U.S. patent number RE47,848 [Application Number 15/902,746] was granted by the patent office on 2020-02-11 for biheteroaryl compounds and uses thereof.
This patent grant is currently assigned to Genentech, Inc.. The grantee listed for this patent is Genentech, Inc.. Invention is credited to Anthony Estrada, Malcolm Huestis, Terry Kellar, Joseph Lyssikatos, Alan G. Olivero, Snahel Patel, Michael Siu.
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United States Patent |
RE47,848 |
Estrada , et al. |
February 11, 2020 |
Biheteroaryl compounds and uses thereof
Abstract
The present invention provides for compounds of Formula I and
embodiments and salts thereof for the treatment of diseases (e.g.,
neurodegenerative diseases). R.sup.1, R.sup.2, R.sup.3, X.sup.1,
X.sup.2, A and Cy variable in Formula all have the meaning as
defined herein. ##STR00001##
Inventors: |
Estrada; Anthony (San Carlos,
CA), Olivero; Alan G. (Half Moon Bay, CA), Patel;
Snahel (Foster City, CA), Siu; Michael (Burlingame,
CA), Lyssikatos; Joseph (Piedmont, CA), Huestis;
Malcolm (San Francisco, CA), Kellar; Terry (Burlingame,
CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc. (South San
Francisco, CA)
|
Family
ID: |
51841525 |
Appl.
No.: |
15/902,746 |
Filed: |
February 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
61817966 |
May 1, 2013 |
|
|
|
Reissue of: |
14267011 |
May 1, 2014 |
9266862 |
Feb 23, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/4545 (20130101); A61K 31/553 (20130101); A61P
3/00 (20180101); A61K 35/30 (20130101); A61K
31/506 (20130101); A61K 31/444 (20130101); C07D
471/08 (20130101); A61K 31/55 (20130101); C07D
487/18 (20130101); C07D 405/14 (20130101); A61P
25/14 (20180101); C07D 487/08 (20130101); C07D
471/18 (20130101); A61P 27/06 (20180101); A61P
27/02 (20180101); A61K 31/444 (20130101); A61P
25/20 (20180101); C07D 417/14 (20130101); C07D
495/08 (20130101); A61K 31/506 (20130101); A61P
9/00 (20180101); C07D 403/14 (20130101); C07D
519/00 (20130101); A61P 21/00 (20180101); C07D
413/14 (20130101); A61P 25/18 (20180101); C07D
401/14 (20130101); A61K 35/30 (20130101); C07D
491/08 (20130101); A61K 45/06 (20130101); A61P
9/10 (20180101); A61P 25/28 (20180101); A61P
43/00 (20180101); A61K 31/5377 (20130101); A61K
31/553 (20130101); A61P 25/04 (20180101); C07D
403/04 (20130101); A61P 21/02 (20180101); A61P
21/04 (20180101); A61K 31/5386 (20130101); A61P
25/02 (20180101); A61P 39/02 (20180101); A61P
25/08 (20180101); C07D 487/14 (20130101); A61P
25/00 (20180101); A61P 25/16 (20180101); A61K
31/55 (20130101); A61P 31/18 (20180101); A61K
31/506 (20130101); A61K 2300/00 (20130101); A61K
31/4545 (20130101); A61K 2300/00 (20130101); A61K
31/5377 (20130101); A61K 2300/00 (20130101); A61K
31/5386 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/55 (20060101); A61K 31/553 (20060101); A61K
31/444 (20060101); A61K 31/155 (20060101); A61K
31/506 (20060101); A61K 31/5377 (20060101); C07D
401/14 (20060101); C07D 403/04 (20060101); C07D
405/14 (20060101); C07D 471/18 (20060101); C07D
413/14 (20060101); C07D 487/08 (20060101); A61K
31/5386 (20060101); A61K 45/06 (20060101); C07D
471/08 (20060101); C07D 519/00 (20060101); C07D
495/08 (20060101); C07D 491/08 (20060101); A61K
35/30 (20150101); C07D 403/14 (20060101); A61K
31/4545 (20060101) |
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Sep 2012 |
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WO |
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2012122383 |
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Sep 2012 |
|
WO |
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|
Primary Examiner: Jones; Dwayne C.
Attorney, Agent or Firm: Armstrong Teasdale LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application .Iadd.is a reissue application of U.S. Pat. No.
9,266,862 B2, which was filed as U.S. patent application Ser. No.
14/267,011 on May 1, 2014 and issued on Feb. 23, 2016, and which
.Iaddend.claims the benefit of U.S. Provisional Appl. No.
61/817,966, filed on May 1, 2013, .Iadd.both of .Iaddend.which
.[.is.]. .Iadd.are .Iaddend.incorporated herein by reference in
.[.its.]. .Iadd.their .Iaddend.entirety.
Claims
The invention claimed is:
1. .[.Compounds.]. .Iadd.A compound .Iaddend.of formula (I)
##STR00197## or .[.salts.]. .Iadd.a pharmaceutically acceptable
salt .Iaddend.thereof wherein R.sup.1, R.sup.2 and R.sup.3 are each
independently H, F, Cl, Br, I, .Iadd.CN, .Iaddend.C.sub.1-6 alkyl
or C.sub.1-6 haloalkyl; X.sup.1 is .[.N or.]. C--R.sup.4, wherein
R.sup.4 is selected from the group consisting of --F, --Cl, --Br,
.[.I -(L.sup.1).sub.0-1-C.sub.1-6 alkyl,.]. .Iadd.--I, CN,
-(L.sup.1).sub.0.1-C.sub.1-6 alkyl,
.Iaddend.-(L.sup.1).sub.0-1-C.sub.1-6 haloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl,
-(L.sup.2).sub.0-1-C.sub.3-8 cycloalkyl, -(L.sup.2).sub.0-1-3 to 7
membered heterocycloalkyl, -(L.sup.2).sub.0-1-6-10 membered aryl,
-(L.sup.2).sub.0-1-5-10 membered heteroaryl, wherein L.sup.1 is
selected from the group consisting of --O--, --N(H)--, --S--,
--N(C.sub.1-6alkyl)-, .[..dbd.O.]. .Iadd.and
--C(.dbd.O)--.Iaddend., and L.sup.2 is selected from the group
consisting of --O--, --N(H)--, --N(C.sub.1-6 alkyl)-, --S--,
.[..dbd.O.]. .Iadd.--C(.dbd.O)--.Iaddend., C.sub.1-4 alkylene,
C.sub.1-4 alkenylene, C.sub.1-4 alkynylene, C.sub.1-4 alkoxylene,
C.sub.1-4 aminoalkylene, C.sub.1-4 thioalkylene and C.sub.1-4
heteroalkylene, and wherein R.sup.4 is optionally substituted on
carbon atoms and heteroatoms with R.sup.R4 substituents selected
from the group consisting of F, Cl, Br, I, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, 3-5 membered cycloalkyl, 3-5 membered
heterocycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, C.sub.1-6
dialkylamino, C.sub.1-6 alkylthio, .dbd.O, --NH.sub.2, --CN,
--NO.sub.2 and --SF.sub.5; X.sup.2 is N; A is selected from the
group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12 membered
heterocycloalkyl, wherein A is optionally substituted with 1-5
R.sup.A substituents selected from the group consisting of F, Cl,
Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.A).sub.0-1-3-8
membered cycloalkyl, -(L.sup.A).sub.0-1-3-8 membered
heterocycloalkyl, -(L.sup.A).sub.0-1-5 to 6 membered heteroaryl,
-(L.sup.A).sub.0-1-C.sub.6 aryl,
-(L.sup.A).sub.0-1-NR.sup.R1aR.sup.R1b,
-(L.sup.A).sub.0-1-OR.sup.R1a, -(L.sup.A).sub.0-1-SR.sup.R1a,
.[.-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.Y.sup.1)OR.sup.R1c,.].
-(L.sup.A).sub.0-1-OC(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)R.sup.R1b,
-(L.sup.A).sub.0-1-C(.dbd.O)OR.sup.R1a,
-(L.sup.A).sub.0-1-OC(.dbd.O)R.sup.R1a,
-(L.sup.A).sub.0-1-P(.dbd.O)(OR.sup.R1a)(OR.sup.R1b),
-(L.sup.A).sub.0-1-S(O).sub.1-2R.sup.R1c,
-(L.sup.A).sub.0-1-S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b)
and -(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2(R.sup.R1c), wherein
L.sup.A is selected from the group consisting of C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4 alkenylene, and
C.sub.2-4 alkynylene; wherein R.sup.R1a and R.sup.R1b are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3-8 membered cycloalkyl,
phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered
heterocycloalkyl; R.sup.R1c is selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.A is optionally
substituted on carbon atoms and heteroatoms with R.sup.RA
substituents selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN,
--NO.sub.2, .dbd.O, --SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 (halo)alkyl-C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino; and Cy is selected from the
group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3 to 12
membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein Cy
is optionally substituted on carbon or heteroatoms with R.sup.Cy
substituents selected from the group consisting of F, Cl, Br, I,
--OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl, C.sub.1-8
haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.Cy).sub.0-1-3-8 membered
cycloalkyl, -(L.sup.Cy).sub.0-1-3-8 membered heterocycloalkyl,
-(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl,
-(L.sup.Cy).sub.0-1-phenyl,
-(L.sup.Cy).sub.0-1-NR.sup.RCaR.sup.RCb,
-(L.sup.Cy).sub.0-1-OR.sup.RCa, -(L.sup.Cy).sub.0-1-SR.sup.RCa,
.[.-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.Y.sup.1)OR.sup.RCc,.].
-(L.sup.Cy).sub.0-1-OC(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)R.sup.RCb,
-(L.sup.Cy).sub.0-1-C(.dbd.O)OR.sup.RCa,
-(L.sup.Cy).sub.0-1-OC(.dbd.O)R.sup.RCa,
-(L.sup.Cy).sub.0-1-P(.dbd.O)(OR.sup.RCa)(OR.sup.RCb),
-(L.sup.Cy).sub.0-1-S(O).sub.1-2R.sup.RCc,
-(L.sup.Cy).sub.0-1-S(O).sub.1-2N(R.sup.RCa)(R.sup.RCb),
.[.-(L.sup.Cy).sub.0-1N(R.sup.RCa)S(O).sub.1-2N(R.sup.Rca)(R.sup.RCb).].
.Iadd.-(L.sup.Cy).sub.0-1N(R.sup.RCa)S(O).sub.1-2N(R.sup.RCa)(R.sup.RCb)
.Iaddend.and
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2(R.sup.RCc), wherein
L.sup.Cy is selected from the group consisting of C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4 alkenylene, and
C.sub.2-4 alkynylene; wherein R.sup.RCa and R.sup.RCb are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3-8 membered cycloalkyl,
phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered
heterocycloalkyl; R.sup.RCc is selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.Cy is optionally
substituted on carbon atoms and heteroatoms with from 1 to 5
R.sup.RCy .[.substitutents.]. .Iadd.substituents .Iaddend.selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O,
--SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 (halo)alkyl-C(.dbd.O)--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
2. A compound according to claim 1, .Iadd.or a pharmaceutically
acceptable salt thereof, .Iaddend.wherein either A or Cy is a
polycyclic carbocycle or polycyclic heterocycle.
.[.3. A compound according to claim 1, wherein X.sup.1 is N..].
.[.4. A compound according to claim 1, wherein X.sup.1 is
C--R.sup.4..].
5. A compound according to claim 1, .Iadd.or a pharmaceutically
acceptable salt thereof, .Iaddend.wherein R.sup.4 is selected from
the group consisting of --F, --Cl, --CN,
-(L.sup.2).sub.0-1-C.sub.3-8 cycloalkyl, -(L.sup.2).sub.0-1-3 to 7
membered heterocycloalkyl, -(L.sup.1).sub.0-1-C.sub.1-6 alkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 haloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl, -(L.sup.2).sub.0-1-6-10
membered aryl and -(L.sup.2).sub.0-1-5-10 membered heteroaryl, and
is optionally substituted.
6. A compound according to claim 1, .Iadd.or a pharmaceutically
acceptable salt thereof, .Iaddend.wherein R.sup.4 is selected from
the group consisting of --F, --Cl, C.sub.3-8 cycloalkyl, 3 to 7
membered heterocycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
--(O)--C.sub.3-8 cycloalkyl, --(O)--3 to 7 membered
heterocycloalkyl, --(O)--C.sub.1-6 alkyl and --(O)--C.sub.1-6
haloalkyl, and is optionally substituted.
7. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.4 is selected from the group
consisting of methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl,
monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl,
cyclobutyl and cyclopentyl.
8. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.4 is selected from the group
consisting of .[.(L.sup.2).sub.0-1-phenyl.].
.Iadd.-(L.sup.2).sub.0-1-phenyl.Iaddend.,
-(L.sup.2).sub.0-1-pyridyl, -(L.sup.2).sub.0-1-pyrimidinyl,
-(L.sup.2).sub.0-1pyrazinyl, -(L.sup.2).sub.0-1-pyridazinyl,
-(L.sup.2).sub.0-1-pyrrolyl, -(L.sup.2).sub.0-1-pyrazolyl,
-(L.sup.2).sub.0-1-imidazolyl, -(L.sup.2).sub.0-1-thienyl,
-(L.sup.2).sub.0-1-thiazolyl .[.and.]..Iadd.,
.Iaddend.-(L.sup.2).sub.0-1-thiadiazolyl,
-(L.sup.2).sub.0-1-triazoloyl, -(L.sup.2).sub.0-1-oxazolyl,
-(L.sup.2).sub.0-1-oxadiazolyl, .Iadd.and
.Iaddend.-(L.sup.2).sub.0-1-furanyl and is optionally
substituted.
9. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.4 is selected from the group
consisting of -(L.sup.2).sub.0-1-phenyl and
-(L.sup.2).sub.0-1-pyridinyl, and is optionally substituted.
10. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.4 is --OC(H)(CH.sub.3)-phenyl
wherein said phenyl ring is optionally substituted.
11. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.1, R.sup.2 and R.sup.3 are
each independently selected from the group consisting of F, Cl, CN,
hydrogen, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl.
12. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein R.sup.1, R.sup.2 and R.sup.3 are
each hydrogen.
13. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A and Cy are independently selected
from the group consisting of pyrrolidine, piperidine, azetidine,
azepane, piperazine, 7-azaspiro[3.5]nonane,
3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole,
2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,
6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane,
2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane,
.[.2-azabicyclo[2.1.1]hexane,.]. 9-azabicyclo[4.2.1]nonane,
9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane,
2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and
is optionally substituted.
14. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is selected from the group
consisting of pyrrolidine, piperidine, azetidine, azepane,
piperazine, cyclopropane, cyclobutane, cyclopentane,
7-azaspiro[3.5]nonane, 3-oxabicyclo[3.1.0]hexane,
3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole,
2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,
6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and
is optionally substituted.
15. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is selected from the group
consisting of 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane,
.[.3oxabicyclo[3.1.0]hexane.].
.Iadd.3-oxabicyclo[3.1.0]hexane.Iaddend., azetidine, pyrrolidine,
cyclopropane, cyclobutane, cyclopentane, and is optionally
substituted.
16. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is selected from the group
consisting of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted.
17. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein .[.is.]. A is selected from the
group consisting of methyl, ethyl, isopropyl, ##STR00198##
18. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein Cy is selected from the group
consisting of 2,5-diazabicyclo[2.2.1]heptane, piperidine,
pyrrolidine, azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane,
2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo [3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane,
9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane,
2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane, .Iadd.and
.Iaddend.3-oxa-8-azabicyclo[3.2.1]octane, .Iadd.and .Iaddend.is
optionally substituted.
19. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein Cy is selected from the group
consisting of azetidine, (1S ,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted.
20. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein Cy is selected from the group
consisting of ##STR00199##
21. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is C.sub.1-6 alkyl or C.sub.1-6
dialkylamino, and is optionally substituted.
22. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is methyl or ethyl.
23. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein Cy is C.sub.1-6 alkyl, and is
optionally substituted.
24. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is optionally substituted with
from 1 to 5 R.sup.A substituents selected from the group consisting
of F, Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8
alkyl, C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl,
-(L.sup.A).sub.0-1-3-8 membered cycloalkyl, -(L.sup.A).sub.0-1-3-8
membered heterocycloalkyl, -(L.sup.A).sub.0-1-5 to 6 membered
heteroaryl, .Iadd.and .Iaddend.-(L.sup.A).sub.0-1-C.sub.6 aryl,
wherein L.sup.A is selected from the group consisting of --C(O)--,
--C(O)CH.sub.2--, --OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--,
--N(C.sub.1-3 alkyl)CH.sub.2--, .[.CH.sub.2N(H)--.].
.Iadd.--CH.sub.2N(H)--.Iaddend., .Iadd.and
.Iaddend.--CH.sub.2N(C.sub.1-3 alkyl)-; wherein said 3-8 membered
cycloalkyl is selected from the group consisting of propane,
butane, pentane and hexane; wherein said 3 to 8 membered
heterocycloalkyl is selected from the group consisting of oxetane,
tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine,
piperidine and azepane; wherein said 5 to 6 membered heteroaryl is
selected from the group consisting of pyrrole, pyrazole, imidazole,
thiophene, thiazole, oxazole, .[.trizole.].
.Iadd.triazole.Iaddend., pyridine, pyrimidine, pyrazine, .Iadd.and
.Iaddend.pyridazine; wherein said C.sub.6 aryl is phenyl; and
.[.where in.]. .Iadd.wherein .Iaddend.R.sup.A is optionally
substituted with from 1 to 5 R.sup.RA .[.substitutents.].
.Iadd.substituents .Iaddend.selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
25. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein Cy is optionally substituted with
from 1 to 5 R.sup.Cy substituents selected from the group
consisting of F, Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered cycloalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered heterocycloalkyl,
-(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl, .Iadd.and
.Iaddend.-(L.sup.Cy).sub.0-1-C.sub.6 aryl, wherein L.sup.Cy is
selected from the group consisting of --C(O)--, --C(O)CH.sub.2--,
--OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--, --N(C.sub.1-3
alkyl)CH.sub.2--, .[.CH.sub.2N(H)--,.]. .Iadd.--CH.sub.2N(H)--, and
.Iaddend.--CH.sub.2N(C.sub.1-3 alkyl)-; wherein said 3-8 membered
cycloalkyl is selected from the group consisting of propane,
butane, pentane and hexane; wherein said 3 to 8 membered
heterocycloalkyl is selected from the group consisting of oxetane,
tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine,
piperidine and azepane; wherein said 5 to 6 membered heteroaryl is
selected from the group consisting of pyrrole, pyrazole, imidazole,
thiophene, thiazole, oxazole, .[.trizole.].
.Iadd.triazole.Iaddend., pyridine, pyrimidine, pyrazine, .Iadd.and
.Iaddend.pyridazine; wherein said C.sub.6 aryl is phenyl; and where
in R.sup.Cy is optionally substituted with from 1 to 5 R.sup.RCy
.[.substitutents.]. .Iadd.substituents .Iaddend.selected from, F,
Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
26. A compound .[.of claim.]. of claim 1, .Iadd.or a
pharmaceutically acceptable salt thereof, .Iaddend.wherein Cy is
optionally substituted with 1 to 5 R.sup.Cy substituents selected
from the group consisting of F, Cl, Br, I, CN, OH,
2,3-difluorophen-1-yl-C(.dbd.O)--, 4-fluorophen-1-yl-C(.dbd.O)--,
3-fluorophen-1-yl-C(.dbd.O)--, 3,5-difluorophen-1-yl-C(.dbd.O)--,
3-fluoro-4-methyl-phen-1-yl-C(.dbd.O)--,
2,5-difluorophen-1-yl-C(.dbd.O)--, oxetane, oxetan-3-yl, thiazole,
thiazol-2-yl, --CH.sub.3CH.sub.2C(.dbd.O)--, CH.sub.3C(.dbd.O)--,
CF.sub.3CH.sub.2--, (HO)C(CH.sub.3).sub.2CH.sub.2--,
CH.sub.3OCH.sub.2CH.sub.2--, CH.sub.3OC(CH.sub.3).sub.2C(.dbd.O)--,
CH.sub.3OCH.sub.2C(.dbd.O)--, isopropyl, ethyl and methyl.
27. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein A is optionally substituted with 1
to 5 R.sup.A substituents selected from the group consisting of F,
Cl, Br, I, CN, CH.sub.3O--, CH.sub.3, cyclopropylmethyl, CF.sub.3
and butyl.
28. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein said compound is selected from the
subformula consisting of ##STR00200## ##STR00201##
29. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein said compound is selected from the
subformula consisting of ##STR00202##
30. A compound of claim 1, .Iadd.or a pharmaceutically acceptable
salt thereof, .Iaddend.wherein said compound is selected from the
subformula consisting of ##STR00203## ##STR00204## wherein R.sup.Cy
if present replaces a hydrogen atom attached to a carbon or
nitrogen atom of the Cy ring.
31. A compound of claim 1 selected from the group consisting of:
.[.[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-
-yl]pyrrolidin-1-yl]-phenyl-methanone;
[3-[6-(2-aminopyrimidin-5-yl)-2-methyl-pyrimidin-4-yl]-1-piperidyl]-pheny-
l-methanone;
[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl-
]-1-piperidyl]-phenyl-methanone;
[3-[6-(2-aminopyrimidin-5-yl)-2-methyl-pyrimidin-4-yl]pyrrolidin-1-yl]-ph-
enyl-methanone
6-((1R,3R,5R,7R)-2-azaadamantan-2-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[-
4,5'-bipyrimidin]-2'-amine;.].
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
.[.5-[2-(3,3-difluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
ptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-fluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5--
yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicy-
clo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;.].
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyr-
imidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyr-
imidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-5-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanon-
e;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl-
)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-
-2-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trif-
luoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine-
;.].
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicy-
clo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-meth-
yl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-pr-
opan-2-ol;
.[.[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.-
1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propa-
n-2-ol;.].
.Iadd.1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-
-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-
-yl]-2-methyl-propan-2-ol;.Iaddend.
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[-
2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
.[.5-[2-(3,3-difluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
ptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-fluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5--
yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyc-
lo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyr-
imidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyr-
imidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-5-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanon-
e;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl-
)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-
-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluo-
roethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[-
2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-p-
ropan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-pr-
opan-2-ol;
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]h-
exan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-
-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicy-
clo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo-[3.1.0]hexane-3-yl]ethan-
one;.].
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabi-
cyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3yl]-ethan-
one;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3--
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2--
amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)--
3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-
-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyeth-
yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
.].
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidi-
n-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
.[.5-[2-(3-methoxyazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-dimethylazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3--
yl)-3-fluoro-1H-pyrrolo[2,3-b]pyridine;.].
.Iadd.5-[2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-[(1S,4S)-5-(oxetan-3-yl)-2,5-
-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-
-2-amine;.Iaddend.
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-meth-
oxy-2-methyl-propan-1-one;
.[.[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3--
yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone;-
.].
.Iadd.1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-aza-
bicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-y-
l]-2-methoxy-ethanone;.Iaddend.
3-(difluoromethoxy)-5-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-
-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[2.1.1]hexan-4-yl)-
pyrimidin-4-yl]pyrimidin-2-amine;.].
5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyri-
midin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
3-(difluoromethoxy)-5-[2-(3-fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
.[.5-[2,6-bis[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl-
]pyrimidin-2-amine;.].
5-[2-(3,3-difluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[8-(2,2,2-trifluoroethyl)-8-aza-
bicyclo[3.2.1]octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-isopropyl-2,5-diazabicy-
clo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-ethyl-2,5-diazabicyclo[-
2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-(oxetan-3-yl)-2,5-diaza-
bicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(3S,4R)-3,4-difluoropyrrolidin-1--
yl]pyrimidin-4-yl]pyrimidin-2-amine;.].
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanon-
e;
.[.1-[3-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyr-
imidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]ethanone;
5-[2-(2-fluoro-7-azaspiro[3.5]nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(1R,5S)-3-methyl-3,6-diazabicyclo[3.2.1]octan-6-yl]-6-[(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4,4-difluoroazepan-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-
-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-cyclobutylpiperazin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hep-
tan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
4-(2-aminopyrimidin-5-yl)-N,N-diethyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]heptan-5-yl]pyrimidin-2-amine; 5-[2-(4-methylpip erazin-
1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyri-
midin-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-(1-piperidyl)pyrimi-
din-4-yl]pyrimidin-2-amine;
5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyri-
midin-4-yl]pyrimidin-2-amine;
5-[2-[(3aS,6aR)-5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-2-
-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimi-
din-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyrrolidin-1-yl-pyr-
imidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-difluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(3aR,6aS)-4,4-difluoro-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-
-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimi-
din-2-amine;
5-[2-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(6-azaspiro[2.5]octan-6-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[8-(oxetan-3-yl)-8-azabicyclo[3.2.-
1]octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidi-
n-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-2-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)-
pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-5-yl]-2-methyl-propan-2-ol;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-(2-methoxyethyl)-2,5-di-
azabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;.].
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
.[.1-[6-[6-(2-aminopyrimidin-5-yl)-2-cyclopropyl-pyrimidin-4-yl]-3-azabic-
yclo[3.1.0]hexan-3-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(9-azabicyclo[3.3.1]nonan-9-yl)pyr-
imidin-4-yl]pyrimidin-2-amine;
5-[2-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
ptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-
-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-cyclopropylpiperazin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
ptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-6-[(1S,4S)-2-o-
xa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-[4-(trifluoromethyl-
)-1-piperidyl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[2-(2-aminopyrimidin-5-yl)-6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-pyridyl]-
cyclobutanecarbonitrile;.].
1-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan--
3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyr-
imidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-cyclopropyl-pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy-pyridin-2-amine;
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidi-
n-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-azabicyclo[3.2.1]octan-3-yl)-
pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1S,4S)-5-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)-
pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2,2-dioxo-2-thia-5-azabic-
yclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-(2,2,2-trifluoroethyl)--
2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-azabicyclo[3.2.1]octan-8-yl)pyr-
imidin-4-yl]pyrimidin-2-amine;
1-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-
-yl]cyclobutanecarbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-5-fluoro-6-[(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.2.-
1]octan-8-yl]pyrimidin-4-yl]pyrimidin-2-amine;.].
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,5-diazabicyclo[2.2.1]heptan--
2-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.2.1]octan-8-yl)pyr-
imidin-4-yl]pyrimidin-2-amine;.].
5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]hexan-
-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
.[.5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]he-
xan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyr-
imidin-4-yl]pyrimidin-2-amine;
5-[2-cyclopropyl-6[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-
-4-yl]pyrimidin-2-amine;
8-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-
-yl]-3-methyl-8-azabicyclo[3.2.1]octan-3-ol;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,6-dimethylmorpholin-4-yl)pyrimi-
din-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3--
yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2,6-bis(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine-
;.].
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
2-amino-5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridine-3-carbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-chloro-pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine;
.[.8-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidi-
n-4-yl]-8-azabicyclo[3.2.1]octan-3-ol;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8--
yl)-2-pyridyl]pyrimidin-2-amine;
5-[4,6-bis(3-azabicyclo[2.1.1]hexan-3-yl)-2-pyridyl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8--
yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]-2-pyridyl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,2-dimethylmorpholin-4-yl)pyrimi-
din-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(2-methylpyrrolidin-1-yl)-6-tetrahydropyran-4-yl-pyrimidin-4-yl]pyri-
midin-2-amine; 5-[6-(3-methoxyazetidin-
1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-3-(trifluoromethyl)pyrid-
in-2-amine;
5-[6-(3-fluoroazetidin-1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-3-
-(trifluoromethyl)pyridin-2-amine; 3-chloro-5-[6-(3-fluoroazetidin-
1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyridin-2-amine;
5-[6-(3-fluoroazetidin-1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]py-
rimidin-2-amine;
5-(2,6-dimorpholinopyrimidin-4-yl)pyrimidin-2-amine;.].
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azab-
icyclo
[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amin-
e;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo-
[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
.[.1-[(1R,5S)-6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3--
yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;.].
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicy-
clo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicy-
clo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicy-
clo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
.[.5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3azabicyclo[3.1.0]hexan-6--
yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2-amine;.].
.Iadd.5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexa-
n-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;.Iaddend.
.[.5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3azabicyclo[3.1.0-
]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2amine;.].
.Iadd.5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3-
.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;.Iadden-
d.
5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-
-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
.[.1-[(1R,5S)-6-[6-[6-amino
5-(difluromethoxy)-3-pyridyl]-2-cyclopropyl-pyrmidin-4-yl]-3-azabicyclo[3-
.1.0]hexan-3-yl]-2-methyl-propan-2-ol;.].
.Iadd.1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cycloprop-
yl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;.Ia-
ddend.
.[.1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2(3-azab-
icyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]prop-
an-1one;.].
.Iadd.1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabic-
yclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-
-1-one;.Iaddend.
.[.3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolodin-1-yl]-6-[(1S,4S)-2-o-
xa-5-azabicyclo[2.2.1]heptan-5yl]pyrimidin-4-yl]pyridin-2-amine;.].
.Iadd.3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolidin-1-yl]-6-[(1S,4S)--
2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;.Iadde-
nd.
3-(difluoromethoxy)-5-[2-3-methoxypyrrolidin-1-yl)-6-(2-oxa-5-azabicyc-
lo[2.2.1]heptan-5-yl)pyrimidin-4-yl]pyridin-2-amine;
5-[2-(2-azaspiro[3.3]heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hep-
tan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)-pyridin-2-amine;
.[.5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5yl)-6-(2-oxa-5-azabicy-
clo[2.2.1]heptan-5-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2-amine;-
.].
.Iadd.5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-6-(2-oxa-5--
azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2--
amine; and.Iaddend.
3-(difluoromethoxy)-5-[2-(3-methoxy-3-methyl-azetidin-1-yl)-6-[(1S,4S)-2--
oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
.[.and
6-cyclopropyl-5'-(difluoromethoxy)-4-(1-(oxetan-3-yl)azetidin-3-yl)-[2,3'-
-bipyridin]-6'-amine.]. .Iadd.or a pharmaceutically acceptable salt
thereof.Iaddend..
32. A pharmaceutical composition comprising a compound of claim 1,
.Iadd.or a pharmaceutically acceptable salt thereof, .Iaddend.and a
pharmaceutically acceptable carrier, diluent or excipient.
33. A compound .[.of claim 1 which is
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4]pyridin-2-amine.].
.Iadd.wherein is
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine; or
a pharmaceutically acceptable salt thereof.Iaddend..
34. A compound .[.of claim 1.]. which is
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[-
2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo
[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol.Iadd.; or a
pharmaceutically acceptable salt thereof.Iaddend..
35. A compound .[.of claim 1.]. which is
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo
[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-
-propan-2-ol.Iadd.; or a pharmaceutically acceptable salt
thereof.Iaddend..
36. A compound .[.of claim 1 which is
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)-
pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol.].
.Iadd.which is
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-p-
ropan-2-ol; or a pharmaceutically acceptable salt
thereof.Iaddend..
37. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azab-
icyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine-
.Iadd.; or a pharmaceutically acceptable salt thereof.Iaddend..
38. A compound .[.of claim 1.]. which is
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-meth-
oxy-2-methyl-propan-1-one.Iadd.; or a pharmaceutically acceptable
salt thereof.Iaddend..
39. A compound .[.of claim 1 which is
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)-
pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone.].
.Iadd.which is
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-meth-
oxy-ethanone; or a pharmaceutically acceptable salt
thereof.Iaddend..
40. A compound .[.of claim 1.]. which is
3-(difluoromethoxy)-5-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-
-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine.Iadd.-
; or a pharmaceutically acceptable salt thereof.Iaddend..
41. A compound .[.of claim 1.]. which is
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanon-
e.Iadd.; or a pharmaceutically acceptable salt
thereof.Iaddend..
42. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.;
or a pharmaceutically acceptable salt thereof.Iaddend..
43. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyr-
imidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.; or a
pharmaceutically acceptable salt thereof.Iaddend..
44. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy-pyridin-2-amine.Iadd.; or
a pharmaceutically acceptable salt thereof.Iaddend..
45. A compound .[.of claim 1.]. which is
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidi-
n-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.; or a
pharmaceutically acceptable salt thereof.Iaddend..
46. A compound .[.of claim 1.]. which is
5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]hexan-
-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.; or
a pharmaceutically acceptable salt thereof.Iaddend..
47. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.;
or a pharmaceutically acceptable salt thereof.Iaddend..
48. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azab-
icyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine-
.Iadd.; or a pharmaceutically acceptable salt thereof.Iaddend..
49. A compound .[.of claim 1.]. which is
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone.Iad-
d.; or a pharmaceutically acceptable salt thereof.Iaddend..
.[.50. A compound of claim 1 which is
1-[(1R,5S)-6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)-
pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol..].
51. A compound .[.of claim 1.]. which is
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicy-
clo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Ia-
dd.; or a pharmaceutically acceptable salt thereof.Iaddend..
52. A compound .[.of claim 1.]. which is
5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-
-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iadd.; or a
pharmaceutically acceptable salt thereof.Iaddend..
53. A compound .[.of claim 1.]. which is
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyr-
imidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol.Iadd.;
or a pharmaceutically acceptable salt thereof.Iaddend..
54. A compound .[.of claim 1.]. which is
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2-
.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one-
.Iadd.; or a pharmaceutically acceptable salt thereof.Iaddend..
55. A compound .[.of claim 1.]. which is
3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine.Iadd.;
or a pharmaceutically acceptable salt thereof.Iaddend..
.Iadd.56. A compound selected from the group consisting of:
##STR00205## .Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates to organic compounds useful for
therapy and/or prophylaxis in a mammal, and in particular to
inhibitors of DLK useful for treating neurodegeneration diseases
and disorders.
BACKGROUND OF THE INVENTION
Neuron or axon degeneration plays a central role in the proper
development of the nervous system and is a hall mark of many
neurodegenerative diseases including for example, amyotrophic
lateral sclerosis (ALS), glaucoma, Alzheimer's disease, and
Parkinson's disease, as well a traumatic injury to the brain and
spinal cord. Recent patent publication WO2011/050192, incorporated
herein by reference, describes the role of the Dual Leucine Zipper
Kinase (DLK), also referred to as MAP3K12, to cause neuronal cell
death. Neurodegenerative diseases and injuries are devastating to
patients and caregivers, and also result in great financial
burdens, with annual costs currently exceeding several hundred
billion dollars in the United States alone. Most current treatments
for these diseases and conditions are inadequate. Adding to the
urgency of the problems created by these diseases is the fact that
many such diseases are age related, and thus their incidence is
increasing rapidly as population demographics change. There is a
great need for the development of effective approaches to treating
neurodegenerative diseases and nervous system injuries, including
for example, through the inhibitors of DLK in neurons.
SUMMARY OF THE INVENTION
In one aspect the present inventions provides for compounds of
Formula I (I):
##STR00002## or salts thereof wherein R.sup.1, R.sup.2 and R.sup.3
are each independently H, F, Cl, Br, I, C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl; X.sup.1 is N or C--R.sup.4, wherein R.sup.4 is
selected from the group consisting of --F, --Cl, --Br,
.[.I-(L.sup.1).sub.0-1-C.sub.1-6 alkyl,.]. .Iadd.--I,
-(L.sup.1).sub.0-1-C.sub.1-6alkyl,
.Iaddend.-(L.sup.1).sub.0-1-C.sub.1-6 haloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl,
-(L.sup.2).sub.0-1-C.sub.3-8cycloalkyl, -(L.sup.2).sub.0-1-3 to 7
membered heterocycloalkyl, -(L.sup.2).sub.0-1-6-10 membered aryl,
.Iadd.and .Iaddend.-(L.sup.2).sub.0-1-5-10 membered heteroaryl,
wherein L.sup.1 is selected from the group consisting of --O--,
--N(H)--, --S--, --N(C.sub.1-6 alkyl)-, .[..dbd.O.]. .Iadd.and
--C(.dbd.O)--.Iaddend., and L.sup.2 is selected from the group
consisting of --O--, .[.--N(H.]. .Iadd.--N(H)--.Iaddend.,
--N(C.sub.1-6 alkyl)-, --S--, .[..dbd.O.].
.Iadd.--C(.dbd.O)--.Iaddend., C.sub.1-4 alkylene, C.sub.1-4
alkenylene, C.sub.1-4 alkynylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene and C.sub.1-4 heteroalkylene,
and wherein R.sup.4 is optionally substituted on carbon atoms and
heteroatoms with R.sup.R4 substituents selected from the group
consisting of F, Cl, Br, I, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylamino, C.sub.1-6 dialkylamino, C.sub.1-6
alkylthio, .dbd.O, --NH.sub.2, --CN, --NO.sub.2 and --SF.sub.5;
X.sup.2 is N or CH; A is selected from the group consisting of
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 dialkylamino, 3 to
12 membered cycloalkyl, .Iadd.and .Iaddend.3 to 12 membered
heterocycloalkyl, wherein A is optionally substituted with 1-5
R.sup.A substituents selected from the group consisting of F, Cl,
Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.A).sub.0-1-3-8
membered cycloalkyl, -(L.sup.A).sub.0-1-3-8 membered
heterocycloalkyl, -(L.sup.A).sub.0-1-5 to 6 membered heteroaryl,
-(L.sup.A).sub.0-1-C.sub.6 aryl,
-(L.sup.A).sub.0-1-NR.sup.R1aR.sup.R1b,
-(L.sup.A).sub.0-1-OR.sup.R1a, -(L.sup.A).sub.0-1-SR.sup.R1a,
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.Y.sup.1)OR.sup.R1c,
-(L.sup.A).sub.0-1-OC(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)R.sup.R1b,
-(L.sup.A).sub.0-1-C(.dbd.O)OR.sup.R1a,
-(L.sup.A).sub.0-1-OC(.dbd.O)R.sup.R1a,
-(L.sup.A).sub.0-1-P(.dbd.O)(OR.sup.R1a)(OR.sup.R1b),
-(L.sup.A).sub.0-1-S(O).sub.1-2R.sup.R1c,
-(L.sup.A).sub.0-1-S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b)
and -(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2(R.sup.R1c), wherein
L.sup.A is selected from the group consisting of C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4 alkenylene, and
C.sub.2-4 alkynylene; wherein R.sup.R1a and R.sup.R1b are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3-8 membered cycloalkyl,
phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered
heterocycloalkyl; R.sup.R1c is selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.A is optionally
substituted on carbon atoms and heteroatoms with R.sup.RA
.[.substitutents.]. .Iadd.substituents .Iaddend.selected from, F,
Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino; and Cy is selected from the
group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3 to 12
membered cycloalkyl, .Iadd.and .Iaddend.3 to 12 membered
heterocycloalkyl, wherein Cy is optionally substituted on carbon or
heteroatoms with R.sup.Cy substituents selected from the group
consisting of F, Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered cycloalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered heterocycloalkyl,
-(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl,
-(L.sup.Cy).sub.0-1-phenyl,
-(L.sup.Cy).sub.0-1-NR.sup.RCaR.sup.RCb,
-(L.sup.Cy).sub.0-1-OR.sup.RCa, -(L.sup.Cy).sub.0-1-SR.sup.RCa,
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.Y.sup.1)OR.sup.RCc,
-(L.sup.Cy).sub.0-1-OC(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)R.sup.RCb,
-(L.sup.Cy).sub.0-1-C(.dbd.O)OR.sup.RCa,
-(L.sup.Cy).sub.0-1-OC(.dbd.O)R.sup.RCa,
.[.-(L.sup.Cy).sub.0-1-P(.dbd.O)(OR.sup.RCa)(OR.sup.RCba),.].
.Iadd.-(L.sup.Cy).sub.0-1-P(.dbd.O)(OR.sup.RCa)(OR.sup.RCb),
.Iaddend.-(L.sup.Cy).sub.0-1-S(O).sub.1-2R.sup.RCc,
.[.-(L.sup.Cy).sub.0-1-S(O).sub.0-2N(R.sup.RCa)(R.sup.RCb),.].
.Iadd.-(L.sup.Cy).sub.0-1-S(O).sub.1-2N(R.sup.RCa)(R.sup.RCb),
.Iaddend.-(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2N(R.sup.RCa)(R.sup.R-
Cb) and -(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2(R.sup.RCc),
wherein L.sup.Cy is selected from the group consisting of C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4 alkenylene, and
C.sub.2-4 alkynylene; wherein R.sup.RCa and R.sup.RCb are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3-8 membered cycloalkyl,
phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered
heterocycloalkyl; R.sup.RCc is selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.Cy is optionally
substituted on carbon atoms and heteroatoms with from 1 to 5
R.sup.RCy .[.substitutents.]. .Iadd.substituents .Iaddend.selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O,
--SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 (halo)alkyl-C(.dbd.O)--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, either A or Cy is a polycyclic carbocycle
or polycyclic heterocycle.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, either A or Cy is a bridged bicyclic
carbocycle or bridged bicyclic heterocycle.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, either A or Cy is a C-linked carbocycle or
C-linked heterocycle.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, X.sup.1 is N.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, X.sup.1 is C--R.sup.4.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, X.sup.2 is N.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, X.sup.2 is C(H).
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is selected from the group
consisting of --F, --Cl, --CN, -(L.sup.2).sub.0-1-C.sub.3-8
cycloalkyl, -(L.sup.2).sub.0-1-3 to 7 membered heterocycloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 alkyl, -(L.sup.1).sub.0-1-C.sub.1-6
haloalkyl, -(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl,
-(L.sup.2).sub.0-1-6-10 membered aryl and -(L.sup.2).sub.0-1-5-10
membered heteroaryl, and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is selected from the group
consisting of --F, --Cl, C.sub.3-8 cycloalkyl, 3 to 7 membered
heterocycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
--(O)--C.sub.3-8 cycloalkyl, --(O)-3 to 7 membered
heterocycloalkyl, --(O)--C.sub.1-6 alkyl and --(O)--C.sub.1-6
haloalkyl, and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is selected from the group
consisting of methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl,
monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl,
cyclobutyl and cyclopentyl.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is selected from the group
consisting of (L.sup.2).sub.0-1-phenyl, -(L.sup.2).sub.0-1-pyridyl,
-(L.sup.2).sub.0-1-pyrimidinyl, -(L.sup.2).sub.0-1-pyrazinyl,
-(L.sup.2).sub.0-1-pyridazinyl, -(L.sup.2).sub.0-1-pyrrolyl,
-(L.sup.2).sub.0-1-pyrazolyl, -(L.sup.2).sub.0-1-imidazolyl,
-(L.sup.2).sub.0-1-thienyl, -(L.sup.2).sub.0-1-thiazolyl and
-(L.sup.2).sub.0-1-thiadiazolyl, -(L.sup.2).sub.0-1-triazoloyl,
-(L.sup.2).sub.0-1-oxazolyl, -(L.sup.2).sub.0-1-oxadiazolyl,
-(L.sup.2).sub.0-1-furanyl and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is selected from the group
consisting of -(L.sup.2).sub.0-1-phenyl and
-(L.sup.2).sub.0-1-pyridinyl, and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.4 is --OC(H)(CH.sub.3)-phenyl
wherein said phenyl ring is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.1, R.sup.2 and R.sup.3 are each
independently selected from the group consisting of F, Cl, CN,
hydrogen, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, R.sup.1, R.sup.2 and R.sup.3 are each
hydrogen.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A and Cy are independently selected from
the group consisting of pyrrolidine, piperidine, azetidine,
azepane, piperazine, 7-azaspiro[3.5]nonane,
3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole,
2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,
6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane,
2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane,
.[.2-azabicyclo[2.1.1]hexane,.]. 9-azabicyclo[4.2.1]nonane,
9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane,
2-Thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and
is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is selected from the group consisting of
pyrrolidine, piperidine, azetidine, azepane, piperazine,
cyclopropane, cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane,
3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane,
2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane,
octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane,
2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane,
3-azabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and
is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is selected from the group consisting of
2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, azetidine, pyrrolidine, cyclopropane,
cyclobutane, cyclopentane, and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is selected from the group consisting of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is selected from the group consisting of
methyl, ethyl, isopropyl,
##STR00003##
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is selected from the group consisting
of 2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine,
azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane,
2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane,
9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane,
2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and is
optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is selected from the group consisting
of azetidine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is a 3-12 membered carbocycle or a
C-linked 3-12 membered heterocycle and X.sup.2 is C(H).
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is selected from the group consisting
of
##STR00004##
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is C.sub.1-6 alkyl or C.sub.1-6
dialkylamino, and is optionally substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is methyl or ethyl.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is C.sub.1-6 alkyl, and is optionally
substituted.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is optionally substituted with from 1 to
5 R.sup.A substituents selected from the group consisting of F, Cl,
Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.A).sub.0-1-3-8
membered cycloalkyl, -(L.sup.A).sub.0-1-3-8 membered
heterocycloalkyl, -(L.sup.A).sub.0-1-5 to 6 membered .[.hetero
aryl.]. .Iadd.heteroaryl.Iaddend., .Iadd.and
.Iaddend.-(L.sup.A).sub.0-1-C.sub.6 aryl, wherein L.sup.A is
selected from the group consisting of --C(O)--, --C(O)CH.sub.2--,
--OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--, --N(C.sub.1-3
alkyl)CH.sub.2--, .[.CH.sub.2N(H)--.].
.Iadd.--CH.sub.2N(H)--.Iaddend., --CH.sub.2N(C.sub.1-3 alkyl)-;
wherein said 3-8 membered cycloalkyl is selected from the group
consisting of propane, butane, pentane and hexane; wherein said 3
to 8 membered heterocycloalkyl is selected from the group
consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane,
azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6
membered heteroaryl is selected from the group consisting of
pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole,
.[.trizole.]. .Iadd.triazole.Iaddend., pyridine, pyrimidine,
pyrazine, .Iadd.and .Iaddend.pyridazine; wherein said C.sub.6 aryl
is phenyl; and where in R.sup.A is optionally substituted with from
1 to 5 R.sup.RA .[.substitutents.]. .Iadd.substituents
.Iaddend.selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN,
--NO.sub.2, .dbd.O, --SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 (halo)alkyl-C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is optionally substituted with from 1
to 5 R.sup.Cy substituents selected from the group consisting of F,
Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.Cy).sub.0-1-3-8
membered cycloalkyl, -(L.sup.Cy).sub.0-1-3-8 membered
heterocycloalkyl, -(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl,
.Iadd.and .Iaddend.-(L.sup.Cy).sub.0-1-C.sub.6 aryl, wherein
L.sup.Cy is selected from the group consisting of --C(O)--,
--C(O)CH.sub.2--, --OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--,
--N(C.sub.1-3 alkyl)CH.sub.2--, .[.CH.sub.2N(H)--.].
.Iadd.--CH.sub.2N(H)--.Iaddend., --CH.sub.2N(C.sub.1-3 alkyl)-;
wherein said 3-8 membered cycloalkyl is selected from the group
consisting of propane, butane, pentane and hexane; wherein said 3
to 8 membered heterocycloalkyl is selected from the group
consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane,
azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6
membered heteroaryl is selected from the group consisting of
pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole,
.[.trizole.]. .Iadd.triazole.Iaddend., pyridine, pyrimidine,
pyrazine, .Iadd.and .Iaddend.pyridazine; wherein said C.sub.6 aryl
is phenyl; and where in R.sup.Cy is optionally substituted with
from 1 to 5 R.sup.RCy .[.substitutents.]. .Iadd.substituents
.Iaddend.selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN,
--NO.sub.2, .dbd.O, --SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 (halo)alkyl-C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, Cy is optionally substituted with 1 to 5
R.sup.Cy substituents selected from the group consisting of F, Cl,
Br, I, CN, OH, 2,3-difluorophen-1-yl-C(.dbd.O)--,
4-fluorophen-1-yl-C(.dbd.O)--, 3-fluorophen-1-yl-C(.dbd.O)--,
3,5-difluorophen-1-yl-C(.dbd.O)--,
3-fluoro-4-methyl-phen-1-yl-C(.dbd.O)--,
2,5-difluorophen-1-yl-C(.dbd.O)--, oxetane, oxetan-3-yl, thiazole,
thiazol-2-yl, --CH.sub.3CH.sub.2C(.dbd.O)--, CH.sub.3C(.dbd.O)--,
CF.sub.3CH.sub.2--, (HO)C(CH.sub.3).sub.2CH.sub.2--,
CH.sub.3OCH.sub.2CH.sub.2--, CH.sub.3OC(CH.sub.3).sub.2C(.dbd.O)--,
CH.sub.3OCH.sub.2C(.dbd.O)--, isopropyl, ethyl and methyl.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, A is optionally substituted with 1 to 5
R.sup.A substituents selected from the group consisting of F, Cl,
Br, I, CN, CH.sub.3O--, CH.sub.3, cyclopropylmethyl, CF.sub.3 and
butyl.
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, said compound is selected from the
subformula consisting of
##STR00005## ##STR00006##
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, said compound is selected from the
subformula consisting of
##STR00007##
In one embodiment of Formula I or as a sub-embodiment of any other
embodiment of Formula I, said compound is selected from the
subformula consisting of
##STR00008## wherein R.sup.Cy if present replaces a hydrogen atom
attached to a carbon or nitrogen atom of the Cy ring.
In one embodiment of Formula I the compound is selected from the
group as set forth in Table 1.
In another aspect, the present invention provides for compositions
comprising a compound of Formula I as defined above, or any
embodiment thereof and a pharmaceutically acceptable carrier,
diluent or excipient.
In another aspect, the present invention provides for a method for
inhibiting or preventing degeneration of a central nervous system
(CNS) neuron or a portion thereof, the method comprising
administering to the CNS neuron a compound of formula I. In certain
embodiments, said administering to the CNS neuron is performed in
vitro. In other embodiments, said the method further comprises
grafting or implanting the CNS neuron into a human patient after
administration of the agent. In other embodiment, said CNS neuron
is present in a human patient. In other embodiments, said
administering to the CNS neuron comprises administration of said
compound of formula I in a pharmaceutically acceptable carrier,
diluent or excipient. In another embodiment said administering to
the CNS neuron is carried out by an administration route selected
from the group consisting of parenteral, subcutaneous, intravenous,
intraperitoneal, intracerebral, intralesional, intramuscular,
intraocular, intraarterial interstitial infusion and implanted
delivery device. In another embodiment, said method further
comprising administering one or more additional pharmaceutical
agents. In another embodiment, said administering of a compound of
formula I results in a decrease in JNK phosphorylation, JNK
activity and/or JNK expression. In another embodiment, said the
administering of a compound of formula I results in a decrease of
cJun phosphorylation, cJun activity, and/or cJun expression. In
another embodiment, said the administering of a compound of formula
I results in a decrease in p38 phosphorylation, p38 activity,
and/or p38 expression.
In another aspect, the present invention provides for a method for
inhibiting or preventing degeneration of a central nervous system
(CNS) neuron in a patient having or at risk of developing a
neurodegenerative disease or condition comprising administering to
said patient a therapeutically effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides for a method for
decreasing or preventing one or more symptoms of a
neurodegenerative disease or condition in a patient suffering
therefrom comprising administering to said patient a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides for a method for
decreasing the progression of a neurodegenerative disease or
condition in a patient suffering therefrom comprising administering
to said patient a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof. In certain
embodiments, said neurodegenerative disease of condition is
selected from the group consisting of: Alzheimer's disease,
Huntington's disease, Parkinson's disease, Parkinson's-plus
diseases, amyotrophic lateral sclerosis (ALS), ischemia, stroke,
intracranial hemorrhage, cerebral hemorrhage, trigeminal neuralgia,
glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis,
muscular dystrophy, progressive muscular atrophy, primary lateral
sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy,
spinal muscular atrophy, inherited muscular atrophy, invertebrate
disk syndromes, cervical spondylosis, plexus disorders, thoracic
outlet destruction syndromes, peripheral neuropathies, prophyria,
multiple system atrophy, progressive supranuclear palsy,
corticobasal degeneration, dementia with Lewy bodies,
frontotemporal dementia, demyelinating diseases, Guillain-Barre
syndrome, multiple sclerosis, Charcot-Marie_Tooth disease, prion
disease, Creutzfeldt-Jakob disease, Gerstmann-Strassler-Scheinker
syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform
encephalopathy, Pick's disease, epilepsy, AIDS demential complex,
nerve damage caused by exposure to toxic compounds selected from
the group consisting of heavy metals, industrial solvents, drugs
and chemotherapeutic agents; injury to the nervous system caused by
physical, mechanical or chemical trauma, glaucoma, lattice
dystrophy, retinitis pigmentosa, age-related macular degeneration
(AMD), photoreceptor degeneration associated with wet or dry AMD,
other retinal degeneration, optic nerve drusen, optic neuropthy and
optic neuritis. In certain embodiment, said neurodegenerative
disease of condition in a patient is selected from the group
consisting of: Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis (ALS), In certain embodiment, said
the compound of formula I is administered in combination with one
or more additional pharmaceutical agents.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
As used herein, the term "alkyl", by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain hydrocarbon radical, having the number of carbon atoms
designated (i.e., C.sub.1-8 means one to eight carbons). Examples
of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,
n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl,
n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an
unsaturated alkyl radical having one or more double bonds.
Similarly, the term "alkynyl" refers to an unsaturated alkyl
radical having one or more triple bonds. Examples of such
unsaturated alkyl groups include linear and branched groups
including vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),
2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,
3-butynyl, and the higher homologs and isomers. The term
"cycloalkyl," "carbocyclic," or "carbocycle" refers to hydrocarbon
ring system having specified overall number of ring atoms (e.g., 3
to 12 ring atoms in a 3 to 12 membered cycloalkyl or C.sub.3-12
cycloalkyl) and being fully saturated or having no more than one
double bond between ring vertices for a 3-5 membered cycloalkyl and
being saturated or having no more than two double bonds between
ring vertices for 6 or larger membered cycloalkyl. The monocyclic
or polycyclic ring may be optionally substituted with one or more
oxo groups. As used herein, "cycloalkyl," "carbocyclic," or
"carbocycle" is also meant to refer to polycyclic (including fused
and bridged bicyclic, fused and bridged polyclic and spirocyclic)
hydrocarbon ring system such as, for example,
bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane,
norborene, spirocyclic C.sub.5-12 alkane, etc. As used herein, the
terms, "alkenyl," "alkynyl," "cycloalkyl,", "carbocycle," and
"carbocyclic," are meant to include mono and polyhalogenated
variants thereof.
The term "heteroalkyl," by itself or in combination with another
term, means, unless otherwise stated, a stable straight or branched
chain hydrocarbon radical, consisting of the stated number of
carbon atoms and from one to three heteroatoms selected from the
group consisting of O, N, Si and S, and wherein the nitrogen and
sulfur atoms can optionally be oxidized and the nitrogen heteroatom
can optionally be quaternized. The heteroatom(s) O, N and S can be
placed at any interior position of the heteroalkyl group. The
heteroatom Si can be placed at any position of the heteroalkyl
group, including the position at which the alkyl group is attached
to the remainder of the molecule. A "heteroalkyl" can contain up to
three units of unsaturation, and also include mono- and
poly-halogenated variants, or combinations thereof. Examples
include --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--O--CF.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --S(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH.dbd.N(CH.sub.3)--CH.sub.3. Up to two heteroatoms can be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
The term "heterocycloalkyl," "heterocyclic," or "heterocycle"
refers to a saturated or partially unsaturated ring system radical
having from the indicated number of overall number of stated ring
atoms and containing from one to five heteroatoms selected from N,
O, and S, wherein the nitrogen and sulfur atoms are optionally
oxidized, nitrogen atom(s) are optionally quaternized, as ring
atoms (e.g., a 3 to 12 membered heterocycloalkyl that would have 3
to 12 ring atoms and include at least one heteroatom, which also
could be referred to as a C.sub.2-11 heterocycloalkyl). Unless
otherwise stated, a "heterocycloalkyl," "heterocyclic," or
"heterocycle" ring system can be a monocyclic or a fused, bridged,
or spirocyclic polycyclic (including a fused bicyclic, bridged
bicyclic or spirocyclic) ring system. The monocyclic or polycyclic
ring may be optionally substituted with one or more oxo groups. A
"heterocycloalkyl," "heterocyclic," or "heterocycle" group can be
attached to the remainder of the molecule through one or more ring
carbons or heteroatoms. Non limiting examples of
"heterocycloalkyl," "heterocyclic," or "heterocycle" rings include
pyrrolidine, piperidine, N-methylpiperidine, imidazolidine,
pyrazolidine, butyrolactam, valerolactam, imidazolidinone,
hydantoin, dioxolane, phthalimide, piperidine,
pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine,
thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide,
piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,
tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane,
2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,
(1s,4s)-2-azabicyclo[2.2.2]octane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like. A
"heterocycloalkyl," "heterocyclic," or "heterocycle" can include
mono- and poly-halogenated variants thereof.
The term "alkylene" by itself or as part of another substituent
means a divalent radical derived from an alkane, as exemplified by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and can be branched.
Typically, an alkyl (or alkylene) group will have from 1 to 24
carbon atoms, with those groups having 10 or fewer carbon atoms
being preferred in the present invention. "Alkenylene" and
"alkynylene" refer to the unsaturated forms of "alkylene" having
double or triple bonds, respectively. "Alkylene", "alkenylene" and
"alkynylene" are also meant to include mono and poly-halogenated
variants.
The term "heteroalkylene" by itself or as part of another
substituent means a divalent radical, saturated or unsaturated or
polyunsaturated, derived from heteroalkyl, as exemplified by
--CH.sub.2--CH.sub.2--S--CH.sub.2CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--,
--CH.sub.2--CH.dbd.C(H)CH.sub.2--O--CH.sub.2-- and
S--CH.sub.2--C.ident.C--. The term "heteroalkylene" is also meant
to include mono and poly-halogenated variants.
The term "alkoxylene" and "aminoalkylene" and "thioalkylene" by
itself or as part of another substituent means a divalent radical,
saturated or unsaturated or polyunsaturated, derived from alkoxy,
alkylamino and alkylthio, respectively, as exemplified by
--OCH.sub.2CH.sub.2--, --O--CH.sub.2--CH.dbd.CH--,
--N(H)CH.sub.2C(H)(CH.sub.3)CH.sub.2-- and
--S--CH.sub.2--C.ident.C--. The term "alkoxylene" and
"aminoalkylene" and "thioalkylene" are meant to include mono and
poly halogenated variants
The terms "alkoxy," "alkylamino" and "alkylthio", are used in their
conventional sense, and refer to those alkyl groups attached to the
remainder of the molecule via an oxygen atom ("oxy"), an amino
group ("amino") or thio group, and further include mono- and
poly-halogenated variants thereof. Additionally, for dialkylamino
groups, the alkyl portions can be the same or different.
The terms "halo" or "halogen," by themselves or as part of another
substituent, mean, unless otherwise stated, a fluorine, chlorine,
bromine, or iodine atom. Additionally, terms such as "haloalkyl,"
are meant to include monohaloalkyl and polyhaloalkyl. For example,
the term "C.sub.1-4 haloalkyl" is mean to include trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl,
and the like. The term "(halo)alkyl" as used herein includes
optionally halogenated alkyl. Thus the term "(halo)alkyl" includes
both alkyl and haloalkyl (e.g., monohaloalkyl and
polyhaloalkyl).
The term "aryl" means, unless otherwise stated, a polyunsaturated,
typically aromatic, hydrocarbon ring, which can be a single ring or
multiple rings (up to three rings) which are fused together. The
term "heteroaryl" refers to aryl ring(s) that contain from one to
five heteroatoms selected from N, O, and S, wherein the nitrogen
and sulfur atoms are optionally oxidized, and the nitrogen atom(s)
are optionally quaternized. A heteroaryl group can be attached to
the remainder of the molecule through a heteroatom. Non-limiting
examples of aryl groups include phenyl, naphthyl and biphenyl,
while non-limiting examples of heteroaryl groups include pyridyl,
pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,
benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,
benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl,
indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl,
benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl,
isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,
pyrrolyl, thiazolyl, furyl, thienyl and the like. Optional
substituents for each of the above noted aryl and heteroaryl ring
systems can be selected from the group of acceptable substituents
described further below.
The above terms (e.g., "alkyl," "aryl" and "heteroaryl"), in some
embodiments, will include both substituted and unsubstituted forms
of the indicated radical. Preferred substituents for each type of
radical are provided below.
Substituents for the alkyl radicals (including those groups often
referred to as alkylene, alkenyl, alkynyl, heteroalkyl and
cycloalkyl) can be a variety of groups including, but not limited
to, -halogen, .dbd.O, --OR', --NR'R'', --SR', --SiR'R''R''',
--OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'',
--NR''C(O)R', --NR'''C(O)NR'R'', --NR''C(O).sub.2R',
--NHC(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH,
--NHC(NH.sub.2).dbd.NR', --NR'''C(NR'R'').dbd.N--CN,
--NR'''C(NR'R'').dbd.NOR', --NHC(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'',
--NR'''S(O).sub.2NR'R'', --CN, --NO.sub.2,
--(CH.sub.2).sub.1-4--OR', --(CH.sub.2).sub.1-4--NR'R'',
--(CH.sub.2).sub.1-4--SR', --(CH.sub.2).sub.1-4--SiR'R''R''',
--(CH.sub.2).sub.1-4--OC(O)R', --(CH.sub.2).sub.1-4--C(O)R',
--(CH.sub.2).sub.1-4--CO.sub.2R', --(CH.sub.2).sub.1-4CONR'R'', in
a number ranging from zero to (2m'+1), where m' is the total number
of carbon atoms in such radical. R', R'' and R''' each
independently refer groups including, for example, hydrogen,
unsubstituted C.sub.1-6 alkyl, unsubstituted heteroalkyl,
unsubstituted aryl, aryl substituted with 1-3 halogens,
unsubstituted C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6
thioalkoxy groups, or unsubstituted aryl-C.sub.1-4 alkyl groups,
unsubstituted heteroaryl, .Iadd.or .Iaddend.substituted heteroaryl,
among others. When R' and R'' are attached to the same nitrogen
atom, they can be combined with the nitrogen atom to form a 3-, 4-,
5-, 6-, or 7-membered ring. For example, --NR'R'' is meant to
include 1-pyrrolidinyl and 4-morpholinyl. Other .[.substitutents.].
.Iadd.substituents .Iaddend.for alkyl radicals, including
heteroalkyl.[.,.]. .Iadd.and .Iaddend.alkylene, include for
example, .dbd.O, .dbd.NR', .dbd.N--OR', .dbd.N--CN, .Iadd.and
.Iaddend..dbd.NH, wherein R' include substituents as described
above. When a substituent for the alkyl radicals (including those
groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl
and cycloalkyl) contains an alkylene, alkenylene, .Iadd.or
.Iaddend.alkynylene linker (e.g., --(CH.sub.2).sub.1-4--NR'R'' for
alkylene), the alkylene linker includes halo variants as well. For
example, the linker "--(CH.sub.2).sub.1-4--" when used as part of a
substituent is meant to include difluoromethylene,
1,2-difluoroethylene, etc.
Similarly, substituents for the aryl and heteroaryl groups are
varied and are generally selected from the group including, but not
limited to, -halogen, --OR', --OC(O)R', --NR'R'', --SR', --R',
--CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --C(O)R',
--OC(O)NR'R'', --NR''C(O)R', --NR''C(O).sub.2R', --NR'C(O)NR''R''',
--NHC(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH,
--NHC(NH.sub.2).dbd.NR', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --N.sub.3,
perfluoro-C.sub.1-4 alkoxy, and perfluoro-C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-4--OR', --(CH.sub.2).sub.1-4--NR'R'',
--(CH.sub.2).sub.1-4--SR', --(CH.sub.2).sub.1-4--SiR'R''R''',
--(CH.sub.2).sub.1-4--OC(O)R', --(CH.sub.2).sub.1-4--C(O)R',
--CH.sub.2).sub.1-4--CO.sub.2R', --(CH.sub.2).sub.1-4CONR'R'', in a
number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'' and R''' are
independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, unsubstituted
aryl and heteroaryl, (unsubstituted aryl)-C.sub.1-4 alkyl, and
unsubstituted aryloxy-C.sub.1-4 alkyl. Other suitable substituents
include each of the above aryl substituents attached to a ring atom
by an alkylene tether of from 1-4 carbon atoms. When a substituent
for the aryl or heteroaryl group contains an alkylene, alkenylene,
alkynylene linker (e.g., --(CH.sub.2).sub.1-4--NR'R'' for
alkylene), the alkylene linker includes halo variants as well. For
example, the linker "--(CH.sub.2).sub.1-4--" when used as part of a
substituent is meant to include difluoromethylene,
1,2-difluoroethylene, etc.
As used herein, the term "heteroatom" is meant to include oxygen
(O), nitrogen (N), sulfur (S) and silicon (Si).
As used herein, the term "C-linked" means that the group that the
term describes is attached the remainder of the molecule through a
ring carbon atom.
As used herein, the term "N-linked" means that the group that the
term describes is attached to the remainder of the molecule through
a ring nitrogen atom.
As used herein, the term "chiral" refers to molecules which have
the property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
As used herein, the term "stereoisomers" refers to compounds which
have identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
As used herein a wavy line "" that intersects a bond in a chemical
structure fragment indicates the point of attachment of the bond to
which the wavy bond intersects in the chemical structure fragment
to the remainder of a molecule or structural formula.
As used herein, the representation of a group (e.g., X.sup.d) in
parenthesis followed by a subscript integer range (e.g.,
(X.sup.d).sub.0-2) means that the group can have the number of
occurrences as designated by the integer range. For example,
(X.sup.d).sub.0-1 means the group X.sup.d can be absent or can
occur one time.
"Diastereomer" refers to a stereoisomer with two or more centers of
chirality and whose molecules are not mirror images of one another.
Diastereomers have different physical properties, e.g. melting
points, boiling points, spectral properties, and reactivities.
Mixtures of diastereomers can separate under high resolution
analytical procedures such as electrophoresis and
chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are
non-superimposable mirror images of one another.
Stereochemical definitions and conventions used herein generally
follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms
(1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen,
S., "Stereochemistry of Organic Compounds", John Wiley & Sons,
Inc., New York, 1994. The compounds of the invention can contain
asymmetric or chiral centers, and therefore exist in different
stereoisomeric forms. It is intended that all stereoisomeric forms
of the compounds of the invention, including but not limited to,
diastereomers, enantiomers and atropisomers, as well as mixtures
thereof such as racemic mixtures, form part of the present
invention. Many organic compounds exist in optically active forms,
i.e., they have the ability to rotate the plane of plane-polarized
light. In describing an optically active compound, the prefixes D
and L, or R and S, are used to denote the absolute configuration of
the molecule about its chiral center(s). The prefixes d and l or
(+) and (-) are employed to designate the sign of rotation of
plane-polarized light by the compound, with (-) or 1 meaning that
the compound is levorotatory. A compound prefixed with (+) or d is
dextrorotatory. For a given chemical structure, these stereoisomers
are identical except that they are mirror images of one another. A
specific stereoisomer can also be referred to as an enantiomer, and
a mixture of such isomers is often called an enantiomeric mixture.
A 50:50 mixture of enantiomers is referred to as a racemic mixture
or a racemate, which can occur where there has been no
stereoselection or stereospecificity in a chemical reaction or
process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
As used herein, the term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons.
As used herein, the term "solvate" refers to an association or
complex of one or more solvent molecules and a compound of the
invention. Examples of solvents that form solvates include, but are
not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl
acetate, acetic acid, and ethanolamine. The term "hydrate" refers
to the complex where the solvent molecule is water.
As used herein, the term "protecting group" refers to a substituent
that is commonly employed to block or protect a particular
functional group on a compound. For example, an "amino-protecting
group" is a substituent attached to an amino group that blocks or
protects the amino functionality in the compound. Suitable
amino-protecting groups include acetyl, trifluoroacetyl,
t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and
9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a
"hydroxy-protecting group" refers to a substituent of a hydroxy
group that blocks or protects the hydroxy functionality. Suitable
protecting groups include acetyl and silyl. A "carboxy-protecting
group" refers to a substituent of the carboxy group that blocks or
protects the carboxy functionality. Common carboxy-protecting
groups include phenylsulfonylethyl, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general
description of protecting groups and their use, see P. G. M. Wuts
and T. W. Greene, Greene's Protective Groups in Organic Synthesis
4.sup.th edition, Wiley-Interscience, New York, 2006.
As used herein, the term "mammal" includes, but is not limited to,
humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,
pigs, and sheep.
As used herein, the term "salts" is meant to include salts of the
active compounds which are prepared with relatively nontoxic acids
or bases (e.g., those salts that are pharmaceutically acceptable),
depending on the particular substituents found on the compounds
described herein. When compounds of the present invention contain
relatively acidic functionalities, base addition salts can be
obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired base, either neat or in a suitable
inert solvent. Examples of salts derived from
pharmaceutically-acceptable inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic, manganous, potassium, sodium, zinc and the like. Salts
derived from pharmaceutically-acceptable organic bases include
salts of primary, secondary and tertiary amines, including
substituted amines, cyclic amines, naturally-occurring amines and
the like, such as arginine, betaine, caffeine, choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine and the like. When compounds of the
present invention contain relatively basic functionalities, acid
addition salts can be obtained by contacting the neutral form of
such compounds with a sufficient amount of the desired acid, either
neat or in a suitable inert solvent. Examples of pharmaceutically
acceptable acid addition salts include those derived from inorganic
acids like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or
phosphorous acids and the like, as well as the salts derived from
relatively nontoxic organic acids like acetic, propionic,
isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,
phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge, S. M., et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
The neutral forms of the compounds can be regenerated by contacting
the salt with a base or acid and isolating the parent compound in
the conventional manner. The parent form of the compound differs
from the various salt forms in certain physical properties, such as
solubility in polar solvents, but otherwise the salts are
equivalent to the parent form of the compound for the purposes of
the present invention.
In addition to salt forms, the present invention provides compounds
which are in a prodrug form. As used herein the term "prodrug"
refers to those compounds that readily undergo chemical changes
under physiological conditions to provide the compounds of the
present invention. Additionally, prodrugs can be converted to the
compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
Prodrugs of the invention include compounds wherein an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues, is covalently joined through an amide or
ester bond to a free amino, hydroxy or carboxylic acid group of a
compound of the present invention. The amino acid residues include
but are not limited to the 20 naturally occurring amino acids
commonly designated by three letter symbols and also includes
phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline,
hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate,
hippuric acid, octahydroindole-2-carboxylic acid, statine,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,
ornithine, 3-methylhistidine, norvaline, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine,
methyl-alanine, para-benzoylphenylalanine, phenylglycine,
propargylglycine, sarcosine, methionine sulfone and
tert-butylglycine.
Additional types of prodrugs are also encompassed. For instance, a
free carboxyl group of a compound of the invention can be
derivatized as an amide or alkyl ester. As another example,
compounds of this invention comprising free hydroxy groups can be
derivatized as prodrugs by converting the hydroxy group into a
group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or
phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D.
et al., (1996) Improved oral drug delivery: solubility limitations
overcome by the use of prodrugs Advanced Drug Delivery Reviews,
19:115. Carbamate prodrugs of hydroxy and amino groups are also
included, as are carbonate prodrugs, sulfonate esters and sulfate
esters of hydroxy groups. Derivatization of hydroxy groups as
(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group
can be an alkyl ester optionally substituted with groups including,
but not limited to, ether, amine and carboxylic acid
functionalities, or where the acyl group is an amino acid ester as
described above, are also encompassed. Prodrugs of this type are
described in J. Med. Chem., (1996), 39:10. More specific examples
include replacement of the hydrogen atom of the alcohol group with
a group such as (C.sub.1-6)alkanoyloxymethyl,
1-((C.sub.1-6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-6)alkanoyloxy)ethyl,
(C.sub.1-6)alkoxycarbonyloxymethyl,
N--(C.sub.1-6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-6)alkanoyl, alpha-amino(C.sub.1-4)alkanoyl, arylacyl and
alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each
alpha-aminoacyl group is independently selected from the naturally
occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-6)alkyl).sub.2 or glycosyl (the radical resulting
from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate).
For additional examples of prodrug derivatives, see, for example,
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et
al. (Academic Press, 1985); b) A Textbook of Drug Design and
Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter
5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191
(1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38
(1992); d) H. Bundgaard, et al., Journal of Pharmaceutical
Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm.
Bull., 32:692 (1984), each of which is specifically incorporated
herein by reference.
Additionally, the present invention provides for metabolites of
compounds of the invention. As used herein, a "metabolite" refers
to a product produced through metabolism in the body of a specified
compound or salt thereof. Such products can result for example from
the oxidation, reduction, hydrolysis, amidation, deamidation,
esterification, deesterification, enzymatic cleavage, and the like,
of the administered compound.
Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well known
to those skilled in the art. The metabolite products, so long as
they are not otherwise found in vivo, are useful in diagnostic
assays for therapeutic dosing of the compounds of the
invention.
Certain compounds of the present invention can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In
general, the solvated forms are equivalent to unsolvated forms and
are intended to be encompassed within the scope of the present
invention. Certain compounds of the present invention can exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention.
Certain compounds of the present invention possess asymmetric
carbon atoms (optical centers) or double bonds; the racemates,
diastereomers, geometric isomers, regioisomers and individual
isomers (e.g., separate enantiomers) are all intended to be
encompassed within the scope of the present invention.
The compounds of the present invention can also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the present invention also
embraces isotopically-labeled variants of the present invention
which are identical to those recited herein, bur the for the fact
that one or more atoms are replace by an atom having the atomic
mass or mass number different from the predominant atomic mass or
mass number usually found in nature for the atom. All isotopes of
any particular atom or element as specified are contemplated within
the scope of the compounds of the invention, and their uses.
Exemplary isotopes that can be incorporated in to compounds of the
invention include istopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine, chlorine and iodine, such as .sup.2H
("D"), .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.32P, .sup.33P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I and .sup.125I. Certain isotopically
labeled compounds of the present invention (e.g., those labeled
with .sup.3H or .sup.14C) are useful in compound and/or substrate
tissue distribution assays. Tritiated (.sup.3H) and carbon-14
(.sup.14C) isotopes are usefule for their ease of preparation and
detectability. Further substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Positron emitting isotopes such as
.sup.15O, .sup.13N, .sup.11C, and .sup.18F are useful for positron
emission tomography (PET) studies to examine substrate receptor
occupancy. Isotopically labeled compounds of the present inventions
can generally be prepared by following procedures analogous to
those disclosed in the Schemes and/or in the Examples herein below,
by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent.
The terms "treat" and "treatment" refer to both therapeutic
treatment and/or prophylactic treatment or preventative measures,
wherein the object is to prevent or slow down (lessen) an undesired
physiological change or disorder, such as, for example, the
development or spread of cancer. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms, diminishment of extent of disease or
disorder, stabilized (i.e., not worsening) state of disease or
disorder, delay or slowing of disease progression, amelioration or
palliation of the disease state or disorder, and remission (whether
partial or total), whether detectable or undetectable. "Treatment"
can also mean prolonging survival as compared to expected survival
if not receiving treatment. Those in need of treatment include
those already with the disease or disorder as well as those prone
to have the disease or disorder or those in which the disease or
disorder is to be prevented.
The phrase "therapeutically effective amount" means an amount of a
compound of the present invention that (i) treats or prevents the
particular disease, condition, or disorder, (ii) attenuates,
ameliorates, or eliminates one or more symptoms of the particular
disease, condition, or disorder, or (iii) prevents or delays the
onset of one or more symptoms of the particular disease, condition,
or disorder described herein. In some embodiments, a
therapeutically effective amount is an amount of a chemical entity
described herein sufficient to significantly decrease or delay
neuronal cell death.
The term "administering" as used herein refers to contacting a
neuron or portion thereof with a compound described herein. This
includes administration of the compound to a subject (e.g., a
patient, mammal) in which the neuron or portion thereof is present,
as well as introducing the inhibitor into a medium in which a neuro
or portion thereof is cultured.
The term "patient" as used herein refers to any mammal, including
humans, higher non-human primates, rodenst domestic and farm
animals such as cow, horses, dogs and cats. In one embodiment, the
patient is a human patient.
The term "bioavailability" refers to the systemic availability
(i.e., blood/plasma levels) of a given amount of drug administered
to a patient. Bioavailability is an absolute term that indicates
measurement of both the time (rate) and total amount (extent) of
drug that reaches the general circulation from an administered
dosage form.
The phrases "preventing axon degeneration," "preventing neuron
degeneration," "preventing CNS neuron degeneration," "inhibiting
axon degeneration," "inhibiting neuron degeneration" "inhibiting
CNS neuron degeneration" as used herein include (i) the ability to
inhibit or presenve axon or neuron degeration in patients diagnosed
as having a neurodegerative disease or risk of developing a
neurodegenerative disease and (ii) the ability to inhibit or
prevent further axon or neuron degeneration in patients who are
already suffering from, or have symptoms of a neurodegenerative
disease. Preventing axon or neuron degeneration includes decreasing
or inhbiting axon or neuron degeneration, which may be
characterized by complete or partial inhibition or neuron or axon
degeneration. This can be assessed, for example, by analysis of
neurological function. The above-listed terms also include in vitro
and ex vivo methods. Further, the pharases "preventing neuron
degeneration" and "inhibiting neuron degeneration" in clued such
inhibiton with respect to the entire neuron or a portion thereof,
such as the neuron ell body, axons and dendrites. The
administration of one or more agent as described herein may result
in at least a 10% decrease (e.g., at least 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 100%
decrease in one or more symptoms of a disorder of the nervous
system, a condition of the nervous system that is secondary to a
disease, condition, or therapy having a primary effect outside of
the nervous system; an inusry to the nervous system caused by
physical, mechanical or chemical trauma, pain; and ocular related
neurodegeneration; memory loss; or a psychiatric disorder (e.g.,
tremors, slowness of movement, ataxia, loss of balance,
depressioin, decreased cognitive function, short term memory loss,
long term memory loss, confusion, changes in personality, language
difficultities, loss of sensory perception, sensitivity to touch,
numbness in extremities, muscle weakness, muscle paralysis, muscle
cramps, muscle spasms, significant changes in eating habits,
excessive fear or worry, insomnia, delusions, hallucinations,
fatigue, back pain, chest pain, digestive problems, headache, rapid
heart rate, dizziness, blurred vision, shadows or missing areas of
vision, metamorphopsia, impairment in color vision, decreased
recovery of visual function after exposure to bright light, and
loss in visual contrast sensitivity) in a subject or population
compared to a control subject or population that does not receive
the one or more agent described herein. The administration of one
or more agent as described herein may result in at least a 10%
decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease)
in the number of neurons (or neuron bodies, axons, or dendrites
thereof) that degenerate in a neuron population or in a subject
compared to the number of neurons (or neuron bodies, axons, or
dendrites thereof) that degenerate in neuron population or in a
subject that is not administered the one or more of the agents
described herein. The administration of one or more agent as
described herein may result in at least a 10% decrease (e.g., at
least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, or even 100% decrease) in the likelihood
of developing a disorder of the nervous system; a condition of the
nervous system that is secondary to a disease, condition, or
therapy having a primary effect outside of the nervous system; an
injury to the nervous system caused by physical, mechanical, or
chemical trauma, pain; an ocular-related neurodegeneration; memory
loss; or a psychiatric disorder in a subject or a subject
population compared to a control subject or population not treated
with the one or more compounds described herein.
The term "neuron" as used herein denotes nervous system cells that
include a central cell body or soma, and two types of extensions or
projections: dendrites, by which, in general, the majority of
neuronal signals are conveyed to the cell body, and axons, by
which, in general, the majority of neuronal signals are conveyed
from the cell body to effector cells, such as target neurons or
muscle. Neurons can convey information from tissues and organs into
the central nervous system (afferent or sensory neurons) and
transmit signals from the central nervous systems to effector cells
(efferent or motor neurons). Other neurons, designated
interneurons, connect neurons within the central nervous system
(the brain and spinal column) Certain specific examples of neuron
types that may be subject to treatment according to the invention
include cerebellar granule neurons, dorsal root ganglion neurons,
and cortical neurons.
B. Compounds
In one aspect the present invention provides for novel compounds.
In a first embodiment of such compounds (Embodiment 1; abbreviated
as "E1") the invention provides for compounds of Formula I (I):
##STR00009## or salts thereof wherein R.sup.1, R.sup.2 and R.sup.3
are each independently H, F, Cl, Br, I, C.sub.1-6 alkyl or
C.sub.1-6haloalkyl; X.sup.1 is N or C--R.sup.4, wherein R.sup.4 is
selected from the group consisting of --F, --Cl, --Br,
.[.I-(L.sup.I).sub.0-1-C.sub.1-6 alkyl,.]. .Iadd.--I,
-(L.sup.1).sub.0-1-C.sub.1-6 alkyl,
.Iaddend.-(L.sup.1).sub.0-1-C.sub.1-6 haloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl,
-(L.sup.2).sub.0-1-C.sub.3-8 cycloalkyl, -(L.sup.2).sub.0-1-3 to 7
membered heterocycloalkyl, -(L.sup.2).sub.0-1-6-10 membered aryl,
.Iadd.and .Iaddend.-(L.sup.2).sub.0-1-5-10 membered heteroaryl,
wherein L.sup.1 is selected from the group consisting of --O--,
--N(H)--, --S--, --N(C.sub.1-6 alkyl)-, .[..dbd.O.]. .Iadd.and
--C(.dbd.O)--.Iaddend., and L.sup.2 is selected from the group
consisting of --O--, --N(H)--, --N(C.sub.1-6 alkyl)-, --S--,
.[..dbd.O.]. .Iadd.--C(.dbd.O)--.Iaddend., C.sub.1-4 alkylene,
C.sub.1-4 alkenylene, C.sub.1-4 alkynylene, C.sub.1-4 alkoxylene,
C.sub.1-4 aminoalkylene, C.sub.1-4 thioalkylene and C.sub.1-4
heteroalkylene, and wherein R.sup.4 is optionally substituted on
carbon atoms and heteroatoms with R.sup.R4 substituents selected
from the group consisting of F, Cl, Br, I, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, 3-5 membered cycloalkyl, 3-5 membered
heterocycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, C.sub.1-6
dialkylamino, C.sub.1-6 alkylthio, .dbd.O, --NH.sub.2, --CN,
--NO.sub.2 and --SF.sub.5; X.sup.2 is N or CH; A is selected from
the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 dialkylamino, 3 to 12 membered cycloalkyl, .Iadd.and
.Iaddend.3 to 12 membered heterocycloalkyl, wherein A is optionally
substituted with 1-5 R.sup.A substituents selected from the group
consisting of F, Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl,
-(L.sup.A).sub.0-1-3-8 membered cycloalkyl, -(L.sup.A).sub.0-1-3-8
membered heterocycloalkyl, -(L.sup.A).sub.0-1-5 to 6 membered
heteroaryl, -(L.sup.A).sub.0-1-C.sub.6 aryl,
-(L.sup.A).sub.0-1-NR.sup.R1aR.sup.R1b,
-(L.sup.A).sub.0-1-OR.sup.R1a, -(L.sup.A).sub.0-1-SR.sup.R1a,
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.Y.sup.1)OR.sup.R1c,
-(L.sup.A).sub.0-1-OC(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-C(.dbd.O)N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)C(.dbd.O)R.sup.R1b,
-(L.sup.A).sub.0-1-C(.dbd.O)OR.sup.R1a,
-(L.sup.A).sub.0-1-OC(.dbd.O)R.sup.R1a,
-(L.sup.A).sub.0-1-P(.dbd.O)(OR.sup.R1a)(OR.sup.R1b),
-(L.sup.A).sub.0-1-S(O).sub.1-2R.sup.R1c,
-(L.sup.A).sub.0-1-S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b),
-(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2N(R.sup.R1a)(R.sup.R1b)
and -(L.sup.A).sub.0-1-N(R.sup.R1a)S(O).sub.1-2(R.sup.R1c), wherein
L.sup.A is selected from the group consisting of C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene, C.sub.1-4
aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4 alkenylene, and
C.sub.2-4 alkynylene; wherein R.sup.R1a and R.sup.R1b are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3-8 membered cycloalkyl,
phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered
heterocycloalkyl; R.sup.R1c is selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.A is optionally
substituted on carbon atoms and heteroatoms with R.sup.RA
.[.substitutents.]. .Iadd.substituents .Iaddend.selected from, F,
Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino; and Cy is selected from the
group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 3 to 12
membered cycloalkyl, .Iadd.and .Iaddend.3 to 12 membered
heterocycloalkyl, wherein Cy is optionally substituted on carbon or
heteroatoms with R.sup.Cy substituents selected from the group
consisting of F, Cl, Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5,
C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered cycloalkyl,
-(L.sup.Cy).sub.0-1-3-8 membered heterocycloalkyl,
-(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl,
-(L.sup.Cy).sub.0-1-phenyl,
-(L.sup.Cy).sub.0-1-NR.sup.RCaR.sup.RCb,
-(L.sup.Cy).sub.0-1-OR.sup.RCa, -(L.sup.Cy).sub.0-1-SR.sup.RCa,
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.Y.sup.1)OR.sup.RCc,
-(L.sup.Cy).sub.0-1-OC(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-C(.dbd.O)N(R.sup.RCa)(R.sup.RCb),
-(L.sup.Cy).sub.0-1-N(R.sup.RCa)C(.dbd.O)R.sup.RCb,
-(L.sup.Cy).sub.0-1-C(.dbd.O)OR.sup.RCa,
-(L.sup.Cy).sub.0-1-OC(.dbd.O)R.sup.RCa,
.[.-(L.sup.Cy).sub.0-1-P(.dbd.O)(OR.sup.RCa)(OR.sup.RCba),.].
.Iadd.-(L.sup.Cy).sub.0-1-P(.dbd.O)(OR.sup.RCa)(OR.sup.RCb),
.Iaddend.-(L.sup.Cy).sub.0-1-S(O).sub.1-2R.sup.RCc,
.[.-(L.sup.Cy).sub.0-1-S(O).sub.0-2N(R.sup.RCa)(R.sup.RCb),.].
.Iadd.-(L.sup.Cy).sub.0-1-S(O).sub.1-2N(R.sup.RCa)(R.sup.RCb),
.Iaddend.-(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2N(R.sup.RCa)(R.sup.R-
Cb) and
.[.-(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2(R.sup.RCc),.].
.Iadd.-(L.sup.Cy).sub.0-1-N(R.sup.RCa)S(O).sub.1-2(R.sup.RCc),
.Iaddend.wherein L.sup.Cy is selected from the group consisting of
C.sub.1-4 alkylene, C.sub.1-4 heteroalkylene, C.sub.1-4 alkoxylene,
C.sub.1-4 aminoalkylene, C.sub.1-4 thioalkylene, C.sub.2-4
alkenylene, and C.sub.2-4 alkynylene; wherein R.sup.RCa and
R.sup.RCb are independently selected from the group consisting of
hydrogen, C.sub.1-8 alkyl, C.sub.1-8haloalkyl, 3-8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8
membered heterocycloalkyl; R.sup.RCc is selected from the group
consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, 3 to 8 membered
cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7
membered heterocycloalkyl, and wherein R.sup.Cy is optionally
substituted on carbon atoms and heteroatoms with from 1 to 5
R.sup.RCy .[.substitutents.]. .Iadd.substituents .Iaddend.selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O,
--SF.sub.5, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 (halo)alkyl-C(.dbd.O)--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino.
Further embodiments (E) of the first embodiment of compounds of the
invention, are described below E2. A compound according to E1,
wherein either A or Cy is a polycyclic carbocycle or polycyclic
heterocycle. E3. A compound according to E1 or E2, wherein X.sup.1
is N. E4. A compound according to E1 or E2, wherein X.sup.1 is
C--R.sup.4. E5. A compound of claim E1, E2, E3 or E4, wherein
X.sup.2 is N. E6. A compound of claim, E1, E2, E3 or E4, wherein
X.sup.2 is C(H). E7. A compound according to claim E1, E2, E4, E5
or E6, wherein R.sup.4 is selected from the group consisting of
--F, --Cl, --CN, -(L.sup.2).sub.0-1-C.sub.3-8 cycloalkyl,
-(L.sup.2).sub.0-1-3 to 7 membered heterocycloalkyl,
-(L.sup.1).sub.0-1-C.sub.1-6 alkyl, -(L.sup.1).sub.0-1-C.sub.1-6
haloalkyl, -(L.sup.1).sub.0-1-C.sub.1-6 heteroalkyl,
-(L.sup.2).sub.0-1-6-10 membered aryl and -(L.sup.2).sub.0-1-5-10
membered heteroaryl, and is optionally substituted. E8. A compound
according to claim E1, E2, E4, E5, E6 or E7, wherein R.sup.4 is
selected from the group consisting of --F, --Cl, C.sub.3-8
cycloalkyl, 3 to 7 membered heterocycloalkyl, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, --(O)--C.sub.3-8 cycloalkyl, --(O)-3 to 7
membered heterocycloalkyl, --(O)--C.sub.1-6 alkyl and
--(O)--C.sub.1-6 haloalkyl, and is optionally substituted. E9. A
compound of claim E1, E2, E4, E5, E6, E7 or E8, wherein R.sup.4 is
selected from the group consisting of methoxy, monofluoromethoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy,
cyclopentoxy, methyl, monofluoromethyl difluoromethyl,
trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl. E10. A
compound of claim E1, E2, E4, E5, E6 or E7, wherein R.sup.4 is
selected from the group consisting of (L.sup.2).sub.0-1-phenyl,
-(L.sup.2).sub.0-1-pyridyl, -(L.sup.2).sub.0-1-pyrimidinyl,
-(L.sup.2).sub.0-1-pyrazinyl, -(L.sup.2).sub.0-1-pyridazinyl,
-(L.sup.2).sub.0-1-pyrrolyl, -(L.sup.2).sub.0-1-pyrazolyl,
-(L.sup.2).sub.0-1-imidazolyl, -(L.sup.2).sub.0-1-thienyl,
-(L.sup.2).sub.0-1-thiazolyl and -(L.sup.2).sub.0-1-thiadiazolyl,
-(L.sup.2).sub.0-1-triazoloyl, -(L.sup.2).sub.0-1-oxazolyl,
-(L.sup.2).sub.0-1-oxadiazolyl, -(L.sup.2).sub.0-1-furanyl and is
optionally substituted. E11. A compound of claim E1, E2, E4, E5,
E6, E7 or E10, wherein R.sup.4 is selected from the group
consisting of -(L.sup.2).sub.0-1-phenyl and
-(L.sup.2).sub.0-1-pyridinyl, and is optionally substituted. E12. A
compound of claim E1, E2, E4, E5, E6, E7, E10 or E11, wherein
R.sup.4 is --OC(H)(CH.sub.3)-phenyl wherein said phenyl ring is
optionally substituted. E13. A compound of claim E1, E2, E3, E4,
E5, E6, E7, E8, E9, E10, E11 or E12, wherein R.sup.1, R.sup.2 and
R.sup.3 are each independently selected from the group consisting
of F, Cl, CN, hydrogen, C.sub.1-4 alkyl and C.sub.1-4 haloalkyl.
E14. A compound of claim E1, E2, E3, E 4, E5, E6, E7, E8, E9, E10,
E11, E12 or E13, wherein R.sup.1, R.sup.2 and R.sup.3 are each
hydrogen. E15. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8,
E9, E10, E11, E12, E13 or E14, wherein A and Cy are independently
selected from the group consisting of pyrrolidine, piperidine,
azetidine, azepane, piperazine, 7-azaspiro[3.5]nonane,
3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole,
2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,
6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane,
2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane,
.[.2-azabicyclo[2.1.1]hexane .]. , 9-azabicyclo[4.2.1]nonane,
9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane,
2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and
is optionally substituted. E16. A compound of claim E1, E2, E3, E4,
E5, E6, E7, E8, E9, E10, E11, E12, E13, E14 or E15, wherein A is
selected from the group consisting of pyrrolidine, piperidine,
azetidine, azepane, piperazine, cyclopropane, cyclobutane,
cyclopentane, 7-azaspiro[3.5]nonane, 3-oxabicyclo[3.1.0]hexane,
3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole,
2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane,
6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, morpholine,
hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and
is optionally substituted. E17. A compound of claim E1, E2, E3, E4,
E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15 or E16, wherein A
is selected from the group consisting of 2-azabicyclo[2.1.1]hexane,
3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, azetidine,
pyrrolidine, cyclopropane, cyclobutane, cyclopentane, and is
optionally substituted. E18. A compound of claim E1, E2, E3, E4,
E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16 or E17,
wherein A is selected from the group consisting of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted. E19. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13 or E14, wherein is A is selected from
the group consisting of methyl, ethyl, isopropyl,
##STR00010## E20. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18 or E19, wherein
Cy is selected from the group consisting of
2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine, azetidine,
2-aza-tricyclo[3.3.1.1-3,7]decane,
2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane,
3-oxabicyclo[3.1. 0]hexane, 2-azabicyclo[2.1.1]hexane,
9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane,
2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide,
2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran,
8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and is
optionally substituted. E21. A compound of claim E1, E2, E3, E4,
E5, E 6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18,
E19 or E20, wherein Cy is selected from the group consisting of
azetidine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane,
(1R,5S)-3-azabicyclo[3.1.0]hexane,
(1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane,
(1R,5S)-3-oxabicyclo[3.1.0]hexane,
(1S,5R)-3-oxabicyclo[3.1.0]hexane,
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane and
(1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally
substituted. E22. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13 or E14, wherein Cy is selected from the
group consisting of
##STR00011## E23. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13 or E14, wherein A is C.sub.1-6 alkyl or
C.sub.1-6 dialkylamino, and is optionally substituted. E24. A
compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13 or E14, wherein A is methyl or ethyl. E25. A compound of
claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13 or
E14, wherein Cy is C.sub.1-6 alkyl, and is optionally substituted.
E26. A compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10,
E11, E12, E13, E14, E15, E16, E17, E18 or E23, wherein A is
optionally substituted with from 1 to 5 R.sup.A substituents
selected from the group consisting of F, Cl, Br, I, --OH, --CN,
--NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl,
C.sub.1-8 heteroalkyl, -(L.sup.A).sub.0-1-3-8 membered cycloalkyl,
-(L.sup.A).sub.0-1-3-8 membered heterocycloalkyl,
-(L.sup.A).sub.0-1-5 to 6 membered heteroaryl, .Iadd.and
.Iaddend.-(L.sup.A).sub.0-1-C.sub.6 aryl, wherein L.sup.A is
selected from the group consisting of --C(O)--, --C(O)CH.sub.2--,
--OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--, --N(C.sub.1-3
alkyl)CH.sub.2--, .[.CH.sub.2N(H)--.].
.Iadd.--CH.sub.2N(H)--.Iaddend., --CH.sub.2N(C.sub.1-3 alkyl)-;
wherein said 3-8 membered cycloalkyl is selected from the group
consisting of propane, butane, pentane and hexane; wherein said 3
to 8 membered heterocycloalkyl is selected from the group
consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane,
azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6
membered heteroaryl is selected from the group consisting of
pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole,
.[.trizole.]. .Iadd.triazole.Iaddend., pyridine, pyrimidine,
pyrazine, .Iadd.and .Iaddend.pyridazine; wherein said C.sub.6 aryl
is phenyl; and .[.where in.]. .Iadd.wherein .Iaddend.R.sup.A is
optionally substituted with from 1 to 5 R.sup.RA
.[.substitutents.]. .Iadd.substituents .Iaddend.selected from, F,
Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino. E27. A compound of claim E1,
E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E20,
E21 or E25, wherein Cy is optionally substituted with from 1 to 5
R.sup.Cy substituents selected from the group consisting of F, Cl,
Br, I, --OH, --CN, --NO.sub.2, --SF.sub.5, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl, C.sub.1-8 heteroalkyl, -(L.sup.Cy).sub.0-1-3-8
membered cycloalkyl, -(L.sup.Cy).sub.0-1-3-8 membered
heterocycloalkyl, -(L.sup.Cy).sub.0-1-5 to 6 membered heteroaryl,
.Iadd.and .Iaddend.-(L.sup.Cy).sub.0-1-C.sub.6 aryl, wherein
L.sup.Cy is selected from the group consisting of --C(O)--,
--C(O)CH.sub.2--, --OCH.sub.2--, --CH.sub.2O--, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2OCH.sub.2--, --N(H)CH.sub.2--,
--N(C.sub.1-3 alkyl)CH.sub.2--, .[.CH.sub.2N(H)--.].
.Iadd.--CH.sub.2N(H)--.Iaddend., .Iadd.and
.Iaddend.--CH.sub.2N(C.sub.1-3 alkyl)-; wherein said 3-8 membered
cycloalkyl is selected from the group consisting of propane,
butane, pentane and hexane; wherein said 3 to 8 membered
heterocycloalkyl is selected from the group consisting of oxetane,
tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine,
piperidine and azepane; wherein said 5 to 6 membered heteroaryl is
selected from the group consisting of pyrrole, pyrazole, imidazole,
thiophene, thiazole, oxazole, .[.trizole.].
.Iadd.triazole.Iaddend., pyridine, pyrimidine, pyrazine, .Iadd.and
.Iaddend.pyridazine; wherein said C.sub.6 aryl is phenyl; and
.[.where in.]. .Iadd.wherein .Iaddend.R.sup.Cy is optionally
substituted with from 1 to 5 R.sup.RCy .[.substitutents.].
.Iadd.substituents .Iaddend.selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, .dbd.O, --SF.sub.5, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
(halo)alkyl-C(.dbd.O)--, C.sub.1-4 (halo)alkyl-S(O).sub.0-2--,
C.sub.1-4 (halo)alkyl-N(H)S(O).sub.0-2--, C.sub.1-4
(halo)alkyl-S(O).sub.0-2N(H)--,
(halo)alkyl-N(H)--S(O).sub.0-2N(H)--, C.sub.1-4
(halo)alkyl-C(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-N(H)--C(.dbd.O)--, ((halo)alkyl).sub.2N--C(.dbd.O)--,
C.sub.1-4 (halo)alkyl-OC(.dbd.O)N(H)--, C.sub.1-4
(halo)alkyl-OC(.dbd.O)N(H)--, (halo)alkyl-N(H)--C(.dbd.O)O--,
((halo)alkyl).sub.2N--C(.dbd.O)O--, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino. E28. A compound of claim of
claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14,
E15, E20, E21, E24, E25 or E26, wherein Cy is optionally
substituted with 1 to 5 R.sup.Cy substituents selected from the
group consisting of F, Cl, Br, I, CN, OH,
2,3-difluorophen-1-yl-C(.dbd.O)--, 4-fluorophen-1-yl-C(.dbd.O)--,
3-fluorophen-1-yl-C(.dbd.O)--, 3,5-difluorophen-1-yl-C(.dbd.O)--,
3-fluoro-4-methyl-phen-1-yl-C(.dbd.O)--,
2,5-difluorophen-1-yl-C(.dbd.O)--, oxetane, oxetan-3-yl, thiazole,
thiazol-2-yl, --CH.sub.3CH.sub.2C(.dbd.O)--, CH.sub.3C(.dbd.O)--,
CF.sub.3CH.sub.2--, (HO)C(CH.sub.3).sub.2CH.sub.2--,
CH.sub.3OCH.sub.2CH.sub.2--, CH.sub.3OC(CH.sub.3).sub.2C(.dbd.O)--,
CH.sub.3OCH.sub.2C(.dbd.O)--, isopropyl, ethyl and methyl. E29. A
compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E23 or E26, wherein A is
optionally substituted with 1 to 5 R.sup.A substituents selected
from the group consisting of F, Cl, Br, I, CN, CH.sub.3O--,
CH.sub.3, cyclopropylmethyl, CF.sub.3 and butyl. E30. A compound of
claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14,
E15, E16, E17, E18, E19, E20, E21, E22, E25, E26, E27, E28 or E29,
wherein said compound is selected from the subformula consisting
of
##STR00012## E31. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13, E14, E20, E21, E22, E25, E27, E28 or
E29, wherein said compound is selected from the subformula
consisting of
##STR00013## E32. A compound of claim E1, E2, E3, E4, E5, E6, E7,
E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21,
E22, E24, E26, E27, E28 or E29, wherein said compound is selected
from the subformula consisting of
##STR00014## wherein R.sup.Cy if present replaces a hydrogen atom
attached to a carbon or nitrogen atom of the Cy ring E33. A
compound of claim 1 selected from the group as set forth in Table
1.
C. Synthesis of Compounds
Compounds of the invention as well as key intermediates can be
prepared following the general synthetic schemes described below
(Scheme 1-4). In Schemes 1-4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
X.sup.1 and X.sup.2 have the meaning as described for compounds of
Formula I; halo refers to a halogen atom, e.g., Cl, F, Br, I; and R
where present means a cyclic or noncyclic noninterferring
substituent. More detailed description of the individual reaction
steps, is found in the Examples section below. Those skilled in the
art will appreciate that other synthetic routes may be used to
synthesize the inventive compounds. Although specific starting
materials and reagents are depicted in the Schemes and discussed
below, other starting materials and reagents can be easily
substituted to provide a variety of derivatives and/or reaction
conditions. In addition, many of the compounds prepared by the
methods described below can be further modified in light of this
disclosure using conventional chemistry well known to those skilled
in the art.
In preparing compounds of the invention, protection of remote
functionality (e.g., primary or secondary amine) of intermediates
may be necessary. The need for such protection will vary depending
on the nature of the remote functionality and the conditions of the
preparation methods. Suitable amino-protecting groups include
acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl
(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a
general description of protecting groups and their use, see T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991.
As illustrated in Scheme 1, compounds or intermediates of the
inventions can be prepared by displacement of a halogen atom from a
dihalothiopyrimidine compound (i) with an amine group under basic
conditions. Further treatment of the alkylthio compound (II) under
oxidative conditions provides the oxidized sulfone (iii) compound.
A Suzuki-Miyaura coupling reaction between (iii) and a boronate
reagent (iv) with a Pd(0) catalyst yields compounds and or
intermediates of the invention (v) (See, Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457-2483).
##STR00015##
As illustrated in Scheme 2, compounds or intermediates of the
invention can be prepared by reaction of a trihalo pyrimidine (vi)
with a boronate ester under Pd(0) coupling conditions to provide
biheteroaryl (vii). Subsequent sequential displacement of a
halogens atom of vii with an the same of different amine reagents
under basic conditions, provide biheteroaryl compounds (ix).
##STR00016##
As illustrated in Scheme 3, compounds or intermediates of the
invention can be prepared by Suzuki-Miyaura coupling of
dichloroodopyridine (x) with an amine under Pd(0) catalyzed
conditions (See, Hartwig, J. F. (1997), "Palladium-Catalyzed
Amination of Aryl Halides: Mechanism and Rational Catalyst Design",
Synlett 4: 329-340). Displacement of a chloro group in xi with an
amine followed by Suzuki coupling of the resultant product (xii)
with a boronate ester (iv-b) provides compounds and or
intermediates of the invention xiii.
##STR00017##
##STR00018##
As illustrated in Scheme 4, compounds and or intermediates of the
invention can be prepared by treating a R substituted dichloro
compound (xiv) with an amine under base conditions to produce
compound xv. Subsequent treatment of compound xv under Pd(0)
catalyst couplingh conditions provides compounds and intermediates
of the inventions (xvi).
D. Pharmaceutical Compositions and Administrations
In addition to one or more of the compounds provided above (or
stereoisomers, geometric isomers, tautomers, solvates, metabolites,
isotopes, (pharmaceutically acceptable) salts, or prodrugs
thereof), the invention also provides for compositions and
medicaments comprising a compound of Formula I or any subformula or
any embodiment thereof and at least one pharmaceutically acceptable
carrier, diluent or excipient. The compositions of the invention
can be used for inhibiting DLK activity in patients (e.g.,
humans)
pharmaceutically acceptable carrier, diluent or excipient.
The term "composition," as used herein, is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof
In one embodiment, the invention provides for pharmaceutical
compositions (or medicaments) comprising a compound of Formula I
(or stereoisomers, geometric isomers, tautomers, solvates,
metabolites, isotopes, pharmaceutically acceptable salts, or
prodrugs thereof) and a pharmaceutically acceptable carrier,
diluent or excipient. In another embodiment, the invention provides
for preparing compositions (or medicaments) comprising compounds of
the invention. In another embodiment, the invention provides for
administering compounds of Formula I or I-I and compositions
comprising compounds of Formula I or any embodiment thereof to a
patient (e.g., a human patient) in need thereof.
Compositions are formulated, dosed, and administered in a fashion
consistent with good medical practice. Factors for consideration in
this context include the particular disorder being treated, the
particular mammal being treated, the clinical condition of the
individual patient, the cause of the disorder, the site of delivery
of the agent, the method of administration, the scheduling of
administration, and other factors known to medical practitioners.
The effective amount of the compound to be administered will be
governed by such considerations, and is the minimum amount
necessary to inhibit DLK activity as required to prevent or treat
the undesired disease or disorder, such as for example,
neurodegeneration, amyloidosis, formation of neurofibrillary
tangles, or undesired cell growth. For example, such amount may be
below the amount that is toxic to normal cells, or the mammal as a
whole.
In one example, the therapeutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.01-100 mg/kg, alternatively about e.g.,
0.1 to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day. The daily
does is, in certain embodiments, given as a single daily dose or in
divided doses two to six times a day, or in sustained release form.
In the case of a 70 kg adult human, the total daily dose will
generally be from about 7 mg to about 1,400 mg. This dosage regimen
may be adjusted to provide the optimal therapeutic response. The
compounds may be administered on a regimen of 1 to 4 times per day,
preferably once or twice per day.
The compounds of the present invention may be administered in any
convenient administrative form, e.g., tablets, powders, capsules,
solutions, dispersions, suspensions, syrups, sprays, suppositories,
gels, emulsions, patches, etc. Such compositions may contain
components conventional in pharmaceutical preparations, e.g.,
diluents, carriers, pH modifiers, sweeteners, bulking agents, and
further active agents.
The compounds of the invention may be administered by any suitable
means, including oral, topical (including buccal and sublingual),
rectal, vaginal, transdermal, parenteral, subcutaneous,
intraperitoneal, intrapulmonary, intradermal, intrathecal and
epidural and intranasal, and, if desired for local treatment,
intralesional administration. Parenteral infusions include
intramuscular, intravenous, intraarterial, intraperitoneal,
intracerebral, intraocular, intralesional or subcutaneous
administration.
The compositions comprising compounds of Formula I any embodiment
thereof are normally formulated in accordance with standard
pharmaceutical practice as a pharmaceutical composition. A typical
formulation is prepared by mixing a compound of the present
invention and a diluent, carrier or excipient. Suitable diluents,
carriers and excipients are well known to those skilled in the art
and are described in detail in, e.g., Ansel, Howard C., et al.,
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,
Raymond C. Handbook of Pharmaceutical Excipients. Chicago,
Pharmaceutical Press, 2005. The formulations may also include one
or more buffers, stabilizing agents, surfactants, wetting agents,
lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents, diluents
and other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
Suitable carriers, diluents and excipients are well known to those
skilled in the art and include materials such as carbohydrates,
waxes, water soluble and/or swellable polymers, hydrophilic or
hydrophobic materials, gelatin, oils, solvents, water and the like.
The particular carrier, diluent or excipient used will depend upon
the means and purpose for which a compound of the present invention
is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG
400, PEG 300), etc. and mixtures thereof. The formulations can also
include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
Acceptable diluents, carriers, excipients and stabilizers are
nontoxic to recipients at the dosages and concentrations employed,
and include buffers such as phosphate, citrate and other organic
acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g., Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). A active pharmaceutical ingredient of
the invention (e.g., compound of Formula I or any embodiment
thereof) can also be entrapped in microcapsules prepared, for
example, by coacervation techniques or by interfacial
polymerization, for example, hydroxymethylcellulose or
gelatin-microcapsules and poly-(methylmethacylate) microcapsules,
respectively, in colloidal drug delivery systems (for example,
liposomes, albumin microspheres, microemulsions, nano-particles and
nanocapsules) or in macroemulsions. Such techniques are disclosed
in Remington: The Science and Practice of Pharmacy: Remington the
Science and Practice of Pharmacy (2005) 21.sup.st Edition,
Lippincott Williams & Wilkins, Philidelphia, Pa.
Sustained-release preparations of a compound of the invention
(e.g., compound of Formula I or any embodiment thereof) can be
prepared. Suitable examples of sustained-release preparations
include semipermeable matrices of solid hydrophobic polymers
containing a compound of Formula I or an embodiment thereof, which
matrices are in the form of shaped articles, e.g., films, or
microcapsules. Examples of sustained-release matrices include
polyesters, hydrogels (for example,
poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers
22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et
al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic
acid-glycolic acid copolymers such as the LUPRON DEPOT.TM.
(injectable microspheres composed of lactic acid-glycolic acid
copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric
acid (EP 133,988A). Sustained release compositions also include
liposomally entrapped compounds, which can be prepared by methods
known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A.
82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030,
1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).
Ordinarily, the liposomes are of the small (about 200-800
Angstroms) unilamelar type in which the lipid content is greater
than about 30 mol % cholesterol, the selected proportion being
adjusted for the optimal therapy.
The formulations include those suitable for the administration
routes detailed herein. The formulations can conveniently be
presented in unit dosage form and can be prepared by any of the
methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington: The Science and
Practice of Pharmacy: Remington the Science and Practice of
Pharmacy (2005) 21.sup.st Edition, Lippincott Williams &
Wilkins, Philidelphia, Pa. Such methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more accessory ingredients.
In general the formulations are prepared by uniformly and
intimately bringing into association the active ingredient with
liquid carriers, diluents or excipients or finely divided solid
carriers, diluents or excipients, or both, and then, if necessary,
shaping the product. A typical formulation is prepared by mixing a
compound of the present invention and a carrier, diluent or
excipient. The formulations can be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. A compound of the present invention is typically formulated
into pharmaceutical dosage forms to provide an easily controllable
dosage of the drug and to enable patient compliance with the
prescribed regimen.
In one example, compounds of Formula I or any embodiment thereof
may be formulated by mixing at ambient temperature at the
appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
In one example, a compound of Formula I or an embodiment thereof is
formulated in an acetate buffer, at pH 5. In another embodiment,
the compounds of Formula I or an embodiment thereof are sterile.
The compound may be stored, for example, as a solid or amorphous
composition, as a lyophilized formulation or as an aqueous
solution.
Formulations of a compound of the invention (e.g., compound of
Formula I or an embodiment thereof) suitable for oral
administration can be prepared as discrete units such as pills,
capsules, cachets or tablets each containing a predetermined amount
of a compound of the invention.
Compressed tablets can be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as a
powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets can be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets can optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
Tablets, troches, lozenges, aqueous or oil suspensions, dispersible
powders or granules, emulsions, hard or soft capsules, e.g.,
gelatin capsules, syrups or elixirs can be prepared for oral use.
Formulations of a compound of the invention (e.g., compound of
Formula I or an embodiment thereof) intended for oral use can be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
can contain one or more agents including sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide a palatable preparation. Tablets containing the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are
acceptable. These excipients can be, for example, inert diluents,
such as calcium or sodium carbonate, lactose, calcium or sodium
phosphate; granulating and disintegrating agents, such as maize
starch, or alginic acid; binding agents, such as starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets can be uncoated or can be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax can be employed.
An example of a suitable oral administration form is a tablet
containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100
mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the
invention compounded with about 90-30 mg anhydrous lactose, about
5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone
(PVP) K30, and about 1-10 mg magnesium stearate. The powdered
ingredients are first mixed together and then mixed with a solution
of the PVP. The resulting composition can be dried, granulated,
mixed with the magnesium stearate and compressed to tablet form
using conventional equipment. An example of an aerosol formulation
can be prepared by dissolving the compound, for example 5-400 mg,
of the invention in a suitable buffer solution, e.g. a phosphate
buffer, adding a tonicifier, e.g. a salt such sodium chloride, if
desired. The solution may be filtered, e.g., using a 0.2 micron
filter, to remove impurities and contaminants.
For treatment of the eye or other external tissues, e.g., mouth and
skin, the formulations are preferably applied as a topical ointment
or cream containing the active ingredient(s) in an amount of, for
example, 0.075 to 20% w/w. When formulated in an ointment, the
active ingredient can be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients
can be formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base can include a
polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and
mixtures thereof. The topical formulations can desirably include a
compound which enhances absorption or penetration of the active
ingredient through the skin or other affected areas. Examples of
such dermal penetration enhancers include dimethyl sulfoxide and
related analogs.
The oily phase of the emulsions of this invention can be
constituted from known ingredients in a known manner. While the
phase can comprise merely an emulsifier, it desirably comprises a
mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
invention include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol,
benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
Aqueous suspensions of a compound of the invention (e.g., compound
of Formula I or an embodiment thereof) contain the active materials
in admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, croscarmellose, povidone,
methylcellulose, hydroxypropyl methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension can also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
Formulations of a compound of the invention (e.g., compound of
Formula I or I-I) can be in the form of a sterile injectable
preparation, such as a sterile injectable aqueous or oleaginous
suspension. This suspension can be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation can also be a sterile injectable solution or
suspension in a non-toxic parenterally acceptable diluent or
solvent, such as a solution in 1,3-butanediol or prepared as a
lyophilized powder. Among the acceptable vehicles and solvents that
can be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile fixed oils can
conventionally be employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid can likewise be used in the preparation of
injectables.
The amount of active ingredient that can be combined with the
carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans can contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which can vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion can contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
Formulations suitable for parenteral administration include aqueous
and non-aqueous sterile injection solutions which can contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which can include
suspending agents and thickening agents.
Formulations suitable for topical administration to the eye also
include eye drops wherein the active ingredient is dissolved or
suspended in a suitable carrier, especially an aqueous solvent for
the active ingredient. The active ingredient is preferably present
in such formulations in a concentration of about 0.5 to 20% w/w,
for example about 0.5 to 10% w/w, for example about 1.5% w/w.
Formulations suitable for topical administration in the mouth
include lozenges comprising the active ingredient in a flavored
basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
Formulations for rectal administration can be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration
have a particle size for example in the range of 0.1 to 500 microns
(including particle sizes in a range between 0.1 and 500 microns in
increments microns such as 0.5, 1, 30 microns, 35 microns, etc.),
which is administered by rapid inhalation through the nasal passage
or by inhalation through the mouth so as to reach the alveolar
sacs. Suitable formulations include aqueous or oily solutions of
the active ingredient. Formulations suitable for aerosol or dry
powder administration can be prepared according to conventional
methods and can be delivered with other therapeutic agents such as
compounds heretofore used in the treatment of disorders as
described below.
The formulations can be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and can be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
When the binding target is located in the brain, certain
embodiments of the invention provide for a compound of formula I
(or an embodiment thereof) to traverse the blood-brain barrier.
Certain neurodegenerative diseases are associated with an increase
in permeability of the blood-brain barrier, such that a compound of
formula I (or an embodiment thereof) can be readily introduced to
the brain. When the blood-brain barrier remains intact, several
art-known approaches exist for transporting molecules across it,
including, but not limited to, physical methods, lipid-based
methods, and receptor and channel-based methods.
Physical methods of transporting a compound of formula I (or an
embodiment thereof) across the blood-brain barrier include, but are
not limited to, circumventing the blood-brain barrier entirely, or
by creating openings in the blood-brain barrier.
Circumvention methods include, but are not limited to, direct
injection into the brain (see, e.g., Papanastassiou et al., Gene
Therapy 9:398-406, 2002), interstitial infusion/convection-enhanced
delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A.
91:2076-2080, 1994), and implanting a delivery device in the brain
(see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel
Wafers.TM., Guildford. Pharmaceutical). Methods of creating
openings in the barrier include, but are not limited to, ultrasound
(see, e.g., U.S. Patent Publication No. 2002/0038086), osmotic
pressure (e.g., by administration of hypertonic mannitol (Neuwelt,
E. A., Implication of the Blood-Brain Barrier and its Manipulation,
Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization
by, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat.
Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).
Lipid-based methods of transporting a compound of formula I (or an
embodiment thereof) across the blood-brain barrier include, but are
not limited to, encapsulating the a compound of formula I or I-I
(or an embodiment thereof) in liposomes that are coupled to
antibody binding fragments that bind to receptors on the vascular
endothelium of the blood-brain barrier (see, e.g., U.S. Patent
Application Publication No. 2002/0025313), and coating a compound
of formula I (or an embodiment thereof) in low-density lipoprotein
particles (see, e.g., U.S. Patent Application Publication No.
2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent
Application Publication No. 2004/0131692).
Receptor and channel-based methods of transporting a compound of
formula I (or an embodiment thereof) across the blood-brain barrier
include, but are not limited to, using glucocorticoid blockers to
increase permeability of the blood-brain barrier (see, e.g., U.S.
Patent Application Publication Nos. 2002/0065259, 2003/0162695, and
2005/0124533); activating potassium channels (see, e.g., U.S.
Patent Application Publication No. 2005/0089473), inhibiting ABC
drug transporters (see, e.g., U.S. Patent Application Publication
No. 2003/0073713); coating a compound of formula I or I-I (or an
embodiment thereof) with a transferrin and modulating activity of
the one or more transferrin receptors (see, e.g., U.S. Patent
Application Publication No. 2003/0129186), and cationizing the
antibodies (see, e.g., U.S. Pat. No. 5,004,697).
For intracerebral use, in certain embodiments, the compounds can be
administered continuously by infusion into the fluid reservoirs of
the CNS, although bolus injection may be acceptable. The inhibitors
can be administered into the ventricles of the brain or otherwise
introduced into the CNS or spinal fluid. Administration can be
performed by use of an indwelling catheter and a continuous
administration means such as a pump, or it can be administered by
implantation, e.g., intracerebral implantation of a
sustained-release vehicle. More specifically, the inhibitors can be
injected through chronically implanted cannulas or chronically
infused with the help of osmotic minipumps. Subcutaneous pumps are
available that deliver proteins through a small tubing to the
cerebral ventricles. Highly sophisticated pumps can be refilled
through the skin and their delivery rate can be set without
surgical intervention. Examples of suitable administration
protocols and delivery systems involving a subcutaneous pump device
or continuous intracerebroventricular infusion through a totally
implanted drug delivery system are those used for the
administration of dopamine, dopamine agonists, and cholinergic
agonists to Alzheimer's disease patients and animal models for
Parkinson's disease, as described by Harbaugh, J. Neural Transm.
Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143,
1987.
A compound of formula I (or an embodiment thereof) used in the
invention are formulated, dosed, and administered in a fashion
consistent with good medical practice. Factors for consideration in
this context include the particular disorder being treated, the
particular mammal being treated, the clinical condition of the
individual patient, the cause of the disorder, the site of delivery
of the agent, the method of administration, the scheduling of
administration, and other factors known to medical practitioners. A
compound of formula I (or an embodiment thereof) need not be, but
is optionally formulated with one or more agent currently used to
prevent or treat the disorder in question. The effective amount of
such other agents depends on the amount of a compound of the
invention present in the formulation, the type of disorder or
treatment, and other factors discussed above.
These are generally used in the same dosages and with
administration routes as described herein, or about from 1 to 99%
of the dosages described herein, or in any dosage and by any route
that is empirically/clinically determined to be appropriate.
For the prevention or treatment of disease, the appropriate dosage
of a compound of formula I or I-I (or an embodiment thereof) (when
used alone or in combination with other agents) will depend on the
type of disease to be treated, the properties of the compound, the
severity and course of the disease, whether the compound is
administered for preventive or therapeutic purposes, previous
therapy, the patient's clinical history and response to the
compound, and the discretion of the attending physician. The
compound is suitably administered to the patient at one time or
over a series of treatments. Depending on the type and severity of
the disease, about 1 .mu.g/kg to 15 mg/kg (e.g., 0.1 mg/kg-10
mg/kg) of compound can be an initial candidate dosage for
administration to the patient, whether, for example, by one or more
separate administrations, or by continuous infusion. One typical
daily dosage might range from about 1 .mu.g kg to 100 mg/kg or
more, depending on the factors mentioned above. For repeated
administrations over several days or longer, depending on the
condition, the treatment would generally be sustained until a
desired suppression of disease symptoms occurs. One exemplary
dosage of a compound of formula I (or an embodiment thereof) would
be in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one
or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg
(or any combination thereof) may be administered to the patient.
Such doses may be administered intermittently, e.g., every week or
every three weeks (e.g., such that the patient receives from about
two to about twenty, or, e.g., about six doses of the antibody). An
initial higher loading dose, followed by one or more lower doses
may be administered. An exemplary dosing regimen comprises
administering an initial loading dose of about 4 mg/kg, followed by
a weekly maintenance dose of about 2 mg kg of the compound.
However, other dosage regimens may be useful. The progress of this
therapy is easily monitored by conventional techniques and
assays.
Other typical daily dosages might range from, for example, about 1
g/kg to up to 100 mg/kg or more (e.g., about 1 .mu.g kg to 1 mg/kg,
about 1 .mu.g/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about
5 mg/kg to about 200 mg/kg, about 50 mg/kg to about 150 mg/mg,
about 100 mg/kg to about 500 mg/kg, about 100 mg/kg to about 400
mg/kg, and about 200 mg/kg to about 400 mg/kg), depending on the
factors mentioned above. Typically, the clinician will administer a
compound until a dosage is reached that results in improvement in
or, optimally, elimination of, one or more symptoms of the treated
disease or condition. The progress of this therapy is easily
monitored by conventional assays. One or more agent provided herein
may be administered together or at different times (e.g., one agent
is administered prior to the administration of a second agent). One
or more agent may be administered to a subject using different
techniques (e.g., one agent may be administered orally, while a
second agent is administered via intramuscular injection or
intranasally). One or more agent may be administered such that the
one or more agent has a pharmacologic effect in a subject at the
same time. Alternatively, one or more agent may be administered,
such that the pharmacological activity of the first administered
agent is expired prior the administration of one or more
secondarily administered agents (e.g., 1, 2, 3, or 4 secondarily
administered agents).
E. Indications and Methods of Treatment
In another aspect, the invention provides for methods of inhibiting
the Dual Leucine Zipper Kinase (DLK) in an in vitro (e.g., a nerve
graft of nerve transplant) or in vivo setting (e.g., in a patient)
by contacting DLK present in an in vitro or in vivo setting with
compounds of Formula I or an embodiment thereof. In these methods
of the invention, the inhibition of DLK signaling or expression
with a compound of formula I or an embodiment thereof results in a
downstream decrease in JNK phosphorylation (e.g., a decrease in
JNK2 and/or JNK3 phosphorylation), JNK activity (e.g., a decrease
in JNK2 and/or JNK3 activity), and/or JNK expression (e.g., a
decrease in JNK2 and/or JNK3 expression). Accordingly,
administering one or more compounds of Formula I or an embodiment
thereof according to the methods of the invention can result in
decrease in activity of kinase targets downstream of the DLK
signalling cascade, e.g, (i) a decrease in JNK phosphorylation, JNK
activity, and/or JNK expression, (ii) a decrease in cJun
phosphorylation, cJun activity, and/or cJun expression, and/or
(iii) a decrease in p38 phosphorylation, p38 activity, and/or p38
expression.
Compounds of the invention can be used in methods for inhibiting
neuron or axon degeneration. The inhibitors are, therefore, useful
in the therapy of, for example, (i) disorders of the nervous system
(e.g., neurodegenerative diseases), (ii) conditions of the nervous
system that are secondary to a disease, condition, or therapy
having a primary effect outside of the nervous system, (iii)
injuries to the nervous system caused by physical, mechanical, or
chemical trauma, (iv) pain, (v) ocular-related neurodegeneration,
(vi) memory loss, and (vii) psychiatric disorders. Non-limiting
examples of some of these diseases, conditions, and injuries are
provided below.
Examples of neurodegenerative diseases and conditions that can be
prevented or treated according to the invention include amyotrophic
lateral sclerosis (ALS), trigeminal neuralgia, glossopharyngeal
neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy,
progressive muscular atrophy, primary lateral sclerosis (PLS),
pseudobulbar palsy, progressive bulbar palsy, spinal muscular
atrophy, progressive bulbar palsy, inherited muscular atrophy,
invertebrate disk syndromes (e.g., herniated, ruptured, and
prolapsed disk syndromes), cervical spondylosis, plexus disorders,
thoracic outlet destruction syndromes, peripheral neuropathies,
prophyria, mild cognitive impairment, Alzheimer's disease,
Huntington's disease, Parkinson's disease, Parkinson's-plus
diseases (e.g., multiple system atrophy, progressive supranuclear
palsy, and corticobasal degeneration), dementia with Lewy bodies,
frontotemporal dementia, demyelinating diseases (e.g.,
Guillain-Barre syndrome and multiple sclerosis),
Charcot-Marie-Tooth disease (CMT; also known as Hereditary Motor
and Sensory Neuropathy (HMSN), Hereditary Sensorimotor Neuropathy
(HSMN), and Peroneal Muscular Atrophy), prion disease (e.g.,
Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome
(GSS), fatal familial insomnia (FFI), and bovine spongiform
encephalopathy (BSE, commonly known as mad cow disease)), Pick's
disease, epilepsy, and AIDS demential complex (also known as HIV
dementia, HIV encephalopathy, and HIV-associated dementia).
The methods of the invention can also be used in the prevention and
treatment of ocular-related neurodegeneration and related diseases
and conditions, such as glaucoma, lattice dystrophy, retinitis
pigmentosa, age-related macular degeneration (AMD), photoreceptor
degeneration associated with wet or dry AMD, other retinal
degeneration, optic nerve drusen, optic neuropathy, and optic
neuritis. Non-limiting examples of different types of glaucoma that
can be prevented or treated according to the invention include
primary glaucoma (also known as primary open-angle glaucoma,
chronic open-angle glaucoma, chronic simple glaucoma, and glaucoma
simplex), low-tension glaucoma, primary angle-closure glaucoma
(also known as primary closed-angle glaucoma, narrow-angle
glaucoma, pupil-block glaucoma, and acute congestive glaucoma),
acute angle-closure glaucoma, chronic angle-closure glaucoma,
intermittent angle-closure glaucoma, chronic open-angle closure
glaucoma, pigmentary glaucoma, exfoliation glaucoma (also known as
pseudoexfoliative glaucoma or glaucoma capsulare), developmental
glaucoma (e.g., primary congenital glaucoma and infantile
glaucoma), secondary glaucoma (e.g., inflammatory glaucoma (e.g.,
uveitis and Fuchs heterochromic iridocyclitis)), phacogenic
glaucoma (e.g., angle-closure glaucoma with mature cataract,
phacoanaphylactic glaucoma secondary to rupture of lens capsule,
phacolytic glaucoma due to phacotoxic meshwork blockage, and
subluxation of lens), glaucoma secondary to intraocular hemorrhage
(e.g., hyphema and hemolytic glaucoma, also known as erythroclastic
glaucoma), traumatic glaucoma (e.g., angle recession glaucoma,
traumatic recession on anterior chamber angle, postsurgical
glaucoma, aphakic pupillary block, and ciliary block glaucoma),
neovascular glaucoma, drug-induced glaucoma (e.g., corticosteroid
induced glaucoma and alpha-chymotrypsin glaucoma), toxic glaucoma,
and glaucoma associated with intraocular tumors, retinal
deatchments, severe chemical burns of the eye, and iris
atrophy.
Examples of types of pain that can be treated according to the
methods of the invention include those associated with the
following conditions: chronic pain, fibromyalgia, spinal pain,
carpel tunnel syndrome, pain from cancer, arthritis, sciatica,
headaches, pain from surgery, muscle spasms, back pain, visceral
pain, pain from injury, dental pain, neuralgia, such as neuogenic
or neuropathic pain, nerve inflammation or damage, shingles,
herniated disc, torn ligament, and diabetes.
Certain diseases and conditions having primary effects outside of
the nervous system can lead to damage to the nervous system, which
can be treated according to the methods of the present invention.
Examples of such conditions include peripheral neuropathy and
neuralgia caused by, for example, diabetes, cancer, AIDS,
hepatitis, kidney dysfunction, Colorado tick fever, diphtheria, HIV
infection, leprosy, lyme disease, polyarteritis nodosa, rheumatoid
arthritis, sarcoidosis, Sjogren syndrome, syphilis, systemic lupus
erythematosus, and amyloidosis.
In addition, the methods of the invention can be used in the
treatment of nerve damage, such as peripheral neuropathy, which is
caused by exposure to toxic compounds, including heavy metals
(e.g., lead, arsenic, and mercury) and industrial solvents, as well
as drugs including chemotherapeutic agents (e.g., vincristine and
cisplatin), dapsone, HIV medications (e.g., Zidovudine, Didanosine.
Stavudine, Zalcitabine, Ritonavir, and Amprenavir), cholesterol
lowering drugs (e.g., Lovastatin, Indapamid, and Gemfibrozil),
heart or blood pressure medications (e.g., Amiodarone, Hydralazine,
Perhexyline), and Metronidazole.
The methods of the invention can also be used to treat injury to
the nervous system caused by physical, mechanical, or chemical
trauma. Thus, the methods can be used in the treatment of
peripheral nerve damage caused by physical injury (associated with,
e.g., burns, wounds, surgery, and accidents), ischemia, prolonged
exposure to cold temperature (e.g., frost-bite), as well as damage
to the central nervous system due to, e.g., stroke or intracranial
hemorrhage (such as cerebral hemorrhage).
Further, the methods of the invention can be used in the prevention
or treatment of memory loss such as, for example, age-related
memory loss. Types of memory that can be affected by loss, and thus
treated according to the invention, include episodic memory,
semantic memory, short-term memory, and long-term memory. Examples
of diseases and conditions associated with memory loss, which can
be treated according to the present invention, include mild
cognitive impairment, Alzheimer's disease, Parkinson's disease,
Huntington's disease, chemotherapy, stress, stroke, and traumatic
brain injury (e.g., concussion).
The methods of the invention can also be used in the treatment of
psychiatric disorders including, for example, schizophrenia,
delusional disorder, schizoaffective disorder, schizopheniform,
shared psychotic disorder, psychosis, paranoid personality
disorder, schizoid personality disorder, borderline personality
disorder, anti-social personality disorder, narcissistic
personality disorder, obsessive-compulsive disorder, delirium,
dementia, mood disorders, bipolar disorder, depression, stress
disorder, panic disorder, agoraphobia, social phobia,
post-traumatic stress disorder, anxiety disorder, and impulse
control disorders (e.g., kleptomania, pathological gambling,
pyromania, and trichotillomania).
In addition to the in vivo methods described above, the methods of
the invention can be used to treat nerves ex vivo, which may be
helpful in the context of nerve grafts or nerve transplants. Thus,
the inhibitors described herein can be useful as components of
culture media for use in culturing nerve cells in vitro.
Accordingly, in another aspect, the invention provides for a method
for inhibiting or preventing degeneration of a central nervous
system (CNS) neuron or a portion thereof, the method comprising
administering to the CNS neuron a compound of formula I or an
embodiment thereof
In one embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the administering to the CNS neuron is performed in
vitro.
In another embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the method further comprises grafting or implanting the
CNS neuron into a human patient after administration of the
agent.
In another embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the CNS neuron is present in a human patient.
In another embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the administering to the CNS neuron comprises
administration of said compound of formula I or an embodiment
thereof in a pharmaceutically acceptable carrier, diluent or
excipient.
In another embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the administering to the CNS neuron is carried out by an
administration route selected from the group consisting of
parenteral, subcutaneous, intravenous, intraperitoneal,
intracerebral, intralesional, intramuscular, intraocular,
intraarterial interstitial infusion and implanted delivery
device.
In another embodiment, of the method for inhibiting or preventing
degeneration of a central nervous system neuron or a portion
thereof, the method further comprises administering one or more
additional pharmaceutical agents.
The inhibitors can be optionally combined with or administered in
concert with each other or other agents known to be useful in the
treatment of the relevant disease or condition. Thus, in the
treatment of ALS, for example, inhibitors can be administered in
combination with Riluzole (Rilutek), minocycline, insulin-like
growth factor 1 (IGF-1), and/or methylcobalamin. In another
example, in the treatment of Parkinson's disease, inhibitors can be
administered with L-dopa, dopamine agonists (e.g., bromocriptine,
pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and
lisuride), dopa decarboxylase inhibitors (e.g., levodopa,
benserazide, and carbidopa), and/or MAO-B inhibitors (e.g.,
selegiline and rasagiline). In a further example, in the treatment
of Alzheimer's disease, inhibitors can be administered with
acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and
rivastigmine) and/or NMDA receptor antagonists (e.g., memantine).
The combination therapies can involve concurrent or sequential
administration, by the same or different routes, as determined to
be appropriate by those of skill in the art. The invention also
includes pharmaceutical compositions and kits comprising
combinations as described herein.
In addition to the combinations noted above, other combinations
included in the invention are combinations of inhibitors of
degeneration of different neuronal regions. Thus, the invention
includes combinations of agents that (i) inhibit degeneration of
the neuron cell body, and (ii) inhibit axon degeneration. For
example, inhibitors of GSK and transcription are found to prevent
degeneration of neuron cell bodies, while inhibitors of EGFR and
p38 MAPK are found to prevent degeneration of axons. Thus, the
invention includes combinations of inhibitors of GSK and EGFR
(and/or p38 MAPK), combinations of transcription inhibitors and EGF
(and/or p38 MAPK), and further combinations of inhibitors of dual
leucine zipper-bearing kinase (DLK), glycogen synthase kinase
3.beta. (GSK3), p38 MAPK, EGFF, phosphoinositide 3-kinase (PI3K),
cyclin-dependent kinase 5 (cdk5), adenylyl cyclase, c-Jun
N-terminal kinase (JNK), BCL2-associated X protein (Bax), In
channel, calcium/calmodulin-dependent protein kinase kinase
(CaMKK), a G-protein, a G-protein coupled receptor, transcription
factor 4 (TCF4), and .beta.-catenin. The inhibitors used in these
combinations can be any of those described herein, or other
inhibitors of these targets as described in WO 2011/050192,
incorporated herein by reference.
The combination therapy can provide "synergy" and prove
"synergistic", i.e., the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect can be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined, unit dosage formulation; (2) delivered by alternation or
in parallel as separate formulations; or (3) by some other regimen.
When delivered in alternation therapy, a synergistic effect can be
attained when the compounds are administered or delivered
sequentially, e.g., by different injections in separate syringes,
separate pills or capsules, or in separate infusions. In general,
during alternation therapy, an effective dosage of each active
ingredient is administered sequentially, i.e., serially, whereas in
combination therapy, effective dosages of two or more active
ingredients are administered together.
F. Examples
The invention will be more fully understood by reference to the
following examples. They should not, however, be construed as
limiting the scope of the invention. These examples are not
intended to limit the scope of the present invention, but rather to
provide guidance to a skilled artisan to prepare and use the
compounds, compositions, and methods of the present invention.
While particular embodiments of the present invention are
described, the skilled artisan will appreciate that various changes
and modifications can be made without departing from the spirit and
scope of the invention.
The chemical reactions in the Examples described can be readily
adapted to prepare a number of other compounds of the invention,
and alternative methods for preparing the compounds of this
invention are deemed to be within the scope of this invention. For
example, the synthesis of non-exemplified compounds according to
the invention can be successfully performed by modifications
apparent to those skilled in the art, e.g., by appropriately
protecting interferring groups, by utilizing other suitable
reagents known in the art other than those described, and/or by
making routine modifications of reaction conditions. Alternatively,
other reactions disclosed herein or known in the art will be
recognized as having applicability for preparing other compounds of
the invention. Accordingly, the following examples are provided to
illustrate but not limit the invention.
In the Examples described below, unless otherwise indicated all
temperatures are set forth in degrees Celsius. Commercially
available reagents were purchased from suppliers such as Aldrich
Chemical Company, Lancaster, TCI or Maybridge, and were used
without further purification unless otherwise indicated. The
reactions set forth below were done generally under a positive
pressure of nitrogen or argon or with a drying tube (unless
otherwise stated) in anhydrous solvents, and the reaction flasks
were typically fitted with rubber septa for the introduction of
substrates and reagents via syringe. Glassware was oven dried
and/or heat dried. Column chromatography was conducted on a Biotage
system (Manufacturer: Dyax Corporation) having a silica gel column
or on a silica SEP PAK.RTM. cartridge (Waters); or alternatively
column chromatography was carried out using on an ISCO
chromatography system (Manufacturer: Teledyne ISCO) having a silica
gel column. .sup.1H NMR spectra were recorded on a Varian
instrument operating at 400 MHz. .sup.1H NMR spectra were obtained
in deuterated CDCl.sub.3, d.sub.6-DMSO, CH.sub.3OD or
d.sub.6-acetone solutions (reported in ppm), using
tetramethylsilane (TMS) as the reference standard (0 ppm). When
peak multiplicities are reported, the following abbreviations are
used: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broadened), dd (doublet of doublets), dt (doublet
of triplets). Coupling constants, when given, are reported in Hertz
(Hz).
When possible, product formed in the reaction mixtures were
monitored by LC/MS. High Pressure Liquid Chromatography--Mass
Spectrometry (LCMS) experiments. Example conditions for analysis
include monitoring on an Agilent 1200 Series LC coupled to a 6140
quadrupole mass spectrometer using a Supelco Ascentis Express C18
column with a linear gradient of 5%-95% acetonitrile/water (with
0.1% trifluoroacetic acid in each mobile phase) within 1.4 minutes
and held at 95% for 0.3 minute, or on a PE Sciex API 150 EX using a
Phenomenex DNYC monolithic C18 column with a linear gradient of
5%-95% acetonitrile/water (with 0.1% trifluoroacetic acid in each
mobile phase) within 5 minutes and held at 95% for 1 minute to
determine retention times (R.sub.T) and associated mass ions.
All abbreviations used to described reagents, reaction conditions,
or equipment used are consistent with the definitions set forth in
the "List of standard abbreviations and acronyms" published yearly
by the Journal of Organic Chemistry (an American Chemical Society
journal). The chemical names of discrete compounds of the invention
were obtained using the structure naming features of commonly used
programs including ChemBioDraw Version 11.0, Accelrys' Pipeline
Pilot IUPAC compound naming program.
Example 1
Method A:
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
an-5-yl)-[4,5'-bipyrimidin]-2'-amine
##STR00019##
Step 1: Synthesis of
(1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.-
1]-heptane
##STR00020##
The mixture of 4,6-dichloro-2-(methylthio)pyrimidine (450 mg, 2.31
mmol), DIEA (894 mg, 6.92 mmol) and
2-oxa-5-azabicyclo[2.2.1]heptane (328 mg, 2.42 mmol) in DMF (5 mL)
was stirred at 50.degree. C. for 12 h. Water (20 mL) was added to
and extracted with ethyl acetate (2.times.20 mL). The organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated
to give
(1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo-[2.2-
.1]heptane (550 mg, 92.5% yield) as a white solid, which was used
for next step without further purification LCMS (ESI):
[MH].sup.+=258.0.
Step 2: Synthesis of
(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo--
[2.2.1]heptane
##STR00021##
To a mixture of
(1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.-
1]heptane (550 mg, 2.13 mmol) in DCM (50 mL) was added m-CPBA (1.73
g, 8.53 mmol) portionwise. The reaction mixture was stirred at room
temperature for 1 h. The mixture was washed with Na.sub.2SO.sub.3
(sat aq, 20 mL) and was concentrated in vacuo to afford
(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[-
2.2.1]--heptane (600 mg, 97.0% yield) as a white solid, LCMS (ESI):
[MH].sup.+=289.7, which was used for next step without further
purification.
Step 3: Synthesis of
6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5'-
-bipyrimidin]-2'-amine
##STR00022##
To a microwave vial charged with
(1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[-
2.2.1]-heptane (600 mg, 2.07 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
(641 mg, 2.90 mmol), potassium acetate (284 mg, 2.90 mmol) and
sodium carbonate (307 mg, 2.90 mmol) in acetonitrile/water (1 (5:1,
6.0 mL) was added PdCl.sub.2{PtBu.sub.2(Ph-p-NMe.sub.2)}.sub.2 (147
mg, 0.21 mmol) under nitrogen. The vial was sealed and heated by
microwave irradiation at 140.degree. C. for 40 min. The reaction
mixture was concentrated in vacuo, and resulting residue was
purified by flash column chromatography (5% methanol in
dichloromethane) to provide
6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5'-
-bipyrimidin]-2'-amine (380 mg, 52.7% yield). LCMS (ESI):
[MH].sup.+=349.0.
Step 4: Synthesis of
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hep-
tan-5-yl)-[4,5'-bipyrimidin]-2'-amine
##STR00023##
To the mixture of
6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5'-
-bipyrimidin]-2'-amine (380 mg, 1.09 mmol) and potassium carbonate
(754 mg, 5.45 mmol) in DMSO (5 mL) was added
2-azabicyclo[2.1.1]hexane hydrochloride (326 mg, 2.73 mmol). The
mixture was stirred at 100.degree. C. for 5 h. After removal of the
solvent, the residue was purified by Prep-HPLC (formic acid) to
afford
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hep-
tan-5-yl)-[4,5'-bipyrimidin]-2'-amine (220 mg, 57% yield). LCMS
(ESI): [MH].sup.+=352.1; .sup.1H NMR (400 MHz, DMSO-d6) .delta.
8.91 (s, 2H), 7.00 (s, 2H), 6.30-6.10 (m, 1H), 5.10-4.90 (m, 1H),
4.83 (d, J=6.4 Hz, 1H), 4.70-4.64 (m, 1H), 3.78-3.76 (m, 1H),
3.66-3.64 (m, 1H), 3.45-3.38 (m, 4H), 2.89-2.87 (m, 1H), 1.93-1.86
(m, 4H), 1.32-1.31 (m, 2H).
Method B:
##STR00024## ##STR00025##
Step 1: Synthesis of
5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine
##STR00026##
To a microwave vial charged with 2,4,6-trichloropyrimidine (300 mg,
1.64 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl-
)pyridin-2-amine (518 mg, 1.80 mmol) and cesium carbonate (1.07 g,
3.27 mmol) in acetonitrile/water (4:1, 30 mL) was added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (60
mg, 0.05 mmol) under nitrogen. The mixture was stirred at room
temperature for 16 h. The reaction mixture was concentrated in
vacuo, and resulting residue was purified by flash column
chromatography (15% ethyl acetate in petroleum ether to 50% ethyl
acetate in petroleum ether) to provide
5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine
(300 mg, 59.3% yield). LCMS (ESI): [MH].sup.+=308.7.
Step 2: Synthesis of (1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,-
5-diazabicyclo[2.2.1]heptane-2-carboxylate
##STR00027##
To a solution of
5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine
(300 mg, 0.84 mmol) in tetrahydrofuran (60 mL) was added
(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
hydrochloride (197 mg, 0.84 mmol) and
N-ethyl-N-isopropylpropan-2-amine (2 mL). The mixture was heated at
75.degree. C. for 3 h. After cooling to room temperature, water (50
mL) was added to. The mixture was extracted with ethyl acetate
(3.times.30 mL). The organic layer was dried over sodium sulfate,
concentrated and purified by flash column chromatography (25% ethyl
acetate in petroleum ether to 100% ethyl acetate) to provide
(1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,-
5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 48.1% yield).
TLC (Thin layer chromatography) (petroleum ether (PE): ethyl
acetate (EA)=3:1, R.sub.f=0.3-0.4).
Step 3: Synthesis of (1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexa-
n-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
##STR00028##
To a solution of (1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,-
5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 0.47 mmol) in
DMSO (2 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (68
mg, 0.56 mmol) and potassium carbonate (130 mg, 0.93 mmol). The
mixture was heated at 90.degree. C. for 16 h. After cooling to room
temperature, water (50 mL) was added to. The mixture was extracted
with ethyl acetate (30 mL (3 times)). The organic layer was dried
over sodium sulfate, concentrated and purified by flash column
chromatography (50% ethyl acetate in petroleum ether to 100% ethyl
acetate) to provide (1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexa-
n-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
(130 mg, 53.7% yield). LCMS (ESI): [MH].sup.+=518.0.
Step 4: Synthesis of
5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]he-
ptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine
##STR00029##
To an ice-cooled solution of (1S,4S)-tert-butyl
5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexa-
n-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
(130 mg, 0.25 mmol) in dichloromethane (6 mL) was added
trifluoroacetic acid (3 mL). The mixture was stirred at room
temperature for 0.5 h. After removal of the solvent, the residue
was dissolved with water (30 mL), basified and extracted with
dichloromethane (3.times.30 mL). The organic layer was dried over
sodium sulfate, concentrated to provide
5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]he-
ptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80
mg, 75.0% yield). LCMS (ESI): [MH].sup.+=417.9.
Step 5: Synthesis of
1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo-
[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-
one
##STR00030##
To a solution of
5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]he-
ptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80
mg, 0.22 mmol) in DMSO (2 mL) was added acetic anhydride (46 mg,
0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL). The
mixture was stirred at room temperature for 25 min. The mixture was
concentrated in vacuum and the residue was purified by Prep-HPLC
(BASE) to provide
1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo-
[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-
one (46.34 mg, 40.0% yield). LCMS (ESI): [MH].sup.+=459.9; .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s,
2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H),
4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84
(m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m,
2H), 1.29 (d, J=2.0 Hz, 2H).
Method C:
(1R,5S,6r)-tert-butyl
6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrimidin]-6-yl)-3--
azabicyclo[3.1.0]hexane-3-carboxylate
##STR00031## ##STR00032##
Step 1: Synthesis of (1R,5S,6r)-tert-butyl
6-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00033##
To a solution of
(1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic
acid (2 g, 8.8 mmol) in acetonitrile (150 mL) was added
1,1'-carbonyldiimidazole (1.71 g, 10.56 mmol). After stirring at
20.degree. C. for 1 h, magnesium chloride (827 mg, 8.8 mmol) and
potassium 3-ethoxy-3-oxopropanoate (1.5 g, 8.8 mmol) was added to
and the reaction mixture was stirred at 20.degree. C. for 16 h. The
reaction solution was filtered, concentrated and purified by flash
column (60% ethyl acetate in petroleum ether) to afford
(1R,5S,6r)-tert-butyl
6-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
(1.5 g, 57.7% yield). .sup.1H NMR (400 MHz, Chloroform-d) .delta.
4.21-4.16 (m, 2H), 3.66-3.64 (m, 1H), 3.54 (s, 3H), 3.42-3.90 (m,
2H), 2.15-2.13 (m, 2H), 1.90-1.88 (m, 1H), 1.42 (s, 9H), 1.28-1.24
(m, 3H)
Step 2: Synthesis of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carbox-
ylate
##STR00034##
The mixture of (1R,5S,6r)-tert-butyl
6-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
(7.6 g, 25.6 mmol), carbamimidothioic acid (7.77 g, 102.3 mmol) and
sodium methanolate (5.52 g, 102.3 mmol) in anhydrous methonal (250
mL) was refluxed under N.sub.2 for 16 h. After removal of the
solvent, the residue was adjusted pH to 6 with hydrogen chloride
aqueous solution (2 M). The mixture was filtered and the solid was
the desired product of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carbox-
ylate (7 g, 88.6% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.30 (d, J=13.6 Hz, 2H), 5.45 (s, 1H), 3.57-3.53 (m, 2H),
3.33-3.29 (m, 2H), 2.05-1.99 (m, 2H), 1.58-1.57 (m, 1H), 1.39 (s,
9H).
Step 3: Synthesis of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-ca-
rboxylate
##STR00035##
To the solution of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-mercaptopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carbox-
ylate (7 g, 22.65 mmol) in sodium hydroxide aqueous solution (8%)
was added iodomethane (6.43 g, 45.3 mmol). The resulting solution
was stirred at room temperature for 1 h. The reaction mixture was
adjusted pH=5.about.6 with hydrogen chloride aqueous solution (2
M). The mixture was filtered and the solid was the desired product
of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-ca-
rboxylate (6 g, crude, about 65%, 53.4% yield). LCMS (ESI):
[MH].sup.+=324.1.
Step 4: Synthesis of (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-car-
boxylate
##STR00036##
To a solution of (1R,5S,6r)-tert-butyl
6-(6-hydroxy-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-ca-
rboxylate (6 g, 18.57 mmol, 65%) in dry dichloromethane (250 mL)
was added oxalyl dichloride (2.83 g, 22.3 mmol) and DMF (0.5 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for 2 h and
was poured into ice water including Et.sub.3N. The mixture was
extracted with dichloromethane (250 mL*2). The organic layer was
washed with brine (100 mL), dried over sodium sulfate, concentrated
and purified by flash column chromatography (20% ethyl acetate in
petroleum ether) to afford (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-car-
boxylate (3.8 g, 92.7% yield).
Step 5: Synthesis of (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-
-carboxylate
##STR00037##
To a solution of (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-car-
boxylate (800 mg, 2.35 mmol) in anhydrous dichloromethane (40 mL)
was added m-CPBA (2 g, 11.7 mmol). The reaction mixture was stirred
at room temperature for 1 h. The mixture was extracted with
dichloromethane (2.times.50 mL). The organic layer was washed with
brine (50 mL), dried over sodium sulfate, concentrated and purified
by flash column chromatography (30% ethyl acetate in petroleum
ether) to provide (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-
-carboxylate (700 mg, 80% yield) .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.40 (s, 1H), 3.82-3.70 (m, 2H), 3.54-3.50
(m, 2H), 3.33 (s, 3H), 2.38 (s, 2H), 1.96-1.94 (m, 1H), 1.47 (s,
1H).
Step 6: Synthesis of (1R,5S,6r)-tert-butyl
6-(2'-amino-2-(methylsulfonyl)-[4,5'-bipyrimidin]-6-yl)-3-azabicyclo[3.1.-
0]hexane-3-carboxylate
##STR00038##
To a microwave vial charged with (1R,5S,6r)-tert-butyl
6-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-
-carboxylate (820 mg, 2.2 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (972 mg, 4.4
mmol), and cesium carbonate (1.43 g, 4.4 mmol) in dioxane/water
(5:1, 15 mL) was added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (161
mg, 0.22 mmol) under nitrogen. The vial was sealed and heated by
microwave irradiation at 110.degree. C. for 30 min. The reaction
mixture was concentrated in vacuo, and resulting residue was
purified by flash column chromatography (25% ethyl acetate in
petroleum ether to 100% ethyl acetate) to provide
(1R,5S,6r)-tert-butyl
6-(2'-amino-2-(methylsulfonyl)-[4,5'-bipyrimidin]-6-yl)-3-azabicyclo[3.1.-
0]hexane-3-carboxylate (700 mg, 94.7% yield) LCMS (ESI):
[MH].sup.+=432.8.
Step 7: Synthesis of (1R,5S,6r)-tert-butyl
6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrimidin]-6-yl)-3--
azabicyclo[3.1.0]hexane-3-carboxylate
##STR00039##
To a solution of (1R,5S,6r)-tert-butyl
6-(2'-amino-2-(methylsulfonyl)-[4,5'-bipyrimidin]-6-yl)-3-azabicyclo[3.1.-
0]hexane-3-carboxylate (200 mg, 0.46 mmol) in DMSO (15 mL) was
added 2-azabicyclo[2.1.1]hexane hydrochloride (109.5 mg, 0.92 mmol)
and potassium carbonate (127 mg, 0.92 mmol). The mixture was
stirred at 120.degree. C. for 2 h. After cooling to room
temperature, the mixture was extracted with ethyl acetate
(2.times.20 mL). The organic layer was concentrated and purified by
flash column chromatography (75% ethyl acetate in petroleum ether)
to provide (1R,5S,6r)-tert-butyl
6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrimidin]-6-yl)-3--
azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 70% yield). TLC (EA,
R.sub.f=0.3.about.0.4).
Step 8: Synthesis of
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan--
6-yl)-[4,5'-bipyrimidin]-2'-amine
##STR00040##
To an ice-cooled solution of (1R,5S,6r)-tert-butyl
6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrimidin]-6-yl)-3--
azabicyclo[3.1.0]hexane-3-carboxylate (120 mg, 0.276 mmol) in
dichloromethane (6 mL) was added trifluoroacetic acid (3 mL). The
mixture was warmed to room temperature. After 3 h, the reaction
mixture was concentrated in vacuo to provide
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan--
6-yl)-[4,5'-bipyrimidin]-2'-amine (90 mg, 97.3% yield). The
resulting residue was used without further purification. TLC (EA,
R.sub.f=0).
Step 9: Synthesis of
1-((1R,5S,6r)-6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrim-
idin]-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone
##STR00041##
To a solution of
2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan--
6-yl)-[4,5'-bipyrimidin]-2'-amine (80 mg, 0.24 mmol) and
N-ethyl-N-isopropylpropan-2-amine (62 mg, 0.48 mmol) in
dichloromethane (15 mL) was added acetic anhydride (49 mg, 0.48
mmol). The mixture was stirred at room temperature for 30 min.
After removal of the solvent, the residue was purified by PR-HPLC
(BASE) to provide
1-((1R,5S,6r)-6-(2'-amino-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5'-bipyrim-
idin]-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone (88 mg, 97.2%
yield). LCMS (ESI): [MH].sup.+=377.8; .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.94 (s, 2H), 6.65 (s, 1H), 5.49 (s, 2H),
4.95 (d, J=6.0 Hz, 1H), 3.97 (d, J=12.0 Hz, 1H), 3.72 (s, 2H), 3.54
(s, 3H), 2.95 (s, 1H), 2.30 (s, 2H), 2.06 (s, 3H), 2.00 (s, 2H),
1.70 (s, 1H), 1.45 (s, 2H).
Method D:
Preparation of
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine
##STR00042##
##STR00043##
Step 1: Synthesis of
(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane
##STR00044##
To a microwave vial charged with 2,6-dichloro-4-iodopyridine (100
mg, 0.37 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (49.19 mg,
0.44 mmol) and cesium carbonate (66.29 mg, 0.48 mmol) in dioxane (5
mL) was added Pd.sub.2(dba).sub.3 (3.5 mg, 0.048 mmol) and xantphos
(3.5 mg, 0.048 mmol) under nitrogen. The vial was sealed and heated
by microwave irradiation at 140.degree. C. for 1 h. The reaction
mixture was concentrated in vacuo, and resulting residue was
purified by TLC (PE:EA=2:1) to afford
(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane
(40 mg, 35% yield).
Step 2: Synthesis of
(1S,4S)-5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-chloropyridin-4-yl)-2-oxa--
5-azabicyclo[2.2.1]heptane
##STR00045##
To a microwave vial charged with
(1S,4S)-5-(2,6-dichloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane
(100 mg, 0.41 mmol) and 2-azabicyclo[2.1.1]hexane hydrochloride
(244 mg, 2.04 mmol) in NMP (3 mL) was added cesium carbonate (1.33
g, 4.08 mmol). The vial was sealed and heated by microwave
irradiation at 150.degree. C. for 18 h. The reaction mixture was
concentrated in vacuo, and resulting residue was purified by TLC
(PE:EA=1:1) to afford compound 5 (80 mg, 77.7% yield). LCMS (ESI)
[MH].sup.+=291.8.
Step 3: Synthesis of
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine
##STR00046##
To a microwave vial charged with
(1S,4S)-5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-chloropyridin-4-yl)-2-oxa--
5-azabicyclo[2.2.1]heptane (70 mg, 0.24 mmol),
3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-2-amine (75.53 mg, 0.26 mmol) and potassium carbonate (66.29 mg,
0.48 mmol) in dioxane/water (5:1, 3.0 mL) was added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (3.5
mg, 0.048 mmol) under nitrogen. The vial was sealed and heated by
microwave irradiation at 120.degree. C. for 1 h. The reaction
mixture was concentrated in vacuo, and resulting residue was
purified by PR-HPLC (Basic) to afford
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine (24.55
mg, 24.6% yield). LCMS (ESI) [MH].sup.+=416.1; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, J=74.0
Hz, 1H), 6.42 (s, 1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76-4.74 (m,
2H), 4.62 (s, 1H), 3.73 (d, J=6.8 Hz, 1H), 3.63 (d, J=7.6 Hz, 1H),
3.45 (d, J=8.8 Hz, 1H), 3.33 (s, 2H), 3.10 (d, J=10.4 Hz, 1H),
2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H), 1.27-1.26 (m, 2H).
Method E:
Step 1-Synthesis of
(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2-
.2.1]heptane (70929-339-C)
##STR00047##
To a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (3.41 g,
15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
(2.03 g, 15.0 mmol) in N,N-dimethylacetamide (40.5 mL), was added
N,N-diisopropylethylamine (6.60 mL). The resulting mixture was
stirred at room temperature. After 30 min, the reaction mixture was
concentrated to a solid. The crude material was purified by column
chromatography using an 80 g column, with a gradient of 0% to 100%
ethyl acetate in heptane. The combined fractions containing product
were concentrated under reduced pressure to provide
(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2-
.2.1]heptane (3.03 g). 1H NMR (400 MHz, Chloroform-d) .delta. 6.30
(s, 1H), 3.98-3.81 (m, 3H), 3.45-3.35 (m, 2H), 3.28 (s, 3H),
2.16-1.98 (m, 2H), 1.95-1.86 (m, 1H).
Step 2 Synthesis of
6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5'-
-bipyrimidin]-2'-amine (70929-339-E)
##STR00048##
To a solution of
(1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2-
.2.1]heptane (500 mg, 1.73 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
(382 mg, 1.73 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63.8
mg, 0.0863 mmol) in acetonitrile (6.90 mL) was added potassium
acetate in water (3.45 mL) in a microwave vial equipped with a
stirbar. The mixture was microwaved at 110.degree. C. for 5 min.
The solid was and washed with ethyl acetate (5 mL) filtered under
vacuum, providing
6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5'-
-bipyrimidin]-2'-amine (598 mg, crude). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 9.02 (d, J=5.6, 2.8 Hz, 2H), 7.40-6.97 (m, 1H),
7.28 (s, 2H), 5.14 (d, J=16.0 Hz, 1H), 4.76 (d, J=27.9 Hz, 1H),
3.82 (d, J=7.7, 1.5 Hz, 1H), 3.76-3.66 (m, 1H), 3.60-3.51 (m, 1H),
3.50-3.41 (m, 1H), 3.35 (d, J=6.1 Hz, 3H), 1.95 (d, J=22.0 Hz,
2H).
Step 3 Synthesis of
2-(azetidin-1-yl)-6-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5'-b-
ipyrimidin]-2'-amine
##STR00049##
5-[2-methylsulfonyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrim-
idin-4-yl]pyrimidin-2-amine (30.0 mg, 0.861 mmol), azetidine
hydrochloride (24.7 mg, 0.258 mmol), potassium carbonate (71.4 mg,
0.517 mmol), and 1-methyl-2-pyrrolidinone (0.861 mL) were combined
in a reaction flask and heated to 130.degree. C. for 16 hrs. The
reaction was filtered and purified by reverse phase column
chromatography using a gradient of 20% to 60% acetonitrile in 0.1%
ammonium hydroxide in water. The combined fractions containing
product were concentrated under reduced pressure to provide
2-(azetidin-1-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl-
)-[4,5'-bipyrimidin]-2'-amine 1H NMR (400 MHz, DMSO-d6) .delta.
8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.99 (t,
J=7.5 Hz, 4H), 3.77 (dd, J=7.3, 1.5 Hz, 1H), 3.64 (d, J=7.3 Hz,
1H), 3.43 (dd, J=10.5, 1.5 Hz, 1H), 3.40-3.32 (m, 1H), 3.17 (s,
1H), 2.24 (p, J=7.5 Hz, 2H), 1.85 (s, 2H).
Method F:
Preparation of
6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluor-
omethyl)-[2,3'-bipyridin]-6'-amine
##STR00050##
Step 1: Synthesis of 2,6-dichloro-4-(piperidin-4-yl)pyridine
##STR00051##
To a solution of tert-butyl
4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (2 g, 6.06
mmol) in DCM (2 mL) was added TFA (3 mL). The solution was stirred
at room temperature for 30 min. The reaction solution was
concentrated to afford 2,6-dichloro-4-(piperidin-4-yl)pyridine as
TFA salt, which was used without further purification. LCMS (ESI)
[MH]+=231.1.
Step 2: Synthesis of
2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine
##STR00052##
A solution of 2,6-dichloro-4-(piperidin-4-yl)pyridine (2 g, 8.7
mmol) and oxetan-3-one (6.26 g, 87 mmol) in THF (50 mL) was stirred
at 70.degree. C. for 30 min and then sodium cyanoborohydride (2.74
g, 43.5 mmol) was added to the mixture and the mixture solution was
stirred at 70.degree. C. for additional 30 min. The reaction
solution was filtered and the filtrate was concentrated to give
crude product which was purified by flash column chromatography on
silica gel (30% ethyl acetate in petroleum ether) to afford
2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine. (2 g, 88.7%
yield). LCMS (ESI) [MH]+=286.7.
Step 3: Synthesis of
2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyri-
dine
##STR00053##
A mixture of 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine
(450 mg, 1.57 mmol), 3-methoxyazetidine hydrochloride (963 mg, 7.83
mmol) and DIPEA (3 mL, 16.9 mmol) in DMSO (5 mL) was stirred at
100.degree. C. for 16 h. The mixture was poured into water and
extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, evaporated and purified by flash column
chromatography on silica gel (30% ethyl acetate in petroleum ether)
to give
2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyri-
dine (320 mg, 60.3% yield). LCMS (ESI) [MH]+=337.8
Step 4: Synthesis of
6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluor-
omethyl)-[2,3'-bipyridin]-6'-amine
##STR00054##
To a solution of
2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyri-
dine (80 mg, 0.24 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridi-
n-2-amine (140 mg, 0.48 mmol) and cesium carbonate (160 mg, 0.48
mmol) in dioxane/H2O (5:1, 4 mL) was added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18
mg, 0.024 mmol) under nitrogen. The mixture was irradiated by
microwave at 110.degree. C. for 30 min. The reaction mixture was
filtered, the filtrate was concentrated and purified by Prep-HPLC
to afford
6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluor-
omethyl)-[2,3'-bipyridin]-6'-amine (68.3 mg 61.5%, yield). LCMS
(ESI) [MH]+=464, 1HNMR (400 MHz, CDCl.sub.3), .delta.8.745(s,1H),
.delta.8.363(s,1H), .delta.8.232(s,1H), .delta.8.832(s,1H),
.delta.6.109(s,1H), .delta.5.642(s,2H), .delta.4.74- 4.67(m,4H),
.delta. 4.39-4.22 (m, 3H), .delta. 3.94-3.90 (m, 2H), .delta.
3.63-3.56(m, 1H), .delta. 3.346(s, 3H), .delta. 2.980(d, J=10.8 Hz,
2H), .delta. 2.55-2.46 (m,1H), .delta. 2.06-1.99 (m, 1H), .delta.
1.93-1.87(m, 4H). LCMS:464.0(M+1).
Method G:
6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluoro-
methyl)-[2,3'-bipyridin]-6'-amine
Step 1: 1-(2,6-dichloro-4-pyridyl)cyclobutanecarbonitrile
##STR00055##
To a stirring solution of 2,4,6-trichloropyridine (1.00 g, 5.48
mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous
THF (27 mL) at -78.degree. C. and under nitrogen was added lithium
bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF).
The cooling bath was removed and stirring continued for 1 h. The
reaction was quenched by the addition of sat. aq. NH.sub.4Cl,
extracted with CH.sub.2Cl.sub.2 and organics dried over MgSO.sub.4.
Following concentration, the reaction residue was purified by flash
column chromatography (100:0 heptanes/EtOAc 85:15 heptanes/EtOAc)
to afford the title compound as a white solid (0.995 g, 76%);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34 (s, 2H), 2.92-2.80
(m, 2H), 2.68-2.40 (m, 3H), 2.23-2.08 (m, 1H).
Step 2:
1-[2-(2-aminopyrimidin-5-yl)-6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-p-
yridyl]cyclobutanecarbonitrile
##STR00056##
To a solution of 1-(2,6-dichloro-4-pyridyl)cyclobutanecarbonitrile
(100 mg, 0.440 mmol) in anhydrous DMSO (0.44 mL) was added
2-azabicyclo[2.1.1]hexane hydrochloride (60 mg, 0.48 mmol) and
potassium carbonate (122 mg, 0.881 mmol). The vessel was sealed and
the reaction mixture stirred at 100.degree. C. for 92 h. After
cooling to rt, the mixture was diluted with diethyl ether and
washed with water (2.times.), brine (1.times.) and dried over
MgSO.sub.4 and concentrated to dryness. The following compounds
were added to the crude product: 2-aminopyridine-5-boronic acid
pinacol ester (110 mg, 0.48 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2--
aminoethyl)phenyl)]palladium(II) (16.6 mg, 0.0220 mmol),
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (21.4 mg,
0.0440 mmol), and potassium phosphate tribasic (289 mg, 1.32 mmol).
Under a stream of nitrogen, anhydrous, degassed THF (1.3 mL) and
degassed water (0.22 mL) were added and the vial was sealed
tightly. The reaction mixture was stirred at 80.degree. C. for 3 h,
cooled to rt, and filtered through Celite, rinsing with
CH.sub.2Cl.sub.2. The residue obtained after concentration was
purified by RPLC to afford the title compound as a white solid
(85.4 mg, 58% over 2 steps); .sup.1H NMR (400 MHz, DMSO) .delta.
8.92 (s, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.91 (br s, 2H), 6.46 (d,
J=1.1 Hz, 1H), 4.95-4.81 (m, 1H), 3.44 (s, 2H), 3.01-2.90 (m, 1H),
2.75-2.64 (m, 4H), 2.39-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.41-1.27
(m, 2H).
Method H:
[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]-
-1-piperidyl]-phenyl-methanone
##STR00057##
A solution of tert-butyl
3-(6-chloro-2-methyl-pyrimidin-4-yl)piperidine-1-carboxylate (40
mg, 0.13 mmol, 1.00 equiv),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimi-
din-2-amine (40 mg, 0.14 mmol, 1.10 equiv) and
[1,1'-BIS(DIPHENYLPHOSPHINO)FERROCENE]DICHLOROPALLADIUM(II) (10 mg,
0.013 mmol, 0.1 equiv) in Acetonitrile (1.0 mL) was mixed with 1M
potassium carbonate solution in water (420 uL, 0.42 mmol, 3.2
equiv) and stirred at 90.degree. C. for 2 hr. The reaction mixture
was extracted with DCM (3 mL) and H2O (2 mL). The organic phase was
removed, dried over sodium sulfate, and passed through a filter.
The resulting organic phase was concentrated under vacuum. The
crude product was mixed with methanol (1.0 mL) and 4M hydrogen
chloride in dioxane (325 uL, 1.3 mmol, 10 equiv). The resulting
solution was stirred at room temperature overnight. The reaction
mixture was concentrated under vacuum. A solution of crude product,
benzoic acid (15 mg, 0.13 mmol, 1.0 equiv), HBTU (50 mg, 0.13 mmol,
1.0 equiv) and Triethylamine (90 uL, 0.65 mmol, 5.0 equiv) in DMF
(1.0 mL) was stirred at room temperature overnight. The reaction
mixture was concentrated under vacuum and the crude product was
purified by Prep-HPLC (Column, Sunfire C18 19.times.150; mobile
phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV
254 nm) to give 21.8 mg (38%) of
[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl-
]-1-piperidyl]-phenyl-methanone as an off white solid, .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.63 (s, 1H), 7.66 (s, 2H), 7.46-7.42
(m, 3H), 7.42-7.36 (m, 2H), 7.01 (s, 1H), 4.65-4.37 (m, 1H), 4.08
(q, J=5.3 Hz, 1H), 3.77-3.51 (m, 1H), 3.17 (d, J=5.3 Hz, 2H),
3.14-2.89 (m, 3H), 2.10-2.02 (m, 1H), 1.91-1.50 (m, 3H).
Method I:
1-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-
-yl)pyrimidin-4-yl]cyclobutanecarbonitrile
Step 1: 1-(2,6-dichloropyrimidin-4-yl)cyclobutanecarbonitrile
##STR00058##
To a stirring solution of 2,4,6-trichloropyrimidine (1.00 g, 5.45
mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous
THF (27 mL) at -78.degree. C. and under nitrogen was added lithium
bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF)
over 3 min. The cooling bath was removed after 5 further min, and
stirring continued for 3 h. The reaction was quenched by the
addition of sat. aq. NH.sub.4Cl, extracted with CH.sub.2Cl.sub.2
and organics dried over MgSO.sub.4. Following concentration, the
reaction residue was purified by flash column chromatography (100:0
heptanes/EtOAc-85:15 heptanes/EtOAc) to afford the title compound
as a colorless solid (0.147 g, 12%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.54 (s, 1H), 2.97-2.82 (m, 2H), 2.82-2.67 (m,
2H), 2.51-2.35 (m, 1H), 2.35-2.16 (m, 1H).
Step 2:
1-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1-
]hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile
##STR00059##
Into a vial was weighed
1-(2,6-dichloropyrimidin-4-yl)cyclobutanecarbonitrile (64.2 mg,
0.281 mmol), 2-aminopyridine-5-boronic acid pinacol ester (64.2 mg,
0.281 mmol), tetrakis(triphenylphosphine)palladium(0) (16.3 mg, 5
mol %), and sodium carbonate (90 mg, 0.84 mmol). Under a stream of
nitrogen, anhydrous, degassed THF (0.84 mL) and degassed water
(0.14 mL) were added and the vial was sealed tightly. The reaction
mixture was stirred at 90.degree. C. for 68 h, cooled to rt,
filtered through Celite rinsing with CH.sub.2Cl.sub.2, and
concentrated to dryness. To this crude product was added
2-azabicyclo[2.1.1]hexane hydrochloride (49 mg, 0.39 mmol),
N,N-diisopropylethylamine (0.147 mL, 0.844 mmol), and anhydrous DMF
(1.1 mL). The vessel was sealed and the reaction mixture stirred at
80.degree. C. for 4.5 h. After cooling to rt, the mixture was
concentrated and the residue subjected to RPLC purification to
yield the title compound as a white solid (36.9 mg, 39% over 2
steps); .sup.1H NMR (400 MHz, DMSO) .delta. 8.69 (s, 1H), 8.05 (s,
1H), 7.23 (t, J=74.0 Hz, 2H), 7.20 (s, 1H), 6.70 (br s, 2H), 4.95
(m, 1H), 3.54 (s, 2H), 2.99-2.91 (m, 1H), 2.81 (m, 2H), 2.72-2.60
(m, 2H), 2.32-2.18 (m, 1H), 2.13-1.94 (m, 3H), 1.45-1.38 (m,
2H).
Method J:
Step 1: tert-butyl
3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate
##STR00060##
Under a nitrogen atmosphere, zinc dust (6.91 g, 105 mmol) was
suspended in N,N-dimethylacetamide (10 mL) and 1,2-dibromoethane
(1.08 mL, 12.4 mmol) was added, followed by careful addition of
trimethylsilylchloride (1.61 mL, 12.4 mmol) and was added
cautiously over 5 min while the flask sat on a bed of ice. The bath
was removed, and after stirring for a further 15 min, a solution of
N-(tert-butoxycarbonyl)-3-iodoazetidine (25.1 g, 86.9 mmol) in
N,N-dimethylacetamide (30 mL) was added over 30 min and stirring
was continued for an additional 30 min. In the open atmosphere,
this mixture was filtered through Celite as quickly as possible,
rinsing with N,N-dimethylacetamide (100 mL). The resulting yellow
solution was injected into a separately prepared, nitrogen flushed
vessel containing
[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.56 g,
3.10 mmol), copper(I) iodide (1.18 g, 6.21 mmol) and
2,6-dichloro-4-iodopyridine (17.0 g, 62.1 mmol) and this mixture
was stirred at 80.degree. C. for 19.5 h. After cooling to rt, the
mixture was diluted with EtOAc and washed with water (3.times.). On
the third time, filtration through Celite was necessary to break
the emulsion, following which, the organics were washed with brine
and then dried over MgSO.sub.4. After being freed of volatiles, the
resultant residue was purified by flash column chromatography
(100:0-70:30 heptanes/EtOAc) to afford tert-butyl
3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate as a white
solid (10.98 g, 58%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.22 (s, 2H), 4.35 (dd, J=8.7, 5.6 Hz, 2H), 3.92 (dd, J=8.7, 5.6
Hz, 2H), 3.73-3.61 (m, 1H), 1.47 (s, 9H).
Step 2: 2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine
##STR00061##
A solution of tert-butyl
3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate (0.940 g, 3.10
mmol) in trifluoroacetic acid (3.1 mL) was stirred for 1 h, and
then concentrated to dryness to afford the TFA salt as a white
solid. The solid was re-suspended in anhydrous THF (12.4 mL) and
submitted to the action of triethylamine (2.62 mL, 18.6 mmol) and
3-oxetanone (0.60 mL, 9.3 mmol). After stirring for 10 min, sodium
triacetoxyborohydride (2.07 g, 9.30 mmol) was added and stirring
continued for 18.5 h at 35.degree. C. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 and washed with sat. aq. NaHCO.sub.3
and organics dried over MgSO.sub.4. Concentration gave sufficiently
pure 2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine as a
yellow liquid (640 mg, 80% over 2 steps); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.27 (s, 2H), 4.72 (dd, J=6.5, 5.3 Hz, 2H),
4.54 (dd, J=6.5, 5.3 Hz, 2H), 3.82-3.77 (m, 1H), 3.77-3.71 (m, 2H),
3.67-3.58 (m, 1H), 3.32-3.27 (m, 2H).
Step 3:
6-cyclopropyl-5'-(difluoromethoxy)-4-(1-(oxetan-3-yl)azetidin-3-yl-
)-[2,3'-bipyridin]-6'-amine
##STR00062##
A vial was charged with
2,6-dichloro-4-(1-(oxetan-3-yl)azetidin-3-yl)pyridine (133 mg,
0.513 mmol), palladium(II) acetate (5.8 mg, 5 mol %),
butyldi-1-adamantylphosphine (14.5 mg, 7.5 mol %), potassium
cyclopropyltrifluoroborate (79.9 mg, 0.523 mmol), and cesium
carbonate (502 mg, 1.54 mmol) and purged under nitrogen before the
addition of degassed toluene (2.6 mL) and deionized water (0.25
mL). The mixture was stirred at 110.degree. C. overnight and then
cooled to rt. To the mixture was added
3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine (220 mg, 0.770 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2--
aminoethyl)phenyl)]palladium(II) (38.7 mg, 0.0513 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (50.0 mg,
0.103 mmol), and potassium phosphate tribasic monohydrate (366 mg,
1.54 mmol). The vial was purged with nitrogen gas, sealed, and
stirred at 110.degree. C. for 2 h. After cooling to rt, the mixture
was concentrated to dryness. The reaction residue thus obtained was
purified by flash column chromatography (100:0-80:20
CH.sub.2Cl.sub.2/MeOH) and by RPLC to afford the title compound as
a white solid (22.9 mg, 12% over 2 steps); .sup.1H NMR (400 MHz,
DMSO) .delta. 8.53 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.50 (d, J=1.9
Hz, 1H), 7.17 (t, J=74.0 Hz, 1H), 7.16 (s, 1H), 6.35 (br s, 2H),
4.62-4.50 (m, 2H), 4.45-4.32 (m, 2H), 3.82-3.70 (m, 1H), 3.70-3.60
(m, 3H), 3.28-3.23 (m, 2H), 2.17-2.03 (m, 1H), 1.05-0.85 (m,
4H).
Example 2
The compounds disclosed in Table 1 were prepared following the
synthetic steps described in general Methods A-J as described above
in Example 1 with modifying the starting reactants and/or
intermediates and in those methods as would be known to one skilled
in the art in view of the final compound structures to arrive at
the compounds in Table 1. The compounds disclosed in Table 1 were
tested for DLK inhibitory activity as described in Example 3.
TABLE-US-00001 TABLE 1 DLK Ki MS No (.mu.M) Structure .sup.1H NMR
[MS].sup.+ Method 1 6.43 ##STR00063## 1H NMR (400 MHz, DMSO-d6)
.delta. 8.63 (d, J = 21.2 Hz, 1H), 7.66 (s, 2H), 7.58-7.40 (m, 6H),
4.12-3.89 (m, 1H), 3.80-3.52 (m, 4H), 3.17 (d, J = 4.7 Hz, 1H),
2.66-2.56 (m, 3H), 2.41-2.04 (m, 2H). 429 H
[3-[6-[2-amino-4-(trifluoromethyl)
pyrimidin-5-yl]-2-methyl-pyrimidin-
4-yl]pyrrolidin-1-yl]-phenyl-methanone 2 1.7 ##STR00064## 1H NMR
(400 MHz, DMSO-d6) .delta. 9.02 (s, 2H), 7.79-7.59 (m, 1H),
7.50-7.41 (m, 3H), 7.41-7.36 (m, 2H), 7.24 (s, 2H), 7.12- 6.91 (m,
1H), 4.62- 4.44 (m, 1H), 3.76- 3.53 (m, 1H), 3.19- 2.80 (m, 3H),
2.64- 2.59 (m, 2H), 2.10- 2.02 (m, 1H), 1.89- 1.47 (m, 3H). 375 H
[3-[6-(2-aminopyrimidin-5-yl)-2-
methyl-pyrimidin-4-yl]-1-piperidyl]- phenyl-methanone 3 6.43
##STR00065## 1H NMR (400 MHz, DMSO-d6) .delta. 8.63 (s, 1H), 7.66
(s, 2H), 7.46- 7.42 (m, 3H), 7.42- 7.36 (m, 2H), 7.01 (s, 1H),
4.65-4.37 (m, 1H), 4.08 (q, J = 5.3 Hz, 1H), 3.77-3.51 (m, 1H),
3.17 (d, J = 5.3 Hz, 2H), 3.14-2.89 (m, 3H), 2.10-2.02 (m, 1H),
1.91-1.50 (m, 3H). 443 H [3-[6-[2-amino-4-(trifluoromethyl)
pyrimidin-5-yl]-2-methyl-pyrimidin-
4-yl]-1-piperidyl]-phenyl-methanone 4 1.73 ##STR00066## 1H NMR (400
MHz, DMSO-d6) .delta. 9.05 (s, 1H), 9.00 (s, 1H), 7.83- 7.68 (m,
1H), 7.58- 7.50 (m, 2H), 7.51- 7.39 (m, 3H), 7.28- 7.22 (m, 2H),
4.00- 3.43 (m, 4H), 2.65- 2.55 (m, 3H), 2.42- 2.06 (m, 2H). 361 H
[3-[6-(2-aminopyrimidin-5-yl)-2-
methyl-pyrimidin-4-yl]pyrrolidin-1-yl]- phenyl-methanone 5 0.83
##STR00067## 390 I .Iadd.6((1R,3R,5R,7R)-2-azaadamantan-.Iaddend.
.Iadd.2-yl)-2-(2-azabicyclo[2.1.1]hexan-.Iaddend.
.Iadd.2-yl)-[4,5'-bipyrimidin]-2'amine.Iaddend. 6 0.001
##STR00068## 1H NMR (400 MHz, DMSO-d6) .delta. 8.61 (s, 1H), 7.98
(s, 1H), 7.17 (t, J = 73.9 Hz, 1H), 6.45 (s, 2H), 5.01 (s, 1H),
4.68 (s, 1H), 3.91 (t, 2H), 3.81-3.69 (m, 3H), 3.66 (d, J = 7.4 Hz,
1H), 3.47 (d, J = 10.6, 1.5 Hz, 1H), 3.40-3.23 (m, 1H), 2.46 (q, J
= 7.4, 6.9 Hz, 1H), 1.87 (s, 2H). 441 E
3-(difluoromethoxy)-5-[2-(3,3-di-
fluoropyrrolidin-1-yl)-6-[(1S,4S)-2-
oxa-5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine
7 0.10 ##STR00069## 1H NMR (400 MHz, DMSO-d6) .delta. 8.91 (s, 2H),
7.00 (s, 2H), 4.98 (s, 1H), 4.67 (s, 1H), 4.08 (t, J = 12.1 Hz,
2H), 3.88-3.71 (m, 3H), 3.65 (d, J = 7.4 Hz, 1H), 3.47 (d, J = 10.3
Hz, 1H), 3.37 (s, 1H), 2.17-1.95 (m, 2H), 1.88 (s, 2H), 1.78-1.58
(m, 2H). 390 E 5-[2-(3,3-difluoro-1-piperidyl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 8 0.22 ##STR00070## 1H
NMR (400 MHz, DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 5.11-
4.74 (m, 2H), 4.67 (s, 1H), 3.98 (s, 2H), 3.78 (d, J = 7.0 Hz, 1H),
3.73- 3.55 (m, 3H), 3.45 (d, 1H), 2.00-1.76 (m, 4H), 1.76-1.58 (m,
2H). 372 E 5-[2-(4-fluoro-1-piperidyl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 9 0.11 ##STR00071##
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.94 (s, 2H), 6.68 (s,
1H), 5.34 (s, 2H), 4.97-4.95 (m, 1H), 4.69-4.62 (m, 4H), 3.83-3.78
(m, 1H), 3.55 (s, 2H), 3.14 (d, J = 8.8 Hz, 2H), 2.94- 2.93 (m,
1H), 2.50 (d, J = 8.4 Hz, 2H), 2.35- 2.33 (m, 1H), 2.13 (s, 2H),
1.99 (s, 2H), 1.46- 1.44 (m, 2H). 392.2 C
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(oxetan-3-yl)-3-
azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]pyrimidin-2-amine 10
0.01 ##STR00072## .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.65 (s,
1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.21 (t, J = 73.6 Hz, 1H), 6.72
(s, 2H), 3.78-3.73 (m, 2H), 3.65-3.60 (m, 1H), 3.40-3.35 (m, 1H),
2.27-2.16 (m, 5H), 1.85 (t, J = 3.2 Hz, 1H), 1.00-0.93 (m, 7H).
416.1 C 1-[(1R,5S)-6-[6-[6-amino-5- (difluoromethoxy)-3-pyridyl]-2-
cyclopropyl-pyrimidin-4-yl]-
3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one 11 0.01 ##STR00073##
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.65 (s, 1H), 8.01 (s, 1H),
7.64 (s, 1H), 7.21 (t, J = 73.6 Hz, 1H), 6.72 (s, 2H), 3.76-3.73
(m, 2H), 3.69-3.68 (m, 1H), 3.39-3.36 (m, 1H), 2.26-2.24 (m, 1H),
2.18-2.17 (m, 1H), 2.11-2.10 (m, 1H), 1.94 (s, 3H), 1.86 (t, J =
3.2 Hz, 1H), 1.00-0.97 (m, 4H). 402.1 C 1-[(1R,5S)-6-[6-[6-amino-5-
(difluoromethoxy)-3-pyridyl]- 2-cyclopropyl-pyrimidin-4-
yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone 12 0.01 ##STR00074##
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.91 (s, 1H), 8.36 (s, 1H),
6.79 (s, 2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m,
1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H),
3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H),
1.83-1.81 (m, 2H), 1.29 (d, J = 2.0 Hz, 2H). 459.9 B
1-[(1S,4S)-5-[6-[6-amino-5- (trifluoromethyl)-3-pyridyl]-2-(3-
azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-
2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone 13 0.20 ##STR00075##
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.59 (s, 1H), 8.02 (s,
1H), 6.72 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 4.97- 4.94 (m, 3H),
3.56 (s, 2H), 3.28 (d, J = 8.4 Hz, 2H), 3.15-3.08 (m, 2H),
2.95-2.93 (m, 1H), 2.78 (d, J = 8.4 Hz, 2H), 2.25 (d, J = 2.8 Hz,
1H), 2.12 (s, 2H), 1.99 (s, 2H), 1.49-1.43 (m, 2H). 483.14 C
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2,2,2-trifluoroethyl)- 3-azabicyclo[3.1.0]hexan-6-yl]
pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine 14 0.43
##STR00076## .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.92 (s, 2H),
7.09 (s, 2H), 7.03 (s, 1H), 4.83 (br.s, 1H), 3.43 (s, 2H),
3.26-3.24 (m, 2H), 3.13 (d, J = 8.8 Hz, 2H), 2.89-2.87 (m, 1H),
2.74-2.72 (m, 2H), 2.12-2.11 (m, 1H), 2.03 (s, 2H), 1.93 (s, 2H),
1.30-1.29 (m, 2H). 418.1 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2,2,2-trifluoroethyl)- 3-azabicyclo[3.1.0]hexan-6-yl]
pyrimidin-4-yl]pyrimidin-2-amine 15 0.001 ##STR00077## .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.74 (s, 1H), 8.16 (s, 1H), 7.04 (s,
1H), 6.91 (s, 2H), 4.84-4.82 (m, 1H), 4.05 (s, 1H), 3.45 (s, 3H),
3.19 (d, J = 8.8 Hz, 2H), 2.91-2.89 (m, 1H), 2.35 (s, 2H), 2.26 (s,
1H), 1.98-1.95 (m, 4H), 1.33-1.32 (m, 2H), 1.08 (s, 6H). 491.2 C
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-
3-pyridyl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]-3-
azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol 16 0.001
##STR00078## .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.94 (s, 1H),
8.39 (s, 1H), 7.06 (s, 1H), 6.91 (s, 2H), 4.83-4.81 (m, 1H), 4.02
(s, 1H), 3.42 (s, 2H), 3.16-3.14 (m, 2H), 2.87-2.85 (m, 1H), 2.48
(s, 2H), 2.31 (s, 2H), 2.23 (s, 1H), 1.95-1.92 (m, 4H), 1.29 (d, J
= 2.8 Hz, 2H), 1.05 (s, 6H). 475.0 C
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-
2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-
yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol 17 0.001
##STR00079## .sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.59 (s,
1H), 8.02 (s, 1H), 6.68 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 4.98
(s, 3H), 3.56 (s, 2H), 3.31- 3.28 (m, 2H), 3.01- 2.94 (m, 2H), 2.75
(d, J = 8.4 Hz, 2H), 2.50 (s, 2H), 2.26 (s, 1H), 2.10 (s, 2H), 1.99
(s, 2H), 1.80-1.70 (m, 2H), 1.19 (s, 6H). 473.17 C
.[.[6-amino-5-(difluoromethoxy)-3-pyridyl]-.].
.[.2-(3-azabicyclo[2.1.1]hexan-.].
.[.3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0].].
.[.hexan-3-yl]-2-methyl-propan-2-ol.].
.Iadd.1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-.Iaddend.
.Iadd.3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl).Iaddend..Iadd.-.Iadde-
nd.
.Iadd.pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexane-3-yl]-2-.Iaddend.
.Iadd.methyl-propan-2-ol.Iaddend. 18 0.05 ##STR00080## .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.72 (s, 1H), 8.13 (s, 1H), 7.07 (s,
1H), 6.94 (s, 2H), 4.85-4.83 (m, 1H), 3.74-3.65 (m, 3H), 3.45-3.40
(m, 3H), 2.95-2.91 (m, 1H), 2.23-2.17 (m, 2H), 1.96-1.93 (m, 4H),
1.74 (s, 1H), 1.33 (s, 2H), 1.30-1.22 (m, 1H). 460.9 C
1-[(1R,5S)-6-[6-[6-amino-5- (trifluoromethoxy)-3-pyridyl]-2-(3-
azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-
3-azabicyclo[3.1.0]hexan-3-yl]ethanone 19 0.03 ##STR00081## .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.92 (s, 1H), 8.37 (s, 1H), 7.09 (s,
1H), 6.94 (s, 2H), 4.84-4.82 (m, 1H), 3.71-3.64 (m, 3H), 3.43-3.35
(m, 2H), 3.34-3.31 (m, 1H), 3.26-3.21 (m, 1H), 2.89-2.87 (m, 1H),
2.21-2.14 (m, 2H), 1.94-1.90 (m, 4H), 1 73-1.71 (m, 1H), 1.31 (d, J
= 4.0 Hz, 2H). 445.0 C 1-[(1R,5S)-6-[6-[6-amino-5-
(trifluoromethyl)-3-pyridyl]-2-(3-
azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-
3-azabicyclo[3.1.0]hexan-3-yl]ethanone 20 0.01 ##STR00082## .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 8.62 (s, 1H), 8.17 (s, 1H), 6.85
(s, 1H), 3.80-3.70 (m, 1H), 3.54-3.50 (m, 3H), 3.38 (s, 3H), 3.20
(d, J = 9.6 Hz, 2H), 2.95- 2.90 (m, 1H), 2.71- 2.69 (m, 2H), 2.58-
2.55 (m, 2H), 2.29 (s, 1H), 2.09-2.04 (m, 3H), 1.42-1.41 (m, 1H),
1.29 (s, 3H). 477.14 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2-methoxyethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-
4-yl]-3-(trifluoromethoxy)pyridin-2-amine 21 0.007 ##STR00083##
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.92 (s, 1H), 8.38 (s, 1H),
7.09 (s, 1H), 6.91 (s, 2H), 4.82-4.81 (m, 1H), 3.42-3.37 (m, 8H),
3.36-3.34 (m, 2H), 3.21 (s, 2H), 3.06 (d, J = 9.2 Hz, 1H),
2.87-2.84 (m, 1H), 2.58-2.57 (m, 1H), 2.39 (d, J = 8.8 Hz, 1H),
2.20 (s, 1H), 1.97- 1.93 (m, 3H), 1.29 (d, J = 2.4 Hz, 1H). 461.0 C
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2-methoxyethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-
4-yl]-3-(trifluoromethyl)pyridin-2-amine 22 0.03 ##STR00084##
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.94 (s, 2H), 6.66 (s,
1H), 5.21 (s, 2H), 4.96 (d, J = 6.8 Hz, 1H), 3.54 (s, 2H),
3.50-3.47 (m, 2H), 3.38 (s, 3H), 3.22 (d, J = 8.8 Hz, 2H), 2.96-
2.94 (m, 1H), 2.72- 2.69 (m, 2H), 2.51 (d, J = 8.4 Hz, 2H), 2.35-
2.32 (m, 1H), 2.09 (s, 2H), 1.99 (s, 2H), 1.46- 1.44 (m, 2H). 393.9
C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2-methoxyethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4- yl]pyrimidin-2-amine 23
0.02 ##STR00085## .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.57
(s, 1H), 8.10 (s, 1H), 6.52 (br.s, 1H), 5.08 (br.s, 1H), 4.71 (s,
1H), 3.86 (d, J = 6.8 Hz, 1H), 3.78 (d, J = 7.2 Hz, 1H), 3.52 (d, J
= 10.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.06-2.02 (m, 1H), 2.01-1.96 (m,
2H), 1.08-1.05 (m, 2H), 0.95-0.92 (m, 2H). 394.19 A
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl]
pyrimidin-4-yl]-3-(trifluoromethoxy) pyridin-2-amine 24 1.61
##STR00086## 1H NMR (400 MHz, DMSO-d6) .delta. 8.88 (s, 2H), 6.98
(s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 4.30-4.22 (m, 1H), 4.21-4.13
(m, 2H), 3.86-3.73 (m, 3H), 3.71-3.61 (m, 2H), 3.43 (d, J = 10.4,
2.5 Hz, 1H), 3.24 (s, 3H), 1.89 (s, 2H). 355 E
5-[2-(3-methoxyazetidin-1-yl)-6-[(1S,4S)-
2-oxa-5-azabicyclo[2.2.1]heptan-5-
yl]pyrimidin-4-yl]pyrimidin-2-amine 25 1.09 ##STR00087## 1H NMR
(400 MHz, DMSO-d6) .delta. 8.87 (s, 2H), 6.98 (s, 2H), 4.95 (s,
1H), 4.66 (s, 1H), 3.76 (d, J = 7.2, 1.5 Hz, 1H), 3.68 (s, 3H),
3.64 (d, J = 7.2 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 1.85 (s,
2H), 1.26 (s, 5H). 353 E 5-[2-(3,3-dimethylazetidin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 26 0.01 ##STR00088##
.sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.36 (s, 1H), 7.86 (s,
1H), 6.92 (t, J = 72.0 Hz, 1H), 6.24 (br.s, 1H), 4.96- 4.90 (m,
3H), 4.79- 4.74 (m, 2H), 4.55 (s, 2H), 4.10 (s, 1H), 3.81 (s, 1H),
3.62 (s, 2H), 3.55-3.52 (m, 1H), 3.04-2.97 (m, 3H), 2.11-2.06 (m,
3H), 1.96-1.94 (m, 1H), 1.51-1.44 (m, 2H). 472.0 B
.[.5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0].].
.[.hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-.].
.[.3-fluoro-1H-pyrrolo[2,3-b]pyridine.].
.Iadd.5-[2-(2-azabicyclo[2.1.1]hexan-2-yl)-.Iaddend.
.Iadd.6-[(1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-.Iaddend.-
.Iadd.2-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine.Iaddend.
- 27 0.001 ##STR00089## .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.58
(s, 1H), 7.97 (s, 1H), 7.12 (t, J = 74.0 Hz, 1H), 6.27 (s, 1H),
6.10 (s, 2H), 5.30 (br.s, 1H), 4.97 (s, 1H), 4.86 (d, J = 7.2 Hz,
1H), 3.65-3.57 (m, 2H), 3.48 (s, 3H), 3.44-3.42 (m, 1H), 3.16-3.11
(m, 3H), 2.91-2.89 (m, 1H), 1.95-1.88 (m, 4H), 1.34-1.20 (m, 8H).
516.0 B 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-
3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-
4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-
2-methoxy-2-methyl-propan-1-one 28 0.001 ##STR00090## .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t, J =
73.6 Hz, 1H), 6.47 (s, 2H), 6.16 (br.s, 1H), 4.99 (br.s, 1H),
4.84-4.70 (m, 2H), 4.13-4.09 (m, 1H), 3.92-3.91 (m, 1H), 3.56-3.50
(m, 5H), 3.30-3.24 (m, 5H), 2.90-2.88 (m, 1H), 1.94-1.85 (m, 3H),
1.31-1.20 (m 2H). 488.0 B .[.[6-amino-5-(difluoromethoxy)-3-.].
.[.pyridyl]-2-(3-azabicyclo[2.1.1]hexan-.].
.[.3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1].].
.[.heptan-2-yl]-2-methoxy-ethanone.].
.Iadd.1-.Iaddend..Iadd.[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-.Iad-
dend. .Iadd.pyridyl]-2-(3-azabicycko[2.1.1]hexan-3-yl).Iaddend.
.Iadd.pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-.Iaddend.
- .Iadd.methoxy-ethanone.Iaddend. 29 0.005 ##STR00091## 1H NMR (400
MHz, DMSO-d6) .delta. 8.61 (s, 1H), 7.99 (s, 1H), 7.39- 6.96 (m,
1H), 6.66- 6.12 (m, 3H), 5.51- 5.39 (m, 1H), 5.38- 5.26 (m, 1H),
5.01 (s, 1H), 4.68 (s, 1H), 4.02- 3.84 (m, 2H), 3.79 (d, J = 7.2,
1.6 Hz, 1H), 3.75- 3.56 (m, 3H), 3.47 (d, J = 10.4, 1.4 Hz, 1H),
3.37 (s, 1H), 1.87 (s, 2H). 441 E
3-(difluoromethoxy)-5-[2-[(3R,4S)- 3,4-difluoropyrrolidin-1-yl]-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-
5-yl]pyrimidin-4-yl]pyridin-2-amine 30 0.81 ##STR00092## .sup.1H
NMR (400 MHz, DMSO) .delta. 8.95 (s, 2H), 7.13 (s, 2H), 7.11 (s,
1H), 4.93 (d, J = 7.0 Hz, 1H), 3.51 (s, 2H), 2.98- 2.91 (m, 3H),
2.76 (t, J = 2.8 Hz, 1H), 2.01 (d, J = 16.4 Hz, 4H), 1.47 (dd, J =
3.9, 1.7 Hz, 2H), 1.36 (dd, J = 4.3, 1.7 Hz, 2H), 1.24 (s, 1H). 336
C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(3-azabicyclo[2.1.1]hexan-4-yl) pyrimidin-4-yl]pyrimidin-2-amine
31 0.03 ##STR00093## 1H NMR (400 MHz, DMSO-d6) .delta. 8.57 (s,
1H), 7.94 (s, 1H), 7.35- 6.93 (m, 1H), 6.43 (s, 2H), 4.96 (s, 1H),
4.66 (s, 1H), 3.99 (t, J = 7.4 Hz, 4H), 3.77 (d, J = 7.5, 1.5 Hz,
1H), 3.64 (d, J = 7.4 Hz, 1H), 3.44 (d, J = 10.0 Hz, 1H), 2.31-2.18
(m, 2H), 1.85 (s, 2H). 391 E 5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-
oxa-5-azabicyclo[2.2.1]heptan-5-yl]
pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 32 0.02
##STR00094## 1H NMR (400 MHz, DMSO-d6) .delta. 8.59 (s, 1H), 7.95
(s, 1H), 7.36- 6.95 (m, 1H), 6.46 (s, 2H), 5.58-5.33 (m, 1H), 4.98
(s, 1H), 4.67 (s, 1H), 4.40-4.26 (m, 2H), 4.06 (d, 1H), 4.00 (d, J
= 11.1, 3.2 Hz, 1H), 3.78 (d, J = 7.2, 1.5 Hz, 1H), 3.65 (d, J =
7.4 Hz, 1H), 3.45 (d, J = 10.4 Hz, 1H), 1.86 (s, 2H). 409 E
3-(difluoromethoxy)-5-[2-(3-
fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine 33
1.07 ##STR00095## 1H NMR (400 MHz, DMSO-d6) .delta. 8.90 (s, 2H),
6.97 (s, 2H), 6.32 (s, 1H), 4.97 (s, 2H), 4.69-4.59 (m, 2H),
3.82-3.74 (m, 2H), 3.67 (dd, J = 7.3, 5.9 Hz, 2H), 3.45 (td, J =
8.6, 7.4, 4.3 Hz, 3H), 3.33 (d, J = 8.9 Hz, 2H), 1.89-1.77 (m, 4H).
368 E 5-[2,6-bis[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4- yl]pyrimidin-2-amine 34
0.024 ##STR00096## 427 E 5-[2-(3,3-difluoroazetidin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine 35 0.17 ##STR00097## 1H NMR (400
MHz, DMSO) .delta. 8.95 (s, 2H), 7.10 (s, 2H), 6.99 (s, 1H), 4.91
(d, J = 7.0 Hz, 1H), 3.50 (s, 2H), 3.15 (q, J = 10.2 Hz, 3H),
2.96-2.90 (m, 1H), 2.88-2.80 (m, 1H), 2.01-1.88 (m, 6H), 1.72-1.65
(m, 2H), 1.65-1.56 (m, 2H), 1.35 (dd, J = 4.3, 1.7 Hz, 2H). 446 C
5-[2-(3-azabicyclo[2.1.1]hexan-3-
yl)-6-[8-(2,2,2-trifluoroethyl)-8-
azabicyclo[3.2.1]octan-3-yl]pyrimidin-4- yl]pyrimidin-2-amine 36
0.22 ##STR00098## .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.85
(s, 2H), 6.07 (br.s, 1H), 4.87 (d, J = 6.8 Hz, 1H), 4.54 (br.s,
1H), 3.83 (s, 1H), 3.51 (s, 3H), 3.34- 3.30 (m, 1H), 3.11- 3.08 (m,
1H), 2.89- 2.88 (m, 1H), 2.61- 2.50 (m, 2H), 1.98- 1.92 (m, 4H),
1.38 (d, J = 4.0 Hz, 2H), 1.06 (dd, J = 6.0, 15.2 Hz, 6H). 393.22 B
5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[(1S,4S)-2-isopropyl-2,5-
diazabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 37
0.22 ##STR00099## .sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.86
(s, 2H), 6.11 (br.s, 1H), 4.88 (d, J = 6.8 Hz, 1H), 4.60 (br.s,
1H), 3.70 (s, 4H), 3.40-3.31 (m, 1H), 2.95-2.91 (m, 2H), 2.66-2.56
(m, 3H), 2.00-1.86 (m, 4H), 1.41-1.40 (m, 2H), 1.10 (t, J = 3.2 Hz,
3H). 379.23 B 5-[2-(3-azabicyclo[2.1.1]hexan-3-
yl)-6-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]
heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine 38 0.29 ##STR00100##
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.90 (s, 2H), 6.95 (d, J =
6.4 Hz, 2H), 6.25 (br.s, 1H), 4.83 (d, J = 7.6 Hz, 2H), 4.56 (t, J
= 6.8 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.28 (t, J = 6.4 Hz, 1H),
3.90-3.88 (m, 1H), 3.60-3.50 (m, 1H), 3.45 (s, 2H), 3.20-3.15 (m,
2H), 2.89-2.87 (m, 1H), 2.85-2.81 (m, 1H), 2.68-2.66 (m, 1H), 1.93
(s, 2H), 1.84- 1.82 (m, 1H), 1.80- 1.75 (m, 1H), 1.32- 1.15 (m,
2H). 407.2 B 5-[2-(3-azabicyclo[2.1.1]hexan-3-
yl)-6-[(1S,4S)-2-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-5-yl]
pyrimidin-4-yl]pyrimidin-2-amine 39 0.07 ##STR00101## .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.93 (s, 2H), 7.04 (s, 2H), 6.31 (s,
1H), 5.49-5.34 (m, 2H), 4.85 (d, J = 6.4 Hz, 1H), 3.91-3.84 (m,
2H), 3.69-3.61 (m, 2H), 3.47 (s, 2H), 2.90- 2.88 (m, 1H), 1.94 (s,
2H), 1.32-1.23 (m, 2H). 359.8 B 5-[2-(3-azabicyclo[2.1.1]hexan-3-
yl)-6-[(3S,4R)-3,4-difluoropyrrolidin-
1-yl]pyrimidin-4-yl]pyrimidin-2-amine 40 0.004 ##STR00102## .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t,
J = 74.0 Hz, 1H), 6.47 (s, 2H), 6.17 (br.s, 1H), 4.98 (br.s, 1H),
4.84-4.67 (m, 2H), 3.56-3.54 (m, 1H), 3.50-3.38 (m, 4H), 3.33-3.26
(m, 2H), 2.88 (d, J = 3.2 Hz, 1H), 2.03 (s, 1H), 1.94 (s, 3H),
1.87-1.84 (m, 2H), 1.32-1.31 (m, 2H). 457.9 B
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-
3-pyridyl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]-
2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone 41 0.28 ##STR00103## 1H
NMR (400 MHz, DMSO) .delta. 8.95 (s, 2H), 7.11 (s, 2H), 7.02 (s,
1H), 4.89 (d, J = 7.0 Hz, 1H), 4.57-4.50 (m, 1H), 4.31-4.21 (m,
1H), 3.48 (s, 2H), 3.18- 3.09 (m, 1H), 2.95- 2.90 (m, 1H), 2.00 (s,
3H), 2.00-1.94 (m, 3H), 1.91-1.70 (m, 7H), 1.34 (dd, J = 4.4, 1.8
Hz, 2H). 406 C 1-[3-[6-(2-aminopyrimidin-5-yl)-2-
(3-azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-8-azabicyclo[3.2.1]
octan-8-yl]ethanone 42 0.17 ##STR00104##
5-[2-(2-fluoro-7-azaspiro[3.5]
nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 5.91- 5.77 (m, 1H),
5.18- 5.08 (m, 2H), 4.96 (s, 1H), 4.67 (s, 1H), 4.53- 4.44 (m, 2H),
3.77 (d, J = 7.2, 1.5 Hz, 1H), 3.41- 3.32 (m, 1H), 3.65 (d, J = 7.3
Hz, 1H), 3.45 (dd, J = 10.6, 1.5 Hz, 1H), 3.18 (t, J = 12.1 Hz,
2H), 2.43 (d, J = 7.2 Hz, 1H), 2.37 (d, J = 7.4 Hz, 1H), 1.86 (s,
2H), 1.83-1.72 (m, 2H), 1.72-1.51 (m, 2H). 412 E 43 1.61
##STR00105## 5-[2-[(1R,5S)-3-methyl-3,6-diazabicyclo[3.2.1]
octan-6-yl]-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl]
pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) .delta.
3.14- 2.98 (m, 1H), 2.82- 2.72 (m, 1H), 2.41 (s, 1H), 2.13 (d, J =
3.4 Hz, 3H), 1.96 (d, J = 10.5 Hz, 1H), 1.86 (s, 3H), 1.53 (d, J =
10.6 Hz, 1H), 3.38-3.31 (m, 1H), 8.89 (d, J = 10.6 Hz, 2H), 6.94
(s, 2H), 5.02-4.88 (m, 1H), 4.66 (s, 1H), 4.47-4.27 (m, 1H), 3.77
(d, J = 7.2 Hz, 1H), 3.66 (s, 1H), 3.55-3.39 (m, 3H). 395 E 44 0.07
##STR00106## 5-[2-(4,4-difluoroazepan-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H), 4.67 (s,
1H), 3.87-3.72 (m, 5H), 3.41-3.32 (m, 1H), 3.66 (d, J = 7.2 Hz,
1H), 3.46 (d, J = 10.5, 1.4 Hz, 1H), 2.31-2.17 (m, 2H), 2.10-1.96
(m, 2H), 1.92-1.78 (m, 4H). 404 E 45 1.75 ##STR00107##
5-[2-(4-cyclobutylpiperazin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.89 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H), 4.66 (s,
1H), 3.77 (d, J = 7.5, 1.4 Hz, 1H), 3.71 (t, J = 4.9 Hz, 4H), 3.65
(d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.4 Hz, 1H), 3.33 (s, 1H),
2.74-2.64 (m, 1H), 2.27 (t, J = 5.0 Hz, 4H), 1.97 (qd, J = 7.2 3.1
Hz, 2H), 1.92-1.72 (m, 4H), 1.72-1.54 (m, 2H). 409 E 46 1.61
##STR00108## 5-[2-(2-methyl-2,7-diazaspiro[3.5]
nonan-7-yl)-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]pyrimidin- 4-yl]pyrimidin-2-amine 1H
NMR (400 MHz, DMSO-d6) .delta. 8.88 (s, 2H), 6.97 (s, 2H), 4.95 (s,
1H), 4.66 (s, 1H), 3.76 (d, J = 7.2, 1.5 Hz, 1H), 3.68 (s, 4H),
3.64 (d, J = 7.3 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 2.24 (s,
4H), 2.13 (s, 3H), 1.85 (s, 2H), 1.71 (t, J = 5.3 Hz, 4H). 409 E 47
0.07 ##STR00109## 4-(2-aminopyrimidin-5-yl)-N,N-
diethyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) .delta.
8.88 (s, 2H), 6.94 (s, 2H), 4.93 (s, 1H), 4.66 (s, 1H), 3.77 (d, J
= 7.2, 1.6 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.63-3.51 (m, 4H),
3.45 (d, J = 10.5, 1.4 Hz, 1H), 1.87 (t, 2H), 1.14 (t, 6H). 342 E
48 1.61 ##STR00110## 5-[2-(4-methylpiperazin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.66 (s,
1H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.75-3.68 (m, 4H), 3.41-3.32
(m, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.45 (d, J = 10.5, 1.4 Hz, 1H),
3.17 (s, 1H), 2.34 (t, J = 5.0 Hz, 4H), 2.20 (s, 3H), 1.86 (s, 2H).
369 E 49 0.54 ##STR00111## 5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]-2-(1-piperidyl) pyrimidin-4-yl]pyrimidin-2-amine 1H
NMR (400 MHz, DMSO-d6) .delta. 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s,
1H), 4.66 (s, 1H), 3.82-3.69 (m, 5H), 3.65 (d, J = 7.3 Hz, 1H),
3.49-3.41 (m, 1H), 3.40-3.32 (m, 1H), 1.92-1.80 (m, 2H), 1.67-1.56
(m, 2H), 1.56-1.45 (m, 4H). 354 E 50 0.41 ##STR00112##
5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa-
5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H
NMR (400 MHz, DMSO-d6) .delta. 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s,
1H), 4.66 (s, 1H), 3.99 (t, J = 7.5 Hz, 4H), 3.77 (dd, J = 7.3, 1.5
Hz, 1H), 3.64 (d, J = 7.3 Hz, 1H), 3.43 (dd, J = 10.5, 1.5 Hz, 1H),
3.40- 3.32 (m, 1H), 3.17 (s, 1H), 2.24 (p, J = 7.5 Hz, 2H), 1.85
(s, 2H). 326 E 51 0.20 ##STR00113##
5-[2-[(3aS,6aR)-5,5-difluoro-1,3,3a,4,6,6a-
hexahydrocyclopenta[c]pyrrol-2-
yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.91 (s, 2H), 6.97 (s, 2H), 6.31 (s, 1H), 4.97 (s,
1H), 4.66 (s, 1H), 3.84-3.69 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H),
3.51-3.41 (m, 3H), 2.89 (q, J = 9.3, 8.1 Hz, 2H), 2.48-2.31 (m,
2H), 2.16-1.98 (m, 2H), 1.86 (s, 2H). 416 E 52 0.086 ##STR00114##
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]-2-pyrrolidin-1-yl-pyrimidin-4- yl]pyrimidin-2-amine 1H
NMR (400 MHz, DMSO-d6) .delta. 8.90 (s, 2H), 6.95 (s, 2H), 6.27 (s,
1H), 4.96 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H),
3.65 (d, J = 7.3 Hz, 1H), 3.58- 3.41 (m, 5H), 1.96- 1.79 (m, 6H).
340 E 53 0.27 ##STR00115## 5-[2-(3,3-difluoroazetidin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.91 (s, 2H), 7.03 (s, 2H), 6.35 (s, 1H), 4.99 (s,
1H), 4.68 (s, 1H), 4.41 (t, J = 12.6 Hz, 4H), 3.78 (dd, J = 7.5,
1.5 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.50-3.42 (m, 1H), 3.40-3.31
(m, 1H), 1.87 (s, 2H). 362 E 54 0.16 ##STR00116##
5-[2-(7,7-difluoro-2-azaspiro[3.3]
heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.89 (s, 2H), 7.00 (s, 2H), 4.97 (s, 1H), 4.67 (s,
1H), 4.19 (d, J = 9.3, 3.2 Hz, 2H), 3.94 (d, J = 9.2, 2.8 Hz, 2H),
3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.44 (d, J
= 10.5, 1.5 Hz, 1H),
2.11-1.99 (m, 2H), 1.86 (s, 2H). 402 E 55 0.13 ##STR00117##
5-[2-[(3aR,6aS)-4,4-difluoro-1,3,3a,5,6,6a-
hexahydrocyclopenta[c]pyrrol-2-
yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.91 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.67 (s,
1H), 3.84-3.58 (m, 5H), 3.49-3.41 (m, 2H), 3.04-2.90 (m, 2H),
2.28-2.08 (m, 2H), 2.08-1.96 (m, 1H), 1.86 (s, 2H), 1.68-1.57 (m,
1H). 416 E 56 1.61 ##STR00118## 5-[2-(5-methyl-2,5-diazaspiro[3.4]
octan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.88 (s, 2H), 6.98 (s, 2H), 4.96 (s, 1H), 4.66 (s,
1H), 4.08 (d, J = 9.0, 3.2 Hz, 2H), 3.82-3.71 (m, 3H), 3.65 (d, J =
7.2 Hz, 1H), 3.43 (d, J = 10.6, 1.5 Hz, 1H), 3.17 (d, J = 5.0 Hz,
1H), 2.62 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.05-1.97 (m, 2H),
1.85 (s, 2H), 1.73- 1.62 (m, 2H). 395 E 57 0.12 ##STR00119##
5-[2-(6-azaspiro[2.5]octan-6-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s, 1H), 4.66 (s,
1H), 3.84-3.79 (m, 4H), 3.77 (d, J = 7.2, 1.4 Hz, 1H), 3.66 (d, J =
7.2 Hz, 1H), 3.45 (d, J = 10.5, 1.5 Hz, 1H), 1.86 (s, 2H),
1.41-1.28 (m, 4H), 0.34 (s, 4H). 380 E 58 0.21 ##STR00120##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[8-(oxetan-3-yl)-8-azabicyclo[3.2.1]
octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO)
.delta. 8.95 (s, 2H), 7.09 (s, 2H), 6.99 (s, 1H), 4.92 (d, J = 7.0
Hz, 1H), 4.58 (t, J = 6.2 Hz, 2H), 4.35 (t, J = 5.7 Hz, 2H),
3.73-3.65 (m, 1H), 3.50 (s, 2H), 3.13 (s, 2H), 2.93 (dd, J = 6.8,
3.2 Hz, 1H), 2.90- 2.79 (m, 1H), 2.02- 1.81 (m, 6H), 1.69- 1.57 (m,
4H), 1.35 (dd, J = 4.3, 1.8 Hz, 2H) 420 C 59 0.02 ##STR00121##
1-[6-[6-(2-aminopyrimidin-5-yl)-2- (3-azabicyclo[2.1.1]hexan-3-yl)
pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]ethanone 1H NMR (400
MHz, Chloroform-d) .delta. 8.94 (s, 2H), 6.65 (s, 1H), 5.49 (s,
2H), 4.95 (d, J = 6.0 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.72 (s,
2H), 3.54 (s, 3H), 2.95 (s, 1H), 2.30 (s, 2H), 2.06 (s, 3H), 2.00
(s, 2H), 1.70 (s, 1H), 1.45 (s, 2H). 377.8 C 60 0.01 ##STR00122##
1-[(1S,4S)-2-[6-(2-aminopyrimidin-
5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-
yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]
heptan-5-yl]-2-methyl-propan-2-ol .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.90 (s, 2H), 6.97 (s, 2H), 6.40- 6.14 (m, 1H), 4.83 (d, J
= 6.8 Hz, 1H), 3.99 (s, 1H), 3.68-3.60 (m, 1H), 3.45 (s, 2H), 3.28-
3.27 (m, 2H), 3.04 (d, J = 7.6 Hz, 1H), 2.89- 2.87 (m, 1H), 2.57-
2.54 (m, 1H), 2.45- 2.41 (m, 2H), 1.93- 1.91 (m, 2H), 1.82- 1.71
(m, 2H), 1.32- 1.29 (m, 2H), 1.23- 1.15 (m, 1H), 1.04 (s, 6H).
423.2 B 61 0.01 ##STR00123## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-5-(2-methoxyethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]
pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz, Methanol-d4)
.delta. 8.84 (s, 2H), 6.09 (br.s, 1H), 4.95-4.87 (m, 2H), 4.67
(br.s, 1H), 3.71 (s, 1H), 3.62-3.52 (m, 4H), 3.48-3.45 (m, 1H),
3.34-3.31 (m, 3H), 3.00-2.95 (m, 1H), 2.92-2.90 (m, 1H), 2.76-2.74
(m, 2H), 2.67-2.64 (m, 1H), 1.98-1.94 (m, 3H), 1.88-1.82 (m, 1H),
1.42-1.38 (m, 2H). 409.2 B 62 0.003 ##STR00124##
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.57 (s, 1H), 7.96 (s, 1H), 7.17 (t, J = 74.0 Hz, 1H), 6.44
(s, 2H), 6.30 (br.s, 1H), 4.96 (s, 1H), 4.66 (s, 1H), 3.86-3.76 (m,
3H), 3.64 (d, J = 7.2 Hz, 1H), 3.45-3.40 (m, 4H), 1.85 (s, 2H),
1.61- 1.58 (m, 2H), 0.71- 0.66 (m, 1H), 0.14- 0.11 (m, 1H). 416.8 A
63 0.53 ##STR00125## 1-[6-[6-(2-aminopyrimidin-5-yl)-2-
cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]ethanone
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.98 (s, 2H), 1.17 (s,
1H), 5.32 (s, 2H), 3.99 (d, J = 12.0 Hz, 1H), 3.74- 3.72 (m, 2H),
3.56 (dd, J = 4.0, 12.4 Hz, 1H), 2.33-2.29 (m, 2H), 2.25-2.20 (m,
1H), 2.07 (s, 3H), 1.80-1.78 (m, 1H), 1.13-1.11 (m, 2H), 1.04-1.02
(m, 2H). 336.9 C 64 0.27 ##STR00126##
5-[2-(3-azabicyclo[2.1.1]hexan-3-
yl)-6-(9-azabicyclo[3.3.1]nonan-9-yl)
pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz, DMSO)
.delta. 8.91 (s, 2H), 6.92 (br s, 2H), 6.50 (s, 1H), 5.03 (br s,
1H), 4.80 (d, J = 6.9 Hz, 1H), 4.36 (br s, 1H), 3.44 (s, 2H), 2.85
(m, 1H), 2.18- 1.51 (m, 14H), 1.39- 1.27 (m, 2H). 378 I 65 0.04
##STR00127## 5-[2-[(3S,4R)-3,4-difluoropyrrolidin-
1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.93 (s, 2H), 6.99 (s, 2H), 5.49- 5.38 (m, 1H),
5.38- 5.26 (m, 1H), 5.00 (s, 1H), 4.68 (s, 1H), 3.44- 3.32 (m, 1H),
4.03- 3.84 (m, 2H), 3.78 (d, J = 7.5, 1.5 Hz, 1H), 3.75- 3.57 (m,
3H), 3.46 (d, J = 10.5, 1.6 Hz, 1H), 3.37 (s, 1H), 1.95- 1.80 (m,
2H). 376 E 66 0.03 ##STR00128##
5-[2-(3,3-difluoropyrrolidin-1-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.93 (s, 2H), 6.99 (s, 2H), 5.00 (s, 1H), 4.67 (s,
1H), 3.91 (t, J = 13.5 Hz, 2H), 3.80-3.68 (m, 3H), 3.65 (d, J = 7.3
Hz, 1H), 3.46 (d, 1H), 3.37 (s, 1H), 1.87 (s, 2H). 376 E 67 0.65
##STR00129## 5-[2-(3-fluoroazetidin-1-yl)-6-[(1S,
4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-
yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6)
.delta. 8.89 (s, 2H), 7.00 (s, 2H), 5.45 (d, J = 57.9, 6.1, 3.2 Hz,
1H), 4.97 (s, 1H), 4.67 (s, 1H), 4.40-4.25 (m, 2H), , 4.12-4.03 (m,
1H), 4.03-3.96 (m, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J =
7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.5 Hz, 1H), 3.41- 3.31 (m, 1H),
3.35 (s, 1H), 1.86 (s, 2H). 395 E 68 1.61 ##STR00130##
5-[2-(4-cyclopropylpiperazin-1-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.66 (s,
1H), 3.77 (d, J = 7.5, 1.7 Hz, 1H), 3.74-3.61 (m, 5H), 3.45 (d, J =
10.5, 1.5 Hz, 1H), 3.35 (s, 1H), 2.56 (t, J = 5.0 Hz, 4H), 1.86 (s,
2H), 1.68- 1.59 (m, 1H), 0.43 (m, 2H), 0.36 (q, J = 3.2, 2.6 Hz,
2H). 395 E 69 0.11 ##STR00131## 5-[2-[(1R,4R)-5,5-difluoro-2-
azabicyclo[2.2.1]heptan-2-yl]-6-[(1S,4S)-
2-oxa-5-azabicyclo[2.2.1]heptan-5-
yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6)
.delta. 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 2H), 4.75 (s, 2H),
4.67 (s, 2H), 3.77 (d, J = 7.5, 1.7 Hz, 2H), 3.66 (d, J = 7.4 Hz,
2H), 3.64-3.50 (m, 1H), ), 3.56 (t, J = 8.9 Hz, 1H), 3.50-3.40 (d,
1H), 3.40- 3.35 (m, 3H), 3.45 (d, J = 9.9, 1.7 Hz, 1H), 2.93 (s,
1H), 2.28-2.10 (m, 1H), 2.10-1.96 (m 1H), 1.89 (d, J = 18.5 Hz,
4H). 402 E 70 0.22 ##STR00132##
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]-2-[4-(trifluoromethyl)-1-
piperidyl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.85 (d,
J = 13.2 Hz, 2H), 4.67 (s, 1H), 3.78 (d, J = 7.3, 1.4 Hz, 1H),
2.64-2.52 (m, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.46 (d, J = 10.5, 1.4
Hz, 1H), 3.35 (s, 1H), 2.82 (t, J = 12.8 Hz, 2H), 1.86 (d, J = 11.0
Hz, 4H), 1.45- 1.28 (m, 2H). 422 E 71 0.09 ##STR00133##
1-[2-(2-aminopyrimidin-5-yl)-6-(3- azabicyclo[2.1.1]hexan-3-yl)-4-
pyridyl]cyclobutanecarbonitrile .sup.1H NMR (400 MHz, DMSO) .delta.
8.92 (s, 2H), 7.10 (d, J = 1.1 Hz, 1H), 6.91 (br s, 2H), 6.46 (d, J
= 1.1 Hz, 1H), 4.88 (d, J = 6.8 Hz, 1H), 3.44 (s, 2H), 3.01-2.90
(m, 1H), 2.75-2.64 (m, 4H), 2.39-2.18 (m, 1H), 2.11-1.92 (m, 3H),
1.41-1.27 (m, 2H). 333 G 72 0.04 ##STR00134##
1-[6-[6-amino-5-(difluoromethoxy)-
3-pyridyl]-2-(3-azabicyclo[2.1.1]
hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile .sup.1H NMR (400
MHz, DMSO) .delta. 8.69 (s, 1H), 8.05 (s, 1H), 7.23 (t, J = 74.0
Hz, 2H), 7.20 (s, 1H), 6.70 (br s, 2H), 4.95 (m, 1H), 3.54 (s, 2H),
2.99-2.91 (m, 1H), 2.81 (m, 2H), 2.72- 2.60 (m, 2H), 2.32- 2.18 (m,
1H), 2.13- 1.94 (m, 3H), 1.45- 1.38 (m, 2H). 399 I 73 0.002
##STR00135## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(3-azabicyclo[3.1.0]hexan-3-yl)
pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 1H NMR (400
MHz, Methanol-d4) .delta. 8.26 (s, 1H), 7.78 (s, 1H), 6.72 (t, J =
73.6 Hz, 1H), 5.90 (s, 1H), 4.73-4.68 (m, 1H), 3.62 (br.s, 2H),
3.37 (s, 2H), 3.30 (d, J = 10.4 Hz, 2H), 2.75- 2.73 (m, 1H), 1.83
(s, 2H), 1.51-1.50 (m, 2H), 1.24-1.22 (m, 2H), 0.64-0.61 (m, 1H),
0.02-0.01 (m, 1H). 401.0 A 74 0.05 ##STR00136##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]-3-cyclopropyl-pyridin-2-amine .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 8.54 (s, 1H), 7.91 (s, 1H),
5.92 (s, 1H), 4.96 (d, J = 6.8 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 1H),
3.92- 3.87 (m, 2H), 3.58 (s, 2H), 3.52-4.94 (m, 2H), 2.92-2.90 (m,
1H), 1.96-1.93 (m, 4H), 1.68-1.66 (m, 1H), 1.48-1.46 (m, 2H),
0.96-0.94 (m, 2H), 0.69-0.67 (m, 2H). 390.9 A 75 0.009 ##STR00137##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy- pyridin-2-amine .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 8.28 (s, 1H), 7.23 (s, 1H), 6.21
(br.s, 2H), 5.92 (s, 2H), 4.96 (s, 1H), 4.80 (d, J = 7.2 Hz, 1H),
4.67-4.61 (m, 2H), 3.75 (d, J = 6.4 Hz, 1H), 3.63 (d, J = 7.2 Hz,
1H), 3.43-3.42 (m, 4H), 2.87-2.85 (m, 1H), 1.91-1.83 (m, 4H),
1.32-1.21 (m, 8H). 409.2 A 76 0.008 ##STR00138##
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl]
pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 8.51 (s, 1H), 7.99 (s, 1H), 6.58
(t, J = 73.2 Hz, 1H), 6.29 (s, 1H), 5.12 (br.s, 1H), 4.91 (s, 2H),
4.74 (s, 1H), 3.91-3.87 (m, 2H), 3.51-3.44 (m, 2H), 2.12-2.05 (m,
1H), 2.00-1.92 (m, 2H), 1.15-1.07 (m, 2H), 0.97-0.95 (m, 2H).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.63 (s, 1H), 7.99 (s, 1H),
7.18 (t, J = 74.0 Hz, 1H), 6.80 (br.s, 1H), 6.54 (s, 2H), 5.02 (s,
1H), 4.69 (s, 1H), 3.78 (d, J = 6.8 Hz, 1H), 3.64 (d, J = 7.2 Hz,
1H), 3.48-3.45 (m, 2H), 1.99-1.88 (m, 3H), 0.99-0.88 (m, 4H). 376.1
376.1 A 77 0.16 ##STR00139## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(8-azabicyclo[3.2.1]octan-3-yl) pyrimidin-4-yl]pyrimidin-2-amine
1H NMR (400 MHz, DMSO) .delta. 8.94 (s, 2H), 8.40 (s, 1H), 7.12 (s,
2H), 7.03 (s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 3.81 (s, 2H),
3.04-2.94 (m, 2H), 2.95-2.90 (m, 1H), 2.03-1.95 (m, 4H), 1.94-1.76
(m, 7H), 1.35 (dd, J = 4.4, 1.7 Hz, 2H). 364 C 78 1.61 ##STR00140##
5-[2-[4-(cyclopropylmethyl) piperazin-1-yl]-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4- yl]pyrimidin-2-amine 1H
NMR (400 MHz, DMSO-d6) .delta. 8.92 (s, 2H), 7.00 (s, 2H), 4.98 (s,
1H), 4.68 (s, 1H), 3.78 (d, J = 6.7 Hz, 1H), 3.65 (d, J = 7.4 Hz,
1H), 3.46 (d, J = 10.1 Hz, 1H), 3.10-2.52 (m, 4H), 1.87 (s, 2H),
0.96 (s, 1H), 0.55 (d, J = 7.5 Hz, 2H), 0.21 (s, 2H), 3.10- 2.52
(m, 4H). 409 E 79 0.06 ##STR00141##
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-
4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine 1H NMR
(400 MHz, DMSO-d6) .delta. 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, J =
74.0 Hz, 1H), 6.42 (s, 1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76- 4.74
(m, 2H), 4.62 (s, 1H), 3.73 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 7.6
Hz, 1H), 3.45 (d, J = 8.8 Hz, 1H), 3.33 (s, 2H), 3.10 (d, J = 10.4
Hz, 1H), 2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H), 1.27-1.26 (m, 2H).
416.1 D 80 0.08 ##STR00142## 5-[6-(3-azabicyclo[2.1.1]hexan-3-
yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.91 (s, 2H), 6.99 (s, 2H), 6.38 (br.s, 1H),
4.97-4.91 (m, 2H), 4.62 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.67 (d,
J = 7.2 Hz, 1H), 3.47-3.41 (m, 4H), 2.96-2.90 (m, 1H), 1.98 (s,
2H), 1.87-1.79 (m, 2H), 1.33 (d, J = 2.8 Hz, 2H). 351.8 B 81 0.038
##STR00143## 5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.89 (s, 2H), 7.00 (s, 2H), 6.54- 6.10 (br.s, 1H),
5.08- 4.96 (br.s, 1H), 4.66- 4.62 (m, 1H), 3.84- 3.81 (m, 2H),
3.77- 3.75 (m, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.44- 3.39 (m, 4H),
1.85 (s, 2H), 1.60-1.58 (m, 2H), 0.73-0.66 (m, 1H), 0.14-0.12 (m,
1H). 352.19 B 82 0.034 ##STR00144##
1-[(1S,4S)-5-[6-(2-aminopyrimidin-
5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-
yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]ethanone
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.91 (s, 2H), 7.00 (s, 2H),
6.68- 6.12 (br.s, 1H), 5.11- 4.95 (br.s, 1H), 4.88- 4.65 (m, 2H),
3.55- 3.33 (m, 5H), 3.28- 3.23 (m, 1H), 2.88 (d, J = 6.8 Hz, 1H),
2.02 (s, 2H), 1.93 (s, 3H), 1.86- 1.83 (m, 2H), 1.31 (s, 2H).
393.15 B 83 0.17 ##STR00145##
.[.5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-.].
.[.6-[(1S,4S)-2,2-dioxo-2$].].{circumflex over ( )}.[.{6}-thia-.].
.[.5-azabicyclo[2.2.1]heptan-5-yl].].
.[.pyrimidin-4-yl]pyrimidin-2-amine.]. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.91 (s, 2H), 5.92 (s, 1H), 5.22 (s, 3H),
5.00-4.93 (m, 1H), 4.15-4.12 (m, 1H), 3.80 (s, 1H), 3.75- 3.72 (m,
1H), 3.55 (s, 2H), 3.45-3.41 (m, 1H), 3.21-3.18 (m, 1H), 2.95-2.93
(m, 1H), 2.74-2.71 (m, 1H), 2.50-2.47 (m, 1H), 2.00 (s, 2H), 1.47
(d, J = 4.0 Hz, 2H). 399.8 B
.Iadd.5-[2-(3-azabicyclo[2.1.1]hexane-3-.Iaddend.
.Iadd.yl)-6-[(1S,4S)-2,2-dioxo-2.Iaddend..Iadd..lamda..Iaddend..Iadd.6.I-
addend..Iadd.thia-5-.Iaddend.
.Iadd.azabicyclo[2.2.1]heptain-5-yl]pyrimidin-.Iaddend.
.Iadd.4-yl]pyrimidin-2-amine.Iaddend. 84 0.051 ##STR00146##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-5-(2,2,2-trifluoroethyl)-
2,5-diazabicyclo[2.2.1]heptan-2-yl]
pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz, DMSO-d6)
.delta.
8.91 (s, 2H), 7.00 (s, 2H), 6.50- 6.15 (m, 1H), 4.83 (d, J = 6.8
Hz, 1H), 3.69 (s, 1H), 3.51-3.48 (m, 3H), 3.45-3.40 (m, 2H),
3.08-3.05 (m, 1H), 2.89-2.88 (m, 1H), 2.68-2.64 (m, 1H), 2.02 (s,
1H), 1.87- 1.86 (m, 1H), 1.82- 1.77 (m, 1H), 1.38 (s, 3H),
1.33-1.32 (m, 2H). 433.1 A 85 0.05 ##STR00147##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(8-azabicyclo[3.2.1]octan-8-yl) pyrimidin-4-yl]pyrimidin-2-amine
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.87 (s, 2H), 6.94 (s, 2H),
6.39 (s, 1H), 4.78-4.76 (m, 1H), 4.54 (br.s, 2H), 2.84-2.83 (m,
1H), 2.46 (s, 2H), 1.88 (s, 4H), 1.75-1.67 (m, 5H), 1.42-1.27 (m,
5H). 363.9 A 86 0.21 ##STR00148##
1-[6-(2-aminopyrimidin-5-yl)-2-(3- azabicyclo[2.1.1]hexan-3-yl)
pyrimidin-4-yl]cyclobutanecarbonitrile 1H NMR (400 MHz, DMSO)
.delta. 9.01 (s, 2H), 7.21 (br s, 2H), 7.20 (s, 1H), 5.06-4.80 (m,
1H), 3.54 (s, 2H), 2.99- 2.89 (m, 1H), 2.85- 2.73 (m, 2H), 2.70-
2.59 (m, 2H), 2.34- 2.14 (m, 1H), 2.14- 1.90 (m, 3H), 1.45- 1.33
(m, 2H). 334 I 87 0.21 ##STR00149##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 5-fluoro-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 370
B 88 0.41 ##STR00150## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[3-(oxetan-3-yl)-3-azabicyclo[3.2.1]
octan-8-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO)
.delta. 8.96 (s, 2H), 7.14-7.02 (m, 3H), 4.90 (d, J = 6.0 Hz, 1H),
4.49 (dt, J = 19.6, 6.2 Hz, 4H), 3.57-3.45 (m, 3H), 2.97-2.87 (m,
1H), 2.76-2.66 (m, 4H), 2.62 (s, 1H), 2.10- 2.03 (m, 2H), 1.98 (s,
2H), 1.62 (s, 4H), 1.40- 1.33 (m, 2H). 420 C 89 0.01 ##STR00151##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(trifluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.71 (s, 1H), 8.14 (s, 1H), 6.80 (s, 2H), 6.23 (br.s, 1H),
5.00 (br.s, 1H), 4.82 (d, J = 6.8 Hz, 1H), 4.67 (s, 1H), 3.77 (d, J
= 6.4 Hz, 1H), 3.65 (d, J = 7.2 Hz, 1H), 3.47-3.45 (m, 4H),
2.90-2.88 (m, 1H), 1.94-1.86 (m, 4H), 1.32-1.31 (m, 2H). 434.9 A 90
0.13 ##STR00152## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(2,5-diazabicyclo[2.2.1]heptan-
2-yl)pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.98 (s, 2H), 6.43- 6.09 (m, 1H),
4.90- 4.65 (m, 2H), 3.69- 3.61 (m, 1H), 3.50- 3.39 (m, 5H), 2.88
(d, J = 8.0 Hz, 2H), 2.79- 2.76 (m, 1H), 1.93 (s, 2H), 1.73-1.64
(m, 2H), 1.31-1.28 (m, 2H). 351.18 B 91 0.1 ##STR00153##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(3-azabicyclo[3.2.1]octan-8-yl) pyrimidin-4-yl]pyrimidin-2-amine
1H NMR (400 MHz, DMSO) .delta. 8.95 (s, 2H), 7.08 (s, 2H), 7.01 (s,
1H), 4.89 (d, J = 6.7 Hz, 1H), 3.49 (s, 2H), 2.96- 2.90 (m, 1H),
2.81- 2.68 (m, 5H), 2.55 (s, 2H), 1.97 (d, J = 1.2 Hz, 2H),
1.68-1.51 (m, 4H), 1.35 (dd, J = 4.3, 1.8 Hz, 2H) 364 C 92 0.002
##STR00154## 5-[6-[(1R,4S)-3-azabicyclo[2.2.1]
heptan-3-yl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO) .delta.
8.56 (s, 1H), 7.95 (s, 1H), 7.18 (t, J = 73.9 Hz, 1H), 6.38 (br s,
2H), 6.36-6.00 (m, 1H), 4.82 (d, J = 7.0 Hz, 1H), 4.77-4.45 (m,
1H), 3.45 (s, 2H), 3.42- 3.34 (m, 1H), 3.16- 3.04 (m, 1H), 2.88
(dd, J = 6.9, 3.1 Hz, 1H), 2.61 (s, 1H), 1.93 (s, 2H), 1.73-1.44
(m, 5H), 1.41-1.26 (m, 3H). 415 E 93 0.01 ##STR00155##
5-[6-[(1R,4S)-3-azabicyclo[2.2.1]
heptan-3-yl]-2-(3-azabicyclo[2.1.1]
hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO)
.delta. 8.88 (s, 2H), 6.93 (s, 2H), 6.35-6.10 (m, 1H), 4.82 (d, J =
7.0 Hz, 1H), 4.77-4.42 (m, 1H), 3.44 (s, 2H), 3.37 (d, J = 8.4 Hz,
1H), 3.21- 2.98 (m, 1H), 2.91- 2.83 (m, 1H), 2.61 (d, J = 1.9 Hz,
1H), 1.92 (s, 2H), 1.72-1.52 (m, 4H), 1.51-1.43 (m, 1H), 1.36 (t, J
= 8.6 Hz, 1H), 1.31 (dd, J = 4.3, 1.6 Hz, 2H). 350 E 94 0.028
##STR00156## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(3-azabicyclo[3.1.0]hexan-3-yl) pyrimidin-4-yl]pyrimidin-2-amine
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.89 (s, 2H), 6.97 (s, 2H),
6.19 (s, 1H), 4.82 (d, J = 6.4 Hz, 1H), 3.74 (br.s, 2H), 3.44-3.38
(m, 4H), 2.88-2.87 (m, 1H), 1.92-1.87 (m, 2H), 1.65 (s, 2H), 1.31
(s, 2H), 0.73-0.72 (m, 1H), 0.13-0.12 (m, 1H). 335.8 A 95 0.68
##STR00157## 5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-
5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine
.sup.1H NMR (400 MHz, Methanol-d4) .delta. 8.76 (s, 2H), 6.45
(br.s, 1H), 5.02-4.98 (m, 1H), 4.63 (s, 1H), 3.78-3.77 (m, 1H),
3.70-3.68 (m, 1H), 3.43-3.42 (m, 1H), 3.38-3.30 (m, 1H), 1.98-1.97
(m, 1H), 1.88-1.85 (m, 2H), 1.18-0.97 (m, 2H), 0.86-0.83 (m, 2H).
311.19 A 96 0.14 ##STR00158## 8-[6-(2-aminopyrimidin-5-yl)-2-(3-
azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-3-methyl-8-
azabicyclo[3.2.1]octan-3-ol .sup.1H NMR (400 MHz, DMSO-d6) .delta.
8.90 (s, 2H), 6.97 (s, 2H), 6.41 (s, 1H), 4.81-4.79 (m, 1H),
4.70-4.44 (m, 2H), 3.43 (s, 2H), 2.70- 2.69 (m, 2H), 2.25- 2.24 (m,
2H), 1.92 (s, 2H), 1.80-1.73 (m, 4H), 1.64-1.61 (m, 2H), 1.31-1.30
(m, 2H), 0.95 (s, 3H). 394.2 A 97 0.32 ##STR00159##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(2,6-dimethylmorpholin-4-yl) pyrimidin-4-yl]pyrimidin-2-amine
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.88 (s, 2H), 6.08 (s,
1H), 5.70 (s, 2H), 4.94 (d, J = 7.2 Hz, 1H), 4.21 (d, J = 12.8 Hz,
2H), 3.72- 3.64 (m, 2H), 3.57 (s, 2H), 2.94-2.91 (m, 1H), 2.62-2.56
(m, 2H), 1.98 (d, J = 2.0 Hz, 2H), 1.47 (dd, J = 2.0, 4.4 Hz, 2H),
1.28 (d, J = 6.8 Hz, 6H). 368.0 A 98 0.101 ##STR00160##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(8-oxa-3-azabicyclo[3.2.1]
octan-3-yl)pyrimidin-4-yl]pyrimidin-2- amine .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 8.85 (s, 2H), 6.30 (s, 1H), 4.88- 4.86 (m,
1H), 4.44- 4.43 (m, 2H), 4.12- 4.06 (m, 2H), 3.53 (s, 2H), 3.10
(dd, J = 2.0, 12.8 Hz, 2H), 2.92- 2.90 (m, 1H), 2.00 (s, 1H),
1.95-1.91 (m, 2H), 1.87-1.79 (m, 3H), 1.40 (dd, J = 2.0, 4.4 Hz,
2H). 365.9 A 99 0.043 ##STR00161## 5-[2,6-bis(3-azabicyclo[2.1.1]
hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.97 (s, 2H), 6.34 (s, 1H),
4.84-4.82 (m, 2H), 3.40 (s, 4H), 2.96- 2.86 (m, 2H), 1.95 (d, J =
19.6 Hz, 4H), 1.32- 1.31 (m, 4H). 336.1 A 100 0.001 ##STR00162##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.58 (s, 1H), 7.97 (s, 1H), 7.18 (t, J = 73.6 Hz, 1H), 6.47
(s, 2H), 6.25 (br.s, 1H), 5.00-4.97 (m, 1H), 4.85-4.83 (m, 1H),
4.68 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H),
3.52- 3.46 (m, 4H), 2.90- 2.89 (m, 1H), 1.95-1.87 (m, 4H), 1.32 (s,
2H). 416.9 A 101 0.026 ##STR00163##
2-amino-5-[2-(3-azabicyclo[2.1.1] hexan-3-yl)-6-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]pyrimidin-
4-yl]pyridine-3-carbonitrile .sup.1H NMR (400 MHz, DMSO-d6) .delta.
8.95 (s, 1H), 8.54 (s, 1H), 7.26 (br.s, 2H), 6.50 (br.s, 1H),
5.04-5.01 (m, 1H), 4.86 (s, 1H), 4.68 (s, 1H), 3.78 (d, J = 7.2 Hz,
1H), 3.66 (d, J = 7.2 Hz, 1H), 3.47-3.44 (m, 4H), 2.92-2.89 (m,
1H), 1.95-1.87 (m, 4H), 1.35-1.33 (m, 2H). 375.9 A 102 0.024
##STR00164## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
chloro-pyridin-2-amine .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.67
(s, 1H), 8.23 (s, 1H), 6.66 (s, 2H), 6.30-6.20 (m, 1H), 5.04-4.98
(m, 1H), 4.93-4.83 (m, 1H), 4.71-4.67 (m, 1H), 3.77 (d, J = 6.0 Hz,
1H), 3.66 (d, J = 7.2 Hz, 1H), 3.52-3.44 (m, 4H), 2.90-2.88 (m,
1H), 1.94-1.91 (m, 2H), 1.90-1.86 (m, 2H), 1.33-1.31 (m, 2H). 385.0
A 103 0.018 ##STR00165## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(trifluoromethyl)pyridin-2-amine .sup.1H NMR (400 MHz, DMSO +
H.sub.2O-d6) .delta. 8.76- 8.75 (m, 1H), 8.32- 8.28 (m, 1H), 6.60-
6.10 (m, 1H), 5.20- 5.00 (m, 1H), 4.90- 4.88 (m, 1H), 4.69- 4.70
(m, 1H), 3.79- 3.77 (m, 2H), 3.51- 3.48 (m, 4H), 2.93- 2.91 (m,
1H), 2.02- 1.99 (m, 2H), 1.95- 1.89 (m, 2H), 1.35 (s, 2H). 419.0 A
104 0.069 ##STR00166## 8-[6-(2-aminopyrimidin-5-yl)-2-(3-
azabicyclo[2.1.1]hexan-3-yl)
pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-ol .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.90 (s, 2H), 6.97 (s, 2H), 6.42 (s, 1H),
4.82-4.80 (m, 1H), 4.59-4.54 (m, 4H), 3.90-3.86 (m, 1H), 2.89-2.87
(m, 1H), 2.26-2.25 (m, 2H), 1.99-1.86 (m, 7H), 1.65-1.61 (m, 2H),
1.32-1.30 (m, 2H). 380.1 A 105 1.36 ##STR00167##
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-
4-(3-oxa-8-azabicyclo[3.2.1]octan-
8-yl)-2-pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) .delta.
8.86 (s, 2H), 6.75 (s, 2H), 6.61 (d, J = 1.7 Hz, 1H), 5.81 (d, J =
1.7 Hz, 1H), 4.82-4.72 (m, 1H), 4.35 (s, 2H), 3.68 (d, J = 10.8 Hz,
2H), 3.44 (d, J = 10.9 Hz, 2H), 3.37 (s, 2H), 2.95-2.87 (m, 1H),
1.97-1.91 (m, 6H), 1.30 (dd, J = 4.3, 1.8 Hz, 2H). 365 D 106 0.98
##STR00168## 5-[4,6-bis(3-azabicyclo[2.1.1]
hexan-3-yl)-2-pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO)
.delta. 8.84 (s, 2H), 6.73 (s, 2H), 6.49 (d, J = 1.6 Hz, 1H), 5.67
(d, J = 1.6 Hz, 1H), 4.77 (dd, J = 5.4, 1.6 Hz, 1H), 4.63 (d, J =
6.8 Hz, 1H), 3.36 (s, 2H), 2.96-2.88 (m, 2H), 1.92 (dd, J = 16.5,
1.6 Hz, 4H), 1.35-1.25 (m, 4H). 335 D 107 0.13 ##STR00169##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(3-oxa-8-azabicyclo[3.2.1]octan-
8-yl)pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.92 (s, 2H), 7.00 (s, 2H), 6.52 (s, 1H), 4.82 (d,
J = 6.8 Hz, 1H), 4.65-4.50 (m, 2H), 3.62 (d, J = 10.8 Hz, 4H), 3.53
(d, J = 10.4 Hz, 2H), 2.89- 2.87 (m, 1H), 1.96- 1.86 (m, 6H), 1.32
(dd, J = 2.0, 4.4 Hz, 2H). 366.1 A 108 0.32 ##STR00170##
5-[6-(3-azabicyclo[2.1.1] hexan-3-yl)-4-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]-2- pyridyl]pyrimidin-2-amine 1H NMR
(400 MHz, DMSO) .delta. 8.85 (s, 2H), 6.75 (s, 2H), 6.44 (s, 1H),
5.57 (s, 1H), 4.78- 4.76 (m, 2H), 4.65 (s, 1H), 3.75 (dd, J = 7.3,
1.1 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.47 (dd, J = 9.7, 1.3 Hz,
1H), 3.36 (s, 2H), 3.12 (d, J = 9.8 Hz, 1H), 2.90 (dt, J = 6.2, 2.8
Hz, 1H), 1.93- 1.82 (m, 4H), 1.33- 1.27 (m, 2H). 351 D 109 0.48
##STR00171## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-(2,2-dimethylmorpholin-4-yl) pyrimidin-4-yl]pyrimidin-2-amine No
NMR 368 C 110 0.02 ##STR00172##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.91 (s, 2H), 6.99 (s, 2H), 6.30- 6.10 (m, 1H),
5.10- 4.90 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 4.70- 4.64 (m, 1H),
3.85- 3.76 (m, 1H), 3.66- 3.64 (m, 1H), 3.45- 3.38 (m, 4H), 2.91-
2.87 (m, 1H), 1.93- 1.86 (m, 4H), 1.34- 1.29 (m, 2H). 352.1 A 111
0.15 ##STR00173## 5-[2-(2-methylpyrrolidin-1-yl)-6-
tetrahydropyran-4-yl-pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400
MHz, DMSO) .delta. 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H),
4.29-4.21 (m, 1H), 3.96-3.91 (m, 2H), 3.63-3.48 (m, 2H), 3.43 (td,
J = 11.2, 3.4 Hz, 2H), 2.78-2.70 (m, 1H), 2.09-1.96 (m, 2H),
1.92-1.85 (m, 1H), 1.82-1.73 (m, 4H), 1.71-1.64 (m, 1H), 1.25 (d, J
= 6.2 Hz, 3H). 341 C 112 0.06 ##STR00174##
5-[2-(2-methylpyrrolidin-1-yl)-6-
tetrahydropyran-4-yl-pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400
MHz, DMSO) .delta. 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H), 4.25
(dd, J = 6.1, 4.2 Hz, 1H), 3.94 (dd, J = 9.7, 2.3 Hz, 2H), 3.64-
3.49 (m, 2H), 3.43 (td, J = 11.3, 3.1 Hz, 2H), 2.79-2.69 (m, 1H),
2.10-1.95 (m, 2H), 1.91-1.72 (m, 5H), 1.72-1.63 (m, 1H), 1.25 (d, J
= 6.3 Hz, 3H). 341 C 113 0.74 ##STR00175##
5-[6-(3-methoxyazetidin-1-yl)-4-[1-
(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-
3-(trifluoromethyl)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.75 (s, 1H), 8.36 (s, 1H), 6.96 (s, 1H),
6.11 (s, 1H), 5.64 (s, 2H), 4.74- 4.67 (m, 4H), 4.38- 4.23 (m, 3H),
3.93- 3.90 (m, 2H), 3.63- 3.56 (m, 1H), 3.35 (s, 3H), 2.98 (d, J =
10.8 Hz, 2H), 2.54-2.46 (m, 1H), 2.06-1.99 (m, 2H), 1.93-1.88 (m,
4H). 464.0 F 114 0.69 ##STR00176##
5-[6-(3-fluoroazetidin-1-yl)-4-[1-
(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-
3-(trifluoromethyl)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.76 (s, 1H), 8.36 (s, 1H), 6.89 (s, 1H),
6.14 (s, 1H), 5.53 (s, 2H), 4.74- 4.69 (m, 5H), 4.38- 4.31 (m, 2H),
4.20- 4.11 (m, 2H), 3.63- 3.60 (m, 1H), 3.00- 2.98 (m, 2H), 2.54-
2.49 (m, 1H), 2.04- 1.90 (m, 6H). 452.0 F 115 0.49 ##STR00177##
3-chloro-5-[6-(3-fluoroazetidin-1-yl)-
4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyridin-2-amine .sup.1H
NMR (400 MHz, Methanol-d4) .delta. 8.52 (s, 1H), 8.20 (s, 1H), 7.01
(s, 1H), 6.24 (s, 1H), 5.66-5.34 (m, 1H), 4.72-4.71 (m, 2H),
4.66-4.62 (m, 2H), 4.40-4.31 (m, 2H), 4.14-4.11 (m, 1H), 4.08-4.05
(m, 1H), 3.56-3.53 (m, 1H), 2.94-2.92 (m, 2H), 2.61-2.52 (m, 1H),
2.03-2.00 (m, 2H), 1.97-1.78 (m, 4H). 418.15 F 116 1.61
##STR00178## 5-[6-(3-fluoroazetidin-1-yl)-4-[1-
(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyrimidin-2-amine .sup.1H NMR
(400 MHz, Methanol-d4) .delta. 8.86 (s, 2H), 7.01 (s, 1H), 6.26 (s,
1H), 5.53-5.36 (m, 1H), 4.74-4.71 (m, 2H), 4.65-4.62 (m, 2H),
4.40-4.31 (m, 2H), 4.14-4.05 (m, 2H), 3.56-3.52 (m, 1H), 2.93 (d, J
= 12.0 Hz, 2H), 2.64-2.56 (m, 1H), 2.03-1.99 (m, 2H), 1.97-1.81 (m,
4H). 385.16 F 117 0.71 ##STR00179##
5(2,6-dimorpholinopyrimidin-4-yl)pyrimidin-2-amine 1H NMR (400 MHz,
DMSO) .delta. 8.93 (s, 2H), 7.00 (s, 2H), 6.60 (s, 1H), 3.70-3.60
(m, 16H). 344 G 118 0.001 ##STR00180##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(2-methoxyethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-
4-yl]-3-(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.56 (s, 1H), 8.01 (s, 1H), 6.71 (s, 1H),
6.57 (t,
J = 73.6 Hz, 1H), 4.97- 4.93 (m, 3H), 3.55 (s, 2H), 3.50-3.47 (m,
2H), 3.38 (s, 3H), 3.22 (d, J = 8.4 Hz, 2H), 2.94- 2.92 (m, 1H),
2.72- 2.69 (m, 2H), 2.52- 2.50 (m, 2H), 2.32 (s, 1H), 2.09 (s, 2H),
1.98 (s, 2H), 1.46-1.44 (m, 2H). 459.15 C 119 0.002 ##STR00181##
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-
(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-
3-azabicyclo[3.1.0]hexan-3-yl]ethanone .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.58 (s, 1H), 8.03 (s, 1H), 6.71 (s, 1H),
6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 3H), 3.97 (d, J = 12.0 Hz, 1H),
3.73 (s, 2H), 3.56 (s, 2H), 3.00-2.95 (m, 1H), 2.31 (s, 2H),
2.07-2.00 (m, 5H), 1.72 (s, 1H), 1.60 (d, J = 3.6 Hz, 1H), 1.47 (s,
2H). 443.15 C 120 0.01 ##STR00182##
1-[(1R,5S)-6-[6-(2-aminopyrimidin-5-
yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)
pyrimidin-4-yl]-3-azabicyclo[3.1.0]
hexan-3-yl]-2-methyl-propan-2-ol .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.95 (s, 2H), 6.65 (s, 1H), 5.31 (s, 2H),
4.97 (d, J = 7.2 Hz, 1H), 3.56 (s, 2H), 3.30 (d, J = 9.2 Hz, 2H),
2.98-2.93 (m, 2H), 2.75 (d, J = 8.8 Hz, 2H), 2.50 (s, 2H), 2.10 (s,
1H), 2.02 (s, 2H), 1.99 (s, 2H), 1.46-1.45 (m, 2H), 1.19 (s, 6H).
408.15 C 121 0.003 ##STR00183##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]
hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.58 (s, 1H), 8.03 (s,
1H), 6.72 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 4.97- 4.93 (m, 3H),
4.71- 4.67 (m, 2H), 4.69- 4.61 (m, 2H), 3.82- 3.79 (m, 1H), 3.56
(s, 2H), 3.14 (d, J = 8.8 Hz, 2H), 2.95-2.93 (m, 1H), 2.50 (d, J =
8.4 Hz, 2H), 2.35-2.34 (m, 1H), 2.13 (s, 2H), 1.99 (s, 2H),
1.49-1.45 (m, 2H). 457.12 C 122 0.02 ##STR00184##
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]
pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine .sup.1H NMR (400
MHz, Chloroform-d) .delta. 8.86 (s, 1H), 8.41 (s, 1H), 6.71 (s,
1H), 4.98-4.92 (m, 1H), 4.69-4.62 (m, 2H), 4.62-4.59 (m, 2H),
3.82-3.75 (m, 1H), 3.55 (s, 2H), 3.12 (d, J = 8.8 Hz, 2H), 2.93-
2.92 (m, 1H), 2.49 (d, J = 8.4 Hz, 2H), 2.35- 2.33 (m, 1H), 2.12
(s, 2H), 2.00-1.98 (m, 2H), 1.45-1.43 (m, 2H). 458.9 C 123 0.02
##STR00185## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-
6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]
pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 8.73 (s, 1H), 8.15 (s, 1H), 7.10 (s,
1H), 6.92 (s, 2H), 4.85-4.83 (m, 1H), 4.57-4.54 (m, 2H), 4.46-4.43
(m, 2H), 3.72-3.69 (m, 1H), 3.45 (s, 2H), 3.06 (d, J = 8.8 Hz, 2H),
2.91-2.89 (m, 1H), 2.40 (d, J = 8.4 Hz, 2H), 2.29 (s, 1H), 2.05 (s,
2H), 1.96 (s, 2H), 1.33-1.32 (m, 2H). 474.9 C 124 0.02 ##STR00186##
5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.58 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H),
6.58 (t, J = 73.2 Hz, 1H), 4.97 (s, 2H), 4.69-4.59 (m, 4H),
3.81-3.75 (m, 1H), 3.12 (d, J = 8.8 Hz, 2H), 2.49 (d, J = 8.4 Hz,
2H), 2.42-2.40 (m, 1H), 2.18-2.15 (m, 1H), 2.11 (s, 2H), 1.11- 1.08
(m, 2H), 1.00- 0.97 (m, 2H). 416.1 C 125 0.11 ##STR00187##
5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.53 (s, 1H), 7.97 (s, 1H), 7.14 (s, 1H),
6.52 (t, J = 73.6 Hz, 1H), 4.93 (s, 2H), 3.26-3.20 (m, 2H),
3.05-3.00 (m, 2H), 2.71 (d, J = 8.8 Hz, 2H), 2.27-2.25 (m, 1H),
2.11-2.10 (m, 1H), 2.04 (s, 2H), 1.18- 1.03 (m, 2H), 0.96- 0.91 (m,
2H). 442.1 C 126 0.003 ##STR00188##
5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3-
azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.55 (s, 1H), 8.02 (s, 1H), 7.17 (s, 1H),
6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 2H), 3.46 (t, J = 6.4 Hz, 2H),
3.36 (s, 3H), 3.21 (d, J = 9.2 Hz, 2H), 2.70- 2.67 (m, 2H), 2.49
(d, J = 8.8 Hz, 2H), 2.38 (s, 1H), 2.17-2.15 (m, 1H), 2.06 (s, 2H),
1.11- 1.18 (m, 2H), 0.99- 0.96 (m, 2H). 418.2 C 127 0.001
##STR00189##
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-
cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-
yl]-2-methyl-propan-2-ol .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 8.60 (s, 1H), 8.05 (s, 1H), 7.18 (s, 1H), 6.60 (t, J = 73.2
Hz, 1H), 4.99 (s, 2H), 3.30 (d, J = 8.8 Hz, 2H), 2.92-2.85 (m, 1H),
2.75 (d, J = 8.4 Hz, 2H), 2.51 (s, 2H), 2.34 (s, 1H), 2.20-2.16 (m,
1H), 2.10 (s, 2H), 1.19 (s, 6H), 1.14-1.11 (m, 2H), 1.10-1.00 (m,
2H). 432.2 C 128 0.008 ##STR00190##
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-
2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-
3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.57 (s, 1H), 8.02 (s, 1H), 6.69 (s, 1H),
6.58 (t, J = 73.6 Hz, 1H), 5.01- 4.94 (m, 3H), 3.98 (d, J = 8.4 Hz,
1H), 3.75- 3.66 (m, 2H), 3.57- 3.55 (m, 3H), 2.95- 2.94 (m, 1H),
2.32- 2.26 (m, 4H), 2.00 (s, 2H), 1.70-1.68 (m, 1H), 1.46-1.45 (m,
2H), 1.16 (t, J = 7.6 Hz, 3H). 457.15 C 129 0.001 ##STR00191##
3-(difluoromethoxy)-5-[2-[(3S)-3-
fluoropyrrolidin-1-yl]-6-[(1S,4S)-2-
oxa-5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine
1H NMR (400 MHz, DMSO-d6) .delta. 8.60 (s, 1H), 7.99 (s, 1H), 7.17
(t, J = 73.8 Hz, 1H), 6.43 (s, 2H), 5.51-5.30 (m, 1H), 4.99 (s,
1H), , 4.67 (s, 1H), 3.93-3.74 (m, 3H), 3.74-3.44 (m, 4H), 3.35 (s,
1H), 2.28- 2.01 (m, 2H), 1.92- 1.82 (m, 2H). 423 E 130 0.022
##STR00192## 3-(difluoromethoxy)-5-[2-(3-
methoxypyrrolidin-1-yl)-6-(2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4- yl]pyridin-2-amine 1H NMR
(400 MHz, DMSO-d6) .delta. 8.59 (s, 1H), 7.98 (s, 1H), 7.16 (t,
1H), 6.41 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.06-3.99 (m, 1H),
3.78 (d, J = 7.4 Hz, 1H), 3.70-3.53 (m, 4H), 3.46 (d, J = 10.1 Hz,
2H 3.35 (s, 1H), 3.26 (s, 3H), 2.06-1.93 (m, 2H), 1.86 (s, 2H). 435
E 131 0.01 ##STR00193## 5-[2-(2-azaspiro[3.3]heptan-2-yl)-6-
[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-
(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) .delta.
8.57 (s, 1H), 7.94 (s, 1H), 7.15 (t, 1H), 6.43 (s, 2H), 4.95 (s,
1H), 4.66 (s, 1H), 3.95 (s, 4H), 3.77 (d, J = 7.3 Hz, 1H), 3.64 (d,
J = 7.3 Hz, 1H), 3.43 (d, J = 10.4 Hz, 1H), 3.35 (s, 1H), 2.15 (t,
J = 7.6 Hz, 4H), 1.91-1.71 (m, 4H). 431 E 132 0.014 ##STR00194##
5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-6-
(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)
pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.59 (s, 1H), 7.97 (s, 1H), 7.16 (t, J = 73.8 Hz,
1H), 6.42 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.50 (t, J = 5.6 Hz,
1H), 3.85 (q, J = 7.4 Hz, 1H), 3.81- 3.68 (m, 4H), 3.65 (d, J = 7.3
Hz, 1H), 3.59- 3.50 (m, 1H), 3.45 (d, J = 10.1 Hz, 1H), 3.35 (s,
1H), 2.99-2.87 (m, 1H), 2.14-1.98 (m, 1H), 1.93-1.73 (m, 3H). 447 E
133 0.08 ##STR00195## 3-(difluoromethoxy)-5-[2-(3-methoxy-3-methyl-
azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]
heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine 1H NMR (400 MHz,
DMSO-d6) .delta. 8.58 (s, 1H), 7.94 (s, 1H), 7.37- 6.94 (m, 1H),
6.45 (s, 2H), 4.97 (s, 1H), 4.67 (s, 1H), 3.97-3.89 (m, 2H),
3.85-3.73 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.4 Hz,
1H), 3.40-3.30 (m, 1H), 3.20 (s, 3H), 1.86 (s, 2H), 1.44 (s, 3H).
435 E 134 0.02 ##STR00196## 6-cyclopropyl-5'-(difluoromethoxy)-
4-(1-(oxetan-3-yl)azetidin-3-yl)-[2,3'-bipyridin]-6'-amine .sup.1H
NMR (400 MHz, DMSO) .delta. 8.53 (d, J = 1.9 Hz, 1H), 7.94 (s, 1H),
7.50 (d, J = 1.9 Hz, 1H), 7.17 (t, J = 74.0 Hz, 1H), 7.16 (s, 1H),
6.35 (br s, 2H), 4.62- 4.50 (m, 2H), 4.45- 4.32 (m, 2H), 3.82- 3.70
(m, 1H), 3.70- 3.60 (m, 3H), 3.28- 3.23 (m, 2H), 2.17- 2.03 (m,
1H), 1.05- 0.85 (m, 4H) J
Example 3
DLK TR-FRET inhibition assay: DLK kinase reactions (20 .mu.L)
containing 5 nM N-terminally GST-tagged DLK (catalytic domain amino
acid 1-520) (Carna Bioscience), 40 nM N-terminally HIS-tagged MKK4
K131M substrate, and 30 .mu.M ATP in kinase reaction buffer (50 mM
HEPES, pH 7.5, 0.01% Triton X-100, 0.01% Bovine .gamma.-Globulins,
2 mM DTT, 10 mM MgCl.sub.2 and 1 mM EGTA), and testing compound 1:3
serial diluted starting at 20 uM were incubated at ambient
temperature for 60 minutes in 384 well OptiPlate (Perkin Elmer). To
quench kinase reactions and detect phosphorylated MKK4, 15 .mu.L of
TR-FRET antibody mixture containing 2 nM anti-phosphorylated MKK4
labeled with Europium cryptate (Cisbio) and 23 nM anti-HIS labeled
with D2 (Cisbio) in detection buffer (25 mM Tris pH 7.5, 100 mM
NaCl, 100 mM EDTA, 0.01% Tween-20, and 200 mM KF) was added to the
reaction mixture. The detection mixture was incubated for 3 hours
at ambient temperature and the TR-FRET was detected with an
EnVision multilabel plate reader (Perkin-Elmer) using the
LANCE/DELFIA Dual Enh label from Perkin-Elmer (excitation filter:
UV2 (TRF) 320 and emission filters: APC 665 and Europium 615).
Compounds of formula I as set forth in Table 1 in Example 1
inhibited the DLK kinase with the K.sub.is in micromolar
(.mu.M).
* * * * *
References