirred for about 8 h at about 5.degree. C. Water (340 mL) and THF
(30 mL) were added, and the mixture stirred for about 30 min at
about 25.degree. C. Aqueous sodium chloride (15% w/v, 60 mL) was
added to the solution and the layers separated. The aqueous layer
was extracted with EtOAc (60 mL). The combined organic layers were
washed with aqueous NaCl (15% w/v, 3.times.100 mL). The solution
was concentrated and the crude oil was dissolved in methanol (150
mL) and water (150 mL) was added to the slurry which is stirred for
about 1 h at ambient temperature before being cooled to about
10.degree. C. and stirred overnight. The white solid was filtered
and washed with chilled 1:1 MeOH/H2O (20 mL) and water (60 mL). The
solid was dried in the vacuum oven to afford
2-(2-methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-oxo-ethyl-
ide (23.8 g, 90% yield). .sup.1H NMR (400 MHz, DMSO) .delta. 7.30
(ddd, J=15.0, 10.7, 4.6 Hz, 8H), 7.21-7.14 (m, 2H), 4.67 (s, 1H),
3.71-3.52 (m, 4H), 3.39 (d, J=3.9 Hz, 6H), 3.13-2.99 (m, 1H),
2.48-2.39 (m, 1H), 2.05-1.84 (m, 2H), 1.82-1.66 (m, 2H), 1.43-1.30
(m, 1H), 0.90 (d, J=6.9 Hz, 3H).
Step K:
1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-
-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone
##STR01125##
[2022] To a 40 mL vial,
2-(2-methyl-4-(dibenzylamino)cyclopentyl)-dimethylsulfoxonium-2-oxo-ethyl-
ide (4.02 g, 10.1 mmol), 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine
(2.92 g, 10.1 mmol), and chloro (1,5-cyclooctadiene) iridium(I)
dimer (0.17 g, 0.3 mmol, Alfa Aesar) was added. The reaction vessel
was purged with N.sub.2 for about 10 min. To the reaction vessel,
degassed CH.sub.3Cl (13 mL) was added via syringe. The reaction
mixture was purged with N.sub.2 for about 10 min and stirred under
an atmosphere of N.sub.2 at about 70.degree. C. for about 68 h. The
reaction mixture was allowed to cool to ambient temperature. The
reaction mixture was purified by silica gel flash chromatography
eluting with a gradient of 0-25% EtOAc in heptane to yield
1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrol-
o[2,3-b]pyrazin-2-ylamino)ethanone (8.61 g, 56%) as tan foam.
.sup.1H NMR (400 MHz, DMSO) .delta. 7.91-7.80 (m, 4H), 7.42-7.34
(m, 2H), 7.33-7.23 (m, 9H), 7.21-7.13 (m, 2H), 6.52 (d, J=3.5 Hz,
1H), 4.23-4.04 (m, 2H), 3.63-3.48 (m, 4H), 3.19-3.09 (m, 1H),
3.08-2.99 (m, 1H), 2.32 (s, 3H), 2.29-2.18 (m, 1H), 1.94-1.71 (m,
3H), 1.37-1.23 (m, 1H), 0.86 (d, J=7.8 Hz, 3H).
Step L:
(1S,3S,4R)--N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-
-8-yl)-4-methylcyclopentanamine
##STR01126##
[2024] To a 250 mL round-bottomed flask
1-((1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrol-
o[2,3-b]pyrazin-2-ylamino)ethanone (11.2 g, 17.51 mmol) in
acetonitrile (60 ml) was added. The mixture was cooled with an ice
bath and TFA (2.70 ml, 35.0 mmol) and TFAA (24.46 ml, 175 mmol) was
added. The resulting mixture was warmed and stirred at about
40.degree. C. for about 42 h. The reaction was then cooled in an
ice bath and quenched with methanol (7 mL). After warming to
ambient temperature and stirring for about 1 h, it was poured into
ethyl acetate (100 mL) and aqueous sodium carbonate (10% w/v, 200
mL). The layers were separated and the organic layer concentrated.
The residue was dissolved in THF (120 ml) and 2N sodium hydroxide
(35.0 ml, 70.0 mmol) was added. The reaction mixture was warmed to
about 60.degree. C. and stirred for about 16 h. After cooling to
ambient temperature, 2-methyl-tetrahydrofuran (100 mL) and brine
(100 mL) were added and the layers separated. The aqueous layer was
extracted with 2-methyl-tetrahydrofuran (50 mL) and the combined
organic layers washed with brine (50 mL). The organic layer was
concentrated, dissolved in EtOH (100 mL) and treated with charcoal
(500 mg) for about 1 h. The charcoal was filtered off and the
ethanol removed under reduced pressure. The residue was taken up in
CHCl.sub.3 (50 mL) warmed to about 50.degree. C. and heptane (50
mL) was added. After cooling to ambient temperature, the product
was collected, washed with 1:2 CHCl.sub.3:heptane (30 mL) and dried
in a vacuum oven to afford
(1S,3S,4R)--N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)--
4-methylcyclopentanamine as a tan solid (5.1 g, 67%).sup.1H NMR
(400 MHz, DMSO) .delta. 12.18 (s, 1H), 8.52 (s, 1H), 7.60 (s, 1H),
7.44-7.29 (m, 8H), 7.22 (t, J=7.2 Hz, 2H), 6.84 (d, J=3.4 Hz, 1H),
3.86 (dd, J=17.6, 8.8 Hz, 1H), 3.77-3.59 (m, 4H), 3.41-3.17 (m,
2H), 2.64-2.53 (m, 1H), 2.32-2.06 (m, 3H), 1.49-1.30 (m, 1H), 0.40
(d, J=7.0 Hz, 3H).
Step M:
(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methy-
lcyclopentanamine hydrochloride
##STR01127##
[2026] To a 1.8 L stainless steel pressure bottle
(1S,3S,4R)--N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)--
4-methylcyclopentanamine (49 g, 112 mmol), 10% Pd(OH).sub.2/C (20
g, Johnson Mathey) and ethanol (750 ml) was added under nitrogen.
The reactor was purged with nitrogen then hydrogen. The vessel was
pressurized with hydrogen to about 30 psig. The mixture was
agitated for about 22 hrs at about 50.degree. C. After cooling to
ambient temperature, the reaction was filtered through a buchner
funnel containing a glass fiber filter to remove the catalyst.
Conc. HCl (12 M, 16.7 mL) was added and concentrated under reduced
pressure. The residue was suspended in ethanol (100 mL) and EtOAc
(100 mL), the solids collected by filtration, washed with 1:1
EtOAc:EtOH (30 mL) and dried in a vacuum oven to afford
(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclop-
entanamine hydrochloride as an off-white solid (33.3 g, 86%).
.sup.1H NMR (400 MHz, DMSO) .delta. 13.11 (s, 1H), 8.90 (s, 1H),
8.65-8.42 (m, 4H), 7.88 (t, J=3.1 Hz, 1H), 7.21 (s, 1H), 4.20 (dd,
J=17.3, 8.6 Hz, 1H), 3.75-3.52 (m, 1H), 2.77-2.63 (m, 1H),
2.61-2.52 (m, 1H), 2.33 (ddd, J=31.4, 17.8, 8.8 Hz, 2H), 1.54 (dt,
J=12.7, 6.4 Hz, 1H), 0.50 (d, J=7.0 Hz, 3H).
Step N:
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-me-
thylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide
##STR01128##
[2028] To a 2 L flask
(1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclop-
entanamine hydrochloride (248.0 g, 733 mmol), water (1240 ml), THF
(124 ml) and activated carbon (24.12 g) was added and stirred for
about 10 min. The resulting mixture was filtered through celite
rinsing with a mixture of water (100 mL) and THF (24 mL). Potassium
carbonate (668 g, 4836 mmol) and THF (1736 ml) were added and a
solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524
mmol, Matrix) in THF (620 ml) was added over about 1 hr. After
cooling to ambient temperature the layers were separated and the
aqueous layer extracted with THF (500 mL). The combined organic
layers were washed with aqueous ammonium chloride (3.times.100 mL)
and concentrated to approximately 1 L. Water (1770 mL) was added
slowly at about 50.degree. C. and the slurry cooled to about
23.degree. C. The solids were collected by filtration, washed with
35% THF in water (750 mL) and dried in a vacuum oven. The crude
material was dissolved in MeOH (4.5 L) and treated with activated
carbon (28.3 g). After filtering through celite and rinsing with
MeOH (500 mL), the solution was concentrated under reduced pressure
to approximately 1 L and water (800 mL) was added slowly at about
50.degree. C. then cooled to 35.degree. C. when additional water
(360 mL) was added. The product was collected by filtration, washed
with 1:1 MeOH:water (2.times.350 mL) and dried in a vacuum oven to
afford
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3, 3, 3-trifluoropropane-1-sulfonamide (215.3 g, 71%) as
a white crystalline solid (m.p. 225.degree. C.). .sup.1H NMR (400
MHz, DMSO) .delta. 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H),
7.38 (s, 1H), 7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt,
J=10.1, 7.8 Hz, 1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H),
2.61-2.40 (m, 2H), 2.40-2.29 (m, 1H), 2.23 (dd, J=13.3, 6.9 Hz,
1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m, 1H), 1.20-0.99 (m, 1H), 0.17
(d, J=7.0 Hz, 3H).
Example #8*
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1--
yl)cyclopentylamino)thiazole-5-carbonitrile
##STR01129##
[2029] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01130##
[2031] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01131##
[2033] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01132##
[2035] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01133##
[2037] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR01134##
[2039] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. and ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep internal temperature below about 10.degree. C.
The resulting mixture was stirred at ambient temperature for about
0.5 h to give a clear yellow solution, and methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, coned under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as a beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01135##
[2041] A 5 L round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL,
4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The
reaction was heated at reflux for about 6 h then cooled to ambient
temperature and added dropwise to NaHCO.sub.3 (8% w/v aqueous, 3.5
L). The resulting biphasic mixture was extracted with MTBE
(2.times.1.5 L). The combined organic layers were washed with brine
(1 L), dried over anhydrous MgSO.sub.4 and coned under reduced
pressure to give 191 g of crude material that was purified by
vacuum distillation (97-99.degree. C., 0.600 mm Hg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H NMR
(CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m,
1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
Step G: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR01136##
[2043] A round bottom flask was charged with 10 wt % Pd/C (10 g,
9.4 mmol). The flask was cooled to about 0.degree. C. and EtOAc
(400 mL) was added under a nitrogen atmosphere. The cooling bath
was removed and ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8
g, 263 mmol) was added. Hydrogen gas was bubbled through the
mixture for about 5 min and the mixture was then stirred under a
hydrogen atmosphere for about 48 h. The hydrogen source was removed
and the mixture was bubbled with nitrogen for about 5 min and was
filtered through a pad of Celite.RTM.. The filter cake was rinsed
with EtOAc (400 mL). The filtrate was concd under reduced pressure
to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1
mixture cis:trans) (48.0 g, 99%) as a yellow liquid: .sup.1H NMR
(CDCl.sub.3) .delta. 4.23-4.10 (m, 2H), 3.22 (m, 1H), 2.59-2.50 (m,
1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46 (m, 1H),
1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).
Step H: ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate
##STR01137##
[2045] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE
(1.8 L). The solution was cooled to about 0.degree. C. and AcOH (45
mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added
dropwise, resulting in the formation of a thick suspension. The
reaction mixture was warmed to about 10.degree. C. and additional
DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781
mmol) was added portionwise and the reaction mixture was stirred at
ambient temperature for about 20 h. The reaction mixture was slowly
poured into stirred saturated aqueous NaHCO.sub.3 (1.5 L), followed
by the portionwise addition of solid NaHCO.sub.3 (175 g). The
mixture was stirred for about 2 h and the organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, and concd under
reduced pressure. The crude yellow oil was purified by silica gel
chromatography eluting with 0-20% EtOAc in heptane to yield ethyl
4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as
a white solid: LC/MS (Table 1, Method a) R.sub.t=3.26 min; MS m/z:
366 (M+H).sup.+
Step I: ethyl 4-amino-2-ethylcyclopentanecarboxylate
##STR01138##
[2047] To a vessel containing a slurry of 20 wt % Pd(OH).sub.2 on C
(12.9 g, 18.4 mmol) in EtOH (1.0 L) was added ethyl
4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol).
The reaction was shaken for about 90 min at about 50.degree. C.
under about 30 psi of hydrogen. After removal of the hydrogen
source, a nitrogen atmosphere was introduced and the resulting
mixture was filtered through a pad of Celite.RTM. and the filtrate
was concd under reduced pressure to give ethyl
4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow
syrup: .sup.1H NMR (CDCl.sub.3) .delta. 4.03-3.88 (m, 2H), 3.17 (m,
1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m,
1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m,
2H), 0.78-0.69 (m, 3H).
Step J: (1S,2R,4S)-ethyl
4-acetamido-2-ethylcyclopentanecarboxylate
##STR01139##
[2049] A solution of ethyl 4-amino-2-ethylcyclopentanecarboxylate
(49.0 g, 264 mmol) in pyridine (214 mL, 2645 mmol) was cooled to
about 0.degree. C. Acetic anhydride (125 mL, 1322 mmol) was added
and stirring was continued at about 0.degree. C. for about 15 min.
The resulting solution was warmed to ambient temperature and
stirred for about 12 h. The reaction was concd under reduced
pressure and EtOAc (500 mL) and HCl (1 N aqueous, 200 mL) were
added. The layers were separated and the organic layer was washed
with HCl (1 N aqueous, 200 mL), saturated aqueous NaHCO.sub.3
(2.times.200 mL) and brine (150 mL), dried over anhydrous
MgSO.sub.4, filtered through a pad of Florisil.RTM. while washing
with EtOAc (600 mL), and concd under reduced pressure to give an
off-white solid (52 g) that was purified by using General Procedure
AA (Table 2, Method 24, R.sub.t=8.2 min, or =positive) to give
(1S,2R,4S)-ethyl 4-acetamido-2-ethylcyclopentanecarboxylate (20.3
g, 34%): LC/MS (Table 1, Method a) R.sub.t=1.82 min; MS m/z: 228
(M+H).sup.+.
Step K: (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic
acid
##STR01140##
[2051] To a flask containing (1S,2R,4S)-ethyl
4-acetamido-2-ethylcyclopentanecarboxylate (9.44 g, 41.5 mmol) was
added NaOH (2 N aqueous, 141 mL, 282 mmol). After stirring at
ambient temperature for about 12 h, the reaction was acidified to
about pH 1 by the addition of 6 N aqueous HCl (50 mL) and extracted
with EtOAc (3.times.500 mL). The combined organic layers were
washed with brine (100 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure to give crude
(1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (7.25 g,
88%): LC/MS (Table 1, Method a) R.sub.t=1.51 min; MS m/z: 200
(M-H).sup.+.
Step L:
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)cyclopentyl)acetamide
##STR01141##
[2053] To a mixture of
(1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g,
15.2 mmol) in DCM (90 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol,
Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL,
55.4 mmol). After stirring at ambient temperature for about 2 h,
the reaction was diluted with water (60 mL). The layers were
separated and the aqueous layer was extracted with DCM (3.times.50
mL). The combined organic layers were washed with brine (50 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-5% MeOH in DCM to give
N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazi-
necarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan
foam: LC/MS (Table 1, Method a) R.sub.t=1.96 min; MS m/z: 485
(M+H).sup.+. To a solution of impure
N--((S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazi-
necarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in
1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl
chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at
about 80.degree. C. for about 2 h, and then cooled to about
0.degree. C. and saturated aqueous NaHCO.sub.3 and EtOAc (100 mL
each) were added. The layers were separated and the aqueous layer
was extracted with additional EtOAc (2.times.100 mL). The combined
organic layers were washed with brine (100 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The crude material was purified by silica gel chromatography
eluting with a gradient of 50-100% EtOAc/MeOH/Et.sub.2NH (90:9:1)
in EtOAc to give
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][,
2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g,
66%): LC/MS (Table 1, Method a) R.sub.t=2.03 min; MS m/z: 467
(M+H).sup.+.
Step M:
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
-a]pyrazin-1-yl)cyclopentanamine
##STR01142##
[2055] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)acetamide (6.0 g, 12.86 mmol, Example #8
Step L) in 1,4-dioxane (78 mL) was added HCl (6 N aqueous, 75 mL,
450 mmol). The reaction mixture was heated at about 95.degree. C.
for about 16 h. The reaction was cooled to ambient temperature and
the solvent was removed under reduced pressure. The residue was
diluted with DCM (50 mL) and washed with saturated aqueous
NaHCO.sub.3 (100 mL). The aqueous portion was extracted with
additional DCM (3.times.50 mL) and the combined organic layers were
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-100%
DCM/MeOH/NH.sub.4OH (950:45:5) in DCM to give
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (3.05 g, 56%) as a tan solid: LC/MS
(Table 1, Method a) R.sub.t=1.85 min; MS m/z: 425 (M+H).sup.+.
Step N:
2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[-
4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile
##STR01143##
[2057] A mixture of
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanamine (0.20 g, 0.47 mmol), EtOH (1.3 mL), DIEA
(0.33 mL, 1.88 mmol), and 2-chlorothiazole-5-carbonitrile (0.082 g,
0.56 mmol, Ark Pharm) was heated in a CEM microwave at about
150.degree. C. for about 30 min (250 psi maximum pressure, 5 min
maximum ramp, 300 maximum watts). The reaction mixture was cooled
to ambient temperature and concd under reduced pressure. The crude
oil was dissolved in DCM (10 mL) and washed with water (2.times.10
mL). The organic layer was dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The crude mixture was
purified by silica gel chromatography eluting with a gradient of
0-70% EtOAc in DCM to give
2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 84%):
LC/MS (Table 1, Method c) R.sub.t=1.53 min; MS m/z: 533
(M+H).sup.+.
Step O:
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentylamino)thiazole-5-carbonitrile
##STR01144##
[2059] A mixture of
2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 0.39
mmol), 1,4-dioxane (4.5 mL), EtOH (3.5 mL) and Na.sub.2CO.sub.3 (2
N aqueous, 5.8 mL, 15.7 mmol) was heated at about 50.degree. C. for
about 12 h. The reaction mixture was neutralized to pH 7 by the
addition of AcOH (0.3 mL), washed with water (2.times.5 mL) and
extracted with DCM (3.times.5 mL). The organic layer was dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The crude material was purified by silica gel chromatography
eluting with a gradient of 0-5% MeOH in DCM to give
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentylamino)-thiazole-5-carbonitrile (0.09 g, 60%): LC/MS
(Table 1, Method c) R.sub.t=1.95 min; MS m/z: 379 (M+H).sup.+.
Example #9
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]oc-
tan-1-yl)pyrrolidine-1-sulfonamide
##STR01145##
[2060] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01146##
[2062] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01147##
[2064] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01148##
[2066] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01149##
[2068] HCl (4 M in 1,4-dioxane, 226 mL, 902 mmol) was added to a
mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL). The reaction was heated at
about 60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of crude solid. The
solid was stirred with a mixture of saturated aqueous NaHCO.sub.3
and EtOAc (1:1, 400 mL). After about 1 h, the solid was collected
by vacuum filtration, washed with ice cold water (3.times.30 mL)
and EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: tert-butyl
4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2-
.2]octan-1-ylcarbamate
##STR01150##
[2070] A round bottom flask was charged with
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.75 g, 11.1 mmol),
4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid
(3.0 g, 11 mmol, Prime Organics), HATU (4.23 g, 11.1 mmol), TEA
(6.2 mL, 44 mmol), and DCM (65 mL). The reaction mixture was
stirred at ambient temperature for about 16 h. The reaction mixture
was diluted with water (30 mL) and the initial layers that formed
were separated. The remaining aqueous emulsion was filtered through
Celite.RTM.. The filtrate layers were separated and the aqueous
layer was extracted with additional DCM (60 mL). The organic layer
was washed with water (3.times.50 mL), dried over anhydrous
MgSO.sub.4, filtered, and coned under reduced pressure. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-100% EtOAc in DCM to afford tert-butyl
4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2-
.2]octan-1-ylcarbamate as a brown amorphous solid (5.38 g, 87%):
LC/MS (Table 1, Method a) R.sub.t=2.40 min; MS m/z 555
(M+H).sup.+.
Step F:
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bic-
yclo[2.2.2]octan-1-amine
##STR01151##
[2072] To a solution of tert-butyl
4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.-
2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol), TEA (6.1 mL, 44.0 mmol)
in 1,4-dioxane (110 mL) was added SOCl.sub.2 (2.0 mL, 27.5 mmol).
The reaction mixture was heated at about 80.degree. C. for about 2
h then cooled to ambient temperature. The reaction mixture was
washed with saturated aqueous NaHCO.sub.3 (3.times.50 mL). The
aqueous portion was filtered to give
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1,
Method a) R.sub.t=1.28 min; MS m/z: 437 (M+H).sup.+. The remaining
filtrate was extracted with EtOAc (10 mL). The organic layer was
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure to afford crude tert-butyl
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material
was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8
mL) was added. The reaction mixture was heated at about 50.degree.
C. for about 3 h. The precipitate formed was filtered, dissolved in
DCM (50 mL), and washed with saturated aqueous NaHCO.sub.3
(3.times.20 mL). The layers were separated and the organic portion
was dried over anhydrous MgSO.sub.4, filtered, and concd under
reduced pressure to give additional
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS
(Table 1, Method a) R.sub.t=1.28 min; MS m/z: 437 (M+H).sup.+.
Step G:
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[-
2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide
##STR01152##
[2074] A round bottom flask was charged with
4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.-
2.2]octan-1-amine (0.12 g, 0.28 mmol), DIEA (0.48 mL, 2.8 mmol) in
DMA (2.75 mL). Pyrrolidine-1-sulfonyl chloride (0.07 g, 0.41 mmol,
Matrix) was added dropwise and reaction mixture was stirred at
ambient temperature for about 1 h. K.sub.2CO.sub.3 (0.190 g, 1.37
mmol) was added and the reaction mixture was stirred at ambient
temperature for about 16 h. The solvent was removed under reduced
pressure. The crude material was purified by flash chromatography
on silica gel eluting with a gradient of 0-10% MeOH in DCM to give
N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo-
[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide, which was dissolved in
NaOH (1 N aqueous, 1.10 mL, 1.10 mmol) and 1,4-dioxane (1 mL) and
heated at about 50.degree. C. for about 1 h. The crude material was
purified by preparative reverse phase HPLC (Table 2, Method 1) to
give
N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)pyrrolidine-1-sulfonamide (0.042 g, 37%) as a white
solid: LC/MS (Table 1, Method a) R.sub.t=1.81 min; MS m/z 416
(M+H).sup.+.
Example #10*
(3R,4R)-phenyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate
##STR01153##
[2075] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01154##
[2077] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01155##
[2079] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine
hydrochloride
##STR01156##
[2081] A 5 L reactor was charged with
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (98.8 g, 281 mmol), zinc
dust (3.50 g, 53.3 mmol), palladium(II) trifluoroacetate (4.0 g, 12
mmol), and racemic-2-(di-t-butylphosphino)-1,1'-binapthyl (9.8 g,
24.7 mmol). The flask was equipped with a powder addition device
into which zinc cyanide (10.0 g, 157 mmol) was placed to be added
at a later step. The vessel was purged with argon for no longer
than about 30 min and then argon sparged DMA (2 L) was added to the
reactor. The mixture was stirred and heated to about 50.degree. C.
while maintaining an argon atmosphere. The resulting dark brown
solution was further heated to about 95.degree. C. while adding the
zinc cyanide, from the powder addition device, portionwise over
about 15 min. Upon reaching about 95.degree. C., the brown mixture
was stirred for about an additional 16 h. The reaction mixture was
cooled to ambient temperature, resulting in the precipitation of
salts. The mixture was filtered through a Buchner funnel containing
filter-aid and the filter cake was washed with DMA (20 mL). A
solution of the crude product in DMA was added to cold
(<10.degree. C.) water (16 L) and stirred for about 30 min. The
resulting suspension was filtered and the filter cake was rinsed
again with water (1 L). The resulting wet cake was dried in a
vacuum oven at about 50.degree. C. The crude solid was dissolved in
DCM (1.5 L) and further dried over anhydrous MgSO.sub.4. After
filtration, the solution was passed through a pad of silica (140
g), using DCM as the eluent until only predominantly impurities
were detected eluting off the pad. The solvent was removed under
reduced pressure and the crude solid was triturated with MeOH/DCM
(4:1, 10 volumes of solvent per gram of crude solid) at ambient
temperature for about 5 h. The solid was filtered and washed with
MeOH (300 mL). The product was dried in a vacuum oven to provide
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as a
white solid: .sup.1H NMR (CDCl.sub.3) 8.67 (s, 1H), 8.21 (d, J=4.2
Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d,
J=4.2 Hz, 1H), 2.42 (s, 3H). A 2-L 316-stainless steel pressure
reactor was charged with 5 wt % Pd/C (15.4 g of 63.6 wt % water wet
material, 5.6 g dry basis, 2.6 mmol Johnson Matthey A503032-5),
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol),
THF (1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL,
369 mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,
pressurized, and maintained at 40 psi with hydrogen supplied from a
high pressure reservoir. The mixture was vigorously agitated at
about 25.degree. C. After about 5 h the reactor was vented and
purged with nitrogen to remove most of the dissolved hydrogen, and
the reaction mixture was filtered to remove the catalyst. The
reactor and catalyst cake were rinsed with THF: water (1:1,
2.times.40 mL). The combined filtrate and rinses were concd and
EtOH (500 mL) was added then removed under reduced pressure. After
two further azeotropes using EtOH (2.times.500 mL), the crude
residue was concd under reduced pressure to give a residue (76 g)
that was suspended in EtOH (550 mL) and stirred at ambient
temperature for about 4 h. The solid was collected by filtration
and washed with cold EtOH (50 mL). The wet cake was dried in a
vacuum oven to provide
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(51.2 g, 82%) as a white solid: LC/MS (Table 1, Method a)
R.sub.t=1.44 min; MS m/z: 303 (M+H).sup.+.
Step D: 4-methylpiperidine-3-carboxylic acid hydrochloride
##STR01157##
[2083] AcOH (380 mL) was added to 4-methylnicotinic acid
hydrochloride (50.5 g, 291 mmol, Maybridge) and PtO.sub.2 (5.05 g,
22.2 mmol, Johnson Matthey) in a 600 mL stainless steel reactor.
The mixture was stirred under 220 psi of hydrogen at ambient
temperature for about 14 hr. The supernatant solution was filtered
through a nylon membrane and rinsed with enough AcOH until only the
catalyst remained. The filtrate was concd under reduced pressure to
give a clear oil that solidified upon cooling to ambient
temperature to give crude 4-methylpiperidine-3-carboxylic acid with
AcOH as an excipient (88.94 g, 170%): LC/MS (Table 1, Method b)
Rt=0.44 min; MS m/z: 144 (M+H).sup.+.
Step E: (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate
(2S,3S)-2,3-dihydroxysuccinate
##STR01158##
[2085] Crude racemic 4-methylpiperidine-3-carboxylic acid
hydrochloride (.about.70% chemical purity, approximately 15:1
cis:trans) in AcOH (2:1, 300 g) was dissolved in EtOH (1500 mL) and
sparged with HCl (gas) for about 15 min. The reaction mixture was
fitted with a balloon to allow for expansion then heated to about
85.degree. C. After about 48 h, the reaction mixture was cooled to
ambient temperature and concd in vacuo to provide a thick syrup
containing racemic ethyl 4-methylpiperidine-3-carboxylic acid
hydrochloride (260 g). To this ester was added CHCl.sub.3 (1000 mL)
followed by saturated aqueous NaHCO.sub.3 (500 mL) and NH.sub.4OH
(15% aqueous, 500 mL). The organic layer was separated and the
aqueous layer was further extracted with CHCl.sub.3 (1000 mL). The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and then concd in vacuo to provide crude ethyl
4-methylpiperidine-3-carboxylate (200 g) as an oil. To a slurry of
(2S,3S)-2,3-dihydroxysuccinic acid (150 g, 1001 mmol) in MeOH (200
mL) was added a solution of crude ethyl
4-methylpiperidine-3-carboxylate (200 g, 1168 mmol) in EtOAc (3000
mL). The mixture was stirred rapidly for about 3 h and the
resulting solids were collected by filtration to provide the
(2S,3S)-2,3-dihydroxysuccinate salt as a white solid (245 g)
(approximately 15:1 cis:trans, er=48:52 for cis stereoisomers). The
solids were dissolved in MeOH (1000 mL) and EtOAc (3000 mL) was
slowly added until solids began to form. After about 30 min, the
solids were collected by filtration and partially dried in vacuo to
provide a stereo-enriched mixture containing (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate as
a white solid (145 g) (approximately 15:1 cis:trans, er=60:40 for
(3R,4R):(3S,4S) enantiomers). The above solids were dissolved in
MeOH (1000 mL) and divided into four lots. Each lot (250 mL) was
diluted with MeOH (500 mL) and EtOAc (3000 mL) was slowly added to
the solution until solids formed. After about 4-15 h, the solids
were collected by filtration and dried in vacuo to provide multiple
lots of partially resolved (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate,
these were combined and dissolved in MeOH (1000 mL) and EtOAc (4000
mL) was slowly added. After stirring for about 1 h the solids were
collected by filtration to provide (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2, 3-dihydroxysuccinate
(4.5 g) (approximately 15:1 cis:trans, er=98:2 for (3R,4R):(3S,4S)
enantiomers), chiral analytical LC (Table 2, Method 30) minor
isomer R.sub.t=12.2 min; MS m/z: 343
(M+(2S,3S)-2,3-dihydroxysuccinate+Na).sup.+; major isomer
R.sub.t=10.6 min; MS m/z: 343
(M+(2S,3S)-2,3-dihydroxysuccinate+Na).sup.+
Step F:
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid
##STR01159##
[2087] To a flask charged with (3R,4R)-ethyl
4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate
(36.9 g, 115 mmol) was added a solution of HCl (6 N aqueous, 191
mL). The reaction mixture was heated to about 60.degree. C. After
about 2 h, the reaction mixture was heated to about 90.degree. C.
After about 4 h the reaction mixture was cooled to ambient
temperature and concd in vacuo. To the residue was added
NaHCO.sub.3 (122 g, 1148 mmol) and di-tert-butyl dicarbonate (37.6
g, 172 mmol) followed by a mixture of 1,4-dioxane (500 mL) and
water (500 mL). After about 2 h, Et.sub.2O (500 mL) and water (500
mL) were added to the reaction mixture. The pH was adjusted to
about 4 with 1 N aqueous HCl. The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concd in vacuo
to provide a white solid. The solid was slurried in heptane and
filtered to provide
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid (25 g, 89%) as a white solid: LC/MS (Table 1, Method b)
R.sub.t=1.90 min; MS m/z: 244 (M+H).sup.+.
Step G: (3R,4R)-tert-butyl
4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperi-
dine-1-carboxylate
##STR01160##
[2089] To a slurry of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(34.0 g, 100 mmol, Example #5, Step C),
(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic
acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700
mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at
ambient temperature for about 45 min. The reaction was washed with
saturated aqueous NaHCO.sub.3 (300 mL). The organic layer was
separated, dried over anhydrous Na.sub.2SO.sub.4, filtered then
coned in vacuo. The resulting residue was purified by
chromatography on silica gel (330 g) using 33-100% EtOAc in heptane
to give
(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)met-
hylcarbamoyl)piperidine-1-carboxylate (53 g, 96%) as a pale-yellow
foam: LC/MS (Table 1, Method b) R.sub.t=2.40 min; MS m/z: 528
(M+H).sup.+.
Step H: (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate
##STR01161##
[2091] A mixture of
(3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)met-
hyl-carbamoyl)-piperidine-1-carboxylate (53 g, 100 mmol) and
Lawesson's reagent (22.4 g, 55.2 mmol) in 1,4-dioxane (500 mL) was
heated at about 80.degree. C. for about 1 h. The reaction was
allowed to cool to ambient temperature and then was partitioned
between EtOAc (1000 mL) and saturated aqueous NaHCO.sub.3 (700 mL).
The organic layer was washed with additional saturated aqueous
NaHCO.sub.3 (700 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered then concd in vacuo. The resulting residue was dissolved
in 1,4-dioxane (500 mL) then mercury (II) trifluoroacetate (54.0 g,
127 mmol) was added. The reaction was stirred at about 25.degree.
C. for about 1 h. The reaction was partitioned with saturated
aqueous Na.sub.2S.sub.2O.sub.3 (500 mL)/water (500 mL) with DCM
(1000 mL). The layers were filtered through Celite.RTM. and the
Celite.RTM. pad was washed with DCM (500 mL). The combined layers
were separated then the organic layer was washed with saturated
aqueous NaHCO.sub.3 (800 mL). The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and then concd in
vacuo. The resulting residue was purified on silica gel (330 g)
using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate (40.5 g, 79%) as a yellow foam: LC/MS (Table 1,
Method b) R.sub.t=2.62 min; MS m/z: 510 (M+H).sup.+.
Step I:
(3R,4R)-tert-butyl-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-
-4-methylpiperidine-1-carboxylate
##STR01162##
[2093] To a solution of (3R,4R)-tert-butyl
4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-
e-1-carboxylate (40 g, 78 mmol) in 1,4-dioxane (160 mL) was added
NaOH (1 N aqueous, 157 mL). The mixture was heated at about
60.degree. C. for about 1 h. The mixture was allowed to cool to
ambient temperature. The mixture was partitioned with HCl (4 N
aqueous, 50 mL) and extracted with DCM (2.times.300 mL). The
combined organic extracts were washed with brine (400 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered then coned in vacuo. The
product was purified on silica gel (330 g) using 1-5% MeOH in DCM
to give (3R,4R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (30 g, 99%): LC/MS (Table 1, Method b) R.sub.t=2.00 min; MS
m/z: 356 (M+H).sup.+.
Step J:
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]-
pyrazine hydrochloride
##STR01163##
[2095] To a solution of (3R,4R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (27.9 g, 78 mmol) in 1,4-dioxane (400 mL) was added HCl (4
N in 1,4-dioxane, 58.9 mL, 235 mmol). The resulting suspension was
heated at about 60.degree. C. for about 1 h. The reaction was
allowed to cool to ambient temperature and then was filtered,
washed with 1,4-dioxane (100 mL) followed by Et.sub.2O (100 mL), to
give
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (20.6 g, 89%) as a tan solid: LC/MS (Table 1,
Method b) R.sub.t=1.27 min; MS m/z: 256 (M+H).sup.+.
Step K: (3R,4R)-phenyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate
##STR01164##
[2097] To a solution of
1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-
e hydrochloride (0.06 g, 0.21 mmol) in MeCN (1 mL) at about
0.degree. C. was added TEA (0.06 mL, 0.41 mmol), THF (0.6 mL) and
DMAP (0.006 g, 0.050 mmol) then phenyl chloroformate (0.026 mL,
0.206 mmol) and stirred for about 1 h. The reaction mixture was
warmed to ambient temperature and concd under reduced pressure. The
crude residue was dissolved in DCM (3 mL) and washed with water (2
mL), dried over anhydrous MgSO.sub.4, filtered, and concd under
reduced pressure. The crude residue was dissolved in DCM (5 mL) and
washed with water (2 mL) and brine (2 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The
material was purified by RP-HPLC (Table 1, Method g) to give
(3R,4R)-phenyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carb-
oxylate (0.010 g, 11%): LC/MS (Table 1, Method b) R.sub.t=1.95 min;
MS m/z 376 (M+H).sup.+.
Example #11*
(R)-cyclopentyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
##STR01165##
[2098] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01166##
[2100] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was concd under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01167##
[2102] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine
hydrochloride
##STR01168##
[2104] A 5 L reactor was charged with
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (98.8 g, 281 mmol), zinc
dust (3.50 g, 53.3 mmol), palladium(II) trifluoroacetate (4.0 g, 12
mmol), and racemic-2-(di-t-butylphosphino)-1,1'-binapthyl (9.8 g,
24.7 mmol). The flask was equipped with a powder addition device
into which zinc cyanide (10.0 g, 157 mmol) was placed to be added
at a later step. The vessel was purged with argon for no longer
than about 30 min and then argon sparged DMA (2 L) was added to the
reactor. The mixture was stirred and heated to about 50.degree. C.
while maintaining an argon atmosphere. The resulting dark brown
solution was further heated to about 95.degree. C. while adding the
zinc cyanide, from the powder addition device, portionwise over
about 15 min. Upon reaching about 95.degree. C., the brown mixture
was stirred for about an additional 16 h. The reaction mixture was
cooled to ambient temperature, resulting in the precipitation of
salts. The mixture was filtered through a Buchner funnel containing
filter-aid and the filter cake was washed with DMA (20 mL). A
solution of the crude product in DMA was added to cold
(<10.degree. C.) water (16 L) and stirred for about 30 min. The
resulting suspension was filtered and the filter cake was rinsed
again with water (1 L). The resulting wet cake was dried in a
vacuum oven at about 50.degree. C. The crude solid was dissolved in
DCM (1.5 L) and further dried over anhydrous MgSO.sub.4. After
filtration, the solution was passed through a pad of silica (140
g), washed with additional solvent until only predominantly
impurities were detected eluting off the pad. The solvent was
removed and the crude solid was triturated with MeOH/DCM (4:1, 10
volumes of solvent per gram of crude solid) at ambient temperature
for about 5 h. The solid was filtered and washed with MeOH (300
mL). The product was dried in a vacuum oven to provide
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as a
white solid: .sup.1H NMR (CDCl.sub.3) 8.67 (s, 1H), 8.21 (d, J=4.2
Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d,
J=4.2 Hz, 1H), 2.42 (s, 3H). A 2 L 316-stainless steel pressure
reactor was charged with 5 wt % Pd/C (15.4 g of 63.6 wt % water wet
material, 5.6 g dry basis, 2.6 mmol, Johnson Matthey A503032-5),
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol),
THF (1.1 L), deionized water (165 mL), HCl (37 wt % aqueous, 30 mL,
369 mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,
pressurized, and maintained at 40 psi with hydrogen supplied from a
high pressure reservoir. The mixture was vigorously agitated at
about 25.degree. C. After about 5 h the reactor was vented and
purged with nitrogen to remove most of the dissolved hydrogen, and
the reaction mixture was filtered to remove the catalyst. The
reactor and catalyst cake were rinsed with THF:water (1:1,
2.times.40 mL). The combined filtrate and rinses were concd and
EtOH (500 mL) was added. After two additional solvent switches with
EtOH (2.times.500 mL), the crude residue was concd under reduced
pressure to give a residue (76 g) that was suspended in EtOH (550
mL) and stirred at ambient temperature for about 4 h. The solid was
collected by filtration and washed with cold EtOH (50 mL). The wet
cake was dried in a vacuum oven to provide
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride
(51.2 g, 82%) as a white solid: LC/MS (Table 1, Method a)
R.sub.t=1.44 min; MS m/z: 303 (M+H).sup.+.
Step D: (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-ca-
rboxylate
##STR01169##
[2106] DIEA (7.7 mL, 44.3 mmol) was added to a solution of
(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (5
g, 14.7 mmol) in DCM (78 mL) and the reaction was stirred at
ambient temperature for about 10 min followed by the addition of
(R)--N-Boc-piperidine-3-carboxylic acid (3.38 g, 14.7 mmol,
CNH-Technologies) and HATU (5.61 g, 14.7 mmol). The mixture was
stirred for about 1 h, then water (30 mL) was added, and the layers
were separated. The organic layer was washed with saturated aqueous
NaHCO.sub.3 (30 mL) and brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-5% MeOH in DCM to afford crude (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-ca-
rboxylate (7.58 g, 94%): LC/MS (Table 1, Method b) R.sub.t=2.30
min; MS m/z: 514 (M+H).sup.+.
Step E: (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-
-1-carboxylate
##STR01170##
[2108] To a solution of (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-c-
arboxylate (7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added
Lawesson's reagent (3.37 g, 8.32 mmol) and the reaction mixture was
heated to about 60.degree. C. for about 2 h then cooled to ambient
temperature and concd under reduced pressure. The crude residue was
dissolved in EtOAc (40 mL) and washed with saturated aqueous
NaHCO.sub.3, (3.times.40 mL), brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The crude
material was purified by silica gel chromatography eluting with a
gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine--
1-carboxylate (5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method
b) R.sub.t=2.60 min; MS m/z: 530 (M+H).sup.+.
Step F: (R)-tert-butyl
3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbo-
xylate
##STR01171##
[2110] To a solution of (R)-tert-butyl
3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-piperidine-
-1-carboxylate (5.61 g, 10.3 mmol) in 1,4-dioxane (96 mL) was added
mercury (II) trifluoroacetate (4.38 g, 10.3 mmol). The reaction
mixture was stirred at ambient temperature for about 2 h then
filtered through a pad of Celite.RTM.. The Celite.RTM. pad was
rinsed with EtOAc (50 mL) and the filtrate was concd under reduced
pressure. The crude residue was dissolved in EtOAc (40 mL) and the
organic phase was washed with saturated aqueous NaHCO.sub.3
(2.times.40 mL) and brine (30 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The crude material was
purified by silica gel chromatography eluting with a gradient of
0-5% MeOH in DCM to afford (R)-tert-butyl 3-(6-tosyl-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (4.4 g,
87%): LC/MS (Table 1, Method b) R.sub.t=2.49 min; MS m/z: 496
(M+H).sup.+.
Step G: (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
##STR01172##
[2112] To a solution of (R)-tert-butyl
3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbo-
xylate (4.44 g, 8.96 mmol) in 1,4-dioxane (54 mL) was added NaOH (2
N aqueous, 8.9 mL, 18 mmol), and the resulting mixture was heated
at about 60.degree. C. for about 3 h. The reaction was cooled to
ambient temperature and EtOAc (30 mL) and saturated aqueous
NH.sub.4Cl (20 mL) were added. The organic layer was separated and
the aqueous layer was further extracted with EtOAc (40 mL). The
combined organic layers were washed with brine (40 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The material was purified by silica gel chromatography eluting with
a gradient of 0-10% MeOH in DCM to afford (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
(2.80 g, 92%): LC/MS (Table 1, Method b) R.sub.t=1.85 min; MS m/z:
342 (M+H).sup.+.
Step H:
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride
##STR01173##
[2114] A round bottom flask was charged with (R)-tert-butyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
(2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in
1,4-dioxane, 6.2 mL, 24.6 mmol). The reaction mixture was heated at
about 60.degree. C. for about 18 h. The reaction mixture was cooled
to ambient temperature and Et.sub.2O (40 mL) was added and the
mixture was stirred for about 15 min. The solid was collected by
vacuum filtration, while washed with Et.sub.2O (50 mL), and then
dried in a vacuum oven at about 60.degree. C. to afford
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (2.4 g, 94%) as an off-white solid: LC/MS (Table 1,
Method b) R.sub.t=0.81 min; MS m/z 242 (M+H).sup.+.
Step I: (R)-cyclopentyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
##STR01174##
[2116] To a solution of
(R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
hydrochloride (0.06 g, 0.19 mmol) in THF (1 mL) was added TEA (0.08
mL, 0.57 mmol) and the reaction was stirred at ambient temperature
for about 10 min. To the reaction mixture was added cyclopentyl
chloroformate (0.02 mL, 0.15 mmol, Waterstone) and the mixture was
stirred at about 45.degree. C. for about 18 h. The reaction mixture
was cooled to ambient temperature and concd under reduced pressure.
The crude material was dissolved in DCM (5 mL) and washed with
water (5 mL). The organic layer was separated and the aqueous layer
was back extracted with DCM (2 mL). The combined organic extracts
were dried over anhydrous MgSO.sub.4, filtered, and concd under
reduced pressure. The material was purified by silica gel
chromatography eluting with a gradient of 0-5% MeOH in DCM to
afford (R)-cyclopentyl
3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate
(0.015 g, 21%): LC/MS (Table 1, Method b) R.sub.t=1.87 min; MS m/z:
354 (M+H).sup.+.
Example #12
(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic
acid
##STR01175##
[2117] Step A: (E)-ethyl
3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acryl-
ate
##STR01176##
[2119] To a solution of
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
(0.026 g, 0.056 mmol, Preparation #MM.1) and PdCl.sub.2(dppf)*DCM
adduct (0.005 g, 0.006 mmol) in THF (1 mL) was added (E)-ethyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.052 g,
0.23 mmol) and Na.sub.2CO.sub.3 (0.021 g, 0.20 mmol) followed by
water (0.25 mL). The reaction mixture was heated to about
65.degree. C. After about 15 h, the reaction mixture was cooled to
ambient temperature and directly purified by chromatography on
silica gel (12 g) eluting with 20-80% EtOAc:DCM (1:1) in heptane to
provide (E)-ethyl
3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acryl-
ate (0.045 g, 70%) as a yellow solid: LC/MS (Table 1, Method a)
R.sub.t=3.15 min; MS m/z: 493 (M+H).sup.+.
Step B:
(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)ac-
rylic acid
##STR01177##
[2121] To a solution of (E)-ethyl
3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acryl-
ate (0.064 g, 0.13 mmol) in 1,4-dioxane (5 mL) was added NaOH (2 N
aqueous, 1.30 mL, 2.60 mmol). The reaction mixture was heated to
about 65.degree. C. After about 15 h, the reaction mixture was
cooled to ambient temperature and the pH of the reaction mixture
was adjusted to about pH 1 with concentrated HCl. The mixture was
partially coned in vacuo to remove the 1,4-dioxane and the
resulting yellow solid was collected by filtration and dried in
vacuo to
provide(E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)ac-
rylic acid (0.015 g, 37.2%): LC/MS (Table 1, Method a) R.sub.t=1.85
min; MS m/z: 311 (M+H).sup.+.
Example #13
3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic
acid
##STR01178##
[2123] To solution of ethyl
3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propa-
noate (0.031 g, 0.063 mmol, prepared using W from Example #12Step
A) in 1,4-dioxane (3 mL) was added NaOH (2 N aqueous, 1.57 mL, 3.13
mmol). The reaction mixture was heated to about 65.degree. C. After
about 2 h, the reaction mixture was cooled to ambient temperature
and the pH of the mixture was adjusted to about 1 with 1 N aqueous
HCl. The reaction mixture was concd in vacuo and purified by
chromatography on silica gel (12 g) eluting with 2-10% MeOH in DCM
to provide
3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic
acid (0.005 g, 26%) as a tan solid: LC/MS (Table 1, Method a)
R.sub.t=1.68 min; MS m/z: 313 (M+H).sup.+.
Example #14*
N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01179##
[2125] To a solution of
N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-
-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.090 g, 0.16
mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU
and DIEA, and Q with Lawesson's reagent and mercury (II)
trifluoroacetate) in THF (3 mL) at about 0.degree. C. was added
BH.sub.3*DMS (2 M in THF, 0.040 mL, 0.079 mmol). After about 2 h,
additional BH.sub.3*DMS (2 M in THF, 0.040 mL, 0.079 mmol) was
added to the reaction mixture. After about 6 h total, a premixed
solution of H.sub.2O.sub.2 (30% aqueous, 0.324 mL, 3.17 mmol) and
NaOH (2 N aqueous, 0.793 mL, 1.58 mmol) was added to the reaction
mixture. After stirring for about 15 h, EtOAc (20 mL) and water (20
mL) were added to the reaction mixture. The organic layer was
separated, washed with brine (20 mL), and concd in vacuo. The crude
residue was purified by chromatography on silica gel (12 g) eluting
with EtOAc to provide
N-((1S,3R,4S)-3-ethyl-4-(3-(3-hydroxypropyl)-6H-imidazo[1,5-a]pyrrolo[2,3-
-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.025 g, 37%)
as a white solid: LC/MS (Table 1, Method a) R.sub.t=1.70 min; MS
m/z: 432 (M+H).sup.+.
Example #15
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopro-
panesulfonamide
##STR01180##
[2127] To a solution of tert-butyl
1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate
(0.175 g, 0.511 mmol, Example #D.1.42) in DCM (10 mL) was added HCl
(4 N in 1,4-dioxane, 1.28 mL, 5.11 mmol). After about 4 h at
ambient temperature, the reaction mixture was concd in vacuo. The
residue was suspended in DCM (10 mL) and DIEA (0.446 mL, 2.56 mmol)
was added to the reaction mixture resulting in a nearly homogeneous
mixture. To the mixture was added cyclopropanesulfonyl chloride
(0.079 g, 0.56 mmol). After about 2 h at ambient temperature,
additional cyclopropane-sulfonyl chloride (0.079 g, 0.56 mmol) was
added. After about 6 h at ambient temperature, saturated aqueous
NaHCO.sub.3 (10 mL) was added to the reaction mixture. The organic
layer was separated and the aqueous layer was extracted with DCM
(3.times.10 mL). The combined organic layers were concd in vacuo
and purified by chromatography on silica gel (40 g) eluting with
50-90% MeCN in DCM to provide
N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopr-
opane-sulfonamide (0.125 g, 70%) as a tan solid: LC/MS (Table 1,
Method a) R.sub.t=1.42 min; MS m/z: 347 (M+H).sup.+.
Example #16
1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
##STR01181##
[2129] To a solution of
3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
(0.27 g, 0.056 mmol, Preparation #MM.1) and PdCl.sub.2(dppf)*DCM
adduct (0.0046 g, 0.0056 mmol) in THF (1 mL) was added a solution
of phenylboronic acid (0.12 g, 0.098 mmol) and Na.sub.2CO.sub.3
(0.009 g, 0.084 mmol) in water (0.25 mL). The reaction mixture was
heated to about 60.degree. C. After about 6 h, the reaction mixture
was cooled to ambient temperature and was diluted with EtOAc (5 mL)
and brine (5 mL). The organic layer was separated and concd in
vacuo. The residue was dissolved in 1,4-dioxane (5 mL) and NaOH (2
N aqueous, 1 mL) was added. The reaction mixture was heated to
about 65.degree. C. After about 15 h, the reaction mixture was
cooled to ambient temperature and HCl (1 N aqueous, 3 mL) and EtOAc
(5 mL) were added. The organic layer was separated, concd in vacuo,
and the residue was purified by chromatography on silica gel (12 g)
eluting with 20-80% EtOAc in DCM to provide
1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine
(0.005 g, 28%) as a solid: LC/MS (Table 1, Method a) R.sub.t=2.75
min; MS m/z: 317 (M+H).sup.+.
Example #17*
N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]-
pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01182##
[2131] To a solution of
N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-
-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.17 g, 0.299
mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU
and DIEA, and Q with Lawesson's reagent and mercury (II)
trifluoroacetate) in 1,4-dioxane (5 mL) and water (1.7 mL) was
added sodium periodate (0.26 g, 1.2 mmol) followed by osmium
tetroxide (4 wt % in water, 0.117 mL, 0.015 mmol). After about 48 h
at ambient temperature, the reaction mixture was diluted with water
(about 50 mL) and EtOAc (30 mL). The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and coned in
vacuo. The crude aldehyde was dissolved in EtOH (10 mL) and
NaBH.sub.4 (0.023 g, 0.599 mmol) was added to the reaction mixture.
After about 2 h at ambient temperature, HCl (1 N aqueous, about 3
mL) was added. After stirring for about 30 min, the reaction
mixture was concd in vacuo. The residue was partitioned between
EtOAc (30 mL) and saturated aqueous NaHCO.sub.3 (30 mL). The
organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd in vacuo. The crude alcohol was dissolved in
1,4-dioxane (10 mL) and NaOH (2 N aqueous, 1.5 mL, 2.99 mmol) was
added. The reaction mixture was heated to about 80.degree. C. After
about 4 h, the reaction mixture was cooled to ambient temperature
and diluted with EtOAc (30 mL) and saturated aqueous NH.sub.4Cl (30
mL). The organic layer was separated, concd in vacuo, and purified
by chromatography on silica gel eluting with 10-50% MeCN in DCM to
provide
N-((1S,3R,4S)-3-ethyl-4-(3-(hydroxymethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.007 g, 6%) as
a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.59 min; MS m/z:
404 (M+H).sup.+.
Example #18*
N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01183##
[2133] To a solution of
N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-
-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.170 g, 0.299
mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU
and DIEA, Q with Lawesson's reagent and mercury (II)
trifluoroactate) in 1,4-dioxane (5 mL) and water (1.67 mL) was
added sodium periodate (0.26 g, 1.198 mmol) followed by osmium
tetroxide (4 wt % in water, 0.12 mL, 0.015 mmol). After about 4 h
at ambient temperature, the reaction mixture was diluted with water
(about 50 mL) and the resulting precipitate was collected by
filtration. The crude aldehyde was dissolved in EtOH (10 mL) and
NaBH.sub.4 (0.023 g, 0.60 mmol) was added to the reaction mixture.
After about 2 h at ambient temperature, HCl (1 N aqueous, about 3
mL) was added to the reaction mixture. After stirring for about 30
min, the reaction mixture was concd in vacuo. The residue was
partitioned between EtOAc (20 mL) and saturated aqueous NaHCO.sub.3
(20 mL). The organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd in vacuo. The crude alcohol
was dissolved in 1,4-dioxane (10 mL) and NaOH (2 N aqueous, 1.50
mL, 2.99 mmol) was added. The reaction mixture was heated to about
80.degree. C. After about 4 h, the reaction mixture was cooled to
ambient temperature and diluted with EtOAc (30 mL) and saturated
aqueous NH.sub.4Cl (30 mL). The organic layer was separated, concd
in vacuo, and purified by chromatography on silica gel (40 g)
eluting with 5% MeOH in DCM to provide
N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3--
e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.025 g, 20%)
as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.67 min; MS
m/z: 418 (M+H).sup.+.
Example #19*
N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,5-a]pyrr-
olo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01184##
[2135] To a solution of
N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-
-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.28 g, 0.48 mmol,
prepared using H with Preparation #12, Preparation #Z.1, HATU and
DIEA, Q with Lawesson's reagent and mercury (II) trifluoroacetate)
in 1,4-dioxane (5 mL) and water (1.5 mL) was added sodium periodate
(0.21 g, 0.97 mmol) followed by osmium tetroxide (4 wt % in water,
0.19 mL, 0.024 mmol). After about 4 h, the reaction mixture was
diluted with DCM (10 mL) and water (10 mL), the organic layer was
separated and concd in vacuo. The crude aldehyde was dissolved in
EtOH (5 mL) and NaBH.sub.4 (0.18 g, 4.8 mmol) was added to the
reaction mixture. After about 4 h, HCl (1 N aqueous, 10 mL) and DCM
(20 mL) were added to the reaction mixture. The organic layer was
separated and concd in vacuo. The residue was purified by silica
gel chromatography eluting with EtOAc in DCM to give crude alcohol
(0.061 g). To a solution of the crude alcohol in DCM (1 mL) was
added DIEA (0.047 mL, 0.27 mmol) followed by methanesulfonyl
chloride (0.0092 mL, 0.12 mmol). After about 2 h, the reaction
mixture was diluted with DCM (10 mL) and saturated aqueous
NaHCO.sub.3 (10 mL). The organic layer was separated, concd in
vacuo, and diluted with DMF (1.0 mL). Sodium methanethiolate (0.075
g, 1.1 mmol) was added to the reaction mixture. After stirring at
ambient temperature for about 15 h, the reaction mixture was heated
to about 50.degree. C. After about 4 h, the reaction mixture was
cooled to ambient temperature and diluted with DCM (10 mL) and
saturated aqueous NaHCO.sub.3 (10 mL). The organic layer was
separated, concd in vacuo, and purified by chromatography on silica
gel (40 g) eluting with 20-80% MeCN in DCM. The fractions
containing the thioether were combined and concd in vacuo. The
crude thioether was dissolved in DCM (1 mL) and treated with
OXONE.RTM. tetrabutylammonium salt (0.114 g, 0.320 mmol). After
about 4 h, the reaction mixture was diluted with DMSO (1 mL) and
partially concd in vacuo to remove DCM. The crude mixture was
purified by RP-HPLC (Table 1, Method k). The fractions containing
the desired sulfone were combined and concd in vacuo. The residue
was further purified by chromatography on silica gel (12 g) eluting
with 5% MeOH in DCM to provide
N-((1S,3R,4S)-3-ethyl-4-(3-(2-(methylsulfonyl)ethyl)-6H-imidazo[1,
5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide
(0.002 g, 1.4%) as a solid: LC/MS (Table 1, Method a) R.sub.t=1.82
min; MS m/z: 480 (M+H).sup.+.
Example #20
(cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclop-
entyl)methanol
##STR01185##
[2137] To a solution of
5-((cis-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-
-1-yl)cyclopentyl)methoxy)pyrazine-2-carbonitrile (0.145 g, 0.267
mmol, prepared using P from Preparation #11 with LAH, JJ with
5-chloropyrazine-2-carbonitrile [ArkPharm], TT with TFA, A from
Example #1 Step D, HATU, and TEA, B with TEA) in 1,4-dioxane (2.7
mL) was added Na.sub.2CO.sub.3 (2 N aqueous, 2.7 mL). The reaction
was heated at about 50.degree. C. for about 16 h. EtOH (2 mL) was
added to the reaction mixture. The reaction was kept at about
50.degree. C. for about 16 h and then cooled to ambient
temperature. The material was purified by RP-HPLC (Table 1, Method
d) to give
(cis-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-
pentyl)methanol (0.024 g, 31%) as the product: LC/MS (Table 1,
Method b) R.sub.t=1.63 min; MS m/z 286 (M+H).sup.+.
Example #21
1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine
##STR01186##
[2138] Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine
##STR01187##
[2140] A solution of 4-chloro-3-iodopyridin-2-amine (4.00 g, 15.7
mmol, Adesis) in concd H.sub.2SO.sub.4 (45 mL) was cooled to about
0.degree. C. in an ice bath. Potassium nitrate (3.50 g, 34.6 mmol)
was added in four portions over about 10 min. The resulting
solution was stirred at about 0.degree. C. for about 1 h, then at
ambient temperature for about 4 h. The reaction mixture was slowly
poured over crushed ice (total volume 1 L) resulting in formation
of a solid that was collected by vacuum filtration and dried under
vacuum to give 4-chloro-3-iodo-5-nitropyridin-2-amine (2.2 g, 47%)
as a yellow solid: LC/MS (Table 1, Method c) R.sub.t=1.48 min; MS
m/z 298 (M-H).sup.-.
Step B:
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine
##STR01188##
[2142] To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine
(5.30 g, 17.7 mmol) in THF (90 mL) was added TEA (15.0 mL, 108
mmol). The reaction mixture was degassed and purged with nitrogen 3
times. Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g,
0.88 mmol, Strem), copper(I) iodide (0.17 g, 0.89 mmol), and
trimethylsilylacetylene (5.4 mL, 39 mmol) were added to the
reaction mixture, degassed, and purged 3 times with nitrogen. The
reaction was heated at about 60.degree. C. for about 16 h. The
reaction mixture was cooled to ambient temperature. The reaction
mixture was filtered and washed with THF (200 mL). The filtrate was
concd under reduced pressure. DCM (100 mL) was added to the residue
and the precipitate that formed was filtered and collected to give
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77
g). The remaining filtrate was coned under reduced pressure and the
crude material was purified by flash chromatography on silica gel
eluting with a gradient of 0-100% EtOAc in DCM. The purified
material was combined with the 0.77 g of precipitate to afford
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22
g, 47%) as a yellow solid: LC/MS (Table 1, Method c) R.sub.t=1.62
min; MS m/z 268 (M-H).sup.-.
Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine
##STR01189##
[2144] To a solution of
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.36
g, 8.76 mmol) in DMF (30 mL) was added potassium fluoride on
alumina (40 wt %, 3.2 g, 22 mmol). The suspension was stirred at
about ambient temperature for about 2 h. Activated charcoal (0.23
g) was added and the suspension was filtered though Celite.RTM.,
washed with DMF (200 mL). The solvent was removed under reduced
pressure and the residue was triturated with petroleum ether (50
mL, b.p. 30-60.degree. C.). The solid was filtered, washed with
petroleum ether (4.times.25 mL, b.p. 30-60.degree. C.), and dried
in vacuo to give 4-chloro-3-ethynyl-5-nitropyridin-2-amine (2.12 g,
89%) as a brown solid: LC/MS (Table 1, Method c) R.sub.t=1.32 min;
MS m/z 196 (M-H).sup.-.
Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
##STR01190##
[2146] To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine
(0.16 g, 0.81 mmol) in DMF (3 mL) was added
chloro(1,5-cyclooctadiene)rhodium (I) dimer (0.02 g, 0.04 mmol) and
tris(4-fluorophenyl)phosphine (0.128 g, 0.405 mmol). The reaction
mixture was degassed by bubbling argon for 15 min. The reaction
mixture was heated at about 80.degree. C. for about 45 min. The
solvent was removed under reduced pressure and the residue was
suspended in ether (10 mL). The precipitate was collected by
filtration and dried to give
4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g, 83%, contains
approximately 6% mol of DMF and approximately 3% mol of
tris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1,
Method a) R.sub.t=2.05 min; MS m/z 198 (M+H).sup.+.
Step E: N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine
##STR01191##
[2148] To a solution of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
(0.182 g, 0.921 mmol) in DMF (5 mL) was added cyclohexylamine (0.55
g, 5.5 mmol). The reaction mixture was stirred at ambient
temperature for about 2 h. The solvent was removed under reduced
pressure and EtOAc (100 mL) and water (20 mL) were added. The
layers were separated and the organic layer was washed with water
(3.times.25 mL) and brine (20 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd to give
N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.20, 57%)
as a brown residue: LC/MS (Table 1, Method c) R.sub.t=1.53 min; MS
m/z 261 (M+H).sup.+.
Step F: N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine
##STR01192##
[2150] To a solution of
N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.15 g, 0.57
mmol) in EtOH (10 mL) was added tin (II) chloride dihydrate (0.65
g, 2.9 mmol). The reaction mixture was heated at about 55.degree.
C. for about 1 h. The solvent was removed under reduced pressure
and EtOAc (75 mL) and saturated aqueous NaHCO.sub.3 (25 mL) were
added. The solid that formed was collected by vacuum filtration,
washed with EtOAc (25 mL), and discarded. The filtrate was washed
with saturated aqueous NaHCO.sub.3 (3.times.20 mL), dried over
anhydrous MgSO.sub.4, filtered, and concd to give
N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.107 g, 87%)
as a brown residue: LC/MS (Table 1, Method c) R.sub.t=1.21 min; MS
m/z 231 (M+H).sup.+.
Step G:
1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine
##STR01193##
[2152] To a solution of
N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.084 g, 0.36
mmol) in triethyl orthoformate (1 mL, 6 mmol) was added
p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol). The
reaction mixture was heated at about 80.degree. C. for about 1 h.
p-Toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol) was added
and the reaction mixture was stirred at about 80.degree. C. After
about 1 h, p-toluenesulfonic acid monohydrate (0.002 g, 0.011 mmol)
was added and the reaction mixture was stirred at about 80.degree.
C. for about 2 h. The reaction mixture was cooled to ambient
temperature and concd under reduced pressure. The reaction was
purified by RP-HPLC (Table 1, Method m) to give
1-cyclohexyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.002
g, 2%) as a brown solid: LC/MS (Table 1, Method a) R.sub.t=1.90
min; MS m/z 241 (M+H).sup.+.
Example #22
1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrro-
lo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01194##
[2153] Step A: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01195##
[2155] In a 5 L round bottom flask, sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol, [Example #1, step E]), KCl (126 g, 1687 mmol),
and AcOH (241 mL, 4218 mmol, JT Baker) in toluene (1850 mL) and
water (130 mL) were heated at reflux for about 6 h. The reaction
mixture was allowed to cool to ambient temperature for about 16 h.
The reaction mixture was added dropwise to an aqueous solution of
NaHCO.sub.3 (3.5 L, 8%). The aqueous layer was extracted with MTBE
(2.times.1.5 L). The combined organic layers were washed with brine
(1 L), dried over anhydrous MgSO.sub.4, filtered, and concd under
reduced pressure. The crude material was purified by vacuum
distillation (80-98.degree. C., 0.6 mmHg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160.4 g, 69%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.05-6.02 (m, 1H), 4.28-4.14 (m, 2H),
3.75 (m, J=0.9, 1.8, 3.8, 6.7, 1H), 2.69 (dd, J=3.1, 18.4, 1H),
2.61 (dd, J=6.9, 18.4, 1H), 2.52 (dq, J=7.4, 24.2, 1H), 2.40 (dq,
J=7.4, 16.1, 1H), 1.30 (t, J=7.2, 3H), 1.21 (t, J=7.4, 3H).
Step B: ethyl 2-ethyl-4-oxocyclopentanecarboxylate
##STR01196##
[2157] In a 1 L round-bottomed jacketed flask, copper(I) chloride
(0.679 g, 6.86 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4.27 g, 6.86
mmol), and sodium tert-butoxide (0.6.59 g, 6.86 mmol) in toluene
(250 mL) were added to give a brown solution. The mixture was
stirred at ambient temperature for 15 min after which the solution
became brown. The solution was cooled to about 5.degree. C. and
polymethylhydrosiloxane (18.29 mL, 274 mmol) was added and the
reaction mixture was stirred at about 5.degree. C. for about 40
min. The solution was cooled to about -15.degree. C. and a solution
of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 137
mmol) and tert-butyl alcohol (69.9 mL, 741 mmol) in toluene (250
mL) was added in one portion and the reaction stirred at about
-15.degree. C. for about 120 h. The reaction mixture was quenched
by the addition of 1:1 ethanol/toluene (350 mL) and Celite.RTM. 545
(25 g). The mixture was stirred for about 3 h and allowed to warm
to ambient temperature. The reaction mixture was concd in vacuo,
chasing with heptane. Heptane (350 mL) was added to the residue and
solids were removed by filtration. The filtrate was concd in vacuo
and the crude product was purified by silica gel chromatography
using a gradient of 10 to 50% EtOAc in heptane over 7 column
volumes to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate as a
scalemic mixture of diastereomers, predominantly (1S,2R)-ethyl
2-ethyl-4-oxocyclopentanecarboxylate (13.68 g, 54%) as a colorless
oil. H NMR (400 MHz, CDCl.sub.3) .delta. 4.17 (qd, J=7.1, 1.5, 2H),
3.25-3.18 (m, 1H), 2.55 (m, J=4.7, 3.5, 1.7, 1H), 2.46-2.29 (m,
3H), 2.21 (m, J=11.6, 9.8, 1.3, 1H), 1.53 (m, J=14.8, 7.4, 6.1,
1H), 1.42-1.30 (m, 1H), 1.27 (t, J=7.1, 3H), 0.98 (t, J=7.4,
3H).
Step C: (ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate
##STR01197##
[2159] To a solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate
(12.82 g, 69.6 mmol, 86% ee, predominantly 1S, 2R) in MeOH (183 mL)
was added sodium borohydride (3.29 g, 87 mmol) portion-wise. The
suspension was stirred at ambient temperature for about 16 h.
Saturated aqueous NH.sub.4Cl (200 mL) was added and the reaction
was stirred for about 3 h. The white precipitate that formed was
filtered and washed with Et.sub.2O (100 mL). The filtrate was
poured into Et.sub.2O (300 mL). The solid was filtered and washed
with Et.sub.2O (50 mL). The layers were separated and the aqueous
layer was extracted with Et.sub.2O (2.times.150 mL). The combined
organic layers were washed with brine (2.times.150 mL), dried over
anhydrous MgSO.sub.4, filtered and concd under reduce pressure
(keeping bath temperature about 25.degree. C. and vacuum >50
psi) to give a crude product as a thick light yellow oil. The oil
was washed with pentane (5.times.80 mL). The combined pentane
layers were dried over anhydrous MgSO.sub.4, filtered and concd to
give an oil which was purified by silica gel chromatography using
1:1 EtOAc:pentane to give ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate as a scalemic mixture of
diastereomers predominantly (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (12.38 g, 96%) as a clear
oil; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.34-4.25 (m, 1H),
4.23-4.09 (m, 2H), 3.43-3.17 (m, 1H), 2.88 (td, J=7.1, 2.2, 1H),
2.40 (dt, J=14.0, 7.8, 1H), 2.09-1.91 (m, 3H), 1.33-1.24 (m, 4H),
0.95 (t, J=7.4, 3H).
Step D: (ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
##STR01198##
[2161] To a solution of ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (10.0 g, 53.7 mmol) in DMF
(18 mL) was added TBDMS-Cl (9.72 g, 64.5 mmol) and imidazole (9.15
g, 134 mmol). The reaction mixture was stirred at ambient
temperature for about 3 h. Heptane (50 mL) was added to the
reaction and the layers were separated. The bottom layer was
extracted with heptane (2.times.30 mL). The combined organic
extracts were washed with water (2.times.30 mL), brine (30 mL),
dried over anhydrous MgSO.sub.4, filtered and concd to give ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
(15.87 g, 52.8 mmol, 98%) as a colorless oil; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.13 (m, 3H), 2.79 (m, 1H), 2.09 (m, 1H), 1.99
(m, 3H), 1.50-1.24 (m, 6H), 0.89 (m, 12H), 0.05 (s, 6H).
Step E: ethyl
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate
##STR01199##
[2163] To a solution of ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
(0.100 g, 0.333 mmol) in MeCN (2.2 mL) was added triethylsilane
(0.080 mL, 0.499 mmol) and bismuth(III) bromide (0.010 g, 0.022
mmol). The reaction mixture was stirred at ambient temperature for
about 1 min followed by dropwise addition of
dihydro-2H-pyran-4(3H)-one (0.050 g, 0.499 mmol). The reaction
mixture was stirred at ambient temperature for about 15 min. The
reaction was filtered through an Acrodisc.RTM. and the solvent was
removed under reduced pressure. To a solution of ethyl
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate
(0.200 g, 0.666 mmol) in MeCN (4.5 mL) was added triethylsilane
(0.160 mL, 1.00 mmol) and bismuth(III) bromide (0.020 g, 0.045
mmol). The reaction mixture was stirred at ambient temperature for
about 1 min followed by dropwise addition of
dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol). The reaction
mixture was stirred at ambient temperature for about 15 min. The
reaction was filtered through an Acrodisc.RTM. and the solvent was
removed under reduced pressure. The residues were dissolved in DCM
(2 mL) each, combined, and the crude material was purified by
silica gel chromatography using a gradient of 10-100% EtOAc in
heptane to give ethyl
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate
(0.253 g, 98%) as a colorless oil; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.13 (q, J=7.1, 2H), 4.05-3.98 (m, 1H),
3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m, 2H), 2.80 (q,
J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H),
1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2,
1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).
Step F:
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic
acid
##STR01200##
[2165] To a solution of ethyl
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid
(0.250 g, 0.925 mmol) in p-dioxane (15 mL) was added aqueous NaOH
(1 M, 5.00 mL, 5.00 mmol) to give a colorless solution. The
reaction was heated at about 70.degree. C. for about 8 h. The
reaction mixture was cooled to ambient temperature. The solvent was
removed under reduced pressure. The solution was diluted with
Et.sub.2O (30 mL). The layers were separated and the aqueous layer
was extracted with Et.sub.2O (30 mL). The organic layer was set
aside. The aqueous layer was acidified with 5 N HCl (2 mL) to about
pH 2. The solution was diluted with Et.sub.2O (30 mL). The layers
were separated and the aqueous layer was extracted with Et.sub.2O
(3.times.30 mL). The combined organic extracts were dried over
anhydrous MgSO.sub.4, filtered and coned under reduced pressure to
give 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic
acid containing 6 mol % of 1,4-dioxane as an excipient (0.194 g,
85%) as a colorless oil; LC/MS (Table 1, Method b) R.sub.t=1.71
min; MS m/z: 243 (M+H).sup.+.
Step G:
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N'-(5-tosyl-1H-pyrrolo[2,3-
-b]pyrazin-2-yl)cyclopentanecarbohydrazide
##STR01201##
[2167] To a solution of
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.233 g, 0.767
mmol, WO2009152133 Preparation #9) and
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid
(0.190 g, 0.767 mmol) in DCM (8.00 mL) was added HATU (0.350 g,
0.920 mmol, Novabiochem) and TEA (0.43 mL, 3.07 mmol). The
resulting suspension was stirred at ambient temperature for about 4
h. The reaction was partitioned between DCM (50 mL) and water (25
mL) and the layers were separated. The organic layer was washed
with water (2.times.25 mL) and brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd to give a brown residue. The crude
material was purified by silica gel chromatography using a gradient
of 1-10% MeOH in DCM to give
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyra-
zin-2-yl)cyclopentanecarbohydrazide (0.300 g, 74%); LC/MS (Table 1,
Method b) R.sub.t=2.20 min; MS m/z: 528 (M+H).sup.+.
Step H:
1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H--
pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01202##
[2169] To a solution of
2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyraz-
in-2-yl)cyclopentanecarbohydrazide (0.150 g, 0.284 mmol) in
p-dioxane (5.00 mL) was added DIEA (0.200 mL, 1.146 mmol) and
thionyl chloride (0.031 mL, 0.426 mmol). The reaction mixture was
heated at about 80.degree. C. for about 1 h, then cooled to ambient
temperature. The reaction mixture was diluted with EtOAc (50 mL),
washed with H.sub.2O (3.times.25 mL) and brine (2.times.25 mL). The
aqueous layers were back extracted with EtOAc (2.times.30 mL). The
combined organic layers were dried with anhydrous MgSO.sub.4,
filtered and concd to give
1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.145 g, 100%); LC/MS (Table
1, Method b) R.sub.t=2.26 min; MS m/z: 510 (M+H).sup.+.
Step I:
1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01203##
[2171] To a solution of
1-(2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6-tosyl-6H-pyrrolo-
[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.145 g, 0.285 mmol)
inp-dioxane (6.00 mL) was added an aqueous solution of NaOH (1 N,
1.50 mL, 1.50 mmol). The reaction mixture was stirred at about
55.degree. C. for about 45 min, then cooled to ambient temperature.
The reaction mixture was acidified to about pH 2 by the addition of
aqueous HCl (1 N, 6 mL). The aqueous layer was extracted with DCM
(3.times.20 mL). The combined organic layers were dried over
anhydrous MgSO.sub.4, filtered and coned to give a brown residue.
The crude material was purified by silica gel chromatography using
a gradient of 1-10% MeOH in DCM. The stereoisomers were separated
using AA (Table 2, Method 32, R.sub.t=15.5 min, or =negative) to
give
1-((1S,2R,4S)-2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentyl)-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.048 g, 48%): LC/MS
(Table 1, Method a) R.sub.t=1.70 min; MS m/z: 356 (M+H).sup.+.
Example #23
N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cycl-
opentyl)cyclopropanesulfonamide
##STR01204##
[2172] Step A: 4-chloro-3-iodo-5-nitropyridin-2-amine
##STR01205##
[2174] A solution of 4-chloro-3-iodopyridin-2-amine (0.25 g, 0.982
mmol, Boa Pharma) in concd H.sub.2SO.sub.4 (1.95 mL) was cooled to
about 0.degree. C. before the portion wise addition of potassium
nitrate (0.21 g, 2.2 mmol) over 10 min. The reaction was stirred
for about 4 h at about 0.degree. C. The reaction mixture was slowly
pipetted over a solution of ammonium hydroxide and crushed ice (10
mL) in an ice bath. The pH of the reaction was maintained above 9
by the incremental addition of ammonium hydroxide. The resulting
precipitate is filtered and dried to afford
4-chloro-3-iodo-5-nitropyridin-2-amine (0.085 g, 29%) as a
green-tinted solid LC/MS (Table 1, Method n) R.sub.t=0.64 min; MS
m/z: 298 (M-H).sup.-.
Step B:
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine
##STR01206##
[2176] To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine
(5.30 g, 17.7 mmol) in THF (90 mL) was added TEA (15.0 mL, 108
mmol). The reaction mixture was degassed and purged with nitrogen 3
times. Bis(triphenylphosphine)-palladium(II)dichloride (0.62 g,
0.88 mmol, Strem), copper(I) iodide (0.17 g, 0.89 mmol), and
trimethylsilylacetylene (5.4 mL, 39 mmol) were added to the
reaction mixture, degassed, and purged 3 times with nitrogen. The
reaction was heated at about 60.degree. C. for about 16 h. The
reaction mixture was cooled to ambient temperature. The reaction
mixture was filtered and washed with THF (200 mL). The filtrate was
concd under reduced pressure. DCM (100 mL) was added to the residue
and the precipitate that formed was filtered and collected to give
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77
g). The remaining filtrate was concd under reduced pressure and the
crude material was purified by flash chromatography on silica gel
eluting with a gradient of 0-100% EtOAc in DCM. The purified
material was combined with the 0.77 g of precipitate to afford
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22
g, 47%) as a yellow solid: LC/MS (Table 1, Method c) R.sub.t=1.62
min; MS m/z 268 (M-H).sup.-.
Step C: 4-chloro-3-ethynyl-5-nitropyridin-2-amine
##STR01207##
[2178] To a solution of
4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98
g, 7.34 mmol) in DMF (25 mL) was added potassium fluoride on
alumina (40 wt %, 2.67 g, 18.35 mmol). The suspension was stirred
at ambient temperature for about 1 h. Activated charcoal (0.3 g)
was added and the suspension was filtered though Celite.RTM.,
washing with DMF (150 mL). The solvent was removed under reduced
pressure and the crude material was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to
afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g, 71%) as a
yellow solid: LC/MS (Table 1, Method n) R.sub.t=0.59 min; MS m/z:
196 (M-H).sup.-.
Step D: 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
##STR01208##
[2180] To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine
(0.16 g, 0.81 mmol) in DMF (3 mL) was added
chloro(1,5-cyclooctadiene)rhodium (I) dimer (0.02 g, 0.04 mmol) and
tris(4-fluorophenyl)phosphine (0.128 g, 0.405 mmol). The reaction
mixture was degassed by bubbling argon for 15 min. The reaction
mixture was heated at about 80.degree. C. for about 45 min. The
solvent was removed under reduced pressure and the residue was
suspended in ether (10 mL). The precipitate was collected by
filtration and dried to give
4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g, 83%, contains
approximately 6% mol of DMF and approximately 3% mol of
tris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1,
Method a) R.sub.t=2.05 min; MS m/z 198 (M+H).sup.+.
Step E:
N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonam-
ide
##STR01209##
[2182] To a mixture of
(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic
acid (Preparation #Z.1, 1.00 g, 3.83 mmol) in t-BuOH (19.1 mL) was
added DPPA (0.826 mL, 3.83 mmol) and TEA (1.17 mL, 8.42 mmol). The
reaction mixture was heated at about 70.degree. C. for about 45
min. The reaction mixture was cooled to ambient temperature and
coned under reduced pressure. The crude material was purified by
silica gel chromatography eluting with a gradient of 0-10% MeOH in
DCM. The material was dried under reduced pressure to give
N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide
with 30 mol % of t-BuOH as an excipient (0.97 g, 98%) as a
colorless oil: LC/MS (Table 1, Method n) R.sub.t=0.56 min; MS m/z
259 (M+H).sup.+-.
Step F:
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide
hydrochloride
##STR01210##
[2184] A mixture of
N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide
(0.972 g, 3.76 mmol) and aqueous HCl (6 N, 31.4 mL, 188 mmol) was
heated at about 100.degree. C. for about 60 h. Aqueous HCl (12 N, 5
mL) was added and the reaction mixture was heated at about
100.degree. C. for about 18 h. The reaction mixture was cooled to
ambient temperature and concd under reduced pressure. The residue
was treated with Et.sub.2O (10 mL) and EtOAc (10 mL). The mixture
was concd under reduced pressure. Water (5 mL) was added and the
sample was lyophilized to give
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropane-sulfonamide
hydrochloride (0.859 g, 85%) as a white solid: LC/MS (Table 1,
Method a) R.sub.t=1.28 min; MS m/z 233 (M+H).sup.+.
Step G:
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamin-
o)cyclopentyl)cyclopropanesulfonamide
##STR01211##
[2186] To a mixture of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine
(0.158 g, 0.800 mmol) in DMF (8.7 mL) was added DIEA (0.419 mL,
2.399 mmol) and
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide.hydrochl-
oride (0.215 g, 0.800 mmol). The reaction mixture was heated at
about 60.degree. C. for about 60 h. The temperature was increased
to about 70.degree. C. for about 2 h then DIEA (0.279 mL, 1.599
mmol) and
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide
hydrochloride (0.093 g, 0.346 mmol) were added. The reaction
mixture was heated at about 70.degree. C. for about 2 h. Additional
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide
hydrochloride (0.060 g, 0.223 mmol) was added and the reaction
mixture was heated at about 70.degree. C. for about 30 min.
Additional DIEA (0.279 mL, 1.599 mmol) was added and the reaction
mixture was heated at about 70.degree. C. for about 1 h. The
reaction mixture was cooled to ambient temperature and concd in
vacuo. The residue was dissolved in EtOAc (25 mL) and washed with
water (20 mL). The organic layer was separated, dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure.
The crude material was purified by silica gel chromatography
eluting with a gradient of 0-5% MeOH in DCM to give
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclo-
pentyl)cyclopropanesulfonamide (0.134 g, 41%) as an orange solid:
LC/MS (Table 1, Method n) R.sub.t=0.66 min; MS m/z 394
(M+H).sup.+.
Step H:
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin--
4-ylamino)cyclopentyl)cyclopropanesulfonamide
##STR01212##
[2188] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclo-
pentyl)cyclopropanesulfonamide (0.123 g, 0.314 mmol) in DMF (3.0
mL) at about 0.degree. C. was added NaH (60% in mineral oil, 0.015
g, 0.37 mmol). The reaction mixture was stirred for about 5 min.
4-Methylbenzene-1-sulfonyl chloride (0.060 g, 0.314 mmol) was added
and the reaction mixture was stirred for about 30 min. Additional
NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added and the
reaction mixture was stirred for about 10 min. Additional NaH (60%
in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction
mixture was stirred for about 15 min. Additional
4-methylbenzene-1-sulfonyl chloride (0.012 g, 0.063 mmol) was added
and the reaction mixture was stirred for about 40 min. The reaction
mixture was concd under reduced pressure. The residue was dissolved
in EtOAc (25 mL) and washed with water (15 mL). The organic layer
was separated, dried over anhydrous MgSO.sub.4, filtered and concd
under reduced pressure to give
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylami-
no)cyclopentyl)-cyclopropanesulfonamide (0.218 g) as a red-orange
oil containing 40 mol % DMF and 1 equivalent EtOAc: LC/MS (Table 1,
Method n) R.sub.t=0.88 min; MS m/z 548 (M+H).sup.+.
Step I:
N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamin-
o)-4-ethylcyclopentyl)cyclopropanesulfonamide
##STR01213##
[2190] To a suspension of
N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylami-
no)cyclopentyl)cyclopropanesulfonamide (0.172 g, 0.314 mmol) in
EtOH (6 mL) was added tin (II) chloride dihydrate (0.142 g, 0.628
mmol). The reaction mixture was heated at about 75.degree. C. for
about 15 h. Tin (II) chloride dihydrate (0.128 g, 0.565 mmol) was
added and the reaction mixture was heated at about 70.degree. C.
for about 40 min then heated at about 80.degree. C. for about 3 h.
The reaction was cooled to ambient temperature and the solvent was
removed under reduced pressure.
[2191] The reaction mixture was diluted with EtOAc (20 mL) and
washed with 1N aqueous NaOH (10 mL), water (10 mL) and brine (10
mL). The organic layer was separated, dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. EtOH (10 mL)
was added and the mixture was concd under reduced pressure to give
N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-et-
hylcyclopentyl)cyclopropanesulfonamide (0.160 g, 98%) as a yellow
oil: LC/MS (Table 1, Method n) R.sub.t=0.75 min; MS m/z 518
(M+H).sup.+.
Step J:
N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridi-
n-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide
##STR01214##
[2193] A mixture of
N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-et-
hylcyclopentyl)cyclopropanesulfonamide (0.160 g, 0.309 mmol),
trimethyl orthoformate (3.42 mL, 30.9 mmol) and toluene-4-sulfonic
acid hydrate (0.006 g, 0.031 mmol) in MeOH (3.1 mL) was heated at
about 65.degree. C. for about 1 h then heated at about 60.degree.
C. for about 14 h. The reaction mixture was cooled to ambient
temperature and concd under reduced pressure. The residue was
dissolved in EtOAc (10 mL) and washed with saturated aqueous
NaHCO.sub.3 (5 mL), water (5 mL), and brine (5 mL). The organic
layer was separated, dried over anhydrous MgSO.sub.4, filtered and
concd under reduced pressure to give
N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)cyclopentyl)cyclopropanesulfonamide as a yellow solid (0.130 g,
76%): LC/MS (Table 1, Method n) R.sub.t=0.76 min; MS m/z 528
(M+H).sup.+.
Step K:
N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)cyclopentyl)cyclopropanesulfonamide
##STR01215##
[2195] A mixture of
N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-
-yl)cyclopentyl)cyclopropanesulfonamide (0.119 g, 0.214 mmol) and
1N aqueous NaOH (0.428 mL, 0.428 mmol) in 1,4-dioxane (2 mL) was
heated at about 80.degree. C. for about 40 min. Aqueous NaOH (1 N,
0.428 mL, 0.428 mmol) was added and the reaction mixture was heated
at about 80.degree. C. for about for 3.5 h. The reaction mixture
was cooled to ambient temperature and concd under reduced pressure.
The residue was dissolved in EtOAc (10 mL) and water (10 mL). The
pH was adjusted to about 5 by the addition of 1 N aqueous HCl. The
organic layer was separated, dried over anhydrous MgSO.sub.4,
filtered and concd under reduced pressure. The residue was
triturated with Et.sub.2O (5 mL) and the solvent was removed by
pippette. The residue was dried under reduced pressure to give a
bright yellow solid that was purified by chiral chromatography
[Table 2, Method 39, R.sub.t=16.6 min, or =negative) to give
N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyc-
lopentyl)cyclopropanesulfonamide (0.036 g, 45%): LC/MS (Table 1,
Method a) R.sub.t=1.71 min; MS m/z 374 (M+H).sup.+.
Example #24
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentyl)cyclopropanesulfonamide
##STR01216##
[2196] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01217##
[2198] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01218##
[2200] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with 100% DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate
##STR01219##
[2202] CO was bubbled into an orange solution of
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF
(2.50 L) within a 5 L round bottom flask for about 2 min.
Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2
mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were
added and the flask was fitted with a balloon of CO. The mixture
was heated at about 95.degree. C. under an atmosphere of CO (1
atmosphere). After stirring overnight, the reaction mixture was
cooled to ambient temperature overnight and poured into ice water
(3.2 L). The mixture was stirred for about 10 min and the
precipitate was collected by filtration, while washing with water,
and dried for 1 h. The crude material was dissolved in DCM,
separated from residual water, dried over anhydrous MgSO.sub.4,
filtered, added silica gel, and coned under reduced pressure to
prepare for chromatography. The crude material was purified by
silica gel column chromatography eluting with 0-5% MeOH in DCM to
yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5
mol % DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table
1, Method a) R.sub.t=2.35 min; MS m/z 332 (M+H).sup.+.
Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid
##STR01220##
[2204] HCl (6 N aqueous, 714 mL) was added to a yellow solution of
methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g,
53.6 mmol) in 1,4-dioxane (715 mL) within a 2 L round bottom flask,
and the mixture was heated at about 60.degree. C. for about 16 h.
The reaction mixture was cooled to ambient temperature. The organic
solvent was removed under reduced pressure and the precipitate was
collected, washed with water, and dried to yield
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%)
as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.63 min; MS
m/z 316 (M-H).sup.-.
Step E: tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
##STR01221##
[2206] In a 500 mL round bottom flask,
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3
mmol), DPPA (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100 mmol) in
t-BuOH (200 mL) were added to give an orange suspension. The
mixture was heated at about 70.degree. C. for about 16 h, cooled to
ambient temperature and the insoluble material was filtered. The
solvent was removed under reduced pressure and the crude material
was purified by silica gel column chromatography eluting with
25-60% EtOAc in heptane over 30 min to yield tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as an
off-white solid: LC/MS (Table 1, Method a) R.sub.t=2.79 min; MS m/z
389 (M+H).sup.+.
Step F: sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
##STR01222##
[2208] In a 12 L round bottom flask, NaH (60% dispersion in mineral
oil, 159 g, 3985 mmol) was added in portions to stirred anhydrous
THF (4004 mL) to give a gray suspension. The mixture was cooled to
about 5.degree. C. in an ice/salt bath before ethyl acetoacetate
(506 mL, 3985 mmol, Alfa Aesar) in anhydrous THF (200 mL) was added
dropwise via an addition funnel over about 1 h during which time
the temperature gradually increased to about 18.degree. C. After
the addition was complete, the reaction was stirred at ambient
temperature for about 1 h and then a solution of methyl
4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF
(200 mL) was added dropwise via an addition funnel over about 1 h.
The resulting mixture was stirred at ambient temperature for about
2 h and then heated at about 50.degree. C. for about 16 h. The
reaction mixture was coned in vacuo. The orange solid was cooled to
about 5.degree. C. and an ice/water mixture (2 L) was added. The
suspension was mixed by rotating on the rotovap without vacuum for
about 30 min. The solid was collected by filtration and washed with
ice-cold water (750 mL). Once most of the solvent (about 90%) had
been removed, the wet solid was triturated with MeCN (750 mL),
stirred for about 30 min and then the solid was collected by
filtration while washing with Et.sub.2O (2.times.500 mL). The solid
was dried in air for about 16 h and then in vacuo at about
55.degree. C. to give sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 98%): .sup.1H NMR (DMSO-d.sub.6) .delta. 3.95 (q, J=7.1 Hz,
2H), 3.48 (s, 3H), 2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H),
1.15 (t, J=7.1 Hz, 3H).
Step G: ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate
##STR01223##
[2210] In a 5 L round bottom flask, sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392
mL, 6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL)
were heated at reflux for about 6 h. The reaction mixture was
allowed to cool to ambient temperature for about 16 h. The reaction
mixture was then poured into a 12 L flask and diluted with water (3
L). Solid NaHCO.sub.3 (450 g, 5.3 mol) was added cautiously
portionwise with stirring over about 1 h. After about an additional
30 min of stirring, the basic aqueous phase was separated and
further extracted with Et.sub.2O (4.times.400 mL). The combined
organic layers were washed with water (4.times.500 mL) and brine
(500 mL), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to yield a yellow oil that was purified by
vacuum distillation (92-94.degree. C., 0.4 mmHg) to give ethyl
2-methyl-4-oxocyclopent-2-enecarboxylate (229 g, 69%) as a yellow
oil: .sup.1H NMR (CDCl.sub.3) .delta. 6.04-6.01 (m, 1H), 4.26-4.17
(m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s, 3H),
1.32-1.27 (t, J=7.1 Hz, 3H).
Step H: ethyl 2-methyl-4-oxycyclopentanecarboxylate
##STR01224##
[2212] In a 1 L round bottom flask jacketed flask, copper(I)
chloride (0.736 g, 7.43 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4.63 g, 7.43
mmol), and sodium tert-butoxide (0.714 g, 7.43 mmol) in toluene
(250 mL) were added to give a yellow solution. The mixture was
stirred at ambient temperature for about 15 min. after which the
solution became brown. The solution was cooled to about 5.degree.
C. and polymethylhydrosiloxane (14.86 mL, 223 mmol) was added and
the solution was stirred at about 5.degree. C. for about 40 min.
The solution was cooled to about -15.degree. C. and a solution of
ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 149 mmol)
and tert-butyl alcohol (61.7 mL, 654 mmol) in toluene (250 mL) was
added in one portion. The reaction was stirred at -15.degree. C.
for 144 h. The reaction mixture was quenched by the addition of 1:1
ethanol/toluene (350 mL) and Celite.RTM. 545 (25 g). The mixture
was stirred and allowed to warm to ambient temperature. The
reaction mixture was concd in vacuo, chasing with heptane. Heptane
(350 mL) was added to the residue and solids were removed by
filtration. The filtrate was concd in vacuo and the crude product
was purified by silica gel chromatography using a gradient of 10 to
50% EtOAc in heptane over 7 column volumes to give ethyl
2-methyl-4-oxocyclopentanecarboxylate (scalemic mixture of
diastereomers), predominantly (1S,2R)-ethyl
2-methyl-4-oxocyclopentanecarboxylate (11.2 g, 42% yield) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.19 (qd,
J=7.1, 0.6, 2H), 3.17 (ddd, J=8.1, 6.8, 5.6, 1H), 2.76-2.56 (m,
2H), 2.67-2.46 (m, 2H), 2.43-2.29 (m, 2H), 2.16 (ddd, J=18.3, 7.8,
1.7, 1H), 1.29 (t, J=7.2, 3H), 1.06 (d, J=7.0, 3H).
Step I: ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
##STR01225##
[2214] A round bottom flask was charged with ethyl
2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE
(180 mL). The solution was cooled to about 0.degree. C. and AcOH
(5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were
added dropwise, resulting in formation of a thick suspension. The
reaction mixture was warmed to about 10.degree. C. and sodium
triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise. The
reaction mixture was stirred at ambient temperature for about 20 h
then slowly poured into stirred saturated aqueous NaHCO.sub.3 (300
mL) and stirred for about 20 min. The layers were separated and the
aqueous phase was extracted with DCM (3.times.100 mL). The combined
organic extracts were washed with brine (2.times.100 mL), dried
over anhydrous Na.sub.2SO.sub.4, and concd under reduced pressure.
The crude yellow oil was purified via silica gel chromatography
eluting with a gradient of 0-30% EtOAc in heptane to give ethyl
4-(dibenzylamino)-2-methylcyclopentanecarboxylate (scalemic mixture
of diastereomer), predominantly (1S,2R,4S)-ethyl
4-(dibenzylamino)-2-methylcyclopentanecarboxylate) (15.5 g, 75%) as
a colorless oil: .sup.1H NMR (pyridine-d.sub.5) .delta. 7.53 (dd,
J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06
(m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H),
3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m,
1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5
Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Step J: 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
##STR01226##
[2216] Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
(3.65 g, 10.38 mmol) was dissolved in a mixture of HCl (6 N
aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture
was heated at about 60.degree. C. for about 72 h. The organic
solvent was removed under reduced pressure. The aqueous phase was
neutralized by the addition of saturated aqueous NaHCO.sub.3 (40
mL) and extracted with EtOAc (50 mL). The organic layer was washed
with brine (40 mL), dried over anhydrous MgSO.sub.4 and concd under
reduced pressure to yield
4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%)
as a white amorphous solid: LC/MS (Table 1, Method a) R.sub.t=1.66
min; MS m/z 324 (M+H).sup.+.
Step K:
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone
##STR01227##
[2218] Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a
solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
(7.34 g, 22.7 mmol) in DCM (100 mL), (note: mild gas evolution)
followed by a dropwise addition of DMF (0.26 mL, 3.41 mmol). The
mixture was stirred at ambient temperature for about 14 h. The
solvent was removed under reduced pressure to yield a beige
amorphous solid, which was dissolved in THF and MeCN (1:1, 100 mL).
The resulting solution was added to a solution of
trimethylsilyldiazomethane (2 M in Et.sub.2O, 39.7 mL, 79 mmol) in
THF and MeCN (1:1, 100 mL) at about 0.degree. C. The resulting
mixture was stirred at about 0.degree. C. for about 3 h and then
was quenched by a dropwise addition of HBr (48% aqueous, 25 mL, 221
mmol). The resulting mixture was neutralized by a dropwise addition
of saturated aqueous NaHCO.sub.3 (300 mL) and the layers were
separated. The organic layer was dried over anhydrous MgSO.sub.4
and concd under reduced pressure. The residue was purified by
silica gel chromatography eluting with 5% to 45% of EtOAc in
heptane to yield
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g,
69%) as a yellow oil: LC/MS (Table 1, Method a) R.sub.t=2.90 min;
MS m/z 400, 402 (M+H).sup.+.
Step L: tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate
##STR01228##
[2220] A solution of tert-buty
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol,
Example #3 Step E) in DMF (5 mL) was added dropwise to a suspension
of NaH (60% dispersion in mineral oil, 0.058 g, 1.45 mmol) in DMF
(5 mL), at about 0.degree. C. The resulting mixture was stirred at
about 0.degree. C. for about 30 min and then added dropwise to a
solution of
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g,
1.8 mmol) in DMF (10 mL) at about 0.degree. C. The resulting
mixture was stirred at about 0.degree. C. for about 1 h and the
solvent was removed under reduced pressure. The residue was
partitioned between saturated aqueous NaHCO.sub.3 and EtOAc (100 mL
each). The organic phase was separated, dried over anhydrous
MgSO.sub.4 and concd under reduced pressure to yield tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous
solid: LC/MS (Table 1, Method a) R.sub.t=3.30 min; MS m/z 708
(M+H).sup.+.
Step M:
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,-
3-b]pyrazin-2-ylamino)ethanone
##STR01229##
[2222] tert-Butyl
2-(4-(dibenzylamino-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,-
3-b]pyrazin-2-yl)carbamate (6.19 g, 8.75 mmol) was dissolved in HCl
(4 N in 1,4-dioxane, 25 mL). The reaction mixture was stirred at
ambient temperature for about 2 h. The solvent was removed under
reduced pressure and the residue was partitioned between saturated
aqueous NaHCO.sub.3 and EtOAc (100 mL each). The organic phase was
washed with brine (80 mL), dried over anhydrous MgSO.sub.4 and
concd under reduced pressure to yield
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.2 g, 98%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=3.00 min; MS m/z 608
(M+H).sup.+.
Step N:
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]py-
razin-8-yl)cyclopentanamine
##STR01230##
[2224] A mixture of
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.32 g, 8.75 mmol) and Lawesson's reagent
(1.88 g, 4.64 mmol) was heated at about 60.degree. C. for about 2
h. Lawesson's reagent (1.88 g, 4.64 mmol) was added. The reaction
mixture was stirred at about 60.degree. C. for about 1 h. The
solvent was removed under reduced pressure and the residue was
purified by silica gel chromatography eluting with a gradient of
0-8% MeOH in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=2.99 min; MS m/z 590
(M+H).sup.+.
Step O:
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-met-
hylcyclopentanamine
##STR01231##
[2226]
N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyr-
azin-8-yl)cyclopentanamine (4.47 g, 7.58 mmol) was dissolved in
1,4-dioxane (40 mL). NaOH (2 N aqueous, 4 mL) was added and the
reaction mixture was heated at about 90.degree. C. for about 80
min. The organic solvent was removed under reduced pressure and the
residue was treated with saturated aqueous NH.sub.4Cl (70 mL) and
extracted with DCM (2.times.60 mL). The combined organic extracts
were washed with brine (70 mL), dried over anhydrous MgSO.sub.4 and
concd under reduced pressure. The residue was purified by silica
gel chromatography eluting with a gradient of 0-8% MeOH in DCM to
yield
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentan-amine (1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method
a) R.sub.t=2.31 min; MS m/z 436 (M+H).sup.+.
Step P:
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-i-
midazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine
##STR01232##
[2228] To the suspension of sodium hydride (60% dispersion in
mineral oil, 0.382 g, 9.55 mmol) in DMF (50 mL) was added drop-wise
a solution of
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentanamine (3.96 g, 9.09 mmol) in DMF (50 mL) at 0.degree. C. The
resulting solution was stirred at ambient temperature for about 10
min. SEM chloride (1.774 mL, 10.0 mmol) was added drop-wise and the
solution was stirred for about 1 h. The solvent was removed under
reduced pressure and the residue was partitioned between water and
EtOAc (200 mL each). The organic layer was washed with brine (100
mL), dried over anhydrous MgSO.sub.4, filtered and concd. The
residue was purified by silica gel chromatography eluting with
10-80% EtOAc in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[-
1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.1 g, 60%
yield) as an off-white amorphous solid. LC/MS (Table 1, Method a)
R.sub.t=3.32 min; MS m/z 566 (M+H).sup.+.
Step Q:
3-Methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]-
pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine
##STR01233##
[2230] To a solution of
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[-
1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.0 g, 5.30
mmol) in trifluoroethanol (200 mL) was added 20% wet palladium
hydroxide on carbon (0.6 g, 4.27 mmol). The mixture was stirred
under 40 psi of hydrogen at about 50.degree. C. for about 90 min.
The catalyst was removed by filtration through a pad of Celite.RTM.
and the filtrate was concd under reduced pressure to yield
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentanamine (2.0 g, 98% yield) as a brown
amorphous solid. LC/MS (Table 1, Method a) R.sub.t=1.86 min; MS m/z
386 (M+H).sup.+.
Step R:
N-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-
-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide
##STR01234##
[2232] To a solution of
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentanamine (0.27 g, 0.7 mmol) and DIEA
(0.18 mL, 1.05 mmol) in DCM (5 mL) was added cyclopropanesulfonyl
chloride (0.098 g, 0.7 mmol) drop-wise. The resulting mixture was
stirred at ambient temperature for about 1 h. Another 0.18 mL of
DIEA and 0.098 g of cyclopropanesulfonyl chloride were added and
the reaction was continued for about 3 h. The solvent was removed
and the residue was partitioned between saturated aqueous ammonium
chloride and EtOAc (20 mL each). The organic layer was washed with
brine (10 mL), dried over anhydrous MgSO.sub.4, filtered and concd.
The residue was purified by silica gel chromatography (100% DCM for
5 min, then to 6% MeOH in DCM over next 30 min) to yield
N-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,
2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide
(0.18 g, 52% yield) as an off-white solid. LC/MS (Table 1, Method
a) R.sub.t=2.45 min; MS m/z 490 (M+H).sup.+.
Step S:
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-me-
thylcyclopentyl)cyclopropanesulfonamide
##STR01235##
[2234] To the solution of
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide (0.18 g,
0.368 mmol) in DCM (2.5 mL) was added TFA (0.9 mL). The resulting
mixture was stirred at ambient temperature for about 2 h. The
solvents were removed under reduced pressure and the residue dried
under high vacuum. The residue was dissolved in 1,4-dioxane (3 mL)
and 28% ammonium hydroxide solution in water (2.5 mL). The mixture
was heated at about 60.degree. C. for about 2 h. The solvents were
removed under reduced pressure and the residue was purified by
using general procedure AA (Table 2, Method 32, R.sub.t=20.9 min,
or =negative) to yield
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)cyclopropanesulfonamide (0.088 g, 66% yield) as a white
solid. LC/MS (Table 1, Method a) R.sub.t=1.52 min; MS m/z 360
(M+H).sup.+.
Example #25
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentyl)-3,3-difluoroazetidine-1-sulfonamide
##STR01236##
[2235] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01237##
[2237] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01238##
[2239] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate
##STR01239##
[2241] CO was bubbled into an orange solution of
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF
(2.50 L) within a 5 L round bottom flask for about 2 min.
Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2
mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were
added and the flask was fitted with a balloon of CO. The mixture
was heated at about 95.degree. C. under an atmosphere of CO (1
atmosphere). After stirring overnight, the reaction mixture was
cooled to ambient temperature overnight and poured into ice water
(3.2 L). The mixture was stirred for about 10 min and the
precipitate was collected by filtration, while washing with water,
and dried for 1 h. The crude material was dissolved in DCM,
separated from residual water, dried over anhydrous MgSO.sub.4,
filtered, added silica gel, and coned under reduced pressure to
prepare for chromatography. The crude material was purified by
silica gel column chromatography eluting with 0-5% MeOH in DCM to
yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5
mol % DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table
1, Method a) R.sub.t=2.35 min; MS m/z 332 (M+H).sup.+.
Step D: 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid
##STR01240##
[2243] HCl (6 N aqueous, 714 mL) was added to a yellow solution of
methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g,
53.6 mmol) in 1,4-dioxane (715 mL) within a 2 L round bottom flask,
and the mixture was heated at about 60.degree. C. for about 16 h.
The reaction mixture was cooled to ambient temperature. The organic
solvent was removed under reduced pressure and the precipitate was
collected, washed with water, and dried to yield
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%)
as a yellow solid: LC/MS (Table 1, Method a) R.sub.t=1.63 min; MS
m/z 316 (M-H).sup.-.
Step E: tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate
##STR01241##
[2245] In a 500 mL round bottom flask,
5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 45.3
mmol), DPPA (9.78 mL, 45.3 mmol) and TEA (13.9 mL, 100 mmol) in
t-BuOH (200 mL) were added to give an orange suspension. The
mixture was heated at about 70.degree. C. for about 16 h, cooled to
ambient temperature and the insoluble material was filtered. The
solvent was removed under reduced pressure and the crude material
was purified by silica gel column chromatography eluting with
25-60% EtOAc in heptane over 30 min to yield tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (9.75 g, 54%) as an
off-white solid: LC/MS (Table 1, Method a) R.sub.t=2.79 min; MS m/z
389 (M+H).sup.+.
Step F: sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
##STR01242##
[2247] In a 12 L round bottom flask, NaH (60% dispersion in mineral
oil, 159 g, 3985 mmol) was added in portions to stirred anhydrous
THF (4004 mL) to give a gray suspension. The mixture was cooled to
about 5.degree. C. in an ice/salt bath before ethyl acetoacetate
(506 mL, 3985 mmol, Alfa Aesar) in anhydrous THF (200 mL) was added
dropwise via an addition funnel over about 1 h during which time
the temperature gradually increased to about 18.degree. C. After
the addition was complete, the reaction was stirred at ambient
temperature for about 1 h and then a solution of methyl
4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF
(200 mL) was added dropwise via an addition funnel over about 1 h.
The resulting mixture was stirred at ambient temperature for about
2 h and then heated at about 50.degree. C. for about 16 h. The
reaction mixture was coned in vacuo. The orange solid was cooled to
about 5.degree. C. and an ice/water mixture (2 L) was added. The
suspension was mixed by rotating on the rotovap without vacuum for
about 30 min. The solid was collected by filtration and washed with
ice-cold water (750 mL). Once most of the solvent (about 90%) had
been removed, the wet solid was triturated with MeCN (750 mL),
stirred for about 30 min and then the solid was collected by
filtration while washing with Et.sub.2O (2.times.500 mL). The solid
was dried in air for about 16 h and then in vacuo at about
55.degree. C. to give sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 98%): .sup.1H NMR (DMSO-d.sub.6) .delta. 3.95 (q, J=7.1 Hz,
2H), 3.48 (s, 3H), 2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H),
1.15 (t, J=7.1 Hz, 3H).
Step G: ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate
##STR01243##
[2249] In a 5 L round bottom flask, sodium
4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate
(485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392
mL, 6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL)
were heated at reflux for about 6 h. The reaction mixture was
allowed to cool to ambient temperature for about 16 h. The reaction
mixture was then poured into a 12 L flask and diluted with water (3
L). Solid NaHCO.sub.3 (450 g, 5.3 mol) was added cautiously
portionwise with stirring over about 1 h. After about an additional
30 min of stirring, the basic aqueous phase was separated and
further extracted with Et.sub.2O (4.times.400 mL). The combined
organic layers were washed with water (4.times.500 mL) and brine
(500 mL), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to yield a yellow oil that was purified by
vacuum distillation (92-94.degree. C., 0.4 mmHg) to give ethyl
2-methyl-4-oxocyclopent-2-enecarboxylate (229 g, 69%) as a yellow
oil: .sup.1H NMR (CDCl.sub.3) .delta. 6.04-6.01 (m, 1H), 4.26-4.17
(m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s, 3H),
1.32-1.27 (t, J=7.1 Hz, 3H).
Step H: ethyl 2-methyl-4-oxocyclopentanecarboxylate
##STR01244##
[2251] In a 1 L round-bottomed flask jacketed flask, copper(I)
chloride (0.736 g, 7.43 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4.63 g, 7.43
mmol), and sodium tert-butoxide (0.714 g, 7.43 mmol) in toluene
(250 mL) were added to give a yellow solution. The mixture was
stirred at ambient temperature for about 15 min. after which the
solution became brown. The solution was cooled to about 5.degree.
C. and polymethylhydrosiloxane (14.86 mL, 223 mmol) was added and
the solution was stirred at about 5.degree. C. for about 40 min.
The solution was cooled to about -15.degree. C. and a solution of
ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 149 mmol)
and tert-butyl alcohol (61.7 mL, 654 mmol) in toluene (250 mL) was
added in one portion. The reaction stirred at -15.degree. C. for
144 h. The reaction mixture was quenched by the addition of 1:1
ethanol/toluene (350 mL) and Celite.RTM. 545 (25 g). The mixture
was stirred and allowed to warm to ambient temperature. The
reaction mixture was concd in vacuo, chasing with heptane. Heptane
(350 mL) was added to the residue and solids were removed by
filtration. The filtrate was concd in vacuo and the crude product
was purified by silica gel chromatography using a gradient of 10 to
50% EtOAc in heptane over 7 column volumes to give ethyl
2-methyl-4-oxocyclopentanecarboxylate (scalemic mixture of
diastereomers), predominantly (1S,2R)-ethyl
2-methyl-4-oxocyclopentanecarboxylate (11.2 g, 42% yield) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.19 (qd,
J=7.1, 0.6, 2H), 3.17 (ddd, J=8.1, 6.8, 5.6, 1H), 2.76-2.56 (m,
2H), 2.67-2.46 (m, 2H), 2.43-2.29 (m, 2H), 2.16 (ddd, J=18.3, 7.8,
1.7, 1H), 1.29 (t, J=7.2, 3H), 1.06 (d, J=7.0, 3H).
Step I: ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
##STR01245##
[2253] A round bottom flask was charged with ethyl
2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE
(180 mL). The solution was cooled to about 0.degree. C. and AcOH
(5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were
added dropwise, resulting in formation of a thick suspension. The
reaction mixture was warmed to about 10.degree. C. and sodium
triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise. The
reaction mixture was stirred at ambient temperature for about 20 h
then slowly poured into stirred saturated aqueous NaHCO.sub.3 (300
mL) and stirred for about 20 min. The layers were separated and the
aqueous phase was extracted with DCM (3.times.100 mL). The combined
organic extracts were washed with brine (2.times.100 mL), dried
over anhydrous Na.sub.2SO.sub.4, and concd under reduced pressure.
The crude yellow oil was purified via silica gel chromatography
eluting with a gradient of 0-30% EtOAc in heptane to give ethyl
4-(dibenzylamino)-2-methylcyclopentanecarboxylate (scalemic mixture
of diastereomers), predominantly (1S,2R,4S)ethyl
4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as
a colorless oil: .sup.1H NMR (pyridine-d.sub.5) .delta. 7.53 (dd,
J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06
(m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H),
3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m,
1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5
Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Step J: 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
##STR01246##
[2255] Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate
(3.65 g, 10.38 mmol) was dissolved in a mixture of HCl (6 N
aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture
was heated at about 60.degree. C. for about 72 h. The organic
solvent was removed under reduced pressure. The aqueous phase was
neutralized by the addition of saturated aqueous NaHCO.sub.3 (40
mL) and extracted with EtOAc (50 mL). The organic layer was washed
with brine (40 mL), dried over anhydrous MgSO.sub.4 and concd under
reduced pressure to yield
4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%)
as a white amorphous solid: LC/MS (Table 1, Method a) R.sub.t=1.66
min; MS m/z 324 (M+H).sup.+.
Step K:
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone
##STR01247##
[2257] Oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added to a
solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid
(7.34 g, 22.7 mmol) in DCM (100 mL), (note: mild gas evolution)
followed by a dropwise addition of DMF (0.26 mL, 3.41 mmol). The
mixture was stirred at ambient temperature for about 14 h. The
solvent was removed under reduced pressure to yield a beige
amorphous solid, which was dissolved in THF and MeCN (1:1, 100 mL).
The resulting solution was added to a solution of
trimethylsilyldiazomethane (2 M in Et.sub.2O, 39.7 mL, 79 mmol) in
THF and MeCN (1:1, 100 mL) at about 0.degree. C. The resulting
mixture was stirred at about 0.degree. C. for about 3 h and then
was quenched by a dropwise addition of HBr (48% aqueous, 25 mL, 221
mmol). The resulting mixture was neutralized by a dropwise addition
of saturated aqueous NaHCO.sub.3 (300 mL) and the layers were
separated. The organic layer was dried over anhydrous MgSO.sub.4
and concd under reduced pressure. The residue was purified by
silica gel chromatography eluting with 5% to 45% of EtOAc in
heptane to yield
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g,
69%) as a yellow oil: LC/MS (Table 1, Method a) R.sub.t=2.90 min;
MS m/z 400, 402 (M+H).sup.+.
Step L: tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate
##STR01248##
[2259] A solution of tert-butyl
5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol,
Example #3 Step E) in DMF (5 mL) was added dropwise to a suspension
of NaH (60% dispersion in mineral oil, 0.058 g, 1.45 mmol) in DMF
(5 mL), at about 0.degree. C. The resulting mixture was stirred at
about 0.degree. C. for about 30 min and then added dropwise to a
solution of
2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g,
1.8 mmol) in DMF (10 mL) at about 0.degree. C. The resulting
mixture was stirred at about 0.degree. C. for about 1 h and the
solvent was removed under reduced pressure. The residue was
partitioned between saturated aqueous NaHCO.sub.3 and EtOAc (100 mL
each). The organic phase was separated, dried over anhydrous
MgSO.sub.4 and concd under reduced pressure to yield tert-butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous
solid: LC/MS (Table 1, Method a) R.sub.t=3.30 min; MS m/z 708
(M+H).sup.+.
Step M:
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,-
3-b]pyrazin-2-ylamino)ethanone
##STR01249##
[2261] tert-Butyl
2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl-tosyl-5H-pyrrolo[2,3-
-b]pyrazin-2-yl)carbamate (6.19 g, 8.75 mmol) was dissolved in HCl
(4 N in 1,4-dioxane, 25 mL). The reaction mixture was stirred at
ambient temperature for about 2 h. The solvent was removed under
reduced pressure and the residue was partitioned between saturated
aqueous NaHCO.sub.3 and EtOAc (100 mL each). The organic phase was
washed with brine (80 mL), dried over anhydrous MgSO.sub.4 and
coned under reduced pressure to yield
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.2 g, 98%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=3.00 min; MS m/z 608
(M+H).sup.+.
Step N:
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]py-
razin-8-yl)cyclopentanamine
##STR01250##
[2263] A mixture of
1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyr-
azin-2-ylamino)ethanone (5.32 g, 8.75 mmol) and Lawesson's reagent
(1.88 g, 4.64 mmol) was heated at about 60.degree. C. for about 2
h. Additional Lawesson's reagent (1.88 g, 4.64 mmol) was added. The
reaction mixture was stirred at about 60.degree. C. for about 1 h.
The solvent was removed under reduced pressure and the residue was
purified by silica gel chromatography eluting with a gradient of
0-8% MeOH in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-
-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid:
LC/MS (Table 1, Method a) R.sub.t=2.99 min; MS m/z 590
(M+H).sup.+.
Step O:
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-met-
hylcyclopentanamine
##STR01251##
[2265]
N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyr-
azin-8-yl)cyclopentan-amine (4.47 g, 7.58 mmol) was dissolved in
1,4-dioxane (40 mL). NaOH (2 N aqueous, 4 mL) was added and the
reaction mixture was heated at about 90.degree. C. for about 80
min. The organic solvent was removed under reduced pressure and the
residue was treated with saturated aqueous NH.sub.4Cl (70 mL) and
extracted with DCM (2.times.60 mL). The combined organic extracts
were washed with brine (70 mL), dried over anhydrous MgSO.sub.4 and
coned under reduced pressure. The residue was purified by silica
gel chromatography eluting with a gradient of 0-8% MeOH in DCM to
yield
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentan-amine (1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method
a) R.sub.t=2.31 min; MS m/z 436 (M+H).sup.+.
Step P:
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-i-
midazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine
##STR01252##
[2267] To the suspension of sodium hydride (60% dispersion in
mineral oil, 0.382 g, 9.55 mmol) in DMF (50 mL) was added a
solution of
N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcycl-
opentanamine (3.96 g, 9.09 mmol) in DMF (50 mL) drop-wise at about
0.degree. C. The resulting solution was stirred at ambient
temperature for about 10 min. SEM chloride (1.774 mL, 10.0 mmol)
was added drop-wise and the solution was stirred for about 1 h. The
solvent was removed under reduced pressure and the residue was
partitioned between water and EtOAc (200 mL each). The organic
layer was washed with brine (100 mL), dried over anhydrous
MgSO.sub.4, filtered and concd. The residue was purified by silica
gel column chromatography eluting with 10-80% EtOAc in DCM to yield
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-im-
idazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.1 g, 60%
yield) as an off-white amorphous solid. LC/MS (Table 1, Method a)
R.sub.t=3.32 min; MS m/z 566 (M+H).sup.+.
Step Q:
3-Methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]-
pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine
##STR01253##
[2269] To a solution of
N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[-
1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.0 g, 5.30
mmol) in trifluoroethanol (200 mL) was added 20% wet palladium
hydroxide on carbon (0.6 g, 4.27 mmol). The mixture was stirred
under 40 psi of hydrogen at about 50.degree. C. for about 90 min.
The catalyst was removed by filtration through a pad of Celite.RTM.
and the filtrate was concd under reduced pressure to yield
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentanamine (2.0 g, 98% yield) as a brown
amorphous solid. LC/MS (Table 1, Method a) R.sub.t=1.86 min; MS m/z
386 (M+H).sup.+.
Step R:
N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2--
a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide
##STR01254##
[2271] To a solution of
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentanamine (0.50 g, 1.3 mmol) and
2-chloroethyl chlorosulfonylcarbamate (0.288 g, 1.297 mmol,
prepared as detailed in Biorg. Med. Chem. Lett, 2006 16, 3367-3370)
in DCM (16 mL) was added TEA (0.542 mL, 3.89 mmol) drop-wise. The
mixture was stirred at ambient temperature for about 2 h. The
solvent was removed under reduced pressure and the residue was
partitioned between water and EtOAc (30 mL each). The organic layer
was washed with brine (20 mL), dried over anhydrous MgSO.sub.4,
filtered and concd under reduced pressure. The residue was purified
by silica gel chromatography (0% DCM for 5 min, then to 6% MeOH in
DCM over the next 30 min.) to yield
N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrro-
lo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide
(0.24 g, 35% yield) as an off-white solid. LC/MS (Table 1, Method
a) R.sub.t=2.42 min; MS m/z 535 (M+H).sup.+.
Step S:
3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-
-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonam-
ide
##STR01255##
[2273] To a solution of
3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo-
[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide
(0.24 g, 0.449 mmol) in MeCN (1.5 mL) was added
(3,3-difluoroazetidine hydrochloride (0.07 g, 0.539 mmol, Matrix
Scientific) and DIEA (0.196 mL, 1.122 mmol). The mixture was heated
in the microwave at about 120.degree. C. for about 30 min. The
solvent was removed under reduced pressure and the residue was
partitioned between saturated solution of ammonium chloride in
water and EtOAc (20 mL each). The organic layer was washed with
brine (10 mL), dried over anhydrous MgSO.sub.4, filtered and concd
to yield
3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)--
3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfon-
amide (0.2 g, 82% yield) as an off-white amorphous solid. LC/MS
(Table 1, Method a) R.sub.t=2.61 min; MS m/z 541 (M+H).sup.+.
Step T:
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-me-
thylcyclopentyl)-3,3-difluoroazetidine-1-sulfonamide
##STR01256##
[2275] To a solution of
3,3-difluoro-N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidaz-
o[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)azetidine-1-sulfonamide
(0.20 g, 0.370 mmol) in DCM (2.5 mL) was added TFA (0.9 mL) The
resulting mixture was stirred at ambient temperature for about 2 h.
The solvents were removed under reduced pressure and the residue
was dried under high vacuum. The residue was dissolved in
1,4-dioxane (3 mL) and 28% ammonium hydroxide solution in water
(2.5 mL) and the mixture was heated at about 60.degree. C. for
about 2 h. The solvents were removed under reduced pressure and the
residue was purified by using general procedure AA (Table 2, Method
32, R.sub.t=15.3 min, or =negative) to yield
N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyc-
lopentyl)-3, 3-difluoroazetidine-1-sulfonamide (0.077 g, 51%) as a
yellow solid. LC/MS (Table 1, Method a) R.sub.t=1.75 min; MS m/z
411 (M+H).sup.+.
Example #26*
5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolid-
in-3-ylamino)pyrazine-2-carbonitrile oxalate
##STR01257##
[2277] To slurry of palladium hydroxide on carbon (20 mol %, 0.082
g, 0.582 mmol) in EtOH (5 mL) was added a solution of
1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazine (0.115 g, 0.388 mmol, prepared using E from
(2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate
(synthesized as described in. J. Med. Chem. 1988, 31, 1598-1611)
with HCl, J with Example #5, Step C, OO, D with NaOH) in EtOH (2
mL). The reaction mixture was sparged with hydrogen and an
atmosphere of hydrogen was maintained via balloon. After about 2 h
the reaction mixture was filtered and
5-chloropyrazine-2-carbonitrile (0.013 g, 0.019 mmol, ArkPharm) was
added. The reaction mixture was heated at about 70.degree. C. After
about 7 h the reaction mixture was cooled to ambient temperature
and diluted with water (5 mL). The resulting precipitate was
collected by filtration to provide the product as the free base.
The solid was dissolved in EtOAc (5 mL) and oxalic acid dihydrate
(0.054 g, 0.43 mmol) was added. The solids were sonicated briefly
with gentle heating. After cooling to ambient temperature, the
solids were collected by filtration and dried in vacuo to provide
5-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrroli-
din-3-ylamino)pyrazine-2-carbonitrile oxylate, (0.100 g, 56%) as a
tan solid: LC/MS (Table 1, Method a) R.sub.t=1.80 min; MS m/z: 374
(M+H).sup.+.
Example #27*
N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolid-
in-3-yl)-3,3,3-trifluoropropane-1-sulfonamide
##STR01258##
[2279] To slurry of palladium hydroxide on carbon (20 mol %, 0.013
g, 0.019 mmol) in EtOH (5 mL) was added a solution of
1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e-
]pyrazine (0.110 g, 0.371 mmol, prepared using E from
(2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate
(synthesized as described in. J. Med. Chem. 1988, 31, 1598-1611)
with HCl, J with Example #5, Step C, OO, D with NaOH) in EtOH (2
mL). The reaction mixture was sparged with hydrogen and an
atmosphere of hydrogen was maintained via balloon. After about 2 h
the reaction mixture was filtered and concd under reduced pressure
The residue was dissolved in DCM (5 mL) and
3,3,3-trifluoropropane-1-sulfonyl chloride (0.080 g, 0.41 mmol,
Matrix) was added. After about 15 h additional
3,3,3-trifluoropropane-1-sulfonyl chloride (80 mg, 0.408 mmol,
Matrix) was added. After about 2 days the reaction mixture was
partitioned between EtOAc (10 mL) and brine (10 mL). The organic
layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd under reduced pressure. The crude product was
purified by chromatography on silica gel eluting with EtOAc to
provide N-((3S,
SR)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrol-
idin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide (0.025 g,16%) as a
brown solid: LC/MS (Table 1, Method a) R.sub.t=1.81 min; MS m/z:
431 (M+H).sup.+.
Example #28
1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine
##STR01259##
[2280] Step A: ethyl
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
##STR01260##
[2282] To a solution of
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.03 g,
9.81 mmol, Adesis) in THF (49 mL) at about -78.degree. C. was added
sec-BuLi (1.4 M in cyclohexane, 15.4 mL, 21.6 mmol) dropwise. The
reaction was stirred at about -78.degree. C. for about 1 h before
ethyl chloroformate (2.36 mL, 24.5 mmol) was added rapidly. The
reaction mixture was allowed to warm to ambient temperature and was
stirred for about 40 min. The reaction was quenched with saturated
aqueous NH.sub.4Cl (25 mL). EtOAc (50 mL) and water (50 mL) were
added and the layers were separated. The aqueous layer was
extracted with EtOAc (2.times.20 mL) and the combined organic
layers were washed with brine (2.times.20 mL). The organics were
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concd to
dryness under reduced pressure to give a yellow oil. The oil was
purified by silica gel chromatography eluting with a gradient of
0-10% EtOAc in heptane to give ethyl
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(3.78 g, 98%) as a yellow oil: LC/MS (Table 1, Method b)
R.sub.t=3.98 min; MS m/z: 381 (M+H).sup.+.
Step B: ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
##STR01261##
[2284] To a solution of ethyl
4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(4.30 g, 11.3 mmol) in THF (57 mL) at about 0.degree. C. was added
TBAF (1.0 M in THF, 12.6 mL, 12.6 mmol) dropwise and the reaction
mixture was stirred at about 0.degree. C. for about 1 h. The
reaction was warmed to room temperature and stirred for about 30
min. The solvent was removed under reduced pressure and the
resulting oil was partitioned between EtOAc and brine (100 mL
each). The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concd under reduced pressure. The residue was
triturated with DCM and filtered to give ethyl
4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 52%) as
an off white solid: LC/MS (Table 1, Method b) R.sub.t=2.07 min; MS
m/z: 225 (M+H).sup.+.
Step C: ethyl
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
##STR01262##
[2286] To a solution of ethyl
4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 5.88
mmol) in DMF (39 mL) at about 0.degree. C. was added sodium hydride
(60% dispersion in mineral oil, 0.400 g, 10.00 mmol) and the
reaction mixture was stirred at this temperature for about 15 min.
A solution of 4-methylbenzene-1-sulfonyl chloride (2.24 g, 11.8
mmol) in DMF (17 mL) was added dropwise and the reaction mixture
was allowed to warm to ambient temperature for about 2 h. The
reaction mixture was concd under reduced pressure and the residue
was partitioned between EtOAc and water (25 mL each). The aqueous
layer was extracted with EtOAc (2.times.25 mL) and the combined
organic layers were washed with brine, dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The solid
was triturated with heptane, and the precipitates were filtered to
give ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(2.28 g, 102%, 90% purity) as a white solid: LCMS (Table 1, Method
c) R.sub.t=1.64 min; MS m/z: 379 (M+H).sup.+.
Step D: ethyl
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
##STR01263##
[2288] To a solution of ethyl
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g,
5.42 mmol) in n-BuOH (21 mL) was added cyclohexanamine (1.24 mL,
10.8 mmol). The resulting solution was heated at about 110.degree.
C. for about 18 h. The reaction mixture was cooled to ambient
temperature and diluted with water and DCM (50 mL each). The layers
were separated and the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concd to dryness under reduced
pressure. The residue was triturated with heptane and the
precipitates were filtered to give ethyl
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(1.74 g, 73%) as a light yellow solid: LC/MS (Table 1, Method b)
R.sub.t=3.18 min; MS m/z: 442 (M+H).sup.+.
Step E:
(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methano-
l
##STR01264##
[2290] To a solution of ethyl
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(1.71 g, 3.88 mmol) in toluene (43.1 mL) at about -78.degree. C.
was added DIBAL-H (1 M in hexanes, 6.60 mL, 6.60 mmol) dropwise.
The reaction was stirred for about 1 h at about -78.degree. C. and
the reaction mixture was warmed to ambient temperature and stirred
for about 1 h. The reaction was quenched with saturated aqueous
potassium sodium tartrate (15 mL) and the mixture was stirred for
about 1 h. EtOAc (25 mL) was added and the layers were separated.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered through a pad of silica gel while washing with EtOAc (20
mL), and the filtrate was concd under reduced pressure. The residue
was purified by silica gel chromatography eluting with a gradient
of 0-50% EtOAc in DCM to give
(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol
(1.24 g, 80%) as an off white solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 400 (M+H).sup.+.
Step F:
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehy-
de
##STR01265##
[2292] A mixture of
(4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol
(1.12 g, 2.80 mmol) and manganese dioxide (5.48 g, 63.1 mmol) in
chloroform (70 mL) was stirred at ambient temperature for about 18
h. The reaction mixture was diluted with chloroform (100 mL) and
the reaction mixture was filtered through a pad of Celite.RTM.
while washing with chloroform (50 mL). The filtrate was concd under
reduced pressure to give
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
(0.975 g, 87%) as an off white solid: LC/MS (Table 1, Method c)
R.sub.t=1.70 min; MS m/z: 398 (M+H).sup.+.
Step G:
(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrro-
lo[2,3-b]pyridin-4-amine
##STR01266##
[2294] An oven dried flask under nitrogen was charged with
((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (2.23 g,
5.19 mmol) and THF (14 mL). The flask was cooled to about 0.degree.
C. in an ice bath and potassium tert-butoxide (0.591 g, 5.00 mmol)
was added. The mixture was stirred for about 30 min at about
0.degree. C. and a solution of
4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
(0.750 g, 1.89 mmol) in THF (4 mL) was added dropwise over about 10
min. The reaction was allowed to warm to ambient temperature and
stirred for about 16 h. Water (10 mL) was added and the reaction
mixture was extracted with Et.sub.2O (3.times.10 mL). The combined
organic extracts were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd under reduced pressure. The crude oil was
purified by silica gel chromatography eluting 0-50% EtOAc in DCM to
give 5-(2-(1,
3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-am-
ine (0.590 g, 67%) as a mixture of E and Z isomers: LC/MS (Table 1,
Method c) R.sub.t=1.69 min, 1.73 min; MS m/z: 468 (M+H)+, 468
(M+H).sup.+.
Step H:
5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-
-b]pyridin-4-amine
##STR01267##
[2296] To a solution of
(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3--
b]pyridin-4-amine (0.512 g, 1.10 mmol) in EtOAc (19 mL) was added
palladium on carbon (10 mol %, 0.092 g, 0.086 mmol). The reaction
mixture was purged with hydrogen and left under a hydrogen
atmosphere using a balloon for about 1.5 h. The reaction mixture
was filtered through a pad of Celite.RTM. while washing with EtOAc
(10 mL) and the filtrate was concd under reduced pressure to give
5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyri-
din-4-amine (0.499 g, 97%) as an off white foam: LC/MS (Table 1,
Method b) R.sub.t=2.84 min; MS m/z: 470 (M+H).sup.+.
Step I:
1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-[1,6]nap-
hthyridine
##STR01268##
[2298] To a solution of
5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyri-
din-4-amine (0.209 g, 0.445 mmol) in EtOH (2 mL) was added aqueous
HCl (12 N, 0.186 mL, 2.23 mmol) dropwise. The mixture was heated at
about 40.degree. C. for about 2 h and then cooled to about
0.degree. C. in an ice bath. Sodium borohydride (0.118 g, 3.12
mmol) was added portionwise and the mixture was warmed to ambient
temperature. After about 2 h the solvent was removed under reduced
pressure and the residue was partitioned between EtOAc and
saturated aqueous NaHCO.sub.3 (10 mL each). The aqueous phase was
extracted with EtOAc (2.times.5 mL) and the combined organics were
washed with water and brine (5 mL each), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concd under reduced pressure. The
residue was purified by silica gel chromatography eluting with
0-50% EtOAc in heptane to give 1-cyclohexyl-7-tosyl-2, 3,4,
7-tetrahydro-1H-pyrrolo[2,3-h]-[1,6]naphthyridine (0.138 g, 75%) as
a white solid: LC/MS (Table 1, Method b) R.sub.t=3.01 min; MS m/z:
410 (M+H).sup.+.
Step J:
1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-
e
##STR01269##
[2300] To a solution of
1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridi-
ne (0.132 g, 0.323 mmol) in 1,4-dioxane (2.2 mL) was added aqueous
NaOH (2 N, 0.32 mL, 0.65 mmol). The reaction was heated at about
80.degree. C. for about 96 h. Aqueous NaOH (5 N, 0.129 mL, 0.646
mmol) was added and the reaction was continued at about 80.degree.
C. for about 18 h. Aqueous NaOH (5 N, 0.065 mL, 0.323 mmol) was
added and the reaction mixture was heated at about 100.degree. C.
for about 4 h. The reaction was cooled to ambient temperature,
EtOAc and water were added (5 mL each) and the layers were
separated. The aqueous layer was extracted with EtOAc (2.times.5
mL) and the combined organics were washed with water and brine (5
mL each), dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concd under reduced pressure. The residue was purified by silica
gel chromatography eluting with a gradient of 0-100% (95/4.5/0.5)
DCM/MeOH/DEA in DCM to give
1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine
(0.052 g, 64%) as a tan solid: LC/MS (Table 1, Method b)
R.sub.t=1.88 min; MS m/z: 256 (M+H).sup.+.
Example #29
N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)cyclopropanesulfonamide
##STR01270##
[2301] Step A: methyl
4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate
##STR01271##
[2303] To a solution of
4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (7.25 g,
34.2 mmol, Prime Organics) in toluene (150 mL) was added DPPA (7.37
mL, 34.2 mmol) and TEA (4.76 mL, 34.2 mmol) and the reaction
mixture was stirred at ambient temperature for about 1 h. The
reaction mixture was then heated at about 110.degree. C. for about
1 h and tert-butanol (16.1 mL, 171 mmol) was added and the reaction
was heated at about 110.degree. C. for about 14 h. The reaction was
cooled to ambient temperature and washed with saturated aqueous
NaHCO.sub.3 (2.times.50 mL) and brine (50 mL). The organics were
dried over anhydrous Na.sub.2SO.sub.4, filtered and coned under
reduced pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-10% MeOH in DCM to give
methyl
4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate
(4.18 g, 43%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.32 (s, 1H), 3.63 (s, 3H), 1.95-1.76 (m, 12H), 1.42 (s,
9H).
Step B: methyl
4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate
##STR01272##
[2305] To a solution of methyl
4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate
(2.50 g, 8.82 mmol) in DMF (42 mL) at about 0.degree. C. was added
sodium hydride (60% dispersion in mineral oil, 0.706 g, 17.6 mmol).
The reaction mixture was stirred for about 30 min at about
0.degree. C. and TBAI (0.652 g, 1.76 mmol) and benzyl bromide (2.10
mL, 17.7 mmol) were added. The reaction was warmed to ambient
temperature and continued to stir for about 5 h. The solvent was
removed under reduced pressure and the residue was taken up in DCM
(50 mL) and water (30 mL). The layers were separated and the
organic phase was washed with brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. The
resulting oil was purified by silica gel chromatography eluting
with a gradient of 0-30% EtOAc in heptane to give methyl
4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate
(2.71 g, 82%) as a clear colorless oil: LC/MS (Table 1, Method b)
R.sub.t=3.09 min; MS m/z: 374 (M+H).sup.+.
Step C: tert-butyl
benzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate
##STR01273##
[2307] To a solution of methyl
4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate
(2.70 g, 7.23 mmol) in THF (24 mL) at about 0.degree. C. was added
lithium borohydride (0.350 g, 14.46 mmol). The reaction mixture was
warmed to ambient temperature and stirred for about 16 h. The
reaction was cooled to about 0.degree. C. and water (15 mL) was
carefully added. The reaction mixture was warmed to ambient
temperature and was diluted with EtOAc (20 mL). The layers were
separated and the organic layer was washed with brine (2.times.20
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concd
under reduced pressure to provide tert-butyl
benzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.31 g,
92%) as an off white sticky foam: LC/MS (Table 1, Method b)
R.sub.t=2.67 min; MS m/z: 346 (M+H).sup.+.
Step D: tert-butyl
benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate
##STR01274##
[2309] To a solution of tert-butyl
benzyl(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.30 g,
6.66 mmol) in DCM (17 mL) was added Dess-Martin periodinane (4.24
g, 9.99 mmol). After about 4 h, the reaction mixture was diluted
with DCM (20 mL) and washed with saturated aqueous NaHCO.sub.3
(2.times.30 mL), brine (30 mL), dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure. The resulting oil was
purified by silica gel chromatography eluting with a gradient of
0-40% EtOAc in heptane to give tert-butyl
benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.10 g, 48%) as
a clear colorless oil: LC/MS (Table 1, Method b) R.sub.t=2.97 min;
MS m/z: 344 (M+H).sup.+.
Step E: tert-butyl
benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(-
hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
##STR01275##
[2311] To a solution of
5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
(1.33 g, 3.06 mmol, Adesis) in THF (25 mL) at about -78.degree. C.
was added n-BuLi (1.6 M solution in hexanes, 2.00 mL, 3.20 mmol) at
such a rate that the internal temperature did not exceed about
-70.degree. C. The reaction mixture was stirred for about 45 min
and a solution of tert-butyl
benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06
mmol) in THF (6 mL) was added dropwise. The reaction mixture was
stirred at about -78.degree. C. for about 1 h and was slowly warmed
to ambient temperature and stirred for about 1 h. Saturated aqueous
NH.sub.4Cl and EtOAc (10 mL each) were added and the layers were
separated. The aqueous phase was extracted with EtOAc (2.times.10
mL) and the combined organics were washed with brine (10 mL), dried
over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The remaining oil was purified by silica gel
chromatography eluting with a gradient of 0-40% EtOAc in heptane to
give tert-butyl
benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(-
hydroxy)methy) bicyclo[2.2.2]octan-1-yl)carbamate (1.27 g, 64%) as
a clear colorless oil: LC/MS (Table 1, Method o) R.sub.t=3.78 min;
MS m/z: 652 (M+H).sup.+.
Step F: tert-butyl
benzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carb-
onyl)bicyclo[2.2.2]octan-1-yl)carbamate
##STR01276##
[2313] To a solution of tert-butyl
benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(-
hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.26 g, 1.93
mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.64 g,
3.86 mmol). The reaction was stirred at ambient temperature for
about 3 h and was diluted with DCM (10 mL). The mixture was washed
with saturated aqueous NaHCO.sub.3 (2.times.15 mL), brine (15 mL),
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The resulting oil was purified by silica gel
chromatography eluting with a gradient of 0-25% EtOAc in heptane to
give tert-butyl
benzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carb-
onyl)-bicyclo[2.2.2]octan-1-yl)carbamate (0.965 g, 77%) as a yellow
oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H),
7.32-7.24 (m, 3H), 7.23-7.08 (m, 3H), 6.23 (d, J=3.5, 1H), 4.53 (s,
2H), 2.13-2.03 (m, 6H), 1.95-1.83 (m, 6H), 1.81-1.74 (m, 3H), 1.41
(s, 9H), 1.12-1.06 (m, 18H).
Step G: tert-butyl
benzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(hydrazono)-methyl)bic-
yclo[2.2.2]octan-1-yl)carbamate
##STR01277##
[2315] To a solution of tert-butyl
benzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydrazono)methyl)bicyc-
lo[2.2.2]octan-1-yl)carbamate (0.765 g, 1.18 mmol) in EtOH (4 mL)
were added hydrazine (1.85 mL, 58.8 mmol) and AcOH (0.337 mL, 5.88
mmol). The mixture was heated at about 80.degree. C. for about 6
days. The reaction was cooled to ambient temperature and the
solvent was removed under reduced pressure. EtOAc and water (5 mL
each) were added and the layers were separated. The organic layer
was washed with brine (5 mL), dried over anhydrous MgSO.sub.4,
filtered, and coned under reduced pressure. The oil was purified by
silica gel chromatography eluting with a gradient of 0-10% MeOH in
DCM to give tert-butyl
benzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo-
[2.2.2]octan-1-yl)carbamate (0.631 g, 84%, 95% purity) as an off
white solid: LC/MS (Table 1, Method b) R.sub.t=2.72 min, MS m/z:
508 (M+H).sup.+.
Step H: tert-butyl
benzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicycle[2-
.2.2]octan-1-yl)carbamate
##STR01278##
[2317] A microwave reaction vial was charged with tert-butyl
benzyl(4-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-)(hydrazono)methyl)bicyclo-
[2.2.2]octan-1-yl)carbamate (0.700 g, 1.38 mmol) and NMP (11 mL).
Sodium tert-butoxide (0.331 g, 3.44 mmol), palladium acetate (0.031
g, 0.14 mmol) and
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-bu-
tylphosphine (0.076 g, 0.14 mmol) were each added sequentially in
one portion to the solution. The reaction mixture was heated in a
Biotage microwave at about 150.degree. C. for about 2 h (250 psi
maximum pressure, 1 min ramp, 150 max watts). The reaction mixture
was filtered through a pad of Celite.RTM. while washing with EtOAc
(15 mL), and the filtrate was concd under reduced pressure. The
remaining material was transferred to a microwave vial and sodium
tert-butoxide (0.331 g, 3.44 mmol), palladium acetate (0.031 g,
0.138 mmol) and
(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]-ethyl-di-tert-butylphosph-
ine (0.076 g, 0.138 mmol) were added. The reaction mixture was
heated in a Biotage microwave at about 160.degree. C. for about 2 h
(250 psi maximum pressure, 1 min ramp, 150 max watts). The reaction
mixture was filtered through a pad of Celite.RTM. while washing
with EtOAc (20 mL). Water (15 mL) was added and the layers were
separated. The aqueous layer was extracted with EtOAc (2.times.10
mL) and the combined organic layers were washed with water
(3.times.10 mL) and brine (5.times.15 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The dark
residue was purified by silica gel chromatography eluting with a
gradient of 10-100% EtOAc in heptane to give tert-butyl
benzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine-1-yl)bicycle[2-
.2.2]octan-1-yl)carbamate (0.281 g, 40%) as a light brown solid:
LC/MS (Table 1, Method b) R.sub.t=2.57 min; MS m/z: 472
(M+H).sup.+.
Step I:
N-benzyl-4-(3,6-dihdropyrazolo[4,3-d]pyrrol[2,3-b]pyridine-1-yl)bi-
cyclo[2.2.2]octan-1-amine hydrochloride
##STR01279##
[2319] To a solution of tert-butyl
benzyl(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.-
2.2]octan-1-yl)carbamate (0.280 g, 0.543 mmol) in 1,4-dioxane (4
mL) was added aqueous HCl (4 M in 1,4-dioxane, 0.58 mL, 2.3 mmol)
and the reaction mixture was stirred at about 60.degree. C. for
about 2 h. The reaction was cooled to ambient temperature and the
precipitates were filtered while washing with a minimal amount of
Et.sub.2O. The solid was dried under vacuum to give N-benzyl-4-(3,
6-dihdropyrazolo[4,3-d]pyrrol[2,3-b]pyridine-1-yl)bicyclo[2.2.2]octan-1-a-
mine hydrochloride (0.216 g, 98%) as a tan solid.: LC/MS (Table 1,
Method b) R.sub.t=1.46 min; MS m/z: 372 (M+H).sup.+.
Step J:
4-(3,6-dihydropyrazol[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2-
.2]octan-1-amine
##STR01280##
[2321] To a solution of
N-benzyl-4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[-
2.2.2]octan-1-amine hydrochloride (0.150 g, 0.368 mmol) in MeOH (6
mL) was added ammonium formate (0.116 g, 1.84 mmol) and 20%
PdOH.sub.2 on carbon (0.039 g, 0.055 mmol). The reaction mixture
was heated at about 65.degree. C. for about 2 h. The reaction
mixture was filtered through a pad of Celite.RTM. while washing
with EtOAc (about 10 mL) and the solvent was removed under reduced
pressure. Water and EtOAc (10 mL each) were added and the layers
were separated. The aqueous layer was extracted with EtOAc
(5.times.5 mL) and the combined organics were dried over anhydrous
MgSO.sub.4, filtered, and coned under reduced pressure to give
4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]oct-
an-1-amine (0.073 g, 71%) as 15 an off white foam: LC/MS (Table 1,
Method b) R.sub.t=1.08 min; MS m/z: 282 (M+H).sup.+.
Step K:
N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo-
[2.2.2]octan-1-yl)cyclopropanesulfonamide
##STR01281##
[2323] To a mixture of
4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]oct-
an-1-amine (0.075 g, 0.267 mmol) in DMF (2.5 mL) was added TEA
(0.06 mL, 0.40 mmol) and cyclopropanesulfonyl chloride (0.027 mL,
0.27 mmol, Matrix). The reaction mixture was stirred at ambient
temperature for about 16 h. Cyclopropanesulfonyl chloride (0.014
mL, 0.133 mmol, Matrix) was added to the reaction mixture and the
reaction continued to stir at ambient temperature for about 4 h.
The reaction mixture was diluted with water (10 mL) and extracted
with DCM (3.times.10 mL). The combined organic layers were washed
with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concd under reduced pressure. The residue was
purified by silica gel chromatography eluting with a gradient of
0-10% MeOH in DCM to give N-(4-(3,
6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1--
yl)cyclopropanesulfonamide (0.015 g, 15%) as a white solid: LC/MS
(Table 1, Method b) R.sub.t=1.72 min; MS m/z: 386 (M+H).sup.+.
Example #30 and 31
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyrazo-
lo[4,3-d]pyrrolo[2,3-b]pyridine and
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine
##STR01282##
[2324] Step A: tert-butyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate
##STR01283##
[2326] To a solution of ethyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.8 g, 130
mmol, Preparation #EE.1 predominantly 1S, 2R, 4S and 1R, 2S, 4R) in
EtOH (286 mL) was added aqueous NaOH (2 N, 572 mL, 1140 mmol). The
reaction mixture was stirred at about 50.degree. C. for about 16
h.
[2327] The reaction mixture was cooled to ambient temperature and
the organic solvent was removed under reduced pressure. The aqueous
layer was washed with Et.sub.2O (2.times.300 mL), cooled to about
0.degree. C. in an ice bath and acidified to about pH 1 with
aqueous HCl (5 N). The aqueous suspension was extracted with EtOAc
(2.times.400 mL). The combined organics were washed with brine (200
mL), dried over anhydrous MgSO.sub.4, filtered, and concd to give
34.5 g of crude solid. To a solution of the crude carboxylic acid
(15.0 g, 53.9 mmol) in DMF (216 mL) was added iodomethane (6.71 mL,
108 mmol) and K.sub.2CO.sub.3 (14.9 g, 108 mmol). The reaction
mixture was stirred at ambient temperature for about 48 h. Water
and EtOAc (250 mL each) were added and the layers were separated.
The aqueous layer was extracted with EtOAc (2.times.250 mL) and the
combined organics were washed with water (250 mL), brine
(3.times.250 mL), dried over anhydrous MgSO.sub.4, filtered, and
concd under reduced pressure. The oil was purified by silica gel
chromatography eluting with a gradient of 0-50% EtOAc in heptane to
give the methyl ester (14.1 g, 48.1 mmol) as a yellow oil. To a
solution of methyl ester (14.1 g, 48.1 mmol) in THF (160 mL) was
added potassium tert-butoxide (16.2 g, 144 mmol) and the reaction
mixture was stirred at ambient temperature for about 18 h.
Saturated aqueous NH.sub.4Cl (100 mL) was added and the reaction
mixture was diluted with EtOAc (100 mL). The layers were separated
and the organics were washed with brine (50 mL), dried over
anhydrous MgSO.sub.4, filtered and concd under reduced pressure.
The remaining oil was purified by silica gel chromatography eluting
with a gradient of 0-40% EtOAc in heptane to give tert-butyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (11.7 g, 73%,
predominantly 1R, 2R, 4S and 1S, 2S, 4R) as a clear colorless oil:
LC/MS (Table 1, Method c) R.sub.t=1.95 min; MS m/z: 335
(M+H).sup.+.
Step B: 2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol
##STR01284##
[2329] To a solution of tert-butyl
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (11.7 g, 35.0
mmol) in THF (175 mL) at to about 0.degree. C. was added LAH (2 M
in THF, 17.5 mL, 35.0 mmol) dropwise and the reaction mixture was
slowly warmed to ambient temperature and stirred for about 1.5 h.
The reaction was cooled to about 0.degree. C. in an ice bath and
quenched by a successive addition of water (150 mL dropwise),
aqueous NaOH (1 N, 150 mL) and water (100 mL). The resulting
mixture was warmed to ambient temperature and stirred for about 30
min. The mixture was filtered through a pad of Celite.RTM. while
washing with Et.sub.2O (500 mL). The filtrate layers were
separated. The organic layer was washed with brine (2.times.200
mL), dried over anhydrous MgSO.sub.4, filtered, and concd under
reduced pressure to give
2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol (8.62 g, 93%) as
a yellow oil: LC/MS (Table 1, Method b) R.sub.t=2.29 min; MS m/z:
265 (M+H).sup.+.
Step C: 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde
##STR01285##
[2331] To a solution of
2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol (8.60 g, 32.5
mmol) in DCM (163 mL) was added Dess-Martin periodinane (20.7 g,
48.8 mmol). The reaction mixture was stirred at ambient temperature
for about 2.5 h. The reaction mixture was diluted with DCM (100
mL), washed with saturated aqueous NaHCO.sub.3 (2.times.150 mL) and
brine (150 mL), dried over anhydrous MgSO.sub.4, filtered, and
concd under reduced pressure. The resulting oil was purified by
silica gel chromatography eluting with a gradient of 0-50% EtOAc in
heptane to give
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde (6.93 g,
81%) as a yellow oil: LC/MS (Table 1, Method b) R.sub.t=2.59 min;
MS m/z: 263 (M+H).sup.+.
Step D:
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-e-
thyl-4-(4-methoxybenzyloxy)cyclopentyl)methanol
##STR01286##
[2333] To a solution of
5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
(4.99 g, 11.5 mmol, Adesis) in THF (90 mL) at about -78.degree. C.
was added n-BuLi (1.6 M solution in hexanes, 10.7 mL, 17.2 mmol) at
such a rate that the internal temperature did not exceed about
-70.degree. C. After stirring for about 45 min at about -78.degree.
C. a solution of
2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarbaldehyde (3.00 g,
11.4 mmol) in THF (22 mL) was added dropwise and the reaction
mixture was stirred at about -78.degree. C. for about 1 h. The
reaction was slowly warmed to ambient temperature and stirred for
about 0.5 h. The reaction mixture was cooled to about -78.degree.
C., saturated aqueous NH.sub.4Cl (40 mL) was added, and the mixture
was warmed to rt. Water (10 mL) was added and the layers were
separated. The aqueous phase was extracted with EtOAc (3.times.50
mL). The combined organics were washed with brine (50 mL), dried
over anhydrous MgSO.sub.4, filtered and concd under reduced
pressure. The crude oil was purified by silica gel chromatography
eluting with a gradient of 0-40% EtOAc in heptane to give
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4--
(4-methoxybenzyloxy)cyclopentyl)methanol (4.47 g, 68%, 92% purity)
as a yellow oil: LC/MS (Table 1, Method o) R.sub.t=2.64 min; MS
m/z: 571 (M+H).sup.+.
Step E:
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-e-
thyl-4-(4-methoxybenzyloxy)cyclopentyl)methanone
##STR01287##
[2335] To a solution of
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4--
(4-methoxybenzyloxy)cyclopentyl)methanone (4.47 g, 7.20 mmol) in
DCM (40 mL) was added Dess-Martin periodinane (4.58 g, 10.8 mmol).
The reaction mixture was stirred at ambient temperature for about
90 min. The reaction was diluted with DCM (40 mL), washed with
saturated aqueous NaHCO.sub.3 (2.times.60 mL), brine (40 mL), dried
over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure. The crude material was purified by silica gel
chromatography eluting with a gradient of 0-40% EtOAc in heptane to
give
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4--
(4-methoxybenzyloxy)-cyclopentyl)methanone (3.32 g, 81%) as a
yellow oil: LC/MS (Table 1, Method o) R.sub.t=3.04 min; MS m/z: 569
(M+H).sup.+.
Step F:
5-chloro-4-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-(hydrazono)m-
ethyl)-1H-pyrrolo[2,3-b]pyridine
##STR01288##
[2337] To a solution of
(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-ethyl-4--
(4-methoxybenzyloxy)cyclopentyl)methanone (1.01 g, 1.77 mmol) in
EtOH (5.5 mL) were added hydrazine (2.78 mL, 89.0 mmol) and AcOH
(0.508 mL, 8.87 mmol). The reaction mixture was heated at about
80.degree. C. for about 18 h. The reaction was cooled to ambient
temperature and the solvent was removed under reduced pressure.
Water (20 mL) and EtOAc (25 mL) were added and the layers were
separated. The organic layer was washed with saturated aqueous
NaHCO.sub.3 and brine (15 mL each), dried over anhydrous
MgSO.sub.4, filtered and coned under reduced pressure. The crude
oil was purified silica gel chromatography eluting with a gradient
of 0-10% MeOH in DCM to give
5-chloro-4-((2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-(hydrazono)methyl-
)-1H-pyrrolo[2,3-b]pyridine (0.354 g, 47%) as a yellow foam: LC/MS
(Table 1, Method b) R.sub.t=2.40 min, MS m/z: 427 (M+H).sup.+.
Step G:
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihyd-
ropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine and
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine
##STR01289##
[2339] A microwave reaction vial was charged with
5-chloro-4-((2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)(hydrazono)methyl)-
-1H-pyrrolo[2,3-b]pyridine (0.900 g, 2.11 mmol) and NMP (14.1 mL).
Sodium tert-butoxide (0.506 g, 5.27 mmol), palladium(II) acetate
(0.047 g, 0.211 mmol) and
((R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-b-
utylphosphine (0.117 g, 0.211 mmol) were added sequentially and the
mixture was heated in a microwave at about 150.degree. C. for about
1 h (250 psi maximum pressure, 1 min ramp, 150 max watts). EtOAc
(20 mL) was added and the mixture was filtered through a pad of
Celite.RTM. while washing with EtOAc (20 mL). Water (15 mL) was
added and the layers were separated. The aqueous layer was
extracted with EtOAc (2.times.10 mL), the combined organics were
washed with water (3.times.10 mL), brine (5.times.10 mL), dried
over anhydrous MgSO.sub.4, filtered and coned under reduced
pressure. The residue was purified by silica gel chromatography
eluting with a gradient of 40-100% EtOAc in heptane followed by
purification using General Procedure AA to give
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,
6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine or
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,
6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.065 g, 8%, Table
2, Method 35, R.sub.t=20.0 min, or =positive) and
1-((1S,2S,4R)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine or
1-((1R,2R,4S)-2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-3,6-dihydropyraz-
olo[4,3-d]pyrrolo[2,3-b]pyridine (0.058 g, 7%, Table 2, Method 35,
R.sub.t=23.4 min, or =negative): LC/MS (Table 1, Method b)
R.sub.t=2.26 min; MS m/z: 391 (M+H).sup.+.
Example #32
N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01290##
[2341] To the solution of
N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)cyclopropanesulfonamide (0.05 g, 0.134 mmol,
WO2009152133) in DMF (4 mL), KOH (0.022 g, 0.401 mmol) was added
and the mixture was stirred at rt for about 5 min. Tosyl cyanide
(0.024 g, 0.134 mmol) was added and stirring was continued for
about 2 h. The solvent was removed under reduced pressure and the
residue purified by preparative HPLC (Table 1, Method q) to yield
N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.0025 g, 5%) as
an off-white solid: LC/MS (Table 1, Method a) R.sub.t=1.84 min; MS
m/z: 400 (M+H).sup.+.
Example #33*
N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyr-
idin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01291##
[2342] Step A:
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
##STR01292##
[2344] To a suspension of
4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.00 g, 11.1
mmol, Adesis) in DMF (30 mL) was added NaH (60% dispersion in
mineral oil, 0.500 g, 12.5 mmol) forming a yellow solution. The
reaction mixture was stirred at ambient temperature for about 30
min then 4-methylbenzene-1-sulfonyl chloride (2.40 g, 12.6 mmol)
was added. The reaction mixture was stirred at ambient temperature
for about 30 min and poured into ice water (about 50 mL). The solid
was collected via vacuum filtration, while washing with water
(about 15 mL), and dried in a vacuum oven to give
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.22 g,
87%) as an off white solid.: LC/MS (Table 1, Method b) R.sub.t=2.56
min; MS m/z: 335 (M+H).sup.+.
Step B:
(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1H-pyrrolo[2-
,3-b]pyridine
##STR01293##
[2346] A round bottom flask was charged with
((1,3-dioxolan-2-yl)methyl)triphenylphosphoum bromide (5.29 g, 12.3
mmol) and THF (29.0 mL). The flask was cooled to about 0.degree. C.
in an ice bath and potassium tert-butoxide (1.38 g, 12.3 mmol) was
added. The mixture was stirred for about 30 min at about 0.degree.
C. and a suspension of
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.50 g,
4.48 mmol) in THF (8.30 mL) was added dropwise. The reaction was
warmed to ambient temperature and stirred for about 16 h. Aqueous
sodium hydroxide (2 M, 4.50 mL, 9.00 mmol) was added and the
reaction mixture was heated to about 55.degree. C. for about 1 h.
Water and ether (10 mL each) were added and the layers were
separated. The aqueous phase was extracted with ether (3.times.10
mL), the combined organics were dried over anhydrous
Na.sub.2SO.sub.4 and filtered. About 50% of the solvent was removed
under reduced pressure and the remaining organic was filtered
through silica gel washing with ether (about 15 mL). The filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel chromatography eluting with a gradient of 0-50% EtOAc
in DCM to give a white solid. The solid was dissolved in DMF (12
mL) and NaH (60% dispersion in mineral oil, 0.179 g, 4.49 mmol) was
added. The reaction mixture was stirred at ambient temperature for
about 30 min then 4-methylbenzene-1-sulfonyl chloride (0.684 g,
3.59 mmol) was added. The reaction was stirred at ambient
temperature for about 30 min and poured into ice water (about 30
mL). EtOAc (30 mL) was added and the layers were separated. The
aqueous phase was further extracted with EtOAc (2.times.30 mL) and
the combined organics were washed with brine (2.times.20 mL), dried
over anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure. The resulting oil was purified by silica gel
chromatography eluting with a gradient of 0-50% EtOAc in heptane to
give
(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]py-
ridine (0.90 g, 50%) as an off white foam.: LC/MS (Table 1, Method
b) R.sub.t=2.65 min; MS m/z: 405 (M+H).sup.+ and R.sub.t=2.70 min;
MS m/z: 405 (M+H).sup.+.
Step C:
5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]p-
yridine
##STR01294##
[2348] A mixture of
(E/Z)-5-(2-(1,3-dioxolan-2-yl)vinyl)-4-chloro-1-tosyl-1-pyrrolo[2,3-b]pyr-
idine (0.900 g, 2.22 mmol) and 10 wt % Pd/C (0.118 g, 0.111 mmol)
was purged with N.sub.2 and evacuated under vacuum (3.times.).
After the third evacuation EtOAc (23 mL) was added. The flask was
purged with N.sub.2 and evacuated under vacuum (3.times.). After
the 3rd evacuation the flask was placed under a hydrogen atmosphere
for about 1 h. The hydrogen atmosphere was replaced with N.sub.2
and the reaction mixture was filtered through a pad of Celite.RTM.
washing with EtOAc (about 10 mL) and the filtrate was concentrated
under reduce pressure to give
5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine
(0.530 g, 59%) as a thick oil which solidified upon standing: LC/MS
(Table 1, Method b) R.sub.t=2.71 min; MS m/z: 407 (M+H).sup.+.
Step D:
3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal
##STR01295##
[2350] To a solution of
5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine
(0.520 g, 1.28 mmol) in THF (4.2 mL) was added aqueous HCl (6 M,
0.639 mL, 3.83 mmol). The reaction mixture was stirred at ambient
temperature for about 2 h and was heated to about 50.degree. C. for
about 1 h. The reaction was cooled to ambient temperature and water
(0.64 mL) was added and the reaction stirred for about 16 h. The pH
was adjusted to about 7 with saturated aqueous NaHCO.sub.3 and
EtOAc (about 10 mL) was added. The layers were separated and the
aqueous phase was extracted with EtOAc (10 mL). The combined
organics were dried over anhydrous MgSO.sub.4, filtered and
concentrated under reduced pressure. Acetone (12 mL) and pyridinium
p-toluenesulfonate (0.096 g, 0.383 mmol) were added. The reaction
was heated at reflux for about 2 h. The reaction was cooled to
ambient temperature and concentrated under reduced pressure. The
residue was purified by silica gel chromatography eluting with a
gradient of 0-50% EtOAc in DCM to give
3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.44 g,
84%, 90% purity) as an off white foam.: LC/MS (Table 1, Method b)
R.sub.t=2.50 min; MS m/z: 363 (M+H).sup.+.
Step E:
N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl-
)propylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide
##STR01296##
[2352] To a mixture of
3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.420
g, 1.04 mmol) and
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamid- e
(0.290 g, 1.25 mmol, prepared using OOO from Example #23 step E
with NaOH) in DCE (4.00 mL) was added glacial acetic acid (0.089
mL, 1.6 mmol). The reaction mixture stirred for about 15 min at
ambient temperature and sodium triacetoxyborohydride (0.331 g, 1.56
mmol) was added. The reaction was left stirring at ambient
temperature for about 72 h. Saturated aqueous NaHCO.sub.3 (about 5
mL) was slowly added followed by DCM (5 mL). The layers were
separated and the aqueous phase was extracted with DCM (2.times.5
mL). The combined organics were dried over anhydrous MgSO.sub.4,
filtered and concentrated under reduced pressure. The remaining
yellow oil was purified by silica gel chromatography eluting with a
gradient of 0-50% EtOAc in heptane to give
N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propyl-
amino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.330 g, 55%) as
a white foam.: LC/MS (Table 1, Method b) R.sub.t=2.10 min; MS m/z:
579 (M+H).sup.+.
Step F:
N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-
-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01297##
[2354] A microwave vial was charged with a solution of
N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propyl-
amino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.345
mmol) in 1-propanol (1.70 mL). DIEA (0.180 mL, 1.04 mmol) and
potassium iodide (0.057 g, 0.345 mmol) were added and the reaction
mixture was heated in a Biotage.RTM. microwave at about 150.degree.
C. for about 30 min. The reaction was resubmitted to microwave
heating at about 180.degree. C. for about 1 h. The reaction was
resubmitted to microwave heating at about 180.degree. C. for about
10 h. The reaction mixture was transferred to a round bottom flask
and silica gel (about 1 g) was added. The solvent was removed under
reduced pressure and the resulting silica gel mixture was purified
by silica gel chromatography eluting with a gradient of 0-10% MeOH
in DCM to give N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2, 3, 4,
7-tetrahydro-1H-pyrrolo[2,3-h][1,
6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.050 g,
27%) as a yellow foam.: LC/MS (Table 1, Method b) R.sub.t=2.52 min;
MS m/z: 543 (M+H).sup.+.
Step G:
N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]-
naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide
##STR01298##
[2356] To a solution of
N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6-
]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.041 g,
0.076 mmol) in 1,4-dioxane was added aqueous NaOH (5 N, 0.106 mL,
0.529 mmol). The reaction was heated to about 80.degree. C. for
about 16 h. The reaction mixture was cooled to ambient temperature
and water (5 mL) and EtOAc (10 mL) were added. The layers were
separated and the aqueous phase was extracted with EtOAc
(2.times.10 mL). The combined organics were dried over anhydrous
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography eluting with a
gradient of 0-10% MeOH in DCM to give
N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthy-
ridin-1-yl)cyclopentyl)cyclopropane-sulfonamide (0.02 g, 72%) as a
white solid.: LC/MS (Table 1, Method a) R.sub.t=1.48 min; MS m/z:
389 (M+H).sup.+.
Example #34*
N-((1S,3S,4R)-3-(2,3-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)-4-et-
hylcyclopentyl)cyclopropanesulfonamide
##STR01299##
[2357] Step A:
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde
##STR01300##
[2359] To a suspension of
4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.00 g, 11.1
mmol, Adesis) in DMF (30 mL) was added NaH (60% dispersion in
mineral oil, 0.500 g, 12.5 mmol) forming a yellow solution. The
reaction mixture was stirred at ambient temperature for about 30
min then 4-methylbenzene-1-sulfonyl chloride (2.40 g, 12.6 mmol)
was added. The reaction mixture was stirred at ambient temperature
for about 30 min and poured into ice water (about 50 mL). The solid
was collected via vacuum filtration, while washing with water
(about 15 mL), and dried in a vacuum oven to give
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.22 g,
87%) as an off white solid.: LC/MS (Table 1, Method b) R.sub.t=2.56
min; MS m/z: 335 (M+H).sup.+.
Step B:
(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-
e
##STR01301##
[2361] To a suspension of (methoxymethyl)triphenylphosphonium
chloride (1.28 g, 3.73 mmol) in THF (14.8 mL) at about 0.degree. C.
was added dropwise potassium tert-butoxide (1 M solution in THF,
3.70 mL, 3.70 mmol). The reaction mixture was stirred for about 30
min at about 0.degree. C. and a suspension of
4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.00 g,
2.99 mmol) in THF (1.80 mL) was added. The reaction mixture was
warmed to ambient temperature and stirred for about 4 h. The
reaction was neutralized with 1 M aqueous HCl and then EtOAc and
water (10 mL each) were added. The layers were separated and the
aqueous phase was extracted with EtOAc (2.times.10 mL). The
combined organics were dried over anhydrous MgSO.sub.4, filtered
and concentrated under reduced pressure. The remaining solid was
purified by silica gel chromatography eluting with a gradient of
0-50% EtOAc in heptane to give
(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
(0.96 g, 89%) as an off white solid.: LC/MS (Table 1, Method b)
R.sub.t=2.83 min; MS m/z: 363 (M+H).sup.+ and R, =2.86 min; MS m/z:
363 (M+H).sup.+
Step C:
N-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl-
)ethylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide
##STR01302##
[2363] To a mixture of
(E/Z)-4-chloro-5-(2-methoxyvinyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
(0.95 g, 2.62 mmol) in THF (26 mL) was added aqueous HCl (1 M, 6.55
mL, 6.55 mmol). The reaction mixture was heated at reflux for about
16 h. The reaction was cooled to ambient temperature and the pH was
adjusted to about 7 with saturated aqueous NaHCO.sub.3. DCM (about
30 mL) was added and the layers were separated. The aqueous phase
was extracted with DCM (2.times.20 mL). The combined organics were
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The residue was taken up in DCE (13 mL) and
N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide
(0.608 g, 2.62 mmol, prepared using OOO from Example #23 step E
with NaOH) and glacial acetic acid (0.150 mL, 2.62 mmol) were
added. Sodium triacetoxyborohydride (0.832 g, 3.93 mmol) was added
and the reaction was left stirring at ambient temperature for about
16 h. The reaction was diluted with DCM (20 mL) and saturated
aqueous NaHCO.sub.3 (20 mL) was added. The layers were separated
and the aqueous phase was extracted with DCM (2.times.10 mL). The
combined organics were washed with brine (10 mL), dried over
anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
eluting with a gradient of 25-100% EtOAc in heptane to give
N-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyla-
mino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.45 g, 30%) as
an off white solid.: LC/MS (Table 1, Method a) R.sub.t=1.87 min; MS
m/z: 565 (M+H).sup.+.
Step D:
N-((1S,3S,4R)-3-(2,3-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)--
yl)-4-ethylcyclopentyl)cyclopropanesulfonamide
##STR01303##
[2365] A microwave vial was charged with a solution of
N-((1S,3S,4R)-3-(2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyla-
mino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.350 g, 0.619
mmol) in 1-propanol (3.2 mL). DIPEA (0.324 mL, 1.86 mmol) and
potassium iodide (0.154 g, 0.929 mmol) were added and the reaction
was heated in a Biotage.RTM. microwave for about 10 h at about
180.degree. C. EtOAc and water (10 mL each) were added to the
reaction mixture and the layers were separated. The aqueous phase
was extracted with EtOAc (2.times.10 mL). The combined organics
were dried over anhydrous MgSO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography eluting with a gradient of 0-100% DCM/MeOH/Et2NH
(950/45/5) in DCM and the solvent was removed under reduced
pressure. The solid was further purified by preparative HPLC (Table
1, Method w) to give to give N-((1S,3S,4R)-3-(2,
3-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyc-
lopropanesulfonamide with 30 mol % ammonium acetate as an excipient
(0.099 g, 38%) as a white solid.: LC/MS (Table 1, Method a)
R.sub.t=1.70 min; MS m/z: 375 (M+H).sup.+.
Example #35 and #35.1
1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine and
1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-
-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01304##
[2366] Step A: ethyl
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate
##STR01305##
[2368] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22,
Step B) in DCM (22 mL). To the flask were added ethylene glycol
(0.91 mL, 16 mmol), triethylorthoformate (2.0 mL, 12 mmol), and
p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The reaction
mixture was stirred at rt for about 24 h. The solution was concd
under reduced pressure to give brown oil that was dissolved in
EtOAc and purified by silica gel chromatography eluting with a
gradient of 0-50% EtOAc in heptane. The product containing
fractions were combined and concd to dryness under reduced pressure
to give ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate as a
light yellow oil (1.6 g, 83%): LC/MS (Table 1, Method c) MS m/z 229
(M+H).sup.+; .sup.1H NMR (CDCl) .delta. 4.14 (q, 2H), 3.90 (m, 4H),
2.99 (q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H), 2.05-1.99 (m,
1H), 1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m, 1H),
1.31-1.24 (m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).
Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid
##STR01306##
[2370] A round bottom flask was charged with ethyl
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol)
and sodium hydroxide (aqueous 1 N, 14.0 mL, 14.0 mmol). The
solution was stirred overnight at rt. To the solution was added DCM
(30 mL) followed by the addition of 20% aqueous citric acid (about
20 mL) to reach pH of about 2. The layers were separated and the
aqueous solution was extracted with DCM (2.times.30 mL) and
DCM/EtOAc (1:1, 30 mL). The combined extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid as a
clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c)
R.sub.t=1.20 min; MS m/z: 201 (M+H).sup.+.
Step C:
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[-
4.4]nonane-7-carbohydrazide
##STR01307##
[2372] A 50 mL round bottom flask was charged with
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,
Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic
acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction
mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6
mmol) and the resulting yellow suspension was stirred at rt for
about 3 h. To the reaction solution was added DCM (25 mL) and the
solution was washed with water and brine (20 mL each). The organic
layer was dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a brown oil. The crude product was
purified by silica gel chromatography eluting with a gradient of:
0-10% MeOH in DCM. The product containing fractions were concd
under reduced pressure to give
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]non-
ane-7-carbohydrazide as a foam (0.50 g, 89%): LC/MS (Table 1,
Method c) R.sub.t=1.49 min; MS m/z: 486 (M+H).sup.+.
Step D:
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine
##STR01308##
[2374] A round bottom flask was charged with
8-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nona-
ne-7-carbohydrazide (4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To
the flask was added DIEA (8.81 mL, 50.5 mmol) followed by the
addition of thionyl chloride (0.770 mL, 10.6 mmol). The mixture was
heated to about 75.degree. C. for about 90 min. Additional thionyl
chloride (0.074 mL, 1.0 mmol) was added and heating was continued
for about 1 h. The reaction was cooled to rt and stirred overnight.
The solution was diluted with DCM (75 mL) and washed with water (50
mL). The layers were separated and the organic layer was dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give a dark brown oil. The crude product was purified via flash
silica gel chromatography eluting with a gradient of 0-60% acetone
in heptane. The product containing fractions were combined and
concd to give material that was loaded onto a second column eluting
with a gradient of 0-60% acetone in heptane. The product containing
fractions were combined and concd under reduced pressure to give
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine as a tan powder (3.0 g, 64%): LC/MS (Table
1, Method c) R.sub.t=1.44 min; MS m/z: 468 (M+H).sup.+.
Step E:
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]-
triazolo[4,3-a]pyrazine
##STR01309##
[2376] To the solution of
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine (3.76 g, 8.04 mmol) in 1,4-dioxane (55
mL), aqueous sodium hydroxide solution (2N, 12 mL) was added and
the reaction mixture was heated at about 60.degree. C. for about 90
min. The solvent was removed and the residue partitioned between
saturated solution of ammonium chloride in water and EtOAc (75 mL
each). The aqueous phase was further washed with EtOAc (60 mL); the
combined organic extracts were washed with brine (65 mL), dried
over anhydrous magnesium sulfate, filtered, and concentrated to
yield a brown solid. The solid was triturated in ether (20 mL) and
the precipitate was collected by filtration and dried to yield
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazol-
o[4,3-a]pyrazine (2.22 g, 88%) as a beige solid. LC/MS (Table 1,
Method a) R.sub.t=1.71 min; MS m/z: 314 (M+H).sup.+.
Step F:
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)et-
hoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01310##
[2378] To a suspension of sodium hydride (60% dispersion in mineral
oil, 0.355 g, 8.87 mmol) in DMF (45 mL), the solution of
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6H-pyrrolo[2,3-e][1,2,4]triazol-
o[4,3-a]pyrazine (2.78 g, 8.87 mmol) in DMF (45 mL) was added
dropwise at about 0.degree. C. and the resulting solution was
stirred at this temperature for about 20 min. SEM Cl (1.75 mL, 8.87
mmol) was added dropwise and the resulting mixture was stirred
overnight while being gradually warmed up. The solvent was removed
under reduced pressure and the residue was partitioned between
EtOAc and water (120 mL each). The aqueous phase was further washed
with EtOAc (50 mL); the combined organic extracts were washed with
brine (100 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated to yield
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)-m-
ethyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (3.87 g,
98%) as a brown amorphous solid. LC/MS (Table 1, Method a)
R.sub.t=2.49 min; MS m/z: 444 (M+H).sup.+.
Step G:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][-
1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone
##STR01311##
[2380] To a solution of
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-((2-(trimethylsilyl)ethoxy)me-
thyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (3.87 g, 8.72
mmol) in THF (30 mL), was added aqueous HCl (1N, 26.2 mL) at about
0.degree. C. The ice bath was removed and the reaction was stirred
at ambient temperature for about 6 h. THF was removed under reduced
pressure. The aqueous phase was neutralized by the addition of
saturated aqueous NaHCO.sub.3 and was extracted with EtOAc
(2.times.50 mL). The combined organic extracts were washed with
brine (60 mL), dried over anhydrous MgSO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography using 20 to 80% EtOAc in DCM to yield
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanone (2.84 g, 81%) as a yellow
amorphous solid. LC/MS (Table 1, Method a) R.sub.t=2.44 min; MS
m/z: 400 (M+H).sup.+.
Step H:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][-
1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone
##STR01312##
[2382] A solution of
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.296 g, 0.741 mmol) in
THF (2.96 mL) was cooled to about 0.degree. C. and to it was added
DIBAL-H (1M in cyclohexane, 1.482 mL, 1.482 mmol). The reaction was
stirred for about 45 min. The reaction was quenched with MeOH (3
mL). To the reaction mixture was added saturated aqueous NH.sub.4Cl
(10 mL) and EtOAc (10 mL). The organic layer was collected and
washed with brine (10 mL), dried over anhydrous MgSO.sub.4,
filtered and concentrated under reduced pressure to provide the
crude material. The crude material was purified by silica gel
column chromatography using 0-5% MeOH/CH.sub.2Cl.sub.2 to provide a
scalemic mixture enriched in
(1S,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-
-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (148 mg, 0.369
mmol, 50%) and a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-
-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (60 mg, 0.149
mmol, 20%) both as amorphous solids. LC/MS (Table 1, Method a)
R.sub.t=2.37 min; MS m/z: 402 (M+H).sup.+ and R.sub.t=2.16 min; MS
m/z: 402 (M+H).sup.+ respectively.
Step I:
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][-
1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate
##STR01313##
[2384] To a solution of the scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-
-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.5 g, 1.245
mmol) and TEA (0.347 mL, 2.49 mmol) in DCM (13 mL) was added MsCl
(0.107 mL, 1.37 mmol) dropwise, and the reaction mixture was
stirred at room temperature overnight. The solvent was removed
under reduced pressure and the residue purified by silica gel
column chromatography using 10 to 70% EtOAc in DCM to yield
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.48 g,
80%) as a white amorphous solid. LC/MS (Table 1, Method a)
R.sub.t=2.54 min; MS m/z: 480 (M+H).sup.+
Step J:
1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclo-
pentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine and
1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-
-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]
##STR01314##
[2386] To a solution of 3-cyclopropyl-1H-1,2,4-triazole (0.054 g,
0.494 mmol) in DMF (3 mL), sodium hydride (0.019 g, 0.486 mmol, 60%
dispersion in mineral oil) was added at about 0.degree. C. and the
reaction mixture was stirred for about 10 min. The temperature was
raised to about 50.degree. C. and
3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.079 g,
0.165 mmol) was added. The reaction mixture was stirred at about
75.degree. C. overnight. The solvent was removed under reduced
pressure and the residue partitioned between water and EtOAc (10 mL
each). The aqueous phase was further washed with EtOAc (7 mL); the
combined extracts were washed with brine (10 mL), dried over
anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to yield a mixture of
1-(4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2-(tri-
methylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
and
1-(4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2--
(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][,
2,4]triazolo[4,3-a]pyrazine. This mixture was dissolved in DCM (3
mL) and 2 mL of trifluoroacetic acid was added. The resulting
mixture was stirred at ambient temperature for about 2 h. The
solvents were removed under reduced pressure. The residue was
dissolved in 1,4-dioxane (3 mL); 2 mL of concentrated NH.sub.4OH (4
mL) solution in water was added. The mixture was heated at about
60.degree. C. for about 2 hours. The solvents were removed under
reduced pressure and the residue was purified by HPLC (Table 2,
Method 32) to yield
1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-
-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.028 g, 25%
yield) [Example #35] and
1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-
-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.013 g, 12%
yield) [Example #35.1] both as white solids. LC/MS (Table 1, Method
a) R.sub.t=1.74 min; MS m/z: 363 (M+H).sup.+ and LC/MS (Table 1,
Method a) R.sub.t=1.73 min; MS m/z: 363 (M+H).sup.+
Examples #36 and #37
(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N--
(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-
-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
##STR01315##
[2387] Step A: (Z)-ethyl pent-2-enoate
##STR01316##
[2389] To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF
(100 mL) and pyridine (10.00 mL) was added ethyl pent-2-ynoate
(5.22 mL, 39.6 mmol). The reaction mixture was sparged with
hydrogen for about 10 min and an atmosphere of hydrogen was
maintained via balloon. After about 15 h the reaction mixture was
filtered through a pad of Celite.RTM., diluted with Et.sub.2O (30
mL) and washed with saturated aqueous CuSO.sub.4 (40 mL), followed
by water (40 mL). The organic layer was separated, dried over
anhydrous MgSO.sub.4, filtered, and concd in vacuo to provide crude
(Z)-ethyl pent-2-enoate (5 g, 98%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.05 (t, 3H), 1.28 (t, 3H), 2.65 (m, 2H), 4.18 (q, 2H),
5.72 (m, 1H), 6.21 (m, 1H).
Step B: (cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate
##STR01317##
[2391] To a solution of
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL,
39.0 mmol) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol) in DCM (50
mL) was added TFA (0.030 mL, 0.390 mmol) at rt. After about 2 days,
the reaction mixture was concd in vacuo to provide crude
(cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%)
as an oil. LC/MS (Table 1, Method a) R.sub.t=1.62 min; MS m/z: 262
(M+H).sup.+.
Step C: (cis)-ethyl 4-ethylpyrrolidine-3-carboxylate
##STR01318##
[2393] A parr shaker was charged with PdOH.sub.2 on carbon (2.243
g, 3.19 mmol) and (cis)-ethyl
1-benzyl-4-ethylpyrrolidine-3-carboxylate (16.7 g, 63.9 mmol)
followed by EtOH (100 mL). The reaction mixture was degassed and
purged with hydrogen gas and shaken on the parr shaker at 60 psi
for about 4 days at ambient temperature. The reaction mixture was
degassed and purged with nitrogen. The suspension was filtered
through a pad of Celite.RTM. washing with EtOH (.about.900 mL). The
solvent was removed under reduced pressure to afford (cis)-ethyl
4-ethylpyrrolidine-3-carboxylate (8.69 g, 79%) as an oil: LC/MS
(Table 1, Method a) R.sub.t=1.11 min; MS m/z: 172 (M+H).sup.+. Step
D: (cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic
acid
##STR01319##
[2394] To a flask charged with (cis)-ethyl
4-ethylpyrrolidine-3-carboxylate (8.69 g, 50.7 mmol) was added
aqueous HCl (6N, 130 mL, 782 mmol). The solution was heated at
about 75.degree. C. for about 12 h. aqueous HCl (6N, 100 mL, 599
mmol) was added and stirred at about 80.degree. C. for about 20 h.
Aqueous HCl (6N, 100 mL, 599 mmol) was added and continued stirring
at about 80.degree. C. for about 20 h. The reaction mixture was
cooled to ambient temperature and the solvent was removed under
reduced pressure. 1,4-Dioxane (275 mL) and water (50 mL) were added
followed by portionwise addition of Na.sub.2CO.sub.3 (13.5 g, 127
mmol). Di-tert-butyl dicarbonate (13.3 g, 60.9 mmol) was added and
the reaction mixture was stirred at ambient temperature for about
16 h. The solid was filtered and washed with EtOAc (250 mL). The
aqueous layer was acidified with aqueous HCl (1N) to about pH 3-4.
The layers were partitioned and the aqueous layer was extracted
with EtOAc (3.times.100 mL). The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4, filtered and removed under reduced
pressure. As the organic layer was almost fully concentrated (about
10 mL remaining), a solid precipitated. Heptane (30 mL) was added
and the solid was filtered washing with heptane to afford
(cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid
(3.9 g, 32%) as an off white solid as product: LC/MS (Table 1,
Method c) R.sub.t=0.57 min; MS m/z: 242 (M-H).sup.-.
Step E: (cis)-tert-butyl
3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyr-
rolidine-1-carboxylate
##STR01320##
[2396] To a suspension of
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 16.48 mmol,
Example 1, Step D) and
(cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid
(4.01 g, 16.48 mmol) in DCM (70 mL) were added TEA (5.75 mL, 41.2
mmol) and HATU (6.90 g, 18.15 mmol, Novabiochem). The resulting
suspension was stirred at about 25.degree. C. for about 2 h. The
reaction mixture was transferred to a separatory funnel and washed
with saturated aqueous NaHCO.sub.3 (4.times.30 mL). The organic
layer was dried over anhydrous MgSO.sub.4, filtered, and coned in
vacuo to give a brown foam. The crude material was purified via
flash chromatography on silica gel by dry loading the compound onto
the column and eluting with 50-100% EtOAc in DCM/petroleum ether
(1:1) to afford (cis)-tert-butyl
3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyr-
rolidine-1-carboxylate with EtOAc as an excipient (9.41 g, 100%) as
a tan foam: LC/MS (Table 1, Method a) R.sub.t=2.45 min; MS m/z: 529
(M+H).sup.+.
Step F:
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]t-
riazolo[4,3-a]pyrazine
##STR01321##
[2398] To a solution of (cis)-tert-butyl
3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyr-
rolidine-1-carboxylate (9.4 g, 16.41 mmol) in 1,4-dioxane (150 mL),
TEA (7.00 mL, 50.2 mmol) and thionyl chloride (1.80 mL, 24.6 mmol)
were each added sequentially in one portion to the solution. The
reaction was heated at about 70.degree. C. for about 18 h. The
solvent was removed under reduced pressure. A solution of HCl (4 M
in 1,4-dioxane, 41.0 mL, 164 mmol) was added in one portion and the
reaction was stirred for about 3 h. Et.sub.2O (100 mL) was added
and the solid was filtered. The solids were combined with the
mother liquor and the solvent was removed under reduced pressure.
The solid was partially dissolved in EtOAc (650 mL) and washed with
aqueous saturated NaHCO.sub.3 (150 mL). An emulsion formed and was
filtered through Celite.RTM. washing with EtOAc. The solid on top
of the Celite.RTM. layer was product. The solid was scraped off of
the Celite.RTM. and dissolved in a solution of 10% MeOH in DCM (150
mL). The organic layer was washed with water (2.times.30 mL). The
combined organic layers were washed with saturated aqueous sodium
bicarbonate (4.times.150 mL), dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to afford
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazine (5.88 g, 80%) as a brown foam: LC/MS (Table 1,
Method a) R.sub.t=1.55 min; MS m/z: 411 (M+H).sup.+.
Step G:
(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]py-
razin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
##STR01322##
[2400] To a solution of 2,2,2-trifluoroethanamine (0.080 g, 0.804
mmol) in DMF (3 mL) was added CDI (0.150 g, 0.926 mmol). The
resulting solution was stirred at about 65.degree. C. for about 2
h.
1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo-
[4,3-a]pyrazine (0.250 g, 0.609 mmol) was added and the reaction
continued stirring at about 65.degree. C. for about 2 h. The
reaction was cooled to about ambient temperature. The solvent was
removed under reduced pressure. The crude material was purified by
flash chromatography on silica gel eluting with a gradient of 0-10%
MeOH in afford
(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.306 g,
94%) as a brown residue: LC/MS (Table 1, Method a) R.sub.t=2.19
min; MS m/z: 536 (M+H).sup.+.
Step H:
(3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-
-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
##STR01323##
[2402] To a solution of
(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.306 g,
0.571 mmol) in 1,4-dioxane (10 mL) was added aqueous NaOH (1 N,
1.50 mL, 1.50 mmol). The reaction was heated at about 50.degree. C.
for about 1 h. The layers were partitioned between DCM (25 mL) and
water (10 mL). The aqueous layer was acidified with 20% aqueous
citric acid to about pH 4 and extracted with DCM (4.times.25 mL).
The combined organic layers were dried over anhydrous MgSO.sub.4,
filtered, and concd under reduced pressure to give a brown residue.
The crude material was purified by flash chromatography on silica
gel eluting with a gradient of 0-10% MeOH in DCM to give a racemic
mixture of products as a brown residue. The compound was further
purified using chiral preparative HPLC (Table 2, Method 55) to
afford (3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][,
2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-ca-
rboxamide (R.sub.t=14.5 min, or =negative) (0.031 g, 14%)[Example
#36]: LC/MS (Table 1, Method a) R.sub.t=1.62 min; MS m/z: 382
(M+H).sup.+ and
(3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-
-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (R.sub.t=17.3 min,
or =positive) (0.033 g, 15%)[Example #37]: LC/MS (Table 1, Method
a) R.sub.t=1.62 min; MS m/z: 382 (M+H).sup.+.
Example #38
5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole
##STR01324##
[2403] Step A: ethyl
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate
##STR01325##
[2405] A round bottom flask was charged with ethyl
2-ethyl-4-oxocyclopentanecarboxylate (1.5 g, 8.1 mmol, Example #22,
Step B) in DCM (22 mL). To the flask were added ethylene glycol
(0.91 mL, 16 mmol), triethylorthoformate (2.0 mL, 12 mmol) and
p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The reaction
mixture was stirred at rt for about 24 h. The solution was concd
under reduced pressure to give brown oil that was dissolved in
EtOAc and purified by silica gel chromatography eluting with a
gradient of 0-50% EtOAc in heptane. The product containing
fractions were combined and concd to dryness under reduced pressure
to give ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate as a
light yellow oil (1.6 g, 83%): LC/MS (Table 1, Method c) MS m/z 229
(M+H); .sup.1H NMR (CDCl) .delta. 4.14 (q, 2H), 3.90 (m, 4H), 2.99
(q, 1H), 2.32-2.27 (m, 1H), 2.26-2.11 (m, 1H), 2.05-1.99 (m, 1H),
1.96-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.46-1.39 (m, 1H), 1.31-1.24
(m, 1H), 1.26 (t, 3H), 0.90 (t, 3H).
Step B: 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid
##STR01326##
[2407] A round bottom flask was charged with ethyl
8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol)
and aqueous sodium hydroxide (1 N, 14.0 mL, 14.0 mmol). The
solution was stirred overnight at rt. To the solution was added DCM
(30 mL) followed by the addition of 20% aqueous citric acid (about
20 mL) to reach pH of about 2. The layers were separated and the
aqueous solution was extracted with DCM (2.times.30 mL) and
DCM/EtOAc (1:1, 30 mL). The combined extracts were dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid as a
clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c)
R.sub.t=1.20 min; MS m/z: 201 (M+H).sup.+.
Step C:
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[-
4.4]nonane-7-carbohydrazide
##STR01327##
[2409] A 50 mL round bottom flask was charged with
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol,
Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic
acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction
mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6
mmol) and the resulting yellow suspension was stirred at rt for
about 3 h. To the reaction solution was added DCM (25 mL) and the
solution was washed with water and brine (20 mL each). The organic
layer was dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a brown oil. The crude product was
purified by silica gel chromatography eluting with a gradient of
0-10% MeOH in DCM over 25 min. to give
8-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,
4-dioxaspiro[4.4]nonane-7-carbohydrazide as a foam (0.50 g, 89%):
LC/MS (Table 1, Method c) R.sub.t=1.49 min; MS m/z: 486
(M+H).sup.+.
Step D:
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e-
][1,2,4]triazolo[4,3-a]pyrazine
##STR01328##
[2411] A round bottom flask was charged with
8-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nona-
ne-7-carbohydrazide (4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To
the flask was added DIEA (8.81 mL, 50.5 mmol) followed by the
addition of thionyl chloride (0.770 mL, 10.6 mmol). The mixture was
heated to about 75.degree. C. for about 90 min. Additional thionyl
chloride (0.074 mL, 1.0 mmol) was added and heating was continued
for about 1 h. The reaction was cooled to rt and stirred overnight.
The solution was diluted with DCM (75 mL) and washed with water (50
mL). The layers were separated and the organic layer was dried over
anhydrous MgSO.sub.4, filtered, and concd under reduced pressure to
give a dark brown oil. The crude product was purified via flash
silica gel chromatography eluting with a gradient of 0-60% acetone
in heptane. The product containing fractions were combined and
concd to give material that was loaded onto a second column eluting
with a gradient of 0-60% acetone in heptane. The product containing
fractions were combined and concd under reduced pressure to give
1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4-
]triazolo[4,3-a]pyrazine as a tan powder (3.0 g, 64%): LC/MS (Table
1, Method c) R.sub.t=1.44 min; MS m/z: 468 (M+H).sup.+.
Step E:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentanone
##STR01329##
[2413] A round bottom flask was charged with
1-((7S,8R)-8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3--
e][1,2,4]triazolo[4,3-a]pyrazine (3.56 g, 7.61 mmol) and THF (20
mL). To the solution was added aqueous HCl (6N, 3.81 mL, 22.8 mmol)
and the mixture was stirred at rt for about 2 h. The solvent was
removed under reduced pressure and DCM (75 mL) and water (50 mL)
were added. The layers were separated and the organic solution was
dried over anhydrous MgSO.sub.4, filtered, and concd under reduced
pressure to give
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cy-
clopentanone as a brown foam (2.99 g, 93%): LC/MS (Table 1, Method
c) R.sub.t=1.40 min; MS m/z: 424 (M+H).sup.+.
Step F: ethyl
2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazi-
n-1-yl)cyclopentylidene)acetate
##STR01330##
[2415] To a slurry of sodium hydride (0.227 g, 5.67 mmol, 60%
dispersion in oil) in THF (30 mL) was added ethyl
2-(diethoxyphosphoryl)acetate (1.18 mL, 5.90 mmol). After about 30
min a solution of
(cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentanone (2.00 g, 4.72 mmol) in THF (1.0 mL) was added.
After about 4 h EtOAc and sat NaHCO.sub.3 were added. The organic
layer was separated coned in vacuo and purified by flash
chromatography on silica gel eluting with 20-100% EtOAc in DCM to
afford ethyl
2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazi-
n-1-yl)cyclopentylidene)acetate (2.08 g, 89%): LC/MS (Table 1,
Method c) R.sub.t=2.52-2.56 min; MS m/z: 494 (M+H).sup.+ as a
mixture of diastereomers and ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentylidene)acetate (0.150 g, 9%), as a mixture of
diastereomers: LC/MS (Table 1, Method a) R.sub.t=1.85-1.89; MS m/z:
340 (M+H).sup.+.
Step G: ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentylidene)acetate
##STR01331##
[2417] To a solution of ethyl
2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazi-
n-1-yl)cyclopentylidene)acetate (1.9 g, 3.85 mmol) in THF (30 mL)
at 0.degree. C. was added a solution of TBAF (11.55 mL, 11.55 mmol,
1 M in THF). After about 10 min, TBAF (7.70 mL, 7.70 mmol, 1 M in
THF) was added. After about 1 h EtOAc and brine were added to the
reaction mixture. After about one h the organic layer was
separated, concd in vacuo and purified by flash chromatography on
silica gel eluting with EtOAc to afford ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentylidene)acetate (1.3 g, 100%) as a mixture of
diastereomers: LC/MS (Table 1, Method a) R.sub.t=1.86-1.90 min; MS
m/z: 340 (M+H).sup.+.
Step H: ethyl
2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate and
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate
##STR01332##
[2419] To a slurry of PdOH.sub.2 on carbon (0.134 g, 0.192 mmol) in
THF (20 mL) was added a solution of ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentylidene)acetate (1.3 g, 3.83 mmol) in THF (5 mL). The
reaction mixture was sparged with hydrogen and an atmosphere of
hydrogen was maintained via balloon. After about 3 days the
reaction mixture was filtered through Celite.RTM., concd in vacuo
and purified by flash chromatography on silica gel eluting with
EtOAc to afford ethyl
2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)c-
yclopentyl)acetate (1.3 g, 99% yield) as a dark brown/black solid.
The compound was further purified by chiral preparative HPLC (Table
2, method 47) to afford ethyl
2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate (R.sub.t=12.0 min, or =negative) (0.400 g,
31%): LC/MS (Table 1, Method a) R.sub.t=1.85 min; MS m/z: 342
(M+H).sup.+ and ethyl
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyr-
azin-1-yl)cyclopentyl)acetate (R.sub.t=13.7 min, or =negative)
(0.420 g, 32%) as a white solid: LC/MS (Table 1, Method a)
R.sub.t=1.84 min; MS m/z: 342 (M+H).sup.+.
Step I:
5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]p-
yrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole
##STR01333##
[2421] To a solution of ethyl
2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-
-yl)cyclopentyl)acetate (0.100 g, 0.293 mmol) in toluene (0.20 mL)
and MeOH (0.20 mL) was added (Z)--N-hydroxy-2-methoxyacetimidamide
(0.300 g, 2.89 mmol, Tyger) and K.sub.2CO.sub.3 (0.100 g, 0.726
mmol). The solution was heated in a CEM microwave at about
130.degree. C. for about 1 h (250 psi maximum pressure, 1 min ramp,
300 max watts). The solvent was removed under reduced pressure. The
residue was diluted with DCM (3 mL) and a small amount of MeOH. The
crude material was purified by flash chromatography on silica gel
eluting with a gradient of 0-10% MeOH in DCM. The residue was
dissolved in EtOAc and heptane was added. The solvent was coned.
The solid was dried in a heated vacuum oven (about 70.degree. C.)
for about 20 h to afford
5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole (0.062
g, 56%) as a white solid: LC/MS (Table 1, Method a) R.sub.t=1.79
min; MS m/z: 382 (M+H).sup.+.
Example #39
cis-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine
##STR01334##
[2422] Step A: ethyl 4-(dibenzylamino)cyclohexanecarboxylate
##STR01335##
[2424] A 250 mL flask was charged with ethyl
4-oxocyclohexanecarboxylate (5 g, 28.5 mmol, Alfa Aesar) and THF
(75 mL). The solution was cooled to about 0.degree. C. and AcOH
(2.28 mL, 39.9 mmol) and dibenzylamine (6.18 g, 31.3 mmol) (TCI)
were added dropwise, resulting in formation of a thick suspension.
Na(OAc).sub.3BH (14.3 g, 64.1 mmol) was added portionwise and the
reaction mixture was stirred at ambient temperature for about 72 h.
The reaction mixture was cooled to about 10.degree. C. Water (25
mL) was added and the reaction mixture was stirred for about 15
min. Heptanes (50 mL) were added. The layers were separated and the
organic layer was washed with 10% aqueous AcOH solution (25 mL) and
then with water (10 mL). The organic layer was extracted with 4%
HCl solution twice (40 mL and 20 mL). The combined aqueous layer
was washed with heptanes (20 mL). To the aqueous layer was slowly
added 30% aqueous K.sub.2CO.sub.3 solution (30 g) to adjust the pH
to 10. The aqueous solution was extracted with heptane twice (75 mL
and 15 mL). The combined organic layer was washed with water (30
mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4
and filtered. The filtrate was concd under reduced pressure to give
ethyl 4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 72%) as an
oil which solidified upon standing: LC/MS (Table 1, Method a)
R.sub.t=3.18 and 3.23 min; MS m/z: 352 (M+H).sup.+.
Step B: 4-(dibenzylamino)cyclohexanecarboxylic acid
##STR01336##
[2426] To a 250 mL flask, ethyl
4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 20.5 mmol) and a
solution of conc. H.sub.2SO.sub.4 (7.64 mL, 143 mmol) in water (80
mL) were added. The reaction mixture was stirred at about
90.degree. C. for about 18 h, cooled to about 5.degree. C. and the
pH was adjusted to about 7 with the addition of 50% aqueous NaOH.
The aqueous solution was extracted with ether (300 mL). The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
washed with ether. The filtrate was concd under reduced pressure to
give 4-(dibenzylamino)cyclohexanecarboxylic acid (5.6 g, 85%) as a
solid: LC/MS (Table 1, Method b) R.sub.t=1.65 min; MS m/z: 324
(M+H).sup.+.
Step C: sulfoxonium, dimethyl-,
2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide
##STR01337##
[2428] To a 250 mL flask, 4-(dibenzylamino)cyclohexanecarboxylic
acid (5.6 g, 17.3 mmol), HATU (6.75 g, 17.4 mmol) and TEA (8.45 mL,
60.6 mmol) in THF (60 mL) were added to give a white suspension.
The reaction mixture was stirred at ambient temperature for about 1
h. To a 500 mL flask, trimethylsulfoxonium chloride (6.82 g, 51.9
mmol) and potassium tert-butoxide (6.44 g, 54.5 mmol) in THF (60
mL) were added to give a white suspension. The reaction mixture was
stirred at about 65.degree. C. for about 3 h. The reaction mixture
was cooled to about 5.degree. C. The above activated ester solution
was added dropwise over about 50 min. The reaction mixture was
stirred at about 0-5.degree. C. for about 90 min. The reaction
mixture was quenched by the addition of water (120 mL) dropwise at
about 0-5.degree. C. over about 25 min. The quenched reaction
mixture was stirred at about 0-5.degree. C. for about 30 min, then
at ambient temperature for about 18 h. THF was removed under
reduced pressure to give white suspension. The suspension was
partitioned between EtOAc (300 mL) and water (200 mL). The aqueous
layer was extracted with EtOAc (2.times.100 mL). The combined
organic layer was washed with water (50 mL) and brine (3.times.40
mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concd under reduced pressure. The residue was dissolved in hot
MeOH (100 mL) and concd under reduced pressure. The oil was
dissolved in hot MeOH (60 mL) and concd under reduced pressure to
give a white solid. The solid was dissolved in MeOH (36 g) and
water (12 g) at about 55.degree. C. The solution was cooled to
ambient temperature, then to about 5.degree. C. Additional 3:1
MeOH/water (40 mL) was added to the suspension. The suspension was
filtered, washed with 1:1 MeOH/water (20 mL) and heptane (20 mL).
The collected wet cake was dried at about 60.degree. C. in a vacuum
oven for about 72 h to yield sulfoxonium, dimethyl-,
2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide (5.44 g, 79%) as
white solid: LC/MS (Table 1, Method a) R.sub.t=1.42, 1.45 min; MS
m/z 398 (M+H).sup.+.
Step D:
1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazi-
n-2-ylamino)ethanone
##STR01338##
[2430] To a 100 mL 2-neck round-bottomed flask, sulfoxonium,
dimethyl-, 2-(4-(dibenzylamino)cyclohexyl)-2-oxoethylide (5.4 g,
13.6 mmol), 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (4.7 g, 16.3
mmol, Preparation #E.1.1), and [Ir(COD)Cl].sub.2 (0.365 g, 0.543
mmol. Alfa Aesar) were added. The reaction vessel was purged with
N.sub.2 for about 10 min. To the reaction vessel, pre-degassed DCE
(25 mL) was added via syringe. The reaction mixture was purged with
N.sub.2 for about 10 min and stirred under N.sub.2 at about
70.degree. C. for about 3 h. The reaction mixture was allowed to
cool to ambient temperature and concd under reduced pressure. The
residue was purified by silica gel flash chromatography eluting
with a gradient of 5-70% EtOAc:heptane to yield
1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yla-
mino)ethanone (5.8 g, 65%) as glassy solid: LC/MS (Table 1, Method
a) R.sub.t=3.24 and 3.26 min; MS m/z 608 (M+H).sup.+.
Step E:
N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-y-
l)cyclohexanamine
##STR01339##
[2432] A mixture of
1-(4-(dibenzylamino)cyclohexyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yla-
mino)ethanone (5.8 g, 9.54 mmol) and PFPAA (23.7 g, 76 mmol) in
MeCN (70 mL) was heated at about 50.degree. C. for about 17 h.
PFPAA (4.73 g, 15.2 mmol) was added and the reaction mixture was
heated at about 60.degree. C. for about 7 h and at ambient
temperature for about 72 h. The solvent was removed under reduced
pressure to yield
N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclo-
hexanamine (11.3 g crude, but assumed 5.6 g, 100%) as a foam: LC/MS
(Table 1, Method b) R.sub.t=3.03 and 3.09 min; MS m/z 590
(M+H).sup.+.
Step F:
(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-
cyclohexanamine
##STR01340##
[2434]
N,N-dibenzyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl-
)cyclohexanamine (5.6 g, 9.5 mmol) was dissolved in 1,4-dioxane (80
mL). Aqueous NaOH (2 N, 47.5 mL, 95 mmol) was added and the
reaction mixture was heated at about 60.degree. C. for about 120
min. The organic solvent was removed under reduced pressure and the
residue was extracted with 2-methyl tetrahydrofuran (300 mL). The
aqueous layer was extracted with 2-methyl tetrahydrofuran
(3.times.50 mL). The combined organic extracts were washed with
brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and concd
under reduced pressure. To the residue was added EtOAc (500 mL).
The solid was removed by filtration and the filtrate was dried over
anhydrous Na.sub.2SO.sub.4 and concd under reduced pressure.
Purification by silica gel flash chromatography eluting with a
gradient of 1-8% MeOH in EtOAc yielded
(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohe-
xanamine (1.0 g, 24%): LC/MS (Table 1, Method a) R.sub.t=2.48 min;
MS m/z 436 (M+H).sup.+.
Step G:
(cis)-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanami-
ne
##STR01341##
[2436] To a mixture of
(cis)-N,N-dibenzyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohe-
xanamine (1.0 g, 2.3 mmol) in EtOH (30 mL) was added Pd(OH).sub.2
on carbon (0.64 g, 0.46 mmol) and the resulting mixture was shaken
under hydrogen pressure of about 30 psi on a Parr shaker at about
50.degree. C. for about 7 h. The catalyst was filtered off using a
pad of Celite.RTM. and the filtrate was concd under reduced
pressure. The material was purified by chiral chromatography (Table
2, method 34). The collected fractions were combined, concd under
reduced pressure and chased with EtOH (20 mL). The resulting solid
was dried in a heated vacuum oven at about 60.degree. C. to yield
(cis)-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclohexanamine
(0.353 g, 60%) as a white solid: LC/MS (Table 1, Method a)
R.sub.t=0.85 min; MS m/z 256 (M+H).sup.+.
Example #40
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-2(1H)-one
##STR01342##
[2438] Hydrochloric acid (4 M in 1,4-dioxane, 0.300 mL, 1.20 mmol)
was added to a slurry of
8-(2-methoxypyridin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
(0.016 g, 0.060 mmol, (prepared using D from Preparation #BBBBB.1
and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH, CCCCC with
2-methoxy-4-(tributylstannyl)pyridine [Synthonix],
tetrakis(triphenylphosphinepalladium(0), LiCl, CsF, and CuI, D with
NaOH) in EtOH (0.500 mL) and water (0.050 mL). The reaction vessel
was sealed and the mixture was warmed to about 80.degree. C. After
about 15 h, the mixture was warmed to about 90.degree. C. After
about 65 h, the solution was allowed to cool to ambient
temperature. The volatiles were removed under reduced pressure to
afford
4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-2(1H)-one
(0.0153 g, 94%): LC/MS (Table 1, Method a) R.sub.t=0.73 min; MS m/z
253 (M+H).sup.+.
Example #41
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-
cyclopentyl cyclopropylcarbamate
##STR01343##
[2439] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01344##
[2441] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01345##
[2443] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01346##
[2445] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01347##
[2447] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR01348##
[2449] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. and ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep the internal temperature below about 10.degree.
C. The resulting mixture was stirred at ambient temperature for
about 0.5 h to give a clear yellow solution, and methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, coned under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01349##
[2451] A 5 L round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL,
4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The
reaction was heated at reflux for about 6 h then cooled to ambient
temperature and added dropwise to NaHCO.sub.3 (8% aqueous, 3.5 L).
The resulting biphasic mixture was extracted with MTBE (2.times.1.5
L). The combined organic layers were washed with brine (1 L), dried
over anhydrous MgSO.sub.4 and concd under reduced pressure to give
191 g of crude material that was purified by vacuum distillation
(97-99.degree. C., 0.600 mm Hg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H NMR
(CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m,
1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
Step G: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate
##STR01350##
[2453] A mixture of copper (I) chloride (0.136 g, 1.37 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.854 g, 1.37
mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was
stirred at ambient temperature for about 15 min then cooled to
about 5.degree. C. and polymethylhydrosiloxane (12 mL, 55 mmol) was
added. The reaction mixture was stirred for about 40 min at about
5.degree. C. then cooled to about -12.degree. C. A solution of
ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol)
and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one
portion and the reaction mixture was stirred for about 16 h at
about -12.degree. C. The reaction mixture was quenched by the
addition of MeOH (50 mL). The solvents were removed under reduced
pressure. The residue was dissolved in MeOH (35 mL) and filtered
through a pad of Celite.RTM.. The filtrate was concd under reduced
pressure and the residue was triturated with EtOAc (100 mL) and
filtered. The filtrate was concd under reduced pressure and the
residue was purified using silica gel chromatography (280 g)
eluting with a gradient of 0-10% EtOAc in heptane to give a
scalemic mixture enriched with (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): .sup.1H NMR
(CDCl.sub.3) .delta. 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td,
J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m,
3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz,
3H).
Step H: 3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate
##STR01351##
[2455] To triphenylphosphine (34.9 g, 133 mmol) in THF (150 mL) at
about 0.degree. C. was added a solution of DIAD (26.2 mL, 133 mmol)
in THF (20 mL) through an additional funnel. After about 30 min, a
solution of 4-nitrobenzoic acid (22.26 g, 133 mmol) in THF (150 mL)
was added followed by a solution of a scalemic mixture enriched
with (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate
(16.54 g, 89 mmol) in THF (20 mL) and triethylamine (55.7 mL, 400
mmol). After about 1 h, the ice water bath was removed and the
reaction mixture was stirred at ambient temperature for about 16 h.
The reaction mixture was diluted with heptane (800 mL), washed with
water (200 mL), saturated aqueous NaHCO.sub.3 (150 mL) and brine
(150 mL), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure. After about 300 mL of solvent was removed,
the solid was filtered off and washed with heptane (25 mL). The
filtrate was concentrated under reduced pressure and the residue
was purified using silica gel chromatography eluting with 10-40%
EtOAc in heptane to give a scalemic mixture enriched with
(1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate
(26.77 g, 90%): LC/MS (Table 1, Method b) R.sub.t=2.84 min; MS m/z:
394 (M-H).sup.-.
Step I: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate
##STR01352##
[2457] A 2 L flask was charged with freshly ground sodium hydroxide
(9.55 g, 239 mmol). Ethanol (500 mL) was added and the mixture was
stirred until all solid went into solution. A solution of a
scalemic mixture enriched in
(1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate
(16.02 g, 47.8 mmol) in ethanol (120 mL) was added through an
additional funnel. The reaction mixture was stirred at ambient
temperature overnight. The solid was filtered off while washing
with DCM (100 mL). Saturated aqueous NaHCO.sub.3 (800 mL) was added
to the filtrate and mixture was stirred for about 30 min. The solid
formed was filtered off while washing with DCM (500 mL). The
filtrate was washed with saturated aqueous NaHCO.sub.3 (2.times.200
mL) and brine (300 mL). The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. The residue
was purified using silica gel chromatography eluting with 0-60%
EtOAc in DCM to give a scalemic mixture enriched in
(1S,2R,4R)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (5.49 g,
62%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
4.53 (m, 1H), 4.11 (m, 2H), 3.09 (m 1H), 2.40 (m, 1H), 2.28 (m,
1H), 1.80 (m, 1H), 1.68 (m, 1H), 1.44 (m, 2H), 1.26 (t, 3H), 1.18
(m, 1H), 0.92 (t, 3H).
Step J: 2-ethyl-4-hydroxycyclopentanecarboxylic acid
##STR01353##
[2459] Aqueous sodium hydroxide (1N, 32.4 mL, 32.4 mmol) was added
to a scalemic mixture enriched in (1S,2R,4R)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (3.02 g, 16.21 mmol) and
the reaction mixture was stirred at ambient temperature overnight.
Ether (15 mL) was added and the layers were separated. The aqueous
layer was cooled to about 0.degree. C. Aqueous HCl (5N) was slowly
added to bring pH to about 1. The aqueous suspension was extracted
with EtOAc (4.times.40 mL). The combined organic layers were washed
with brine (50 mL), dried over anhydrous MgSO.sub.4, filtered and
concd under reduced pressure to give a scalemic mixture enriched in
(1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g,
100%): LC/MS (Table 1, Method b) R.sub.t=1.36 min; MS m/z: 157
(M-H).sup.-.
Step K:
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic
acid
##STR01354##
[2461] To a scalemic mixture enriched in
(1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g,
16.21 mmol) in DMF (10.81 mL) was added TBDMSCl (2.93 g, 19.45
mmol) and imidazole (2.76 g, 40.5 mmol). The reaction mixture was
stirred at ambient temperature for about 2 days then extracted with
pentane (3.times.25 mL). The combined pentane layers were washed
with water (25 mL) and brine (25 mL), dried over anhydrous
MgSO.sub.4, filtered and concd under reduced pressure. The residue
was purified using silica gel chromatography eluting with 20-100%
EtOAc in heptane give a scalemic mixture enriched in
(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic
acid (1.13 g, 26%): LC/MS (Table 1, Method b) R.sub.t=3.03 min; MS
m/z: 273 (M+H).sup.+.
Step L:
4-(tert-butyldimethylsilyloxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[2,3--
b]pyrazin-2-yl)cyclopentanecarbohydrazide
##STR01355##
[2463] To a scalemic mixture enriched in
(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic
acid (1.62 g, 5.96 mmol) in DCM (60 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D,
1.86 g, 6.13 mmol), HATU (2.38 g, 6.26 mmol) and TEA (3.32 mL, 23.8
mmol). The reaction mixture was stirred at ambient temperature for
about 1 h. The reaction mixture was diluted with DCM (200 mL),
washed with water (50 mL) and brine (50 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The residue
was purified using silica gel chromatography eluting with 0-30%
EtOAc in DCM to give a scalemic mixture enriched in
(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[-
2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (2.64 g, 79%) as a
brown solid: LC/MS (Table 1, Method b) R.sub.t=3.20 min; MS m/z:
558 (M+H).sup.+.
Step M:
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01356##
[2465] To a scalemic mixture enriched in
(1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (2.6 g, 4.66 mmol) in
1,4-dioxane (46.6 mL) was added diisopropylethylamine (3.26 mL,
18.65 mmol) followed by dropwise addition of thionyl chloride
(0.680 mL, 9.32 mmol). The reaction mixture was stirred at ambient
temperature for about 1 h and then heated at about 70.degree. C.
for about 1 h. The reaction mixture was cooled to ambient
temperature and EtOAc (300 mL) was added. The mixture was washed
with water (80 mL) and brine (80 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure. The residue
was purified by silica gel chromatography eluting with 0-50% EtOAc
in DCM to give a scalemic mixture enriched in
1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.56 g, 62%):
LC/MS (Table 1, Method b) R.sub.t=3.36 min; MS m/z: 540
(M+H).sup.+.
Step N:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentanol
##STR01357##
[2467] A scalemic mixture enriched in
1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.55 g, 2.87 mmol)
was suspended in ethanol (30 mL). Concentrated HCl (0.3 mL, 3.65
mmol) was added dropwise. After about 1 h., the suspension was
sonicated until all solid went into solution. EtOAc (250 mL) was
added and the organics were washed with saturated aqueous
NaHCO.sub.3 (2.times.30 mL) and brine (30 mL), dried over anhydrous
MgSO.sub.4, filtered, and coned under reduce pressure. The residue
was purified using silica gel chromatography eluting with 30-80%
EtOAc in DCM to give a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanol (1.09 g, 90%): LC/MS (Table 1, Method b)
R.sub.t=1.99 min; MS m/z: 426 (M+H).sup.+.
Step O:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl 4-nitrophenyl carbonate
##STR01358##
[2469] To a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanol (1.20 g, 2.82 mmol) in pyridine (10 mL) was
added DMAP (0.103 g, 0.846 mmol) and 4-nitrophenyl
carbonochloridate (0.853 g, 4.23 mmol). The resulting mixture was
stirred at ambient temperature for about 1 h. The reaction mixture
was purified using silica gel chromatography eluting with 0-30%
EtOAc in DCM to give a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.72 g. 43%): LC/MS
(Table 1, Method b) R.sub.t=2.64 min; MS m/z: 591 (M+H).sup.+.
Step P:
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyraz-
in-1-yl)cyclopentyl cyclopropylcarbamate
##STR01359##
[2471] To a scalemic mixture enriched in
(1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.211 g, 0.357 mmol)
in 1,4-dioxane (1.5 mL) was added cyclopropanamine (0.102 g, 1.786
mmol). After about 1 h, aqueous NaOH (1N, 1.5 mL, 1.5 mmol) was
added and the reaction mixture was heated at about 60.degree. C.
for about 30 min then cooled to ambient temperature. The reaction
mixture was extracted with DCM (3.times.5 mL). The combined organic
solvents were coned under reduced pressure. The residue was
purified using silica gel chromatography eluting with 0-100%
EtOAc:MeOH (9:1) in EtOAc to give
(1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl cyclopropylcarbamate (0.0847 g, 67%): LC/MS (Table 1,
Method b) R.sub.t=1.73 min; MS m/z: 355 (M+H).sup.+.
Example #42
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-
cyclopentyl cyclobutylcarbamate
##STR01360##
[2472] Step A:
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine
##STR01361##
[2474] To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494
mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g,
4.94 mmol) in THF (1255 mL) was added PdCl.sub.2(PPh.sub.3).sub.2
(3.47 g, 4.94 mmol). The reaction mixture was cooled at about
-5-0.degree. C. and a solution of (trimethylsilyl)acetylene (65.0
mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min.
The reaction mixture was stirred at about -5-0.degree. C. for about
1.5 h and then allowed to warm to rt overnight. The reaction
mixture was then filtered through a Celite.RTM. pad and washed with
THF until no further product eluted. The filtrate was coned under
reduced pressure to give a brown-orange solid. The solid was
triturated and sonicated with warm petroleum ether (b.p.
30-60.degree. C., 400 mL), cooled to rt, collected, washed with
petroleum ether (b.p. 30-60.degree. C.; 2.times.60 mL), and dried
to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g,
93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b)
R.sub.t=2.51 min; MS m/z: 270, 272 (M+H).sup.+.
Step B: 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01362##
[2476] To a solution of
5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1
mmol) in DMF (60 mL) at about 0.degree. C. was added NaH (60%
dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions.
After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol)
was added and the reaction was allowed to warm slowly to ambient
temperature. After about 16 h, the reaction mixture was poured onto
ice-cold water (120 mL) and the precipitate was collected by vacuum
filtration. The crude solid was dissolved in DCM (15 mL) and
purified by silica gel chromatography eluting with DCM to give
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS
(Table 1, Method c) R.sub.t=1.58 min; MS m/z: 352, 354
(M+H).sup.+.
Step C: tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
##STR01363##
[2478] To a flask was added Pd.sub.2(dba).sub.3 (3.90 g, 4.26
mmol), di-tert-butyl-(2',4',6'-triisopropylbiphenyl-2-yl)phosphane
(3.62 g, 8.52 mmol), and 1,4-dioxane (453 mL). The catalyst-ligand
mixture was degassed via vacuum/nitrogen purge (3 times) and heated
at about 80.degree. C. for about 10 min. Then
2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol),
tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu
(12.28 g, 128 mmol) were added. After an additional vacuum/nitrogen
purge, the reaction was heated at about 80.degree. C. After about
50 min, the reaction mixture was cooled to ambient temperature and
filtered through a pad of silica gel (6 cm in height.times.6 cm in
diameter), topped with Celite.RTM. (1 cm in height.times.6 cm in
diameter), while washing with EtOAc (3.times.150 mL). Water (300
mL) was added to the filtrate and the organic layer was separated.
The aqueous layer was extracted with additional EtOAc (3.times.200
mL). The combined organic extracts were washed with saturated
aqueous NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine (400
mL each), dried over anhydrous MgSO.sub.4, filtered, and concd
under reduced pressure to give a dark brown oil (45 g). The brown
oil was dissolved in DCM (250 mL), silica gel (200 g) was added,
and the mixture was concd under reduced pressure. The resulting
silica mixture was purified using silica gel chromatography eluting
with a gradient of 25-65% EtOAc in heptane to give a mixture of
tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[major regioisomer] and tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate
[minor regioisomer](18.8 g, 50%): LC/MS (Table 1, Method c)
R.sub.t=1.47 min; MS m/z: 404 (M+H).sup.+.
Step D: 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine
##STR01364##
[2480] To a mixture of tert-butyl
2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and
tert-butyl
1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2
g, 122 mmol) in 1,4-dioxane (290 mL) was added HCl (4 M in
1,4-dioxane, 226 mL, 902 mmol). The reaction was heated at about
60.degree. C. for about 2.5 h and then cooled to about
15-20.degree. C. The solid was collected by vacuum filtration,
washed with EtOAc (3.times.50 mL), and then triturated with
Et.sub.2O (60 mL), collected by vacuum filtration and dried to a
constant weight under vacuum to yield 35.6 g of solid. The solid
was stirred with a mixture of saturated aqueous NaHCO.sub.3 and
EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by
vacuum filtration, washed with ice cold water (3.times.30 mL) and
EtOAc (3.times.30 mL), and dried in a vacuum oven to a constant
weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as
a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) R.sub.t=1.88
min; MS m/z: 304 (M+H).sup.+.
Step E: sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
##STR01365##
[2482] A round bottom flask was charged with THF (1.5 L) followed
by the portionwise addition of NaH (60% dispersion in mineral oil,
70.0 g, 1.75 mol). Additional THF (500 mL) was added and the
resulting mixture was cooled to about -10.degree. C. and ethyl
propionylacetate (250 mL, 1.80 mol) was added dropwise over about 1
h in order to keep the internal temperature below about 10.degree.
C. The resulting mixture was stirred at ambient temperature for
about 0.5 h to give a clear yellow solution, and methyl
4-chloroacetoacetate (100 mL, 0.88 mol) was added dropwise over
about 5 min. The resulting mixture was heated at about 50.degree.
C. for about 19 h to give a reddish orange suspension. The reaction
mixture was cooled to ambient temperature, concd under reduced
pressure and the resulting liquid was transferred to a beaker and
diluted with water (350 mL). The mixture was stirred in an ice bath
for about 2 h. The solid was collected by vacuum filtration and the
filter cake was rinsed with water (150 mL) and dried under vacuum
for about 1 h. The solid was suspended in Et.sub.2O (1.5 L),
filtered, washed with Et.sub.2O (1.5 L), and dried under vacuum.
The resulting solid was azeotroped with toluene (1 L) to give a
solid that was re-suspended in Et.sub.2O (1 L) and collected by
vacuum filtration. The filter cake was washed with Et.sub.2O (500
mL) and dried under vacuum to give sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(204.2 g, 89%) as beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
3.94 (q, J=7.1 Hz, 2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66
(s, 2H), 1.13 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).
Step F: ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate
##STR01366##
[2484] A 5 L round bottom flask was charged with sodium
4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate
(316 g, 1205 mmol), KCl (126 g, 1687 mmol, JT-Baker), AcOH (241 mL,
4218 mmol, JT-Baker), toluene (1850 mL) and water (130 mL). The
reaction was heated at reflux for about 6 h then cooled to ambient
temperature and added dropwise to NaHCO.sub.3 (8% aqueous, 3.5 L).
The resulting biphasic mixture was extracted with MTBE (2.times.1.5
L). The combined organic layers were washed with brine (1 L), dried
over anhydrous MgSO.sub.4 and concd under reduced pressure to give
191 g of crude material that was purified by vacuum distillation
(97-99.degree. C., 0.600 mm Hg) to give ethyl
2-ethyl-4-oxocyclopent-2-enecarboxylate (160 g, 69%): .sup.1H NMR
(CDCl.sub.3) .delta. 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m,
1H), 2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H),
1.23-1.18 (m, 3H).
Step G: ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate
##STR01367##
[2486] A mixture of copper (I) chloride (0.136 g, 1.37 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.854 g, 1.37
mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was
stirred at ambient temperature for about 15 min then cooled to
about 5.degree. C. and polymethylhydrosiloxane (12 mL, 55 mmol) was
added. The reaction mixture was stirred for about 40 min at about
5.degree. C. then cooled to about -12.degree. C. A solution of
ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol)
and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one
portion and the reaction mixture was stirred for about 16 h at
about -12.degree. C. The reaction mixture was quenched by the
addition of MeOH (50 mL). The solvents were removed under reduced
pressure. The residue was dissolved in MeOH (35 mL) and filtered
through a pad of Celite.RTM.. The filtrate was concd under reduced
pressure and the residue was triturated with EtOAc (100 mL) and
filtered. The filtrate was concd under reduced pressure and the
residue was purified using silica gel chromatography eluting with a
gradient of 0-10% EtOAc in heptane to give a scalemic mixture
enriched with (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): .sup.1H NMR
(CDCl.sub.3) .delta. 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td,
J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m,
3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz,
3H).
Step H: 2-ethyl-4-hydroxycyclopentanecarboxylic acid
##STR01368##
[2488] Aqueous NaOH (1 N, 12 mL, 12 mmol) was added to a scalemic
mixture enriched in (1S,2R,4S)-ethyl
2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 5.96 mmol). The
reaction mixture was stirred at ambient temperature for about 3
days and then extracted with Et.sub.2O (3.times.25 mL). The
Et.sub.2O extracts were discarded and the aqueous portion was
cooled to about 0.degree. C. Aqueous HCl (5 N) was slowly added to
bring the pH to about 2. The resulting aqueous suspension was
extracted with EtOAc (3.times.40 mL). The combined organic layers
were washed with brine (2.times.80 mL), dried over anhydrous
MgSO.sub.4, filtered, and concd under reduced pressure to give a
scalemic mixture enriched in
(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g,
100%) as clear oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.36 (tdd,
J=2.6, 4.9, 7.4, 1H), 2.95 (td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7,
14.1, 1H), 2.16-1.94 (m, 3H), 1.65-1.49 (m, 1H), 1.49-1.32 (m, 2H),
0.96 (q, J=7.4, 3H).
Step I: 5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one
##STR01369##
[2490] To a scalemic mixture enriched in
(1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g,
5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and
BOP-Cl (1.821 g, 7.15 mmol). The reaction mixture was stirred at
ambient temperature for about 2 h then poured into Et.sub.2O (350
mL). The solid was removed by filtration while washing with
Et.sub.2O (50 mL). The filtrate was concd under reduced pressure to
give a yellow oil which was dissolved in DCM (5 mL) and Et.sub.2O
was added to give a solid. The supernatant was decanted and the
solid was washed with additional Et.sub.2O. The combined organic
extracts were concd under reduced pressure to give a scalemic
mixture enriched in crude
(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about
15 mol % TEA (0.912 g, 99%): .sup.1H NMR (CDCl.sub.3) .delta. 4.85
(s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H),
1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Step J:
2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclop-
entanecarbohydrazide
##STR01370##
[2492] To a scalemic mixture enriched in
(1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96
mmol) in 1,4-dioxane (12 mL) was added
2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g,
5.96 mmol). The reaction mixture was heated at about 80.degree. C.
for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25
mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were
added sequentially. The reaction mixture was stirred at ambient
temperature for about 30 min then aqueous HCl (1 N, 50 mL) was
added dropwise and the reaction mixture was stirred for about 30
min. The layers were separated and the aqueous layer was extracted
with EtOAc (2.times.100 mL). The combined organic extracts were
washed with water (10 mL), saturated aqueous NaHCO.sub.3 (15 mL),
brine (15 mL) and dried over anhydrous MgSO.sub.4, filtered, and
concd under reduced pressure. The residue was purified using silica
gel chromatography eluting with 100% EtOAc to give a scalemic
mixture enriched in
(1S,2R,4S)-2-ethyl-4-hydroxy-N'-(5-tosyl-5H-pyrrolo[2,
3-b]pyrazin-2-yl)cyclopentanecarbo-hydrazide (1.887 g, 71%): LC/MS
(Table 1, Method b) R.sub.t=2.05 min; MS m/z: 444 (M+H).sup.+.
Step K:
4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2,3-b-
]pyrazin-2-yl)cyclopentanecarbohydrazide
##STR01371##
[2494] To a scalemic mixture enriched in
(1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyc-
lopentanecarbo-hydrazide (9.06 g, 20.43 mmol) in DMF (40.9 mL) was
added TBDMSCl (3.69 g, 24.51 mmol) and imidazole (3.48 g, 51.1
mmol). The reaction mixture was stirred at ambient temperature for
about 4 h. The solvent was removed under reduced pressure. The
residue was diluted with EtOAc (200 mL), filtered, and washed with
EtOAc (20 mL). The filtrate was coned under reduced pressure. The
residue was purified using silica gel chromatography eluting with
0-50% EtOAc in DCM to give a scalemic mixture enriched in
(1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N'-(5-tosyl-5H-pyrrolo[-
2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (11.37 g, 100%) as an
orange solid: LC/MS (Table 1, Method b) R.sub.t=3.14 min; MS m/z:
558 (M+H).sup.+.
Step L:
4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrr-
olo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
##STR01372##
[2496] To a scalemic mixture enriched in
(1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N-(5-tosyl-5H-pyrrolo[2-
,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (11.37 g, 20.38 mmol)
in 1,4-dioxane (204 mL) was added DIEA (14.24 mL, 82 mmol) followed
by thionyl chloride (2.98 mL, 40.8 mmol) dropwise over about 25
min. The reaction mixture was stirred at ambient temperature for
about 1 h and heated at about 70.degree. C. for about 1 h. The
reaction mixture was cooled to ambient temperature and EtOAc (600
mL) was added. The organic mixture was washed with water (80 mL)
and brine (80 mL), dried over anhydrous MgSO.sub.4, filtered and
concd under reduced pressure. The residue was purified using silica
gel chromatography eluting with 0-50% EtOAc in DCM to give a
scalemic mixture enriched in
1-((1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (9.58 g, 87%).
LC/MS (Table 1, Method b) R.sub.t=3.24 min; MS m/z: 540
(M+H).sup.+.
Step M:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentanol
##STR01373##
[2498] A scalemic mixture enriched in
1-((1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl--
6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (9.58 g, 17.8 mmol)
was dissolved in ethanol (177 mL). Coned HCl (1.75 mL, 21.3 mmol)
was added dropwise. After about 1 h, EtOAc (700 mL) was added. The
organic mixture was washed with saturated aqueous NaHCO.sub.3
(2.times.120 mL), brine (120 mL), dried over anhydrous MgSO.sub.4,
filtered and concd under reduced pressure. The residue was purified
using silica gel chromatography eluting with 30-100% EtOAc in DCM
to give a scalemic mixture enriched in
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanol (6.73 g, 89%): LC/MS (Table 1, Method b)
R.sub.t=2.11 min; MS m/z: 426 (M+H).sup.+.
Step N:
3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin--
1-yl)cyclopentyl 4-nitrophenyl carbonate
##STR01374##
[2500] To a scalemic mixture enriched in
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentanol (6.11 g, 14.4 mmol) in pyridine (100 mL) was
added DMAP (1.93 g, 15.8 mmol) and 4-nitrophenyl carbonochloridate
(4.34 g, 21.5 mmol). The resulting mixture was stirred at ambient
temperature for about 3.5 h and heated at about 33.degree. C. for
about 1 h. The solid was filtered off and washed with EtOAc (30
mL). The filtrated was coned under reduced pressure. The residue
was purified using silica gel chromatography eluting with 0-30%
EtOAc in heptane to give a scalemic mixture enriched in
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (6.63, 78%). LC/MS
(Table 1, Method b) R.sub.t=2.65 min; MS m/z: 591 (M+H).sup.+.
Step O:
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyraz-
in-1-yl)cyclopentyl cyclobutylcarbamate
##STR01375##
[2502] A solution of a scalemic mixture enriched in
(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyra-
zin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.150 g, 0.254 mmol)
in 1,4-dioxane (1 mL) was added to a solution of cyclobutanamine
(0.090 g, 1.27 mmol) in 1,4-dioxane (0.2 mL). After about 1 h,
aqueous NaOH (1 N, 1.5 mL, 1.50 mmol) was added and the reaction
mixture was heated at about 60.degree. C. for about 2 h before
cooling to rt. The organic solvent was removed under reduced
pressure. The resulting aqueous layer mixture was acidified with
AcOH to pH about 5 and extracted with DCM (3.times.5 mL). The
combined organic extracts were concentrated under reduced pressure.
The residue was purified by preparative HPLC (Table 1 method d) to
give
(1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl-
)cyclopentyl cyclobutylcarbamate (0.0468 g, 50%): LC/MS (Table 1,
Method c) R.sub.t=1.17 min; MS m/z: 369 (M+H).sup.+.
TABLE-US-00056 TABLE 4 Jak3 enzyme data for selected compounds JAK3
enzyme Example# IC.sub.50 A.1.105 B A.1.65 B A.1.78 A AA.1.10 B
AA.1.100 C AA.1.101 A AA.1.102 C AA.1.103 A AA.1.104 A AA.1.106 C
AA.1.107 A AA.1.11 A AA.1.12 A AA.1.16 B AA.1.18 A AA.1.22 A
AA.1.25 A AA.1.29 C AA.1.3 B AA.1.32 B AA.1.33 B AA.1.37 B AA.1.42
C AA.1.43 A AA.1.44 B AA.1.49 A AA.1.5 B AA.1.54 B AA.1.6 A AA.1.60
B AA.1.61 B AA.1.62 B AA.1.63 C AA.1.64 C AA.1.66 C AA.1.67 C
AA.1.76 C AA.1.77 A AA.1.79 A AA.1.8 A AA.1.80 C AA.1.81 A AA.1.9 B
AA.1.90 B AA.1.91 B AA.1.92 A AA.1.93 C AA.1.94 B AA.1.95 C AA.1.96
C AA.1.97 C AA.1.98 A AA.1.99 B D.1.10 B D.1.11 B D.1.12 B D.1.13 B
D.1.21 B D.1.22 B D.1.24 B D.1.25 A D.1.29 B D.1.30 B D.1.31 A
D.1.33 C D.1.35 A D.1.38 B D.1.39 B D.1.45 A D.1.46 A D.1.47 B
D.1.49 B D.1.50 C D.1.51 C D.1.52 B D.1.54 C D.1.56 B D.1.58 B
D.1.59 B D.1.60 C D.1.61 C D.1.62 C D.1.63 C D.1.64 C D.1.65 C
D.1.66 C D.1.67 B D.1.69 C D.1.70 B D.1.71 C D.1.72 B D.1.73 C
D.1.76 B D.1.77 B D.1.78 A D.1.79 A D.1.80 A D.1.81 A D.1.82 B
D.1.83 A D.1.84 B D.2.10 C D.2.11 B D.2.13 A D.2.15 B D.2.19 B
D.2.21 B D.2.22 B D.2.23 C D.2.24 A D.2.5 B D.2.6 C DD.1.1 A
Example # 29 A Example # 30 B Example # 31 B Example #14 A Example
#17 A Example #18 B Example #21 B Example #22 C Example #23 A
Example #24 A Example #25 A Example #26 B Example #27 C Example #28
C Example #3 A Example #32 B Example #4 A Example #5 B Example #6 B
Example #8 B Example #9 B H.1.1 A H.1.10 A H.1.2 A H.1.21 A H.1.25
A H.1.29 A H.1.6 A H.3.14 B H.4.1 B I.1.1 A I.1.2 A I.2.1 A I.2.2 A
I.3.1 B J.1.1 A J.2.1 A J.2.10 A J.2.11 A J.2.12 A J.2.13 A J.2.14
A J.2.15 A J.2.2 A J.2.3 A J.2.5 A J.2.6 A J.2.7 A J.2.8 A J.2.9 A
J.3.1 A J.3.10 A J.3.11 A J.3.2 A J.3.4 A J.3.6 B J.3.7 B J.3.8 B
K.3.1 B K.4.1 A K.5.1 A L.1.2 A L.1.4 A LL.1.1 B LL.1.2 C LL.1.3 C
LL.1.4 C Preparation #GGG.1 B QQ.1.4 A UUU.1.1 A UUU.1.1 A YY.1.1 C
YY.1.2 C Key: A <0.1 .mu.M B 0.1-1 .mu.M C >1 .mu.M
Sequence CWU 1
1
5118PRTArtificialoligopeptide 1Xaa Gly Ala Gly Asp Gln Thr Pro Thr
Pro Thr Arg Phe Leu Lys Arg 1 5 10 15 Pro Xaa
212PRTArtificialoligopeptide 2Xaa Ala Glu Glu Glu Ile Tyr Ala Ala
Phe Phe Ala 1 5 10 310PRTArtificialoligopeptide 3Xaa Glu Glu Glu
Tyr Phe Phe Leu Phe Xaa 1 5 10 425PRTArtificialoligopeptide 4Xaa
His Phe Phe Lys Asn Ile Val Thr Pro Arg Thr Pro Pro Pro Ser 1 5 10
15 Gln Gly Lys Gly Ala Glu Gly Gln Xaa 20 25
58PRTArtificialoligopeptide 5Asp Tyr Lys Asp Asp Asp Asp Lys 1
5
* * * * *