U.S. patent application number 14/164419 was filed with the patent office on 2014-07-24 for tricyclic heteroaryl compounds useful as inhibitors of janus kinase.
This patent application is currently assigned to Vertex Pharmaceuticals Incorporated. The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Youssef Bennani, John P. Duffy, Francesco Salituro, Tianseng Wang.
Application Number | 20140206671 14/164419 |
Document ID | / |
Family ID | 39561862 |
Filed Date | 2014-07-24 |
United States Patent
Application |
20140206671 |
Kind Code |
A1 |
Bennani; Youssef ; et
al. |
July 24, 2014 |
TRICYCLIC HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF JANUS
KINASE
Abstract
The present invention relates to compounds useful as inhibitors
of protein kinases, particularly of JAK family kinases. The
invention also provides pharmaceutically acceptable compositions
comprising said compounds and methods of using the compositions in
the treatment of various disease, conditions, or disorders.
Inventors: |
Bennani; Youssef; (Lorraine,
CA) ; Wang; Tianseng; (Concord, MA) ;
Salituro; Francesco; (Marlborough, MA) ; Duffy; John
P.; (Northborough, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Boston |
MA |
US |
|
|
Assignee: |
Vertex Pharmaceuticals
Incorporated
Boston
MA
|
Family ID: |
39561862 |
Appl. No.: |
14/164419 |
Filed: |
January 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13429826 |
Mar 26, 2012 |
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14164419 |
|
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12434154 |
May 1, 2009 |
8163732 |
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13429826 |
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PCT/US2007/083134 |
Oct 31, 2007 |
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12434154 |
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60855862 |
Nov 1, 2006 |
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Current U.S.
Class: |
514/215 ;
435/184; 514/257; 514/287 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 25/18 20180101; C07D 487/16 20130101; A61P 9/10 20180101; C07D
471/22 20130101; C07D 471/16 20130101; A61P 11/08 20180101; A61P
9/00 20180101; A61P 13/08 20180101; A61P 37/08 20180101; A61P 19/02
20180101; A61P 17/14 20180101; A61P 1/04 20180101; A61P 15/04
20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61P 29/00
20180101; A61P 11/00 20180101; A61P 37/06 20180101; A61P 15/10
20180101; A61P 19/10 20180101; A61P 25/28 20180101; A61P 27/02
20180101; A61P 27/06 20180101; A61P 25/14 20180101; A61P 31/14
20180101; A61P 9/12 20180101; A61P 25/16 20180101; A61P 31/18
20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/215 ;
514/287; 514/257; 435/184 |
International
Class: |
C07D 471/16 20060101
C07D471/16; C07D 471/22 20060101 C07D471/22; C07D 487/16 20060101
C07D487/16 |
Claims
1-20. (canceled)
21. A method of inhibiting JAK kinase activity in an in vitro
biological sample comprising contacting said biological sample with
a compound having the formula (I-a) or a pharmaceutically
acceptable salt thereof: ##STR00199## wherein W is --N(R.sup.F)--,
--C(X)N(R.sup.F)-- or --N(R.sup.F)C(X)--; X is O, S, [hydrogen,
hydrogen] or [hydrogen, R]; X.sup.2 is N or C--R.sup.X2 wherein
R.sup.X2 is hydrogen, halogen, --CN, --NO.sub.2,
--OR.sup.X2B--OC(O)R.sup.X2B--, --OC(O)OR.sup.X2B,
--OC(O)NR.sup.X2AR.sup.X2B, --OC(S)R.sup.X2B, --SR.sup.X2B,
--SC(O)R.sup.X2B, --SC(S)R.sup.X2B, --C(O)OR.sup.X2B,
--C(O)NR.sup.X2AR.sup.X2B, --C(S)NR.sup.X2AR.sup.X2B,
--NR.sup.X2AR.sup.X2B, --S(O)R.sup.X2B, --S(O).sub.2R.sup.X2B,
--S(O).sub.2NR.sup.X2AR.sup.X2B, C.sub.1-4 haloaliphatic,
optionally substituted C.sub.3-8 cycloaliphatic, C.sub.1-6
aliphatic; X.sup.4 is N or C--R.sup.B4, X.sup.5 is N or
C--R.sup.B5, X.sup.6 is N or C--R.sup.B6, and X.sup.7 is N or
C--R.sup.B7, where optionally up to two of X.sup.4, X.sup.5,
X.sup.6, and X.sup.7 are N and each of R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is, independently, hydrogen, halogen, --CN,
--NO.sub.2, --OR, --OC(O)R, --OC(O)OR, --OC(O)NRR', --OC(S)R, --SR,
--SC(O)R, --SC(S)R, --C(O)OR, --C(O)NRR', --C(S)NRR', --NRR',
--S(O)R, --S(O).sub.2R, --S(O).sub.2NRR', optionally substituted
C.sup.1-4 haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl; each of R.sup.F and R.sup.G is, independently,
hydrogen, optionally substituted C.sub.1-6 aliphatic, C.sub.1-4
haloaliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3- to
8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to
12-membered bicyclic heteroaryl, or when W is N(R.sup.F), R.sup.F
and R.sup.G and the intervening atoms together optionally form a
N.dbd.C bond; R.sup.H is hydrogen, optionally substituted C.sub.1-6
aliphatic, C.sub.1-4 haloaliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic
heteroaryl, or 8- to 12-membered bicyclic heteroaryl; R.sup.X2A is
hydrogen, optionally substituted C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl, --C(O)R, --C(O)NRR', --C(O)OR, --S(O)R, --S(O).sub.2R,
or --S(O).sub.2NRR'; each of R, R', and R.sup.X2B is,
independently, hydrogen, optionally substituted C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3- to
8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to
12-membered bicyclic heteroaryl; each of said heterocyclyl and
heteroaryl rings contains one to four heteroatoms independently
selected from oxygen, sulfur, or nitrogen; the optional
substituents on one or more carbon atoms of each of said aryl and
heteroaryl groups are: halogen; --R.sup..smallcircle.;
--OR.sup..smallcircle.; --SR.sup..smallcircle.; 1,2-methylenedioxy;
1,2-ethylenedioxy; phenyl optionally substituted with
R.sup..smallcircle.; --O(Ph) optionally substituted with
R.sup..smallcircle.; --(CH.sub.2).sub.1-2(Ph) optionally
substituted with R.sup..smallcircle.; --CH.dbd.CH(Ph) optionally
substituted with R.sup..smallcircle.; --NO.sub.2; --CN;
--N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.C(S)R.sup..smallcircle.;
--NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(S)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.-
2;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.; --C(O)OR.sup..smallcircle.;
--C(O)R.sup..smallcircle.; --C(S)R.sup..smallcircle.;
--C(O)N(R.sup..smallcircle.).sub.2;
--C(S)N(R.sup..smallcircle.).sub.2;
--B(OR.sup..smallcircle.).sub.2,
--OC(O)N(R.sup..smallcircle.).sub.2; --OC(O)R.sup..smallcircle.;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NOR.sup..smallcircle.)R.sup..smallcircle.;
--S(O).sub.2R.sup..smallcircle.; --S(O).sub.2OR.sup..smallcircle.;
--S(O).sub.2N(R.sup..smallcircle.).sub.2;
--S(O)R.sup..smallcircle.;
--NR.sup..smallcircle.S(O).sub.2N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NH)--N(R.sup..smallcircle.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.sup..smallcircle.;
-L-R.sup..smallcircle.; -L-N(R.sup..smallcircle.).sub.2;
-L-SR.sup..smallcircle.; -L-OR.sup..smallcircle.; -L-(C.sub.3-10
cycloaliphatic), -L-(C.sub.6-10 aryl), -L-(5-10 membered
heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, -L-NO.sub.2, -L-CN, -L-OH,
-L-CF.sub.3; or two substituents, on the same carbon or on
different carbons, together with the carbon or intervening carbons
to which they are bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring, wherein L is a C.sub.1-6
alkylene group in which up to three methylene units are replaced by
--NH--, --NR.sup..smallcircle.--, --O--, --S--, --C(O)O--,
--OC(O)--, --C(O)C(O)--, --C(O)--, --C(O)NH--,
--C(O)NR.sup..smallcircle.--, --C(.dbd.N--CN)--, --NHC(O)--,
--NR.sup..smallcircle.C(O)--, --NHC(O)O--,
--NR.sup..smallcircle.C(O)O--, --S(O).sub.2NH--,
--S(O).sub.2NR.sup..smallcircle.--, --NHS(O).sub.2--,
--NR.sup..smallcircle.S(O).sub.2--, --NHC(O)NH--,
--NR.sup..smallcircle.C(O)NH--, --NHC(O)NR.sup..smallcircle.--,
--NR.sup..smallcircle.C(O)NR.sup..smallcircle., --OC(O)NH--,
--OC(O)NR.sup..smallcircle.--, --NHS(O).sub.2NH--,
--NR.sup..smallcircle.S(O).sub.2NH--,
--NHS(O).sub.2NR.sup..smallcircle.--,
--NR.sup..smallcircle.S(O).sub.2NR.sup..smallcircle.--, --S(O)--,
or --S(O).sub.2--, and wherein each occurrence of
R.sup..smallcircle. is independently selected from hydrogen,
optionally substituted C.sub.1-6 aliphatic, an unsubstituted 5- to
6-membered heteroaryl or heterocyclic ring, phenyl, or
--CH.sub.2(Ph), or, two independent occurrences of
R.sup..smallcircle., on the same substituent or different
substituents, taken together with the atom(s) to which each
R.sup..smallcircle. group is bound, form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered
cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1
to 3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein optional substituents on the aliphatic group of
R.sup..smallcircle. are selected from --NH.sub.2, --NH(C.sub.1-4
aliphatic), --N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, --OH, --O(C.sub.1-4 aliphatic), --NO.sub.2, --CN,
--C(O)OH, C(O)O(C.sub.1-4 aliphatic), O(haloC.sub.1-4 aliphatic),
or haloC.sub.1-4 aliphatic wherein each of the C.sub.1-4 aliphatic
groups of R.sup..smallcircle. is unsubstituted; and the optional
substituents on one or more carbon atoms of each of said aliphatic,
haloaliphatic, cyclo aliphatic, and heterocyclyl groups are as
defined for said aryl and heteroaryl groups and additionally
comprise: .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2,
.dbd.NNHC(O)R*, .dbd.NNHC(O)O(alkyl), .dbd.NNHS(O).sub.2(alkyl), or
.dbd.NR*, wherein each R* is independently selected from hydrogen
or an optionally substituted C.sub.1-6 aliphatic, and where
optional substituents on said aliphatic group of R* are selected
from --NH.sub.2, --NH(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, --OH, --O(C.sub.1-4
aliphatic), --NO.sub.2, --CN, --C(O)OH, --C(O)O(C.sub.1-4
aliphatic), --O(halo-C.sub.1-4 aliphatic), and halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4 aliphatic
groups of R* is unsubstituted.
22. The method according to claim 21, wherein said JAK kinase is
JAK-3.
23. The method according to claim 21, wherein said JAK kinase is
JAK-2.
24. A method of treating or lessening the severity of a disease,
condition, or disorder in a patient, comprising administering a
therapeutically effective amount of a compound having the formula
(I-a) or a pharmaceutically acceptable salt thereof: ##STR00200##
wherein W is --N(R.sup.F)--, --C(X)N(R.sup.F)-- or
--N(R.sup.F)C(X)--; X is O, S, [hydrogen, hydrogen] or [hydrogen,
R]; X.sup.2 is N or C--R.sup.X2, wherein R.sup.X2 is hydrogen,
halogen, --CN, --NO.sub.2, --OR.sup.X2B, --OC(O)R.sup.X2B,
--OC(O)OR.sup.X2B, --OC(O)NR.sup.X2AR.sup.X2B, --OC(S)R.sup.X2B,
--SR.sup.X2B, --SC(O)R.sup.X2B, --SC(S)R.sup.X2B, --C(O)OR.sup.X2B,
--C(O)NR.sup.X2AR.sup.X2B, C(S)NR.sup.X2AR.sup.X2B,
--NR.sup.X2AR.sup.X2B, --S(O)R.sup.X2B, S(O).sub.2R.sup.X2B,
--S(O).sub.2NR.sup.X2AR.sup.X2B, C.sub.1-4 haloaliphatic,
optionally substituted C.sub.3-8 cycloaliphatic, C.sub.1-6
aliphatic; X.sup.4 is N or C--R.sup.B4, X.sup.5 is N or
C--R.sup.B5, X.sup.6 is N or C--R.sup.B6, and X.sup.7 is N or
C--R.sup.B7, where optionally up to two of X.sup.4, X.sup.5,
X.sup.6, and X.sup.7 are N and each of R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is, independently, hydrogen, halogen, --CN,
--NO.sub.2, --OR, --OC(O)R, --OC(O)OR, --OC(O)NRR', --OC(S)R, --SR,
--SC(O)R, --SC(S)R, --C(O)OR, --C(O)NRR', --C(S)NRR', --NRR',
--S(O)R, --S(O).sub.2R, --S(O).sub.2NRR', optionally substituted
C.sub.1-4 haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl; each of R.sup.F and R.sup.G is, independently,
hydrogen, optionally substituted C.sub.1-6 aliphatic, C.sub.1-4
haloaliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3- to
8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to
12-membered bicyclic heteroaryl, or when W is N(R.sup.F), R.sup.F
and R.sup.G and the intervening atoms together optionally form a
N.dbd.C bond; R.sup.H is hydrogen, optionally substituted C.sub.1-6
aliphatic, C.sub.1-4 haloaliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic
heteroaryl, or 8- to 12-membered bicyclic heteroaryl; R.sup.X2A is
hydrogen, optionally substituted C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl, --C(O)R, --C(O)NRR', --C(O)OR, --S(O)R, --S(O).sub.2R,
or --S(O).sub.2NRR'; each of R, R', and R.sup.X2B is,
independently, hydrogen, optionally substituted C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3- to
8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to
12-membered bicyclic heteroaryl; each of said heterocyclyl and
heteroaryl rings contains one to four heteroatoms independently
selected from oxygen, sulfur, or nitrogen; the optional
substituents on one or more carbon atoms of each of said aryl and
heteroaryl groups are: halogen; --R.sup..smallcircle.;
--OR.sup..smallcircle.; --SR.sup..smallcircle.; 1,2-methylenedioxy;
1,2-ethylenedioxy; phenyl optionally substituted with
R.sup..smallcircle.; --O(Ph) optionally substituted with
R.sup..smallcircle.; --(CH.sub.2).sub.1-2(Ph) optionally
substituted with R.sup..smallcircle.; --CH.dbd.CH(Ph) optionally
substituted with R.sup..smallcircle.; --NO.sub.2; --CN;
--N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.C(S)R.sup..smallcircle.;
--NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(S)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.-
2;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.; --C(O)OR.sup..smallcircle.;
--C(O)R.sup..smallcircle.; --C(S)R.sup..smallcircle.;
--C(O)N(R.sup..smallcircle.).sub.2;
--C(S)N(R.sup..smallcircle.).sub.2;
--B(OR.sup..smallcircle.).sub.2,
--OC(O)N(R.sup..smallcircle.).sub.2; --OC(O)R.sup..smallcircle.;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NOR.sup..smallcircle.)R.sup..smallcircle.;
--S(O).sub.2R.sup..smallcircle.; --S(O).sub.2OR.sup..smallcircle.;
--S(O).sub.2N(R.sup..smallcircle.).sub.2;
--S(O)R.sup..smallcircle.;
--NR.sup..smallcircle.S(O).sub.2N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle. S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NH)--N(R.sup..smallcircle.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.sup..smallcircle.;
-L-R.sup..smallcircle.; -L-N(R.sup..smallcircle.).sub.2;
-L-SR.sup..smallcircle.; -L-OR.sup..smallcircle.; -L-(C.sub.3-10
cycloaliphatic), -L-(C.sub.6-10 aryl), -L-(5-10 membered
heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, -L-NO.sub.2, -L-CN, -L-OH,
-L-CF.sub.3; or two substituents, on the same carbon or on
different carbons, together with the carbon or intervening carbons
to which they are bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring, wherein L is a C.sub.1-6
alkylene group in which up to three methylene units are replaced by
--NH--, --NR.sup..smallcircle.--, --O--, --S--, --C(O)O--,
--OC(O)--, --C(O)C(O)--, --C(O)--, --C(O)NH--,
--C(O)NR.sup..smallcircle.--, --C(.dbd.N--CN)--, --NHC(O)--,
--NR.sup..smallcircle.C(O)--, --NHC(O)O--,
--NR.sup..smallcircle.C(O)O--, --S(O).sub.2NH--,
--S(O).sub.2NR.sup..smallcircle.--, --NHS(O).sub.2--,
--NR.sup..smallcircle.S(O).sub.2--, --NHC(O)NH--,
--NR.sup..smallcircle.C(O)NH--, --NHC(O)NR.sup..smallcircle.--,
--NR.sup..smallcircle.C(O)NR.sup..smallcircle., --OC(O)NH--,
--OC(O)NR.sup..smallcircle.--, --NHS(O).sub.2NH--,
--NR.sup..smallcircle.S(O).sub.2NH--,
--NHS(O).sub.2NR.sup..smallcircle.--,
--NR.sup..smallcircle.S(O).sub.2NR.sup..smallcircle.--, --S(O)--,
or --S(O).sub.2--, and wherein each occurrence of
R.sup..smallcircle. is independently selected from hydrogen,
optionally substituted C.sub.1-6 aliphatic, an unsubstituted 5- to
6-membered heteroaryl or heterocyclic ring, phenyl, or
--CH.sub.2(Ph), or, two independent occurrences of
R.sup..smallcircle., on the same substituent or different
substituents, taken together with the atom(s) to which each
R.sup..smallcircle. group is bound, form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered
cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1
to 3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein optional substituents on the aliphatic group of
R.sup..smallcircle. are selected from --NH.sub.2, --NH(C.sub.1-4
aliphatic), --N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, --OH, --O(C.sub.1-4 aliphatic), --NO.sub.2, --CN,
--C(O)OH, C(O)O(C.sub.1-4 aliphatic), O(haloC.sub.1-4 aliphatic),
or haloC.sub.1-4 aliphatic, wherein each of the C.sub.1-4 aliphatic
groups of R.sup..smallcircle. is unsubstituted; and the optional
substituents on one or more carbon atoms of each of said aliphatic,
haloaliphatic, cyclo aliphatic, and heterocyclyl groups are as
defined for said aryl and heteroaryl groups and additionally
comprise: .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2,
.dbd.NNHC(O)R*, .dbd.NNHC(O)O(alkyl), .dbd.NNHS(O).sub.2(alkyl), or
.dbd.NR*, wherein each R* is independently selected from hydrogen
or an optionally substituted C.sub.1-6 aliphatic, and where
optional substituents on said aliphatic group of R* are selected
from --NH.sub.2, --NH(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, --OH, --O(C.sub.1-4
aliphatic), --NO.sub.2, --CN, --C(O)OH, --C(O)O(C.sub.1-4
aliphatic), --O(halo-C.sub.1-4 aliphatic), and halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4 aliphatic
groups of R* is unsubstituted, wherein said disease, condition, or
disorder is allergy, asthma, chronic obstructive pulmonary disease
(COPD), diabetes, osteoarthritis, rheumatoid arthritis, Alzheimer's
disease, Huntington's disease, Parkinson's disease, AIDS-associated
dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis
(MS), schizophrenia, cardiomyocyte hypertrophy, perivascular
fibrosis, benign prostatic hyperplasia, vascular smooth muscle cell
proliferation, endothelial dysfunction,
ischemia/reperfusion-induced injury, stroke, baldness, cancer,
malignoma, hepatomegaly, hypertension, cardiovascular disease,
cardiomegaly, cystic fibrosis, restenosis, psoriasis, inflammation,
hypertension, angina pectoris, cerebrovascular contraction,
peripheral circulation disorder, premature birth, preterm labor,
atherosclerosis, vasospasm, cerebral vasospasm, coronary vasospasm,
retinopathy, neurite outgrowth, glaucoma, erectile dysfunction
(ED), AIDS, a respiratory syncytial viral (RSV) infection,
osteoporosis, Crohn's Disease, colitis, or Raynaud's Disease.
25. The method of claim 24, wherein the compound is represented by
the formula (I-b) or a pharmaceutically acceptable salt thereof:
##STR00201## wherein each of R.sup.H2, R.sup.H3, R.sup.H4,
R.sup.H5, and R.sup.H6 is, independently, hydrogen, halogen, --CN,
--NO.sub.2, --OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR, --OC(S)R,
--SR, --SC(O)R, --SC(S)R, --C(O)OR, --C(O)NRR', --C(S)NRR', --NRR',
--S(O)R, --S(O).sub.2R, --S(O).sub.2NRR', optionally substituted
C.sub.1-4 haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl; and each of R and R' is, independently, hydrogen,
optionally substituted C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic
heteroaryl.
26. The method of claim 25, wherein R.sup.H4 is --OR,
--B(OR).sub.2, --OC(O)R, --OC(O)OR, or --OC(S)R; each of R.sup.B4,
R.sup.B5, and R.sup.B6 is hydrogen; and X.sup.2 is N or C--H.
27. The method of claim 26, wherein R.sup.H4 is --OH.
28. The method of claim 24, wherein W is --N(R.sup.F)--.
29. The method of claim 24, wherein at least one of R.sup.G or
R.sup.H is not hydrogen.
30. The method of claim 29, wherein R.sup.H is an optionally
substituted C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, or 5- to
8-membered monocyclic heteroaryl.
31. The method of claim 30, wherein R.sup.H is an optionally
substituted C.sub.6-10 aryl or 5- to 8-membered monocyclic
heteroaryl.
32. The method of claim 31, wherein the compound is represented by
formula (II-d) or a pharmaceutically acceptable salt thereof:
##STR00202## wherein R.sup.F is hydrogen, optionally substituted
C.sub.1-6 aliphatic, C.sub.1-4 haloaliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl; each of R.sup.H2, R.sup.H3, R.sup.H4, R.sup.H5, and
R.sup.H6 is, independently, hydrogen, halogen, --CN, --NO.sub.2,
--OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR, --OC(S)R, --SR, --SC(O)R,
--SC(S)R, --C(O)OR, --C(O)NRR', --C(S)NRR', --NRR', --S(O)R,
--S(O).sub.2R, --S(O).sub.2NRR', optionally substituted C.sub.1-4
haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic
heteroaryl, 8- to 12-membered bicyclic heteroaryl; and each of R
and R' is, independently, hydrogen, optionally substituted
C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3-
to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to
12-membered bicyclic heteroaryl.
33. The method of claim 32, wherein R.sup.H4 is --OR,
--B(OR).sub.2, --OC(O)R, --OC(O)OR, or --OC(S)R; each of R.sup.B4,
R.sup.B5, and R.sup.B6 is hydrogen; and X.sup.2 is N or C--H.
34. The method of claim 33, wherein R.sup.H4 is --OH.
35. The method of claim 34, wherein the compound is represented by
formula (II-f) or (II-g), or a pharmaceutically acceptable salt
thereof: ##STR00203##
35. The method of claim 34, wherein each of R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is hydrogen.
36. The method of claim 24, wherein each of R.sup.B4, R.sup.B5, and
R.sup.B6 is hydrogen; X.sup.7 is N or C--H; X.sup.2 is N or C--H;
and each of R.sup.B2, R.sup.B3, R.sup.H5, and R.sup.H6 is,
independently, hydrogen, halogen, --CN, --NO.sub.2, --OR,
--B(OR).sub.2, --OC(O)R, --OC(O)OR, --C(O)OR, --C(O)NRR',
--C(S)NRR', --NRR', --S(O).sub.2R, --S(O).sub.2NRR', optionally
substituted C.sub.1-4 haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, wherein each of R and R' is, independently,
hydrogen or optionally substituted C.sub.1-6 aliphatic.
37. The method of claim 24, wherein the compound is any one of the
following compounds or a pharmaceutically acceptable salt thereof:
##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208##
##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213##
##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218##
##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223##
##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228##
##STR00229## ##STR00230## ##STR00231##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
International Patent Application No. PCT/US2007/83134 filed Oct.
31, 2007, which in turn claims the benefit, under 35 U.S.C.
.sctn.111(a), of U.S. Provisional Application No. 60/737,008, filed
on 15 Nov. 2005, and U.S. Provisional Application No. 60/738,646,
filed on 21 Nov. 2005, and U.S. Provisional Application No.
60/855,862, filed on 1 Nov. 2006, the entire contents of each of
the above applications is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as
inhibitors of Janus kinases (JAK). The invention also provides
pharmaceutically acceptable compositions that include the compounds
of the invention and methods of using these compositions in the
treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] The Janus kinases (JAK) are a family of tyrosine kinases
that play a critical role in cytokine signaling. The family
consists of JAK-1, JAK-2, JAK-3 and TYK-2, and the down-stream
substrates of this family of kinases include the signal transducer
and activator of transcription (STAT) proteins. JAK/STAT signaling
has been implicated in the mediation of many abnormal immune
responses, such as allergies and asthma; autoimmune diseases, such
as transplant rejection, rheumatoid arthritis, amyotrophic lateral
sclerosis and multiple sclerosis; as well as in solid and
hematologic malignancies, such as leukemias and lymphomas. JAK-2
has also been implicated in myeloproliferative disorders, which
include polycythemia vera, essential thrombocythemia, chronic
idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis,
chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic
eosinophilic leukemia, hypereosinophilic syndrome, and systematic
mast cell disease.
[0004] Therefore, there is a need to develop compounds that bind to
the JAK family kinases and thereby moderate JAK/STAT signaling.
SUMMARY OF THE INVENTION
[0005] It has been found that compounds of the present invention,
and pharmaceutically acceptable compositions thereof, are effective
as inhibitors of protein kinases, particularly the JAK family
kinases. Accordingly, the invention features compounds having the
formula:
##STR00001##
[0006] or a pharmaceutically acceptable salt or prodrug thereof,
where R.sup.A, R.sup.B, R.sup.C, R.sup.D, R.sup.E, R.sup.F,
R.sup.G, R.sup.H, R.sup.K, W, X.sup.1, X.sup.2, and X.sup.3 are as
defined below.
[0007] The invention also provides pharmaceutical compositions that
include a compound of the invention and a pharmaceutically
acceptable carrier, adjuvant, or vehicle. In addition, the
invention provides methods of treating or lessening the severity of
a disease, condition, or disorder in a patient selected from: a
proliferative disorder, a cardiac disorder, a neurodegenerative
disorder, an autoimmune disorder, a condition associated with organ
transplant, an inflammatory disorder, an immunologically mediated
disorder, or a bone disorder that includes the step of
administering to the patient a therapeutically effective dose of a
compound of the invention or a pharmaceutical composition
thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Terminology
[0008] As used herein, the following definitions shall apply unless
otherwise indicated. For purposes of this invention, the chemical
elements are identified in accordance with the Periodic Table of
the Elements, CAS version, and the Handbook of Chemistry and
Physics, 75.sup.th Ed. 1994. Additionally, general principles of
organic chemistry are described in "Organic Chemistry," Thomas
Sorrell, University Science Books, Sausalito: 1999, and "March's
Advanced Organic Chemistry," 5.sup.th Ed., Smith, M. B. and March,
J., eds. John Wiley & Sons, New York: 2001, the entire contents
of which are hereby incorporated by reference.
[0009] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted," whether preceded by the term
"optionally" or not, refers to the replacement of one or more
hydrogen radicals in a given structure with a non-hydrogen radical
of a specified substituent. Unless otherwise indicated, an
optionally substituted group may have a substituent at each
substitutable position of the group. When more than one position in
a given structure can be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at each position.
[0010] As described herein, when the term "optionally substituted"
precedes a list, said term refers to all of the subsequent
substitutable groups in that list. For example, if X is halogen;
optionally substituted C.sub.1-3 alkyl or phenyl; X may be either
optionally substituted alkyl or optionally substituted phenyl.
Likewise, if the term "optionally substituted" follows a list, said
term also refers to all of the substitutable groups in the prior
list unless otherwise indicated. For example: if X is halogen,
C.sub.1-3 alkyl, or phenyl, wherein X is optionally substituted by
J.sup.X, then both C.sub.1-3 alkyl and phenyl may be optionally
substituted by J.sup.X. As is apparent to one having ordinary skill
in the art, groups such as H, halogen, NO.sub.2, CN, NH.sub.2, OH,
or OCF.sub.3 would not be included because they arc not
substitutable groups. If a substituent radical or structure is not
identified or defined as "optionally substituted," the substituent
radical or structure is unsubstituted.
[0011] Combinations of substituents envisioned by this invention
are preferably those that result in the formation of stable or
chemically feasible compounds. The term "stable," as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and, preferably, their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0012] The term "aliphatic" or "aliphatic group," as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation. Unless otherwise
specified, aliphatic groups contain 1-20 carbon atoms. In some
embodiments, aliphatic groups contain 1-10 carbon atoms. In other
embodiments, aliphatic groups contain 1-8 carbon atoms. In still
other embodiments, aliphatic groups contain 1-6 carbon atoms, and
in yet other embodiments, aliphatic groups contain 1-4 carbon
atoms. Suitable aliphatic groups include, but are not limited to,
linear or branched, substituted or unsubstituted alkyl, alkenyl, or
alkynyl groups. Further examples of aliphatic groups include
methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and
sec-butyl. The terms "alkyl" and the prefix "alk-," as used herein,
are inclusive of both straight chain and branched saturated carbon
chain. The term "alkylene," as used herein, represents a saturated
divalent hydrocarbon group derived from a straight or branched
chain saturated hydrocarbon by the removal of two hydrogen atoms,
and is exemplified by methylene, ethylene, isopropylene and the
like. The term "alkenyl," as used herein, represents monovalent
straight or branched chain hydrocarbon group containing one or more
carbon-carbon double bonds. The term "alkynyl," as used herein,
represents a monovalent straight or branched chain hydrocarbon
group containing one or more carbon-carbon triple bonds.
[0013] The term "cycloaliphatic" (or "carbocycle") refers to a
monocyclic C.sub.3-C.sub.8 hydrocarbon or bicyclic C.sub.8-C.sub.12
hydrocarbon that is completely saturated or that contains one or
more units of unsaturation, but which is not aromatic, that has a
single point of attachment to the rest of the molecule, and wherein
any individual ring in said bicyclic ring system has 3-7 members.
Suitable cycloaliphatic groups include, but are not limited to,
cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of
aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, and cycloheptenyl.
[0014] The term "heterocycle," "heterocyclyl,"
"heterocycloaliphatic," or "heterocyclic" as used herein refers to
a monocyclic, bicyclic, or tricyclic ring system in which one or
more ring members are an independently selected heteroatom and that
is completely saturated or that contains one or more units of
unsaturation, but which is not aromatic, that has a single point of
attachment to the rest of the molecule. In some embodiments, the
"heterocycle," "heterocyclyl," "heterocycloaliphatic," or
"heterocyclic" group has three to fourteen ring members in which
one or more ring members is a heteroatom independently selected
from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the
system contains 3 to 8 ring members.
[0015] Examples of heterocyclic rings include, but are not limited
to, the following monocycles: 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,
2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,
3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,
5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5-imidazolidinyl; and the following bicycles:
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,
benzodithiane, and 1,3-dihydro-imidazol-2-one.
[0016] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon, including any oxidized form of
nitrogen, sulfur, or phosphorus; the quaternized form of any basic
nitrogen; or a substitutable nitrogen of a heterocyclic ring, for
example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl)
or NR.sup.+ (as in N-substituted pyrrolidinyl).
[0017] The term "unsaturated," as used herein, means that a moiety
has one or more units of unsaturation.
[0018] The term "alkoxy," or "thioalkyl," as used herein, refers to
an alkyl group, as previously defined, attached to the principal
carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl")
atom.
[0019] The terms "haloalkyl," "haloalkenyl," and "haloalkoxy" means
alkyl, alkenyl, or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br, or
I.
[0020] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic,
bicyclic, and tricyclic carbocyclic ring systems having a total of
six to fourteen ring members, wherein at least one ring in the
system is aromatic, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "aryl" may be used interchangeably with
the term "aryl ring." Examples of aryl rings would include phenyl,
naphthyl, and anthracene.
[0021] The term "heteroaryl," used alone or as part of a larger
moiety as in "heteroaralkyl," or "heteroarylalkoxy," refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, wherein each ring in the system contains 3 to 7
ring members and that has a single point of attachment to the rest
of the molecule. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic."
[0022] Further examples of heteroaryl rings include the following
monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,
3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl
(e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and
5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl),
isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl,
and the following bicycles: benzimidazolyl, benzofuryl,
benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl
(e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl
(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[0023] In some embodiments, an aryl (including aralkyl, aralkoxy,
aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl,
heteroarylalkoxy, and the like) group may contain one or more
substituents. Suitable substituents on the unsaturated carbon atom
of an aryl or heteroaryl group include: halogen;
--R.sup..smallcircle.; --OR.sup..smallcircle.;
--SR.sup..smallcircle.; 1,2-methylenedioxy; 1,2-ethylenedioxy;
phenyl (Ph) optionally substituted with R.sup..smallcircle.;
--O(Ph) optionally substituted with R.sup..smallcircle.;
--(CH.sub.2).sub.1-2(Ph), optionally substituted with
R.sup..smallcircle.; --CH.dbd.CH(Ph), optionally substituted with
R.sup..smallcircle.; --NO.sub.2; --CN;
--N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.C(S)R.sup..smallcircle.;
--NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(S)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.-
2;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.; --C(O)OR.sup..smallcircle.;
--C(O)R.sup..smallcircle.; --C(S)R.sup..smallcircle.;
--C(O)N(R.sup..smallcircle.).sub.2;
--C(S)N(R.sup..smallcircle.).sub.2;
--B(OR.sup..smallcircle.).sub.2;
--OC(O)N(R.sup..smallcircle.).sub.2; --OC(O)R.sup..smallcircle.;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(NOR.sup..smallcircle.)R.sup..smallcircle.;
--S(O).sub.2R.sup..smallcircle.; --S(O).sub.3R.sup..smallcircle.;
--S(O).sub.2N(R.sup..smallcircle.).sub.2;
--S(O)R.sup..smallcircle.;
--NR.sup..smallcircle.S(O).sub.2N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NH)--N(R.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-2NHC(O)R.sup..smallcircle.;
-L-R.sup..smallcircle.; -L-N(R.sup..smallcircle.).sub.2;
-L-SR.sup..smallcircle.; -L-OR.sup..smallcircle.; -L-(C.sub.3-10
cycloaliphatic), -L-(C.sub.6-10 aryl), -L-(5-10 membered
heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, -L-NO.sub.2, -L-CN, -L-OH,
-L-CF.sub.3; or two substituents, on the same carbon or on
different carbons, together with the carbon or intervening carbons
to which they are bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring, wherein L is a C.sub.1-6
alkylene group in which up to three methylene units are replaced by
--NH--, --NR.sup..smallcircle.--, --O--, --S--, --C(O)O--,
--OC(O)--, --C(O)CO--, --C(O)--, --C(O)NH--,
--C(O)NR.sup..smallcircle.--, --C(.dbd.N--CN), --NHCO--,
--NR.sup..smallcircle.CO--, --NHC(O)O--,
--NR.sup..smallcircle.C(O)O--, --S(O).sub.2NH--,
--S(O).sub.2NR.sup..smallcircle.--, --NHS(O).sub.2--,
--NR.sup..smallcircle.S(O).sub.2--, --NHC(O)NH--,
--NR.sup..smallcircle.C(O)NH--, --NHC(O)NR.sup..smallcircle.--,
--NR.sup..smallcircle.C(O)NR.sup..smallcircle., --OC(O)NH--,
--OC(O)NR.sup..smallcircle.--, --NHS(O).sub.2NH--,
--NR.sup..smallcircle.S(O).sub.2NH--,
--NHS(O).sub.2NR.sup..smallcircle.--,
--NR.sup..smallcircle.S(O).sub.2NR.sup..smallcircle.--, --S(O)--,
or --S(O).sub.2--, and wherein each occurrence of
R.sup..smallcircle. is independently selected from hydrogen,
optionally substituted C.sub.1-6 aliphatic, an unsubstituted 5- to
6-membered heteroaryl or heterocyclic ring, phenyl, or
--CH.sub.2(Ph), or, two independent occurrences of
R.sup..smallcircle., on the same substituent or different
substituents, taken together with the atom(s) to which each
R.sup..smallcircle. group is bound, form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered
cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1
to 3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group of
R.sup..smallcircle. are selected from --NH.sub.2, --NH(C.sub.1-4
aliphatic), --N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, --OH, --O(C.sub.1-4 aliphatic), --NO.sub.2, --CN,
--C(O)OH, --C(O)O(C.sub.1-4 aliphatic), --O(haloC.sub.1-4
aliphatic), or haloC.sub.1-4 aliphatic, wherein each of the
foregoing C.sub.1-4 aliphatic groups of R.sup..smallcircle. is
unsubstituted.
[0024] In some embodiments, an aliphatic or heteroaliphatic group,
or a non-aromatic heterocyclic ring may contain one or more
substituents. Suitable substituents on the saturated carbon of an
aliphatic or heteroaliphatic group, or of a non-aromatic
heterocyclic ring are selected from those listed above for the
unsaturated carbon of an aryl or heteroaryl group and additionally
include the following: .dbd.O, .dbd.S, .dbd.NNHR*,
.dbd.NN(R*).sub.2, .dbd.NNHC(O)R*, .dbd.NNHC(O)O(alkyl),
.dbd.NNHS(O).sub.2(alkyl), or .dbd.NR*, where each R* is
independently selected from hydrogen or an optionally substituted
C.sub.1-6 aliphatic. Optional substituents on the aliphatic group
of R* are selected from --NH.sub.2, --NH(C.sub.1-4 aliphatic),
--N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, --OH,
--O(C.sub.1-4 aliphatic), --NO.sub.2, --CN, --C(O)OH,
--C(O)O(C.sub.1-4 aliphatic), --O(halo-C.sub.1-4 aliphatic), and
halo(C.sub.1-4 aliphatic), where each of the foregoing C.sub.1-4
aliphatic groups of R* is unsubstituted.
[0025] In some embodiments, optional substituents on the nitrogen
of a non-aromatic heterocyclic ring include --R.sup.+,
--N(R.sup.+).sub.2, --C(O)R.sup.+, --C(O)OR.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --S(O).sub.2R.sup.+,
--S(O).sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+S(O).sub.2R.sup.+;
wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6
aliphatic, optionally substituted phenyl, optionally substituted
--O(Ph), optionally substituted --CH.sub.2(Ph), optionally
substituted --(CH.sub.2).sub.1-2(Ph); optionally substituted
--CH.dbd.CH(Ph); or an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, two independent
occurrences of R.sup.+, on the same substituent or different
substituents, taken together with the atom(s) to which each R.sup.+
group is bound, form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said
heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Optional substituents on
the aliphatic group or the phenyl ring of R.sup.+ are selected from
--NH.sub.2, --NH(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, --OH, --O(C.sub.1-4
aliphatic), --NO.sub.2, --CN, --C(O)OH, --C(O)O(C.sub.1-4
aliphatic), --O(halo C.sub.1-4 aliphatic), or halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4 aliphatic
groups of R.sup.+ is unsubstituted.
[0026] As detailed above, in some embodiments, two independent
occurrences of R.sup..smallcircle. (or R.sup.+, or any other
variable similarly defined herein), may be taken together with the
atom(s) to which each variable is bound to form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl
ring. Exemplary rings that are formed when two independent
occurrences of R.sup..smallcircle. (or R.sup.+, or any other
variable similarly defined herein) are taken together with the
atom(s) to which each variable is bound include, but are not
limited to the following: a) two independent occurrences of
R.sup..smallcircle. (or R.sup.+, or any other variable similarly
defined herein) that are bound to the same atom and are taken
together with that atom to form a ring, for example,
N(R.sup..smallcircle.).sub.2, where both occurrences of
R.sup..smallcircle. are taken together with the nitrogen atom to
form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and
b) two independent occurrences of R.sup..smallcircle. (or R.sup.+,
or any other variable similarly defined herein) that are bound to
different atoms and are taken together with both of those atoms to
form a ring, for example where a phenyl group is substituted with
two occurrences of OR.sup..smallcircle.
##STR00002##
these two occurrences of R.sup..smallcircle. are taken together
with the oxygen atoms to which they are bound to form a fused
6-membered oxygen containing ring:
##STR00003##
It will be appreciated that a variety of other rings can be formed
when two independent occurrences of R.sup..smallcircle. (or
R.sup.+, or any other variable similarly defined herein) are taken
together with the atom(s) to which each variable is bound and that
the examples detailed above are not intended to be limiting.
[0027] In some embodiments, an alkyl or aliphatic chain can be
optionally interrupted with another atom or group. This means that
a methylene unit of the alkyl or aliphatic chain is optionally
replaced with said other atom or group. Examples of such atoms or
groups would include, but are not limited to, --NR--, --O--, --S--,
--C(O)O--, --OC(O)--, --C(O)CO--, --C(O)--, --C(O)NR--,
--C(.dbd.N--CN)--, --NRCO--, --NRC(O)O--, --S(O).sub.2NR--,
--NRS(O).sub.2--, --NRC(O)NR--, --OC(O)NR--, --NRS(O).sub.2NR--,
--S(O)--, or --S(O).sub.2--, wherein R is defined herein. Unless
otherwise specified, the optional replacements form a chemically
stable compound. Optional interruptions can occur both within the
chain and at either end of the chain; i.e. both at the point of
attachment and/or also at the terminal end. Two optional
replacements can also be adjacent to each other within a chain so
long as it results in a chemically stable compound. Unless
otherwise specified, if the replacement or interruption occurs at
the terminal end, the replacement atom is bound to an H on the
terminal end. For example, if --CH.sub.2CH.sub.2CH.sub.3 were
optionally interrupted with --O--, the resulting compound could be
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3, or
--CH.sub.2CH.sub.2OH.
[0028] As described herein, a bond drawn from a substituent to the
center of one ring within a multiple-ring system (as shown below),
represents substitution of the substituent at any substitutable
position in any of the rings within the multiple ring system. For
example, Figure a represents possible substitution in any of the
positions shown in Figure b.
##STR00004##
[0029] This also applies to multiple ring systems fused to optional
ring systems (which would be represented by dotted lines). For
example, in Figure c, X is an optional substituent both for ring A
and ring B.
##STR00005##
[0030] If, however, two rings in a multiple ring system each have
different substituents drawn from the center of each ring, then,
unless otherwise specified, each substituent only represents
substitution on the ring to which it is attached. For example, in
Figure d, Y is an optionally substituent for ring A only, and X is
an optional substituent for ring B only.
##STR00006##
[0031] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention.
[0032] The term "protecting group," as used herein, represent those
groups intended to protect a functional group, such as, for
example, an alcohol, amine, carboxyl, carbonyl, etc., against
undesirable reactions during synthetic procedures. Commonly used
protecting groups are disclosed in Greene and Wuts, Protective
Groups In Organic Synthesis, 3.sup.rd Edition (John Wiley &
Sons, New York, 1999), which is incorporated herein by reference.
Examples of nitrogen protecting groups include acyl, aroyl, or
carbamyl groups such as formyl, acetyl, propionyl, pivaloyl,
t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,
trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,
.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
4-nitrobenzoyl and chiral auxiliaries such as protected or
unprotected D, L or D, L-amino acids such as alanine, leucine,
phenylalanine and the like; sulfonyl groups such as
benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming
groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,
phenoxycarbonyl, 4-nitrophenoxy carbonyl,
fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and
the like, arylalkyl groups such as benzyl, triphenylmethyl,
benzyloxymethyl and the like and silyl groups such as
trimethylsilyl and the like. Preferred N-protecting groups are
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,
phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and
benzyloxycarbonyl (Cbz).
[0033] The term "prodrug," as used herein, represents a compound
which is transformed in vivo into a compound of the invention. Such
a transformation can be affected, for example, by hydrolysis in
blood or enzymatic transformation of the prodrug form to the parent
form in blood or tissue. Prodrugs of the compounds of the invention
may be, for example, esters. Esters that may be utilized as
prodrugs in the present invention are phenyl esters, aliphatic
(C.sub.1-C.sub.24) esters, acyloxymethyl esters, carbonates,
carbamates, and amino acid esters. For example, a compound of the
invention that contains an OH group may be acylated at this
position in its prodrug form. Other prodrug forms include
phosphates, such as, for example those phosphates resulting from
the phosphonation of an OH group on the parent compound. A thorough
discussion of prodrugs is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in
Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, and Judkins et al., Synthetic Communications
26(23):4351-4367, 1996, each of which is incorporated herein by
reference.
[0034] Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
Description of Compounds of the Invention
[0035] In one aspect, the present invention features compounds
having the formula:
##STR00007##
wherein [0036] W is --N(R.sup.F)--, --C(X)N(R.sup.F)-- or
--N(R.sup.F)C(X)--; [0037] X is O, S, [hydrogen, hydrogen] or
[hydrogen, R]; [0038] X.sup.2 is N or C--R.sup.X2, wherein R.sup.X2
is hydrogen, halogen, --CN, --NO.sub.2, --OR.sup.X2B,
--OC(O)R.sup.X2B, --OC(O)OR.sup.X2B, --OC(O)NR.sup.X2AR.sup.X2B,
OC(S)R.sup.X2B, --SR.sup.X2B, --SC(O)R.sup.X2B, --SC(S)R.sup.X2B,
--C(O)OR.sup.X2B, --C(O)NR.sup.X2AR.sup.X2B,
--C(S)NR.sup.X2AR.sup.X2B, --NR.sup.X2AR.sup.X2B,
--S(O)R.sup.X2BR.sup.X2B, --S(O).sub.2R.sup.X2B,
--S(O).sub.2NR.sup.X2AR.sup.X2B, C.sub.1-4 haloaliphatic,
optionally substituted C.sub.3-8 cycloaliphatic, C.sub.1-6
aliphatic; [0039] X.sup.4 is N or C--R.sup.B4, X.sup.5 is N or
C--R.sup.B5, X.sup.6 is N or C--R.sup.B6, and X.sup.7 is N or
C--R.sup.B7, where optionally up to two of X.sup.4, X.sup.5,
X.sup.6, and X.sup.7 are N and each of R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is, independently, hydrogen, halogen, --CN,
--NO.sub.2, --OR, --OC(O)R, --OC(O)OR, --OC(O)NRR, --OC(S)R, --SR,
--SC(O)R, --SC(S)R, --C(O)OR, --C(O)NRR, --C(S)NRR, --NRR, --S(O)R,
--S(O).sub.2R, --S(O).sub.2NRR, optionally substituted C.sub.1-4
haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic
heteroaryl, 8- to 12-membered bicyclic heteroaryl; [0040] each of
R.sup.F and R.sup.G is, independently, hydrogen, optionally
substituted C.sub.1-6 aliphatic, C.sub.1-4 haloaliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl, or when W is N(R.sup.F), R.sup.F and R.sup.G and the
intervening atoms together optionally form a N.dbd.C bond; [0041]
R.sup.H is hydrogen, optionally substituted C.sub.1-6 aliphatic,
C.sub.1-4 haloaliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl,
3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered
bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or
8- to 12-membered bicyclic heteroaryl; [0042] R.sup.X2A is
hydrogen, optionally substituted C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to
8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic
heteroaryl, --C(O)R, --C(O)NRR, --C(O)OR, --S(O)R, --S(O).sub.2R,
or --S(O).sub.2NRR; [0043] each of R, R, and R.sup.X2B is,
independently, hydrogen, optionally substituted C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, C.sub.6-10 aryl, 3- to
8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic
heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to
12-membered bicyclic heteroaryl; [0044] each of said heterocyclyl
and heteroaryl rings contains one to four heteroatoms independently
selected from oxygen, sulfur, or nitrogen; [0045] the optional
substituents on one or more carbon atoms of each of said aryl and
heteroaryl groups are: halogen; --R.sup..smallcircle.;
--OR.sup..smallcircle.; --SR.sup..smallcircle.; 1,2-methylenedioxy;
1,2-ethylenedioxy; phenyl optionally substituted with
R.sup..smallcircle.; --O(Ph) optionally substituted with
R.sup..smallcircle.; --(CH.sub.2).sub.1-2(Ph) optionally
substituted with R.sup..smallcircle.; --CH.dbd.CH(Ph) optionally
substituted with R.sup..smallcircle.; --NO.sub.2; --CN;
--N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.C(S)R.sup..smallcircle.;
--NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(S)N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)R.sup..smallcircle.;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)N(R.sup..smallcircle.).sub.-
2;
--NR.sup..smallcircle.NR.sup..smallcircle.C(O)OR.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.; --C(O)OR.sup..smallcircle.;
--C(O)R.sup..smallcircle.; --C(S)R.sup..smallcircle.;
--C(O)N(R.sup..smallcircle.).sub.2;
--C(S)N(R.sup..smallcircle.).sub.2;
--B(OR.sup..smallcircle.).sub.2,
--OC(O)N(R.sup..smallcircle.).sub.2; --OC(O)R.sup..smallcircle.;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NOR.sup..smallcircle.)R.sup..smallcircle.;
--S(O).sub.2R.sup..smallcircle.; --S(O).sub.2OR.sup..smallcircle.;
--S(O).sub.2N(R.sup..smallcircle.).sub.2;
--S(O)R.sup..smallcircle.;
--NR.sup..smallcircle.S(O).sub.2N(R.sup..smallcircle.).sub.2;
--NR.sup..smallcircle.S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(.dbd.NH)--N(R.sup..smallcircle.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.sup..smallcircle.;
-L-R.sup..smallcircle.; -L-N(R.sup..smallcircle.).sub.2;
-L-SR.sup..smallcircle.; -L-OR.sup..smallcircle.; -L-(C.sub.3-10
cycloaliphatic), -L-(C.sub.6-10 aryl), -L-(5-10 membered
heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, -L-NO.sub.2, -L-CN, -L-OH,
-L-CF.sub.3; or two substituents, on the same carbon or on
different carbons, together with the carbon or intervening carbons
to which they are bound, form a 5-7 membered saturated,
unsaturated, or partially saturated ring, wherein L is a C.sub.1-6
alkylene group in which up to three methylene units are replaced by
--NH--, --NR.sup..smallcircle.--, --O--, --S--, --C(O)O--,
--OC(O)--, --C(O)C(O)--, --C(O)--, --C(O)NH--,
--C(O)NR.sup..smallcircle.--, --C(.dbd.N--CN)--, --NHC(O)--,
--NR.sup..smallcircle.C(O)--, --NHC(O)O--,
--NR.sup..smallcircle.C(O)O--, --S(O).sub.2NH--,
--S(O).sub.2NR.sup..smallcircle.--, --NHS(O).sub.2--,
--NR.sup..smallcircle.S(O).sub.2--, --NHC(O)NH--,
--NR.sup..smallcircle.C(O)NH--, --NHC(O)NR.sup..smallcircle.--,
--NR.sup..smallcircle.C(O)NR.sup..smallcircle., --OC(O)NH--,
--OC(O)NR.sup..smallcircle.--, --NHS(O).sub.2NH--,
--NR.sup..smallcircle.S(O).sub.2NH--,
--NHS(O).sub.2NR.sup..smallcircle.--,
--NR.sup..smallcircle.S(O).sub.2NR.sup..smallcircle.--, --S(O)--,
or --S(O).sub.2--, and wherein each occurrence of
R.sup..smallcircle. is independently selected from hydrogen,
optionally substituted C.sub.1-6 aliphatic, an unsubstituted 5- to
6-membered heteroaryl or heterocyclic ring, phenyl, or
--CH.sub.2(Ph), or, two independent occurrences of
R.sup..smallcircle., on the same substituent or different
substituents, taken together with the atom(s) to which each
R.sup..smallcircle. group is bound, form a 5-8-membered
heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered
cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1
to 3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein optional substituents on the aliphatic group of
R.sup..smallcircle. are selected from --NH.sub.2, --NH(C.sub.1-4
aliphatic), --N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, --OH, --O(C.sub.1-4 aliphatic), --NO.sub.2, --CN,
--C(O)OH, C(O)O(C.sub.1-4 aliphatic), O(haloC.sub.1-4 aliphatic),
or haloC.sub.1-4 aliphatic, wherein each of the C.sub.1-4 aliphatic
groups of R.sup..smallcircle. is unsubstituted; and [0046] the
optional substituents on one or more carbon atoms of each of said
aliphatic, haloaliphatic, cyclo aliphatic, and heterocyclyl groups
are as defined for said aryl and heteroaryl groups and additionally
comprise: .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2,
.dbd.NNHC(O)R*, .dbd.NNHC(O)O(alkyl), .dbd.NNHS(O).sub.2(alkyl), or
.dbd.NR*, wherein each R* is independently selected from hydrogen
or an optionally substituted C.sub.1-6 aliphatic, and where
optional substituents on said aliphatic group of R* are selected
from --NH.sub.2, --NH(C.sub.1-4 aliphatic), --N(C.sub.1-4
aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, --OH, --O(C.sub.1-4
aliphatic), --NO.sub.2, --CN, --C(O)OH, --C(O)O(C.sub.1-4
aliphatic), --O(halo-C.sub.1-4 aliphatic), and halo(C.sub.1-4
aliphatic), wherein each of the foregoing C.sub.1-4 aliphatic
groups of R* is unsubstituted.
[0047] In one embodiment, a compound of formula I-a has the
formula:
##STR00008##
wherein each of R.sup.II2, R.sup.II3, R.sup.II4, R.sup.II5, and
R.sup.II6 is, independently, hydrogen, halogen, --CN, --NO.sub.2,
--OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR, --OC(S)R, --SR, --SC(O)R,
--SC(S)R, --C(O)OR, --C(O)NRR, --C(S)NRR, --NRR, --S(O)R,
--S(O).sub.2R, --S(O).sub.2NRR, optionally substituted C.sub.1-4
haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic
heteroaryl, 8- to 12-membered bicyclic heteroaryl. In a further
embodiment, R.sup.H4 is --OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR,
or --OC(S)R; each of R.sup.B4, R.sup.B5, and R.sup.B6 is hydrogen;
and X.sup.2 is N or C--H. Desirably, R.sup.H4 is --OH. In another
further embodiment, one or both of R.sup.H3 and R.sup.H5 is a
halogen. In yet another example, both of R.sup.H3 and R.sup.H5 is a
halogen, such as, for example, fluorine.
[0048] In another embodiment of a compound of formula I-a, W is
--N(R.sup.F)--. In another embodiment, at least one of R.sup.G or
R.sup.H is not hydrogen. In a further embodiment, R.sup.H is an
optionally substituted C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, C.sub.6-10 aryl, 3- to 8-membered monocyclic
heterocyclyl, or 5- to 8-membered monocyclic heteroaryl. Further
still, R.sup.H is an optionally substituted C.sub.6-10 aryl or 5-
to 8-membered monocyclic heteroaryl.
[0049] In yet another embodiment of a compound of formula I-a, or a
pharmaceutically acceptable salt thereof, the compound has the
formula:
##STR00009##
wherein each of R.sup.H2, R.sup.H3, R.sup.H4, R.sup.H5, and
R.sup.H6 is, independently, hydrogen, halogen, --CN, --NO.sub.2,
--OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR, --OC(S)R, --SR, --SC(O)R,
--SC(S)R, --C(O)OR, --C(O)NRR, --C(S)NRR, --NRR, --S(O)R,
--S(O).sub.2R, --S(O).sub.2NRR, optionally substituted C.sub.1-4
haloaliphatic, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
C.sub.6-10 aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to
12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic
heteroaryl, 8- to 12-membered bicyclic heteroaryl.
[0050] In a further embodiment of compounds of formula II-a,
R.sup.H4 is --OR, --B(OR).sub.2, --OC(O)R, --OC(O)OR, or --OC(S)R;
each of R.sup.B4, R.sup.B5, and R.sup.B6 is hydrogen; and X.sup.2
is N or C--H. Further still, in another embodiment, R.sup.H4 is
--OH.
[0051] In another embodiment, compounds of formula I-a have the
formula:
##STR00010##
In a further embodiment of compounds of formula II-f or II-g, each
of R.sup.B4, R.sup.B5, R.sup.B6 and R.sup.B7 is hydrogen.
[0052] In another embodiment for any of the compounds of the
invention, each of R.sup.B4, R.sup.B5, and R.sup.B6 is hydrogen;
X.sup.7 is N or C--H; X.sup.2 is N or C--H; and each of R.sup.H2,
R.sup.H3, R.sup.H5, and R.sup.H6 is, independently, hydrogen,
halogen, --CN, --NO.sub.2, --OR, --B(OR).sub.2, --OC(O)R,
--OC(O)OR, --C(O)OR, --C(O)NRR, --C(S)NRR, --NRR, --S(O).sub.2R,
--S(O).sub.2NRR, optionally substituted C.sub.1-4 haloaliphatic,
C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic, wherein each of R
and R is, independently, hydrogen or optionally substituted
C.sub.1-6 aliphatic.
[0053] In another aspect, the invention features a compound
selected from the group of compounds listed in Table 1.
[0054] JAK-2 and JAK-3 inhibition assays were performed as
described elsewhere herein. Table 1 presents enzyme inhibition data
for certain exemplary compounds, where "A" represents a K.sub.i of
0.25 .mu.M or less, "B" represents a K.sub.i of greater than 0.25
.mu.M and less than or equal to 2.5 and "C" represents a K.sub.i
value of greater than 2.5 .mu.M.
TABLE-US-00001 TABLE 1 JAK- JAK- Structure 2 3 ##STR00011## 1 C B
##STR00012## 2 C C ##STR00013## 3 C B ##STR00014## 4 C C
##STR00015## 5 B B ##STR00016## 6 B B ##STR00017## 7 A B
##STR00018## 8 B B ##STR00019## 9 B B ##STR00020## 10 C C
##STR00021## 11 A B ##STR00022## 12 B B ##STR00023## 13 B B
##STR00024## 14 B B ##STR00025## 15 C C ##STR00026## 16 B C
##STR00027## 17 B B ##STR00028## 18 A B ##STR00029## 19 B B
##STR00030## 20 B B ##STR00031## 21 B B ##STR00032## 22 A B
##STR00033## 23 B B ##STR00034## 24 B B ##STR00035## 25 A B
##STR00036## 26 A B ##STR00037## 27 A A ##STR00038## 28 B B
##STR00039## 29 B B ##STR00040## 30 A A ##STR00041## 31 A B
##STR00042## 32 B C ##STR00043## 33 B B ##STR00044## 34 B B
##STR00045## 35 B B ##STR00046## 36 B B ##STR00047## 37 C C
##STR00048## 38 B B ##STR00049## 39 A B ##STR00050## 40 B B
##STR00051## 41 B C ##STR00052## 42 B B ##STR00053## 43 B C
##STR00054## 44 A B ##STR00055## 45 A B ##STR00056## 46 A A
##STR00057## 47 B B ##STR00058## 48 B B ##STR00059## 49 A B
##STR00060## 50 B C ##STR00061## 51 B B ##STR00062## 52 B B
##STR00063## 53 A A ##STR00064## 54 A B ##STR00065## 55 A A
##STR00066## 56 A A ##STR00067## 57 A A ##STR00068## 58 B B
##STR00069## 59 B C ##STR00070## 60 B C ##STR00071## 61 A A
##STR00072## 62 A A ##STR00073## 63 A A ##STR00074## 64 A A
##STR00075## 65 A A ##STR00076## 66 A A ##STR00077## 67 A A
##STR00078## 68 A A ##STR00079## 69 A A ##STR00080## 70 A B
##STR00081## 71 A A ##STR00082## 72 C B ##STR00083## 73 A A
##STR00084## 74 A A ##STR00085## 75 A A ##STR00086## 76 A A
##STR00087## 77 A A ##STR00088## 78 B B ##STR00089## 79 B B
##STR00090## 80 C C ##STR00091## 81 A A ##STR00092## 82 A A
##STR00093## 83 A A ##STR00094## 84 A A ##STR00095## 85 B B
##STR00096## 86 C C ##STR00097## 87 C C ##STR00098## 88 C C
##STR00099## 89 B C ##STR00100## 90 B B ##STR00101## 91 C C
##STR00102## 92 A A ##STR00103## 93 A A ##STR00104## 94 A A
##STR00105## 95 A A ##STR00106## 96 A B ##STR00107## 97 A A
##STR00108## 98 A B ##STR00109## 99 C B ##STR00110## 100 C B
##STR00111## 101 C C ##STR00112## 102 C C ##STR00113## 103 A A
##STR00114## 104 B B ##STR00115## 105 A A ##STR00116## 106 A A
##STR00117## 107 A A ##STR00118## 108 C C ##STR00119## 109 B B
##STR00120## 110 C C ##STR00121## 111 C C ##STR00122## 112 A A
##STR00123## 113 A A ##STR00124## 114 B B ##STR00125## 115 A A
##STR00126## 116 A A ##STR00127## 117 A A ##STR00128## 118 A A
##STR00129## 119 B B ##STR00130## 120 C C ##STR00131## 121 C C
##STR00132## 122 C C
##STR00133## 123 B C ##STR00134## 124 B B ##STR00135## 125 A A
##STR00136## 126 C C ##STR00137## 127 A B ##STR00138## 128 A A
##STR00139## 129 C C ##STR00140## 130 A B ##STR00141## 131 A B
##STR00142## 132 C C ##STR00143## 133 A A ##STR00144## 134 B B
##STR00145## 135 A A ##STR00146## 136 C C ##STR00147## 137 B C
##STR00148## 138 C C ##STR00149## 139 B B ##STR00150## 140 A A
##STR00151## 141 A B ##STR00152## 142 C C ##STR00153## 143 C C
##STR00154## 144 B C ##STR00155## 145 A B ##STR00156## 146 A A
##STR00157## 147 C C ##STR00158## 148 B B ##STR00159## 149 B C
##STR00160## 150 A A ##STR00161## 151 B B ##STR00162## 152 C C
##STR00163## 153 C C ##STR00164## 154 A A ##STR00165## 155 A A
##STR00166## 156 B B ##STR00167## 157 A A ##STR00168## 158 A A
##STR00169## 159 A A ##STR00170## 160 A A ##STR00171## 161 A B
##STR00172## 162 B B
[0055] In another aspect, the invention features a process for the
preparation of a compound having the formula:
##STR00173##
where X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, R.sup.F,
R.sup.G, and R.sup.H are as defined above for a compound of formula
I-a. The process includes the following steps: (a) reacting a
compound having the formula:
##STR00174##
with a compound having the formula:
##STR00175##
where Z is Cl, Br, I, --OP(O)(OR).sub.2, --OTs, or --OTf; M is
--B(OR).sub.2, --SnR.sub.3, --SiR.sub.3, --ZnR.sub.2, --Mg-Hal,
--Zn-Hal, --Cu-Hal, --ZrCp.sub.2Hal, or --AlR.sub.2, where each R
is, independently, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic,
or C.sub.6-10 aryl; and P is a protecting group, to produce a
compound having the formula:
##STR00176##
(b) removing protecting group P to produce a compound having the
formula:
##STR00177##
and (c) reacting the compound of formula V-a with a compound having
the formula:
##STR00178##
under acidic conditions to produce the compound of formula
II-b.
[0056] In one embodiment, the compound of formula II-b has the
formula:
##STR00179##
[0057] In another aspect, the invention features a process for the
preparation of a compound of having the formula:
##STR00180##
where X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, R.sup.F and
R.sup.H are as defined above for a compound of formula I-a. The
process includes the following steps: [0058] (a) reacting a
compound having the formula:
##STR00181##
[0058] with a compound having the formula:
##STR00182##
wherein
Z is, Cl, Br, I, --OP(O)(OR).sub.2, --OTs, or --OTf and M is
--B(OR).sub.2, --SnR.sub.3, --SiR.sub.3, --ZnR.sub.2,
[0059] --Mg-Hal, --Zn-Hal, --CuHal, --ZrCp.sub.2Hal, or
--AlR.sub.2, where each R is, independently, C.sub.1-6 aliphatic,
C.sub.3-8 cycloaliphatic, or C.sub.6-10 aryl, to produce a compound
having the formula:
##STR00183## [0060] (b) subjecting said compound of formula V-b to
dehydration conditions to produce an intermediate having the
formula:
##STR00184##
[0060] and [0061] (c) reacting said intermediate of formula II-c
with a reducing agent to produce said compound having formula
II-d.
[0062] In one embodiment, each of X.sup.2, X.sup.4, X.sup.5,
X.sup.6, X.sup.7 is C--H.
[0063] In one example, the process provides a compound of formula
II-d having the formula:
##STR00185##
[0064] In another example, R.sup.F is hydrogen and step (c) is not
performed, such that the process produces a compound having the
formula:
##STR00186##
[0065] For compounds of formulae II-f and II-g, R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is as defined for a compound of formula I-a.
In one embodiment, X.sup.2 is C--H and each of R.sup.B4, R.sup.B5,
R.sup.B6, and R.sup.B7 is hydrogen.
Compositions, Formulations, and Administration of Compounds of the
Invention
[0066] The invention also provides pharmaceutical compositions that
include a compound of the invention and a pharmaceutically
acceptable carrier, adjuvant, or vehicle. In one embodiment, the
composition further includes a therapeutic agent selected from: a
chemotherapeutic or anti-proliferative agent, an anti-inflammatory
agent, an immunomodulatory or immunosuppressive agent, a
neurotrophic factor, an agent for treating cardiovascular disease,
an agent for treating destructive bone disorders, an agent for
treating liver disease, an anti-viral agent, an agent for treating
blood disorders, an agent for treating diabetes, or an agent for
treating immunodeficiency disorders. Desirably, the therapeutic
agent is an immunomodulatory or immunosuppressive agent.
[0067] The invention also features the use of a compound of the
invention, or a pharmaceutical composition thereof, for treating or
lessening the severity of a disease, condition, or disorder in a
patient selected from: a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplant, an inflammatory
disorder, an immunologically mediated disorder, or a bone disorder.
The use includes the step of administering to the patient a
therapeutically effective dose of a compound of the invention, or a
pharmaceutical composition thereof. In one embodiment, the use
further includes a step of administering to the patient an
additional therapeutic agent selected from: a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, an agent for treating
cardiovascular disease, an agent for treating destructive bone
disorders, an agent for treating blood disorders, an agent for
treating diabetes, or an agent for treating immunodeficiency
disorders, in which the additional therapeutic agent is appropriate
for the disease being treated and the additional therapeutic agent
is administered together with a compound or composition of the
invention as a single dosage form formulation or separately from a
compound or composition of the invention as part of a multiple
dosage form formulation.
[0068] In an embodiment of any treatment method of the invention,
the disease, condition, or disorder is allergy, asthma, chronic
obstructive pulmonary disease (COPD), diabetes, osteoarthritis,
rheumatoid arthritis, Alzheimer's disease, Huntington's disease,
Parkinson's disease, AIDS-associated dementia, amyotrophic lateral
sclerosis (AML), multiple sclerosis (MS), schizophrenia,
cardiomyocyte hypertrophy, perivascular fibrosis, benign prostatic
hyperplasia, vascular smooth muscle cell proliferation, endothelial
dysfunction, ischemia/reperfusion-induced injury, stroke, baldness,
cancer, malignoma, hepatomegaly, hypertension, cardiovascular
disease, cardiomegaly, cystic fibrosis, restenosis, psoriasis,
inflammation, hypertension, angina pectoris, cerebrovascular
contraction, peripheral circulation disorder, premature birth,
preterm labor, atherosclerosis, vasospasm, cerebral vasospasm,
coronary vasospasm, retinopathy, neurite outgrowth, glaucoma,
erectile dysfunction (ED), AIDS, a respiratory syncytial viral
(RSV) infection, osteoporosis, Crohn's Disease, colitis, or
Raynaud's Disease. Desirably, the disease, condition, or disorder
is atherosclerosis, hypertension, multiple sclerosis, erectile
dysfunction, ischemia/reperfusion-induced injury, stroke, cerebral
vasospasm, coronary vasospasm, cardiac hypertrophy, or glaucoma.
Most desirably, the disease, disorder, or condition is asthma or
transplant rejection.
[0069] The invention also features a method of measurably
inhibiting JAK kinase activity in a biological sample that includes
contacting the biological sample with a compound of the invention,
or a pharmaceutical composition thereof.
[0070] The amount of compound in a composition of this invention is
such that it measurably inhibits a protein kinase, such as, for
example, a JAK family kinase, in a biological sample or in a
patient. The term "measurably inhibit," as used herein means a
measurable change in kinase activity, particularly JAK family
activity, between a sample comprising a compound of this invention
and a JAK kinase and an equivalent sample comprising JAK kinase,
respectively, in the absence of said compound.
[0071] The term "patient," as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0072] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable prodrugs, salts, esters, salts of such esters, or any
other adduct or derivative which upon administration to a patient
in need is capable of providing, directly or indirectly, a compound
as otherwise described herein, or a metabolite or residue
thereof.
[0073] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitory active metabolite or residue thereof. As used herein,
the term "inhibitory active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of a JAK
family kinase.
[0074] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19,
1977, which is incorporated herein by reference. Pharmaceutically
acceptable salts of the compounds of this invention include those
derived from suitable inorganic and organic acids and bases.
Examples of pharmaceutically acceptable, nontoxic acid addition
salts are salts of an amino group formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid and perchloric acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid
or malonic acid or by using other methods used in the art such as
ion exchange. Other pharmaceutically acceptable salts include
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconatc,
dodecylsulfatc, ethanesulfonatc, formate, fumaratc, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethan esulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4 salts.
This invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, C.sub.1-8 sulfonate and
aryl sulfonate.
[0075] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. In Remington: The Science and
Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,
Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia
of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,
1988-1999, Marcel Dekker, New York, the contents of each of which
is incorporated by reference herein, are disclosed various carriers
used in formulating pharmaceutically acceptable compositions and
known techniques for the preparation thereof. Except insofar as any
conventional carrier medium is incompatible with the compounds of
the invention, such as by producing any undesirable biological
effect or otherwise interacting in a deleterious manner with any
other component(s) of the pharmaceutically acceptable composition,
its use is contemplated to be within the scope of this
invention.
[0076] Some examples of materials which can serve as
pharmaceutically acceptable carriers include, but are not limited
to, ion exchangers, alumina, aluminum stearate, lecithin, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, or potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0077] The compositions of the present invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intraocular,
intrahepatic, intralesional and intracranial injection or infusion
techniques. Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable forms of the
compositions of this invention may be aqueous or oleaginous
suspension. These suspensions may be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
arc conventionally employed as a solvent or suspending medium.
[0078] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0079] The pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, carriers commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried cornstarch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0080] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0081] The pharmaceutically acceptable compositions of this
invention may also be administered topically, especially when the
target of treatment includes areas or organs readily accessible by
topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0082] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0083] For topical applications, the pharmaceutically acceptable
compositions may be formulated in a suitable ointment containing
the active component suspended or dissolved in one or more
carriers. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0084] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated, e.g., as micronized suspensions in
isotonic, pH adjusted sterile saline or other aqueous solution, or,
preferably, as solutions in isotonic, pH adjusted sterile saline or
other aqueous solution, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutically acceptable compositions may be formulated in an
ointment such as petrolatum. The pharmaceutically acceptable
compositions of this invention may also be administered by nasal
aerosol or inhalation. Such compositions are prepared according to
techniques well-known in the art of pharmaceutical formulation and
may be prepared as solutions in saline, employing benzyl alcohol or
other suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons, and/or other conventional
solubilizing or dispersing agents.
[0085] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0086] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0087] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally 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 are used in the preparation of injectables.
[0088] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0089] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microcmulsions that arc
compatible with body tissues.
[0090] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0091] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0092] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0093] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0094] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0095] The compounds of the invention are preferably formulated in
dosage unit form for ease of administration and uniformity of
dosage. The expression "dosage unit form" as used herein refers to
a physically discrete unit of agent appropriate for the patient to
be treated. It will be understood, however, that the total daily
usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of
sound medical judgment. The specific effective dose level for any
particular patient or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed,
and like factors well known in the medical arts.
[0096] The amount of the compounds of the present invention that
may be combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated,
the particular mode of administration. Preferably, the compositions
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the inhibitor can be administered to a patient
receiving these compositions.
[0097] Depending upon the particular condition, or disease, to be
treated or prevented, additional therapeutic agents, which are
normally administered to treat or prevent that condition, may also
be present in the compositions of this invention. As used herein,
additional therapeutic agents that are normally administered to
treat or prevent a particular disease, or condition, are known as
"appropriate for the disease, or condition, being treated."
[0098] For example, chemotherapeutic agents or other
anti-proliferative agents may be combined with the compounds of
this invention to treat proliferative diseases and cancer. Examples
of known chemotherapeutic agents include, but are not limited to,
Gleevec.TM., adriamycin, dexamethasone, vincristine,
cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and
platinum derivatives.
[0099] Other examples of agents the inhibitors of this invention
may also be combined with include, without limitation: treatments
for Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating Multiple
Sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebif.RTM.), Copaxone.RTM., and mitoxantrone; treatments for asthma
such as albuterol and Singulair.RTM.; agents for treating
schizophrenia such as zyprcxa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, TL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophophamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
[0100] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
Uses of the Compounds and Compositions of the Invention
[0101] A compound or composition of the invention can be used as a
monotheraphy to treat or lessen the severity of a disease,
condition or disorder in a patient selected from: a proliferative
disorder, a cardiac disorder, a neurodegenerative disorder, a
psychotic disorder, an autoimmune disorder, a condition associated
with organ transplant, an inflammatory disorder, an
immunologically-mediated disorder, a viral disease, or a bone
disorder by administering to the patient a compound or a
composition of the invention in an effective amount.
[0102] The treatment method can further include the additional step
of administering to the patient an additional therapeutic agent
(combination therapy) selected from: a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor,
an anti-psychotic agent, an agent for treating cardiovascular
disease, an agent for treating destructive bone disorders, an agent
for treating liver disease, an anti-viral agent, an agent for
treating blood disorders, an agent for treating diabetes, or an
agent for treating immunodeficiency disorders, wherein the
additional therapeutic agent is appropriate for the disease being
treated and the additional therapeutic agent is administered
together with a compound or composition of the invention as a
single dosage form or separately from the compound or composition
as part of a multiple dosage form.
[0103] Diseases, conditions, or disorders that can be so treated by
monotherapy or combination therapy include allergy, asthma, chronic
obstructive pulmonary disease (COPD), diabetes, osteoarthritis,
rheumatoid arthritis, Alzheimer's disease, Huntington's disease,
Parkinson's disease, AIDS-associated dementia, amyotrophic lateral
sclerosis (AML), multiple sclerosis (MS), schizophrenia,
cardiomyocyte hypertrophy, perivascular fibrosis, benign prostatic
hyperplasia, vascular smooth muscle cell proliferation, endothelial
dysfunction, ischemia/reperfusion-induced injury, stroke, baldness,
cancer, malignoma, hepatomegaly, hypertension, cardiovascular
disease, cardiomegaly, cystic fibrosis, restenosis, psoriasis,
inflammation, hypertension, angina pectoris, cerebrovascular
contraction, peripheral circulation disorder, premature birth,
preterm labor, atherosclerosis, vasospasm, cerebral vasospasm,
coronary vasospasm, retinopathy, neurite outgrowth, glaucoma,
erectile dysfunction (ED), AIDS, a respiratory syncytial viral
(RSV) infection, osteoporosis, Crohn's Disease, colitis, or
Raynaud's Disease.
[0104] In some embodiments, the present invention relates to a
method for treating or lessening the severity of a cancer. In
further embodiments, the present invention relates to a method for
treating or lessening the severity of a cancer selected from brain
(gliomas), breast, colon, head and neck, kidney, lung, liver,
melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid. In
yet further embodiments, the present invention relates to a method
for treating or lessening the severity of pancreatic, prostate, or
ovarian cancer.
[0105] The invention provides a method of inhibiting JAK kinase
activity in a biological sample that includes contacting the
biological sample with a compound or composition of the invention.
The term "biological sample," as used herein, means a sample
outside a living organism and includes, without limitation, cell
cultures or extracts thereof; biopsied material obtained from a
mammal or extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof. Inhibition of
kinase activity, particularly JAK kinase activity, in a biological
sample is useful for a variety of purposes known to one of skill in
the art. Examples of such purposes include, but are not limited to,
biological specimen storage and biological assays. Inhibition of
JAK kinase activity in a biological sample does not relate to
therapeutic methods, such as, for example, blood transfusions or
organ transplantations.
[0106] The invention also provides a method of inhibiting JAK
kinase activity in a patient, comprising administering to the
patient a compound or composition of the invention. In an
embodiment, the invention comprises a method of treating or
lessening the severity of a JAK-mediated condition or disease in a
patient. The term "JAK-mediated disease," as used herein, means any
disease or other deleterious condition in which a JAK family
kinase, in particular JAK-2 or JAK-3, is known to play a role. Such
conditions include, without limitation, immune responses such as
allergic or type I hypersensitivity reactions, asthma, autoimmune
diseases such as transplant rejection, graft versus host disease,
rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple
sclerosis, neurodegenerative disorders such as familial amyotrophic
lateral sclerosis (FALS), as well as in solid and hematologic
malignancies such as leukemias and lymphomas.
[0107] A compound or composition of the invention may also be used
to treat a myeloproliferative disorder. In one embodiment, the
myeloproliferative disorder is polycythemia vera, essential
thrombocythemia, or chronic idiopathic myelofibrosis. In another
embodiment, the myeloproliferative disorder is myeloid metaplasia
with myelofibrosis, chronic myeloid leukemia (CML), chronic
myelomonocytic leukemia, chronic eosinophilic leukemia,
hypereosinophilic syndrome, systematic mast cell disease, atypical
CML, or juvenile myelomonocytic leukemia.
[0108] In certain embodiments of the present invention an
"effective amount" or "effective dose" of the compound or
pharmaceutically acceptable composition is that amount effective
for treating or lessening the severity of one or more of the
aforementioned disorders. The compounds and compositions, according
to the method of the present invention, may be administered using
any amount and any route of administration effective for treating
or lessening the severity of the disorder or disease. The exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the infection, the particular agent, its mode of administration,
and the like. A compound or composition can also be administered
with one or more other therapeutic agents, as discussed above.
[0109] The compounds of this invention or pharmaceutical
compositions thereof may also be used for coating an implantable
medical device, such as prostheses, artificial valves, vascular
grafts, stents and catheters. Vascular stents, for example, have
been used to overcome restenosis (re-narrowing of the vessel wall
after injury). However, patients using stents or other implantable
devices risk clot formation or platelet activation. These unwanted
effects may be prevented or mitigated by pre-coating the device
with a pharmaceutically acceptable composition comprising a
compound of this invention.
[0110] Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121, the contents of each of which are
incorporated by reference herein. The coatings are typically
biocompatible polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics into the composition. Implantable devices coated
with a compound of this invention are another embodiment of the
present invention. The compounds may also be coated on implantable
medical devices, such as beads, or co-formulated with a polymer or
other molecule, to provide a "drug depot," thus permitting the drug
to be released over a longer time period than administration of an
aqueous solution of the drug.
PREPARATION OF THE COMPOUNDS OF THE INVENTION
[0111] The following definitions describe terms and abbreviations
used herein: [0112] ATP adenosine triphosphate [0113] Boc t-butoxyl
carbonyl [0114] dba dibenzylideneacetone [0115] DCM dichloromethane
[0116] DME 1,2-dimethoxyethane [0117] DMF dimethylformamide [0118]
dppf 1,1'-bis(diphenylphosphino)-ferrocene [0119] DTT
dithiothreitol [0120] ESMS electrospray mass spectrometry [0121]
Ether ethyl ether [0122] EtOAc ethyl acetate [0123] Glu glutamic
acid [0124] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic
acid [0125] HPLC high performance liquid chromatography [0126]
LC-MS liquid chromatography-mass spectrometry [0127] Mc methyl
[0128] MeOH methanol [0129] NMP N-methylpyrrolidone [0130] o-tol
ortho-toluoyl [0131] Ph phenyl [0132] tBu tertiary butyl [0133] Tf
trifluorosulfonyl [0134] TFA trifluoacetic acid [0135] Ts
toluenesulfonyl
[0136] In general, the compounds of this invention may be prepared
by methods described herein or known to those skilled in the art
for the preparation of analogous compounds. The following
non-limiting schemes and examples are presented to further
exemplify the invention.
General Synthetic Procedures
[0137] As shown in Scheme 1, a compound of formula III, containing
leaving group Z (such as, for example, a halogen, phosphonate,
tosylate, or triflate) is reacted with a palladium catalyst/ligand
system (such as, for example, Pd(PPh.sub.3).sub.4,
Pd(PtBu.sub.3).sub.4, Pd[P(Me)(tBu.sub.3)].sub.4,
PdCl.sub.2(PPh.sub.3).sub.2, PdCl.sub.2(dppf).sub.2,
Pd.sub.2(dba).sub.3BINAP, or Pd.sub.2(dba).sub.3P(o-tol).sub.3 (see
Fu and Littke, Angew. Chem. Int. Ed. 41:4176-4211, 2002; Nicolaou
et al., Angew. Chem. Int. Ed. 44:4442-4489, 2005; or Hassen et al.,
Chemical Reviews 102(5):1359-1469, 2002) in the presence of a base
and a compound of formula IV, where M is --B(OAlkyl).sub.2 or
--B(OH).sub.2(Suzuki reaction); --Mg-Hal (Kumada reaction);
--Zn-Hal (Negishi reaction); --Sn(Alkyl).sub.3 (Stille reaction);
--Si(Alkyl).sub.3 (Hiyama reaction); --Cu-Hal; --ZrCp.sub.2Cl; or
--AlMe.sub.2; and P is a nitrogen protection group, to produce a
compound of formula V, where X.sup.2, X.sup.4, X.sup.5, X.sup.6,
X.sup.7, and R.sup.F can be defined as indicated elsewhere
herein.
##STR00187##
[0138] The protecting group, P, which can be, for example, an
acetate or a Boc group, is removed by the requisite deprotection
conditions and the resulting compound of formula V-a is reacted
with a compound of formula VI, where R.sup.G and R.sup.H are as
defined elsewhere herein, under acidic conditions to produce a
compound of formula II-b. The acid used can be a mineral acid, such
as, for example, hydrochloric or sulfuric acid; an organic acid,
such as, for example, acetic acid or trifluoroacetic acid; or a
Lewis acid, such as, for example, boron trifluoride. Typically, the
reaction mixture is heated, optionally under microwave radiation,
to affect the cyclization. If desired, the reaction mixture can be
further heated, optionally under microwave irradiation, in the
presence of atmospheric oxygen or another oxidant to produce a
compound in which R.sup.F, R.sup.G, and the carbon and nitrogen
atoms between them form a carbon-nitrogen double bond.
[0139] An alternate procedure useful for the preparation of a
compound of formula II-b, where R.sup.G is hydrogen (e.g., a
compound of formula II-d), or a compound of formula II-e, is shown
in Scheme 2. The coupling of a compound of formula IV-a to a
compound of formula III is performed as described above for the
coupling of a compound of formula IV to a compound of formula III.
The resulting compound of formula V-b is subjected to dehydration
conditions to produce a compound of formula II-c, where X.sup.2,
X.sup.4, X.sup.5, X.sup.6, X.sup.7, R.sup.F, and R.sup.H can be
defined as indicated elsewhere herein. Suitable reagents for this
reaction include, for example, phosphorus oxychloride, thionyl
chloride, phosphorous tribromide, phosphorous pentoxide, or any
other suitable reagent for effecting a Bischler-Napieralski-like
reaction (see, for example, Schmutz et al., Helv. Chem. Acta
50:245, 1967 or Whaley and Govindachari, Org. React. 6:74, 1951).
Typically, the reaction mixture is heated to affect the
cyclization. The compound of formula II-c can then be reduced to
produce a compound of formula II-d. Suitable reducing agents
include hydride reducing agents, such as, for example, sodium
borohydride. Chiral borohydride reagents can also be used to
influence the chirality of the carbon bearing R.sup.H.
Alternatively, when R.sup.F is hydrogen, the reduction step can be
omitted, thereby producing a compound of formula II-e.
##STR00188##
[0140] When the compound of formula VI in Scheme 1 is an alpha-keto
ester and it is reacted with a compound of formula V-a, the result
is a compound of V-c, where R.sup.G is --C(O)OR(R is defined as
indicated elsewhere herein). The 7-membered ring of a compound of
formula V-c can be opened up by reduction, such as, for example, by
hydrogenation, to give a compound of formula VII. Hydrolysis of the
ester to the carboxylic acid of formula VIII and ring closure via
condensation of the carboxylic acid with the amine yields a
compound of formula IX. Such a ring closure can be performed using
conventional condensation reagents known to a person skilled in the
art, including, for example,
1-benzotriazol-1-yloxy-bis(pyrrolidino)uronium hexafluorophosphate
(BBC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium
hexafluorophosphate (HAPyU),
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), 1,3-diisopropylcarbodiimide (DIC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride,
(EDCI) O-(7-azabenzotriazol-1-yl)-tris(dimethylamino)phosphonium
hexafluorophosphate (AOP),
1-benzotriazolyoxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP),
7-azobenzotriazolyoxytris(pyrrolidino)phosphonium
hexafluorophosphate (PyABOP), and
1-benzotriazolyoxytris(pyrrolidino)phosphonium hexafluorophosphate
(PyBOP). When R.sup.F is hydrogen, compounds of formula IX can be
further elaborated by forming an imino triflate (by treatment with
triflic anhydride and base) and using this intermediate in a
catalyzed metallation reaction, such as described above in Scheme
1, to produce compounds of formula I-a in which W is
--NHC(.dbd.X)--, where X is [hydrogen, R].
##STR00189##
[0141] Isomers of compounds of formula IX, where the amide bond has
the reverse orientation, can be prepared as shown in Scheme 4.
Metallation of 1H-pyrrolo[2,3-b]pyridine followed by reaction with
an appropriately substituted imine, forms a compound of formula X,
where R.sup.F is a suitable amine protecting group, such as, for
example, 4-methoxybenzyl or trifluoromethylsulfonyl. Optionally,
R.sup.F is as defined for a compound of formula I-a and the amine
is subsequently protected with protecting group PG.sup.1. A
compound of formula X is reacted with meta-chloroperbenzoic acid
(mCPBA), or another suitable oxidant, to form an N-oxide
intermediate. Subsequent reaction of this intermediate with
tetramethylammonium bromide and methylsulfonyl anhydride forms a
compound of formula XI, which is then treated with a phenylboronic
acid analog that contains an alpha carboxylic acid, which is
protected with a suitable carboxylic acid protecting group
PG.sup.2, to produce a compound of formula XII. Methods for the
preparation of aryl and alkenyl boronic acid analogs and their use
in subsequent coupling reactions has been described in U.S. Pat.
Nos. 6,939,985 and 6,559,310, and in U.S. Patent Application No.
20040133028. Deprotection of both carboxylic acid and amine
protecting groups, followed by amide bond formation, such as, for
example, described above in Scheme 3, forms a compound of formula
XIII. When R.sup.F is hydrogen, compounds of formula IX can be
further elaborated by forming an imino triflate and using this
intermediate in a catalyzed metallation reaction, such as described
above in Scheme 1, to produce compounds of formula I-a in which W
is --C(.dbd.X)NH--, where X is [hydrogen, R].
##STR00190##
[0142] Alternatively, as shown in Scheme 5, a compound of formula
XIV can be reacted with a compound of formula XV in a palladium
catalyzed metallation reaction to produce a compound of formula
XVI. Subsequent reaction of this intermediate with an aldehyde,
such as, for example, R.sup.H--CHO, under acidic conditions
produces a compound of formula XIII. Compounds 126, 127, and 129
were prepared in such a manner.
##STR00191##
Example 1
Synthesis of Compound 5
[0143] As shown in Scheme 6,4-bromo-1H-pyrrolo[2,3-b]pyridine (1.01
g), 2-acetamidophenylboronic acid (1.63 g), Pd(PPh.sub.3).sub.4
(0.345 mg), and 1M Na.sub.2CO.sub.3 (8 mL) were mixed in DME (20
mL) and heated at 95.degree. C. overnight. The reaction was cooled
and water (60 mL) added. Extraction with dichloromethane (3.times.)
and concentration of the combined organic extracts gave
N-(2-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)acetamide (compound
1001), which was treated with concentrated hydrochloric acid (20
mL) and toluene (1 mL) and heated at 128.degree. C. for 30 min.
Evaporation of the volatiles gave a residue, to which saturated
sodium bicarbonate was added. The resulting mixture was extracted
with dichloromethane (3.times.). Concentration of the organics and
purification of the residue via silica gel chromatography (50 to
80% EtOAc/hexane) gave 2-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzenamine
(compound 1002, 1.07 g). To compound 1002 (14 mg) in methanol (1
mL) was added 4N HCl-dioxane (0.05 mL) and benzaldehyde (16 mg).
The reaction mixture was capped and heated at 90.degree. C. for 1
h. About 75% of the methanol was removed by evaporation, followed
by the addition of ethyl ether (5 mL). The resulting solid was
filtered and washed with ether (2.times.) to yield compound 5 as
the hydrochloride salt (22.5 mg).
##STR00192##
[0144] Compounds 1, 6-22, 24-43, 45-46, 60, 64-80, 86-89, 91,
104-108, 110-112, 114, and 119-124, and 128 (see Table 1 for
compound structures) were prepared from compound 1002 by varying
the aldehyde and using a procedure similar to that for the
synthesis of compound 5.
[0145] Compound 23 was obtained by treating compound 8 with
refluxing 6M HCl for 1 hour.
[0146] Compound 90 was obtained by hydrogenation of compound 89
over 10% Pd/C.
[0147] In the preparation of compound 43, compound 44 was also
obtained by HPLC purification.
[0148] Compound 93 was obtained by treating compound 83 with
SnCl.sub.2.2H.sub.2O in refluxing ethanol for 4 hours.
[0149] Compound 58 was obtained via reaction of compound 1002 with
2-ethoxytetrahydropyran in methanol/4M HCl-dioxane at 90.degree. C.
When the same components were reacted in a microwave at 120.degree.
C. for 20 minutes, compound 59 was obtained. Substituting
2-ethoxytetrahydrofuran for 2-ethoxytetrahydropyran in an analogous
microwave procedure produced compound 60.
[0150] Compound 63 was obtained by heating compound 46 in methanol
for 3 days at 90.degree. C.
Example 2
Synthesis of Compound 102
[0151] As shown in Scheme 7, compound 1002 (66 mg),
4-nitrophenylglyoxylic acid (135 mg), 4M HCl-dioxane (0.4 mL), and
methanol (4 mL) were mixed together and heated at 90.degree. C.
overnight. After cooling, addition of ether, and filtration,
compound 98 was obtained as a solid (106 mg). To compound 98 (64
mg) in 3 mL of methanol was added SnCl.sub.2.2H.sub.2O (0.3 g).
After heating at 80.degree. C. for 1 hour, followed by cooling, the
reaction mixture was filtered through Celite.TM. and concentrated
to give compound 102 after purification via silica gel
chromatography.
##STR00193##
Example 3
Synthesis of Compound 125
[0152] As shown in Scheme 8, compound 1002 (58 mg),
4-hydroxyphenylglyoxylic acid (69 mg), 4M HCl-dioxane (0.4 mL), and
methanol (4 mL) were mixed together and heated at 90.degree. C.
overnight. After cooling, the addition of ether and filtration,
compound 103 (0.11 g) was obtained as a yellow solid. To compound
103 (24.4 mg), methanol (2 mL), and 2 drops of concentrated
hydrochloric acid was added 10% Pd/C (8 mg). The resulting
suspension was stirred under a hydrogen balloon for 24 hours.
Filtration through Celite.TM. and evaporation under vacuum gave
compound 1003 (25 mg). Compound 1003 (20 mg) was refluxed in 6 M
hydrochloric acid for 6 hours. Evaporation under vacuum gave the
intermediate carboxylic acid, which was dissolved in DMF (2 mL),
followed by the addition of
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) (40 mg) and diisopropylethylamine (DIEA,
0.02 mL). The resulting mixture was stirred at 40.degree. C.
overnight, followed by the addition of water (20 mL) and TFA (0.1
mL). The crude product was extracted with ethyl acetate (3.times.),
dried over Na.sub.2SO.sub.4, concentrated in vacuo, and purified by
HPLC to obtain compound 125.
##STR00194##
Example 4
Synthesis of Compound 3
[0153] As shown in Scheme 9, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine
(1.02 g, mmol), 2-acetamidophenylboronic acid (1.80 g),
Pd(PPh.sub.3).sub.4 (0.4 g), and 1M Na.sub.2CO.sub.3 (8 mL) were
mixed in DME (20 mL) and heated at 95.degree. C. overnight. The
reaction was cooled and the solvents were removed in vacuo,
followed by the addition of water (60 mL). Extraction with
dichloromethane (3.times.) and concentration of the combined
organic extracts gave, after silica gel chromatography,
N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)acetamide (compound
1004), which was subsequently treated with concentrated
hydrochloric acid (20 mL) and toluene (1 mL). The resulting mixture
was heated for 30 min at 128.degree. C. The volatiles were removed
in vacuo to give a solid, to which saturated sodium bicarbonate was
added. Extraction with 5% MeOH/DCM (3.times.) and concentration
under reduced pressure gave a residue, to which ether was added.
The resulting solid was filtered and washed with ether (2.times.)
to give 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzenamine (compound
1005) as a yellow solid (1.17 g).
[0154] A mixture of compound 1005 (10 mg), benzaldehyde (20 mg), 4M
HCl-dioxane (0.1 mL), and methanol (1 mL) were heated at 95.degree.
C., and the progress of the reaction was monitored by LC-MS. When
the reaction was judged complete, the reaction mixture was
concentrated and ether was added. Compound 3 was filtered off and
obtained as an HCl salt.
##STR00195##
[0155] Compounds 2, 4, 49-50, 55-56, 81-85, 115-116, and 118 (see
Table 1 for compound structures) were prepared from compound 1005
by varying the aldehyde and using a procedure similar to that for
the synthesis of compound 3. Compound 117 was isolated as a side
product during the purification of compound 116
[0156] Compound 92 was prepared by reacting compound 1005 (10.5
mg), 4-hydroxybenzaldehyde (15 mg), and TFA (1 mL) at 140.degree.
C. for 20 minutes under microwave radiation. The crude product was
isolated by removal of the solvents in vacuo, followed by HPLC
purification.
Example 5
Synthesis of Compound 48
[0157] As shown in Scheme 10, 4-bromo-1H-pyrrolo[2,3-b]pyridine
(0.11 g, mmol),
2,2-dimethyl-N-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-p-
yridin-2-yl]-propionamide (0.304 g), Pd(PPh.sub.3).sub.4 (0.04 mg),
and 1M Na.sub.2CO.sub.3 (0.8 mL) were mixed in DME (3 mL) and
heated at 95.degree. C. overnight. The reaction mixture was cooled
and water (20 mL) was added. Extraction with dichloromethane
(3.times.) and concentration of the combined organic extracts gave,
after silica gel chromatography (1:1 ethyl acetate/hexanes),
compound 1006, which was subsequently treated with refluxing
concentrated hydrochloric acid (10 mL) for two days. The liquid was
removed under vacuum to give a solid, to which saturated sodium
bicarbonate was added. Extraction with dichloromethane (3.times.)
and concentration under a reduced pressure gave a residue, to which
ether was added. Filtration gave compound 1007 (48 mg).
[0158] A mixture of compound 1007 (10 mg), 3-fluorobenzaldehyde (20
mg), 4M HCl-dioxane (0.1 mL), and methanol (1 mL) was heated at
160.degree. C. under microwave radiation for 40 minutes. The
reaction mixture was concentrated in vacuo and ether was added.
Compound 48 was filtered off and subsequently purified by HPLC.
##STR00196##
[0159] Compounds 47, 95, and 97 (see Table 1 for compound
structures) were prepared from compound 758545 by varying the
aldehyde and using a procedure similar to that for the synthesis of
compound 48. Compound 96 was isolated as a by-product during the
purification of compound 97.
Example 6
Synthesis of Compound 52
[0160] As shown in Scheme 11, mCPBA (4.75 g) was added to a
solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (3.00 g) in ethyl
acetate (20 mL) at 0.degree. C. The reaction mixture was stirred at
room temperature for 12 hours and the solvents removed in vacuo to
leave a residue, to which aqueous 30% potassium carbonate was
added. Extraction with 10% MeOH/DCM (5.times.) and evaporation gave
the crude N-oxide, which was used directly in the next
reaction.
[0161] To the N-oxide in DMF at 0.degree. C. (10 mL) was added
tetramethyl ammonium bromide (1.00 g) and methylsulfonyl anhydride
(1.5 g). The reaction mixture was stirred at 0.degree. C. for 30
minutes and brought to room temperature over 2 hours. Water (40 mL)
was added, followed by extraction with dichloromethane (3.times.)
and concentration of the combined organics in vacuo. Silica gel
chromatography (0 to 40% EtOAc/DCM) gave
4-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine, which was contaminated
with the corresponding 3-bromo and 3,4-dibromo compounds.
[0162] To the mixture of the bromides (0.128 g) in 1,4-dioxane (4
mL) was added 2-acetamidophenylboronic acid (0.20 g),
PdCl.sub.2dppf.sub.2 (0.04 mg) and potassium phosphate (0.47 g).
The reaction mixture was heated at 90.degree. C. overnight. The
reaction mixture was cooled and water (20 mL) was added. Extraction
with dichloromethane (3.times.) and concentration of the combined
organic extracts gave a mixture of 3- and 4-regional isomers, which
were separated by silica gel chromatography (0 to 100%
EtOAc/hexane) to produce the 4-isomer (compound 1008, 26 mg) as a
pure compound. Compound 1008 was refluxed in concentrated
hydrochloric acid for 50 min. Concentration of the reaction mixture
in vacuo gave compound 1009.
[0163] Compound 1009 (6 mg) was mixed with the
2,6-difluorobenzaldehyde (20 mg) in methanol and 4N HCl-dioxane
(0.1 mL). The resulting solution was heated at 95.degree. C. and
the progress of the reaction was monitored by LC-MS. When the
reaction was judged to be complete, the mixture was concentrated in
vacuo and ether was added. Compound 52 was isolated as the HCl
salt.
##STR00197##
[0164] Compounds 53 and 54 (see Table 1 for compound structures)
were prepared from compound 1009 by varying the aldehyde and using
a procedure similar to that for the synthesis of compound 52.
Example 7
Synthesis of Compound 51
[0165] As shown in Scheme 12, a solution of compound 1010 (19 mg)
in benzene and POCl.sub.3 (0.2 mL) was heated at 90.degree. C. for
2 hours. Additional POCl.sub.3 (0.2 mL) was added and heating was
continued for and additional 2 hours. Evaporation, addition of
saturated sodium bicarbonate, extraction with dichloromethane
(3.times.), and silica gel chromatography (EtOAc) gave compound 51
(7.3 mg).
##STR00198##
Analytical Characterization
[0166] Spectral data for selected compounds of the invention are
presented in Table 2. 1H-NMR spectra were taken at 500 MHz unless
indicated otherwise.
TABLE-US-00002 TABLE 2 Cmpd. ESMS .sup.1H-NMR No. (M + 1) NMR peaks
given as .delta. values 1 342.90 (methanol-d.sub.4) 8.40 (d, 1H),
8.16 (d, 1H), 7.89 (d, 1H), 7.59 (s, 1H), 7.54 (dd, 1H), 7.41 (d,
1H), 7.36 (dd, 1H), 7.31-7.27 (m, 5H), 4.99 (dd, 1H), 4.49 (d, 1H),
4.42 (d, 1H), 3.73 (dd, 1H), 3.51 (dd, 1H) 2 343.20
(methanol-d.sub.4) 8.90 (s, 1H), 8.18 (d, 1H), 7.88 (d, 1H), 7.57
(dd, 1H), 7.35 (d, 1H), 7.12-6.98 (m, 5H), 6.25 (dd, 1H), 4.49 (m,
2H), 4.28 (d, 1H), 3.80 (dd, 1H), 3.70 (dd, 1H) 3 299.20
(methanol-d.sub.4) 8.93 (s, 1H), 8.32 (d, 1H), 7.94 (d, 1H), 7.61
(dd, 1H), 7.46 (d, 1H), 7.41-7.31 (m, 5H), 7.15 (m, 3H) 4 291.20
(methanol-d.sub.4) 9.11 (s, 1H), 8.43 (d, 1H), 7.98 (d, 1H), 7.69
(dd, 1H), 7.59 (d, 1H), 7.18 (d, 1H), 7.07 (dd, 1H) 5 297.90
(methanol-d.sub.4) 8.59 (d, 1H), 8.26 (d, 1H), 8.09 (d, 1H), 7.54
(dd, 1H), 7.37-7.33 (m, 8H), 6.18 (s, 1H) 6 278.20
(methanol-d.sub.4) 8.33 (d, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.48
(s, 1H), 7.46 (dd, 1H), 7.25 (d, 1H), 7.18 (dd, 1H), 3.64 (s, 1H),
0.89 (s, 9H) 7 315.90 (methanol-d.sub.4) 8.46 (d, 1H), 8.14 (d,
1H), 7.97 (d, 1H), 7.40 (dd, 1H), 7.33-7.16 (m, 5H), 7.00 (dd, 1H),
6.90 (dd, 1H), 6.18 (s, 1H), 3.66 (s, 1H) 8 294.20
(methanol-d.sub.4) 8.35 (d, 1H), 8.09 (d, 1H), 7.90 (d, 1H), 7.61
(s, 1H), 7.45 (dd, 1H), 7.21 (dd, 1H), 7.19 (dd, 1H), 5.37 (s, 1H),
4.04 (q, 2H), 1.08 (t, 3H) 9 328.20 (methanol-d.sub.4) 8.60 (d,
1H), 8.22 (d, 1H), 8.06 (d, 1H), 7.55 (dd, 1H), 7.53-7.31 (m, 4H),
7.12 (d, 1H), 6.74 (m, 2H), 6.48 (s, 1H), 4.03 (s, 3H) 10 304.30
(methanol-d.sub.4) 8.36-7.30 (m, 7H), 4.39 (m, 1H), 2.08-0.97 (m,
11H) 11 316.20 (methanol-d.sub.4) 8.49-6.99 (m, 11 H), 5.93 (s,
1H), 3.66 (s, 1H) 12 316.20 (methanol-d.sub.4) 8.56-7.07 (m, 11 H),
6.13 (s, 1H), 3.66 (s, 1H) 13 222.20 (methanol-d.sub.4) 8.49 (d,
1H), 8.28 (d, 1H), 7.97 (d, 1H), 7.67 (s, 1H), 7.65 (d, 1H), 7.58
(dd, 1H), 7.53 (d, 1H), 4.73 (s, 2H) 14 250.10 (methanol-d.sub.4)
8.82 (d, 1H), 8.30 (d, 1H), 8.02 (d, 1H), 7.78 (s, 1H), 7.70 (d,
1H), 7.65 (dd, 1H), 7.64 (d, 1H), 4.91 (dd, 1H), 1.90 (m, 1H), 1.60
(m, 1H), 1.08 (t, 3H) 15 278.20 (methanol-d.sub.4) 8.52 (d, 1H),
8.31 (d, 1H), 8.03 (d, 1H), 7.74 (s, 1H), 7.70 (d, 1H), 7.64 (dd,
1H), 7.60 (d, 1H), 5.08 (dd, 1H), 1.76 (m, 1H), 1.62 (m, 1H), 1.37
(m, 1H), 1.03 (d, 3H), 0.92 (d, 3H) 16 264.20 (methanol-d.sub.4)
8.37-7.26 (m, 6H), 4.34 (dd, 1H), 1.79 (m, 1H), 1.10 (d, 3H), 0.86
(d, 3H) 17 332.00 (methanol-d.sub.4) 8.41 (d, 1H), 8.09 (d, 1H),
7.93 (d, 1H), 7.47 (d, 1H), 7.33 (dd, 1H), 7.24 (dd, 1H), 7.19 (s,
1H), 7.17-7.05 (m, 3H), 6.91 (d, 1H), 6.12 (s, 1H) 18 334.00
(methanol-d.sub.4) 8.49 (d, 1H), 8.21 (d, 1H), 8.02 (d, 1H), 7.51
(dd, 1H), 7.49 (dd, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 7.26 (s, 1H),
7.07 (d, 1H), 7.05 (d, 1H), 6.21 (s, 1H) 19 366.10
(methanol-d.sub.4) 8.49 (d, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.88
(d, 1H), 7.74 (dd, 1H), 7.65 (s, 1H), 7.64 (d, 1H), 7.52 (dd, 1H),
7.39 (dd, 1H), 7.30 (d, 1H), 6.87 (s, 1H), 5.86 (s, 1H) 20 314.20
(methanol-d.sub.4) 8.62-6.61 (m, 10 H), 6.49 (s, 1H) 21 375.90
(methanol-d.sub.4) 8.42-6.95 (m, 10 H), 6.07 (s, 1H) 22 342.20
(methanol-d.sub.4) 8.45-6.74 (m, 10 H), 5.94 (s, 2 H), 5.75 (s, 1H)
23 266.20 (methanol-d.sub.4) 8.41-7.21 (m, 7H), 5.41 (s, 1 H) 24
312.20 (methanol-d.sub.4) 8.32 (d, 1H), 8.14 (d, 1H), 7.84 (d, 1H),
7.40 (dd, 1H), 7.29-7.21 (m, 5H), 7.08 (s, 1H), 7.07 (d, 1H), 6.93
(d, 1H), 4.86 (dd, 1H), 3.05 (dd, 1H), 2.97 (dd, 1H) 25 334.20
(methanol-d.sub.4) 8.41 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.34
(dd, 1H), 7.31 (s, 1H), 7.15 (m, 2H), 7.07 (d, 1H), 6.90 (m, 1H),
6.61 (dd, 1H), 6.08 (s, 1H) 26 334.20 (methanol-d.sub.4) 8.40 (dd,
1H), 8.08 (d, 1H), 7.91 (d, 1H), 7.67-7.54 (m, 2H), 7.35 (dd, 1H),
7.26 (s, 1H), 7.17 (dd, 1H), 7.08 (d, 1H), 7.00 (dd, 1H), 6.01 (s,
1H) 27 334.20 (methanol-d.sub.4) 8.40 (dd, 1H), 8.09 (d, 1H), 7.91
(dd, 1H), 7.34 (dd, 1H), 7.31 (s, 1H), 7.16 (m, 2H), 7.07 (d, 1H),
6.98 (m, 1H), 6.51 (m, 1H), 6.03 (s, 1H) 28 334.20
(methanol-d.sub.4) 8.39 (dd, 1H), 8.09 (d, 1H), 7.91 (dd, 1H), 7.37
(dd, 1H), 7.27 (s, 1H), 7.16 (dd, 1H), 7.08 (d, 1H), 6.82 (m, 3H),
5.75 (s, 1H) 29 352.10 (methanol-d.sub.4) 8.40 (d, 1H), 8.07 (d,
1H), 7.91 (d, 1H), 7.36 (dd, 1H), 7.33 (s, 1H), 7.16 (dd, 1H), 7.07
(d, 1H), 6.86 (m, 1H), 6.61 (m, 1H), 6.04 (s, 1H) 30 352.10
(methanol-d.sub.4) 8.39 (d, 1H), 8.12 (d, 1H), 7.93 (d, 1H), 7.38
(dd, 1H), 7.30 (m, 1H), 7.26 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H),
6.97 (m, 1H), 6.06 (s, 1H) 31 352.10 (methanol-d.sub.4) 8.41 (d,
1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.36 (dd, 1H), 7.33 (s, 1H), 7.21
(ddd, 1H), 7.17 (dd, 1H), 7.07 (d, 1H), 6.71 (ddd, 1H), 6.00 (s,
1H) 32 350.10 (methanol-d.sub.4) 8.41 (d, 1H), 8.08 (d, 1H), 7.92
(d, 1H), 7.34 (dd, 1H), 7.30 (dd, 1H), 7.22 (s, 1H), 7.16 (dd, 1H),
7.07 (s, 1H), 6.91 (dd, 1H), 6.86 (ddd, 1H), 6.08 (s, 1H) 33 350.10
(methanol-d.sub.4) 8.39 (d, 1H), 8.13 (d, 1H), 7.92 (d, 1H), 7.41
(m, 3H), 7.24 (dd, 1H), 7.17 (dd, 1H), 7.08 (dd, 1H), 7.05 (s, 1H),
7.18 (s, 1H) 34 384.10 (methanol-d.sub.4) 8.40 (d, 1H), 8.16 (d,
1H), 7.93 (d, 1H), 7.74-7.50 (m, 4 H), 7.27 (dd, 1H), 7.23 (d, 1H),
6.70 (s, 1H), 5.83 (s, 1H) 35 343.20 (methanol-d.sub.4) 8.43 (d,
1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.46 (dd, 1H), 7.31 (dd, 1H), 7.29
(s, 1H), 7.16 (dd, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 6.16 (s, 1H) 36
316.80 (methanol-d.sub.4) 8.39 (d, 1H), 8.03 (d, 1H), 8.01 (d, 1H),
7.81 (d, 1H), 7.33 (s, 1H), 7.28 (dd, 1H), 7.24 (dd, 1H), 7.11 (dd,
1H), 7.03 (d, 1H), 7.02 (dd, 1H), 6.01 (s, 1H) 37 298.90
(methanol-d.sub.4) 8.59 (d, 1H), 8.42 (d, 1H), 8.06 (dd, 1H), 7.88
(d, 1H), 7.56 (dd, 1H), 7.50 (d, 1H), 7.38 (s, 1H), 7.33 (dd, 1H),
7.16 (dd, 1H), 7.07 (d, 1H), 6.06 (s, 1H) 38 299.20
(methanol-d.sub.4) 8.60 (d, 1H), 8.54 (s, 1H), 8.40 (d, 1H), 8.19
(d, 1H), 8.07 (d, 1H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.31 (dd, 2H),
7.13 (dd, 1H), 7.02 (d, 1H), 5.96 (s, 1H) 39 350.10
(methanol-d.sub.4) 8.39 (d, 1H), 8.08 (d, 1H), 7.90 (d, 1H), 7.37
(m, 2H), 7.21 (s, 1H), 7.16 (dd, 1H), 7.10 (d, 1H), 7.07 (d, 1H),
7.04 (d, 1H), 5.72 (s, 1H) 40 332.20 (methanol-d.sub.4) 8.39 (d,
1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.64-7.55 (m, 2H), 7.35 (m, 2 H),
7.27 (s, 2 H), 7.17 (dd, 1H), 7.07 (d, 1H), 5.70 (s, 1H) 41 366.00
(methanol-d.sub.4) 8.42 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.40
(d, 1H), 7.32 (dd, 1H), 7.29 (s, 1H), 7.14 (dd, 1H), 7.03 (d, 1H),
7.02 (dd, 1H), 6.77 (d, 1H). 6.17 (s, 1H) 42 366.00
(methanol-d.sub.4) 8.38 (d, 1H), 8.15 (d, 1H), 7.92 (d, 1H),
7.66-7.50 (m, 2 H), 7.44 (d, 1H), 7.42 (dd, 1H), 7.25 (d, 1H), 7.22
(d, 1H), 6.84 (s, 1H), 6.36 (s, 1H) 43 299.20 (methanol-d.sub.4)
8.61 (d, 2H), 8.40 (d, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.70 (d,
2H), 7.44 (s, 1H), 7.28 (dd, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 6.05
(s, 1H) 44 297.20 (methanol-d.sub.4) 8.88 (d, 2H), 8.29 (d, 1H),
8.11 (m, 1H), 7.86 (m, 3H), 7.58 (d, 1H), 7.46 (dd, 2H), 7.37 (dd,
1H) 45 346.20 (methanol-d.sub.4) 8.48 (d, 2H), 8.18 (d, 1H), 7.98
(d, 1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 7.26 (s, 1H), 7.23 (dd, 1H),
7.05 (m, 3 H), 5.89 (s, 1H), 3.84 (s, 3H) 46 348.20
(methanol-d.sub.4) 8.45 (d, 2H), 8.14 (d, 1H), 7.96 (d, 1H), 7.43
(dd, 1H), 7.31 (dd, 1H), 7.21 (s, 1H), 7.20 (d, 1H), 6.92 (d, 1H),
6.81 (d, 1H), 6.57 (dd, 1H), 6.12 (s, 1H); Lot 3: (d4-MeOH) 6.24
(1H, s), 6.60 (1H, dd), 6.85 (1H, d), 6.95 (1H, d), 7.28 (1H, d),
7.31 (1H, s), 7.41 (1H, dd), 7.50 (1H, dd), 8.02 (1H, d), 8.20 (1H,
dd), 8.52 (1H, d) 47 335.20 (methanol-d.sub.4) 8.92 (d, 1H), 8.43
(d, 1H), 8.29 (d, 1H), 7.88 (d, 1H), 7.46-7.32 (m, 2H), 7.20 (s,
1H), 7.03 (dd, 2H), 6.38 (s, 1H) 48 317.20 (methanol-d.sub.4) 8.83
(d, 1H), 8.42 (d, 1H), 8.29 (d, 1H), 7.82 (d, 1H), 7.35-7.26 (m, 2
H), 7.24 (s, 1H), 7.09 (d, 1 H), 7.02 (m, 2 H), 5.96 (s, 1H) 49
335.20 (CDCl.sub.3) 10.41 (s, 1H), 9.00 (s, 1H), 8.75 (d, 1H), 7.34
(dd, 1H), 7.31 (dd, 1H), 7.26 (s, 1H), 7.19 (dd, 1H), 6.97 (dd,
2H), 6.88 (d, 1H), 6.80 (s, 1H), 6.04 (s, 1H) 50 317.20
(methanol-d.sub.4) 9.06 (s, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.63
(dd, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 7.27 (s, 1H), 7.20-7.07 (m,
3 H), 7.03 (d, 1H) 51 234.20 (methanol-d.sub.4, for free base) 8.13
(d, 1H), 7.99 (d, 1H), 7.98 (s, 1H), 7.42-7.28 (m, 4 H), 2.47 (s,
3H) 52 368.10 (methanol-d.sub.4) 8.55 (s, 1H), 8.54 (d, 1 H), 7.74
(dd, 1 H), 7.68-7.56 (mn, 3 H), 7.20 (dd, 2 H), 7.14 (s, 1 H), 6.28
(s, 1 H) 53 382.00 (methanol-d.sub.4) 8.50 (s, 1H), 8.41 (d, 1 H),
7.52 (dd, 1 H), 7.46 (dd, 1H), 7.31-7.22 (m, 2 H), 6.95 (dd, 1 H),
6.81-6.56 (m, 2H), 6.31 (s, 1 H) 54 386.10 (methanol-d.sub.4) 8.56
(s, 1H), 8.52 (d, 1 H), 7.70 (dd, 1 H), 7.63 (dd, 1H), 7.54 (m, 2
H), 7.26 (s, 1H), 7.18 (m, 1H), 6.0 (s, 1 H) 55 349.20
(methanol-d.sub.4) 8.94 (s, 1H), 8.11 (d, 1H), 7.48 (dd, 1H), 7.27
(s, 1H), 7.21 (dd, 1H), 7.19 (d, 1H), 6.90 (d, 1H), 6.83 (d, 1H),
6.58 (dd, 1H), 6.04 (s, 1H) 56 353.10 (CDCl.sub.3) 9.60 (s, 1H),
9.01 (s, 1H), 8.75 (dd, 1H), 7.37-6.81 (m, 6H), 6.05 (s, 1H), 4.49
(s, 1H) 57 349.20 (methanol-d.sub.4) 8.45 (d, 1H), 8.32 (d, 1H),
8.12 (d, 1H), 7.54 (d, 1H), 7.09 (dd, 1H), 6.96 (s, 1H), 6.86 (d,
1H), 6.77 (d, 1H), 6.51 (d, 1H), 6.02 (s, 1H) 58 292.30
(methanol-d.sub.4) 8.70 (s, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 7.58
(d, 1H), 7.48 (m, 2H), 7.41 (d, 1H), 3.68 (t, 2H), 3.03 (t, 2H),
1.97 (m, 2H), 1.77 (m, 2H) 59 294.30 (methanol-d.sub.4) 8.33 (d,
1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.48 (dd, 1H), 7.47 (s, 1H), 7.29
(d, 1H), 4.62 (dd, 1H), 3.52 (t, 2 H), 1.76- 1.48 (m, 6 H) 60
280.30 (methanol-d.sub.4) 8.33 (d, 1H), 8.14 (d, 1H), 7.79 (d, 1H),
7.49 (dd, 1H), 7.48 (s, 1H), 7.30 (d, 1H), 4.65 (dd, 1H), 3.56 (t,
2 H), 1.82- 1.64 (m, 4 H) 61 348.20 62 348.20 63 346.20
(methanol-d.sub.4) 8.31 (d, 1H), 8.12 (d, 1H), 7.82 (s, 1H), 7.60
(d, 1H), 7.56 (d, 1H), 7.48 (m, 2H), 7.32 (m, 1H), 7.11 (s, 1H),
6.99 (d, 1H) 64 360.20 (methanol-d.sub.4) 8.39 (d, 1H), 8.14 (d,
1H), 7.83 (d, 1H), 7.41 (dd, 1H), 7.35-6.41 (m, 5 H), 5.61 (s, 1H),
3.66 (s, 3H) 65 314.20 (methanol-d.sub.4) 8.59 (d, 1H), 8.28 (d,
1H), 8.09 (d, 1H), 7.62 (dd, 1H), 7.58 (dd, 1H), 7.38 (s, 1H), 7.37
(d, 1H), 7.17 (d, 2H), 6.78 (d, 2H), 6.13, (s, 1H) 66 330.20
(methanol-d.sub.4) 8.42 (d, 1H), 8.16 (d, 1H), 7.86 (d, 1H), 7.44
(dd, 1H), 7.36 (dd, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.77-6.69 (m,
3H), 5.65 (s, 1H) 67 382.00 (methanol-d.sub.4) 8.39 (d, 1H), 8.11
(d, 1H), 7.90 (d, 1H), 7.39 (dd, 1H), 7.22-7.10 (m, 3 H), 7.17 (s,
2H), 5.61 (s, 1H) 68 362.20 (methanol-d.sub.4) 8.43 (d, 1H), 8.16
(d, 1H), 7.93 (d, 1H), 7.44 (dd, 1H), 7.31 (dd, 1H), 7.20 (d, 1H),
7.20 (s, 1H), 6.77 (s, 1H), 6.60 (d, 1H), 5.73 (s, 1H), 3.77 (s,
3H) 69 330.20 (methanol-d.sub.4) 8.61 (d, 1H), 8.25 (d, 1H), 8.07
(d, 1H), 7.64 (dd, 1H), 7.58 (dd, 1H), 7.53 (d, 1H), 7.52 (dd, 1H),
6.80 (d, 1H), 6.50 (dd, 1H), 6.48 (s, 1H), 6.21 (br s, 1H) 70
378.10 (methanol-d.sub.4) 8.41 (d, 1H), 8.09 (d, 1H), 7.90 (d, 1H),
7.36 (dd, 1H), 7.22 (s, 1H), 7.21 (d, 1H), 7.10 (d, 1H), 6.66 (d,
1H), 6.34 (d, 1H), 6.10 (s, 1H), 3.83 (s, 3H) 71 359.10
(methanol-d.sub.4) 8.44 (d, 1H), 8.10 (d, 1H), 8.04 (d, 1H),
7.96 (d, 1H), 7.40 (s, 1H), 7.32 (dd, 1H), 7.18 (dd, 1H), 6.92 (d,
1H), 6.72 (dd, 1H), 6.46 (s, 1H), 6.28 (d, 1H) 72 330.20
(methanol-d.sub.4) 8.61 (d, 1H), 8.25 (d, 1H), 8.06 (d, 1H), 7.62
(dd, 1H), 7.60 (dd, 1H), 7.56 (dd, 1H), 7.50 (d, 1H), 6.76 (d, 1H),
6.62 (d, 1H), 6.43 (s, 1H), 6.10 (s, 1H) 73 344.20
(methanol-d.sub.4) 8.57 (d, 1H), 8.27 (d, 1H), 8.06 (d, 1H), 7.58
(m, 2H), 7.38 (d, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.77 (m, 2H),
6.07 (s, 1H), 3.77 (s, 3H) 74 348.20 (methanol-d.sub.4) 8.50 (d,
1H), 8.20 (d, 1H), 7.99 (d, 1H), 7.50 (dd, 1H), 7.42 (dd, 1H), 7.26
(m, 3H), 7.09 (d, 1H), 6.88 (d, 1H), 5.88 (s, 1H) 75 440.10
(methanol-d.sub.4) 8.51 (d, 1H), 8.22 (d, 1H), 8.01 (d, 1H), 7.65
(s, 1H), 7.51 (dd, 1H), 7.45 (dd, 1H), 7.28 (d, 1H), 7.26 (s, 1H),
7.15 (d, 1H), 6.80 (d, 1H), 5.88 (s, 1H) 76 422.10
(methanol-d.sub.4) 8.40 (d, 1H), 8.13 (d, 1H), 7.90 (d, 1H),
7.66-7.07 (m, 4 H), 7.04 (s, 1H), 6.65 (s, 1H), 5.92 (s, 1H), 3.56
(s, 3H) 77 392.00 (methanol-d.sub.4) 8.38 (d, 1H), 8.10 (d, 1H),
7.87 (d, 1H), 7.66-7.10 (m, 6 H), 6.85 (d, 1H), 5.60 (s, 1H) 78
469.90 (methanol-d.sub.4) 8.38 (d, 1H), 8.10 (d, 1H), 7.87 (d, 1H),
7.66-7.10 (m, 5 H), 6.85 (d, 1H), 5.60 (s, 1H) 79 342.20
(methanol-d.sub.4) 8.41 (d, 1H), 8.17 (d, 1H), 7.85 (d, 1H),
7.66-6.91 (m, H), 5.61 (s, 1H), 2.18 (s, 6H) 80 332.30
(methanol-d.sub.4) 8.40 (d, 1H), 8.10 (d, 1H), 7.82 (d, 1H),
7.53-7.09 (m, 5 H), 6.53 (s, 1H) 81 349.20 (methanol-d.sub.4) 8.92
(s, 1H), 8.09 (d, 1H), 7.50 (dd, 1H), 7.25 (s, 2H), 7.21 (d, 1H),
7.06 (d, 1H), 6.86 (d, 1H), 5.62 (s, 1H) 82 393.00
(methanol-d.sub.4) 8.80 (s, 1H), 8.53 (d, 1H), 7.44 (s, 1H), 7.29
(dd, 1H), 7.10 (dd, 1H), 7.08 (d, 1H), 7.04 (d, 1H), 6.83 (d, 1H),
6.82 (s, 1H), 5.43 (s, 1H) 83 329.20 (methanol-d.sub.4) 8.88 (s,
1H), 8.19 (d, 1H), 7.45 (dd, 1H), 7.19 (m, 2H), 7.08 (s, 1H), 7.03
(s, 1H), 6.98 (d, 1H), 6.72 (d, 1H), 5.49 (s, 1H), 2.10 (s, 3H) 84
345.20 (methanol-d.sub.4) 8.92 (s, 1H), 8.11 (d, 1H), 7.50 (dd,
1H), 7.24 (d, 1H), 7.20 (s, 2H), 6.96 (s, 1H), 6.75 (d, 1H), 6.70
(d, 1H), 5.60 (s, 1H), 3.79 (s, 3H) 85 375.20 (methanol-d.sub.4)
8.92 (s, 1H), 8.13 (d, 1H), 7.51 (dd, 1H), 7.25 (d, 1H), 7.23 (s,
1H), 7.21 (d, 1H),. 6.63 (s, 2H), 5.60 (s, 1H), 3.75 (s, 6H) 86
342.70 (methanol-d.sub.4) 8.43 (d, 1H), 8.12 (d, 2H), 8.10 (d, 1H),
7.94 (d, 1H), 7.46 (d, 2H), 7.35 (dd, 1H), 7.29 (s, 1H), 7.17 (dd,
1H), 7.09 (d, 1H), 5.93 (s, 1H) 87 356.10 (methanol-d.sub.4) 8.43
(d, 1H), 8.12 (d, 1H), 7.94 (dd, 1H), 7.93 (d, 2H), 7.38 (dd, 1H),
7.36 (d, 2H), 7.22 (s, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 5.88 (s,
1H), 3.87 (s, 3H) 88 342.20 (D.sub.2O) 8.46 (d, 1H), 8.08 (d, 1H),
7.92 (d, 1H), 7.89 (d, 2H), 7.46 (dd, 1H), 7.38 (dd, 1H), 7.33 (s,
1H), 7.27 (d, 2H), 7.15 (s, 1H), 5.95 (s, 1H) 89 438.90
(methanol-d.sub.4) 8.44-7.25 (m, 12 H), 5.07 (s, 2H), 4.60 and 4.51
(2 br s, 1H), 4.14 and 4.03 (2d, 2H), 2.75-1.28 (m, 7H) 90 305.30
(methanol-d.sub.4) 8.31 (br s, 1H), 8.10 (d, 1H), 7.75 (br s, 1H),
7.40 (m, 3H), 7.17 (d, 1H), 7.12 (dd, 1H), 4.31 (br s, 1H), 3.38
(dd, 2H), 2.71 (m, 2H), 2.21 (d, 1H), 1.72 (m, 2H), 1.58 (m, 2H) 91
355.20 (CDCl.sub.3) 8.73 (s, 1H), 8.39 (d, 1H), 8.01 (d, 1H), 7.80
(d, 2H), 7.49 (d, 2H), 7.46 (d, 1H), 7.24 (dd, 1H), 7.15 (dd, 1H),
6.87 (d, 1H), 6.47 (s, 1H), 6.12 (br s, 1H), 5.47 (s, 1H), 3.05 (d,
3H) 92 313.20 (methanol-d.sub.4) 8.90 (d, 1H), 8.85 (s, 1H), 8.21
(s, 1H), 7.82 (d, 2H), 7.63 (dd, 1H), 7.57 (m, 2H), 7.10 (d, 2 H)
93 313.20 (methanol-d.sub.4) 8.25 (d, 1H), 7.95 (d, 1H), 7.48 (d,
1H), 7.21 (dd, 1H), 7.11 (d, 2H), 7.10 (dd, 1H), 7.03 (d, 1H), 6.70
(d, 2H), 6.65 (s, 1H), 5.27 (s, 1H) 94 310.80 (methanol-d.sub.4)
8.31 (d, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 7.62 (d, 1H), 7.61 (d,
2H), 7.50-7.42 (m, 2H), 7.39 (dd, 1H), 6.85 (d, 2H) 95 362.80
(methanol-d.sub.4) 8.65 (d, J = 8.0 Hz, 1 H), 8.49 (d, J = 6.8 Hz,
1 H), 8.35 (d, J = 4.6 Hz, 1 H), 7.96 (d, J = 6.8 Hz, 2 H), 7.36
(s, 1 H), 7.20-7.18 (m, 2 H), 7.05 (dd, J = 8.4, 2.0 Hz, 1 H), 6.83
(d, J = 8.4 Hz, 1 H), 5.80 (s, 1 H), 4.41 (s, 3 H) 96 328.80
(methanol-d.sub.4) 8.60 (d, 1H), 8.46 (d, 1H), 8.33 (d, 1H), 7.94
(d, 2 H), 7.20 (s, 1H), 7.16 (dd, 1H), 7.14 (d, 2H), 6.74 (d, 2H),
5.71 (s, 1H), 4.39 (s, 3 H) 97 314.80 (methanol-d.sub.4) 8.94 (dd,
J = 8.0, 1.4 Hz, 1 H), 8.41 (d, J = 5.9 Hz, 1 H), 8.28 (dd, J =
5.5, 1.6 Hz, 1 H), 7.81 (d, J = 6.0 Hz, 1 H), 7.33 (dd, J = 8.0,
5.5 Hz, 1 H), 7.19 (d, J = Hz, 2 H), 7.04 (s, 1 H), 6.80 (d, J =
Hz, 2H), 5.80 (s, 1 H) 98 400.80 (methanol-d.sub.4) 8.42 (d, J =
6.6 Hz, 1 H), 8.13 (d, J = 8.9 Hz, 2 H), 8.00 (d, J = 8.1 Hz, 1 H),
7.90 (d, J = 6.6 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 2 H), 7.41-7.38 (m,
1 H), 7.34 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.14 (t, J = 7.1
Hz, 1 H), 3.80 (s, 3 H) 99 371.50 (CDCl.sub.3) 8.82 (s, 1 H), 8.38
(d, J = 5.1 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.51-7.39 (m, 4
H), 7.20 (s, 1 H), 7.16-7.13 (m, 1 H), 6.89 (d, J = 7.9 Hz, 1 H),
6.73 (s, 1 H), 6.68 (s, 1 H), 6.49 (s, 1 H), 5.50 (s, 1 H), 5.36
(s, 1 H), 3.71 (s, 3 H) 100 429.50 (methanol-d.sub.4) 8.48 (d, 1
H), 8.07 (d, 1 H), 7.96 (d, 1 H), 7.43 (d, 2 H), 7.34 (dd, 1 H),
7.26 (s, 1H), 7.23 (d, 2 H), 7.18 (dd, 1 H), 7.13 (d, 1 H), 5.50
(s, 1 H), 4.10 (s, 3 H), 3.73 (s, 3 H) 101 487.50
(methanol-d.sub.4) 8.50-7.04 (m, 11 H), 5.68 (s, 1 H), 4.14 (s, 3
H), 4.08 (s, 3 H), 3.67 (s, 3 H) 102 370.90 (CDCl.sub.3) 9.58 (s, 1
H), 8.29 (d, J = 5.3 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.33 (d,
J = 5.3 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 7.02 (s, 1 H), 6.98
(d, J = 8.5 Hz, 2 H), 6.84 (d, J = 7.9 Hz, 1 H), 6.46 (d, J = 8.5
Hz, 2 H), 5.29 (s, 1 H), 3.70 (d, J = 4.0 Hz, H), 3.66 (s, 3 H),
3.55 (br s, 2H) 103 372.50 (methanol-d.sub.4) 8.37 (d, J = 6.6 Hz,
H), 8.02 (d, J = 8.1 Hz, H), 7.88 (d, J = 6.7 Hz, H), 7.40 (dd, J =
7.6 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.16 (dd, J = 7.9 Hz, 1H),
7.14 (s, 1H), 7.06 (dd, J = 1.9, 6.8 Hz, 2 H), 6.71 (d, J = 6.8 Hz,
2 H), 3.70 (s, 3 H) 104 382.40 (methanol-d.sub.4) 8.39 (d, J = 6.4
Hz, 1 H), 8.12-8.11 (m, 1 H), 7.87 (d, J = 6.5 Hz, 1 H), 7.45 (d, J
= 2.0 Hz, 1 H), 7.39 (dd, J = 6.6 and 1.2 Hz, , 1 H), 7.31 (dd, J =
2.1, 8.5 Hz, 1 H), 7.22 (ddd, J = 8, 8 and 0.9 Hz, 1 H), 7.13 (dd,
J = 0.9, 8.1 Hz, 1 H), 7.05 (s, 1 H), 6.90 (d, J = 8.5 Hz, 1 H),
5.65 (s, 1 H) 105 332.40 (methanol-d.sub.4) 8.58 (d, J = 6.4 Hz, 1
H), 8.26 (dd, J = 3.4, 6.0 Hz, 1 H), 8.08 (d, J = 6.5 Hz, 1 H),
7.55 (m, 2 H), 7.42 (s, 1 H), 7.35 (dd, J = 3.4, 5.9 Hz, 1 H), 7.04
(dd, J = 1.9, 11.7 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.89 (dd, J
= 7.9 and 7.9 Hz, H), 6.12 (s, 1 H) 106 350.40 (methanol-d.sub.4)
8.41 (d, J = 6.5 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.92 (d, J =
6.5 Hz, 1 H), 7.41 (dd, J = 8 and 8 Hz, 1 H), 7.23 (d, J = 6.0 Hz,
2 H), 7.14 (d, J = 8.1 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.70
(s, 1 H) 107 332.40 (methanol-d.sub.4) 8.60 (d, 1 H), 8.27 (d, 1
H), 8.10 (d, 1 H), 7.64-7.57 (m, 2 H), 7.49 (s, 1 H), 7.42-7.39 (m,
1 H), 6.81 (dd, 1 H), 6.64 (dd, 1 H), 6.48 (dd, 1 H), 6.36 (s, 1 H)
108 426.50 (methanol-d.sub.4) 8.61 (d, J = 6.2 Hz, 1 H), 8.30 (d, J
= 7.9 Hz, 1 H), 8.08 (d, J = 6.2 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1
H), 7.56 (d, J = 7.6 Hz, 1 H), 7.42 (s, 1 H), 7.29 (d, J = 7.7 Hz,
1 H), 7.12 (s, 1 H), 6.17 (s, 1 H), 1.33 (s, 18 H) 109 220.30
(methanol-d.sub.4) 8.39 (s, 1 H), 8.26 (d, J = 5.4 Hz, 1 H), 8.22
(s, 1 H), 8.10-8.08 (m, 1 H), 7.52 (d, J = 5.5 Hz, 1 H), 7.47-7.44
(m, 2H), 7.18-7.16 (m, 1 H) 110 358.40 (methanol-d.sub.4) 8.40 (d,
H), 8.11 (d, 1 H), 7.87 (d, 1, H), 7.80 (s, 1H), 7.43-7.36 (m, 2
H), 7.22 (dd, 1 H), 7.14 (d, 1 H), 7.07 (s, 1 H), 6.90 (d, 1 H),
5.66 (s, 1 H) 111 372.50 (methanol-d.sub.4) 8.39 (d, J = 6.4 Hz, 1
H), 8.11 (d, J = 8.1 Hz, 1 H), 7.88 (d, J = 6.5 Hz, 1 H), 7.80 (d,
J = 2.3 Hz, 1 H), 7.44 (dd, J = 2.3, 8.6 Hz, 1 H), 7.38 (dd, J = 9
and 9 Hz, 1 H), 7.22 (dd, J = 9.1 and 9.1 Hz, H), 7.13 (d, J = 8.0
Hz, 1 H), 7.06 (s, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 5.65 (s, 1 H),
3.89 (s, 3 H) 112 378.40 (methanol-d.sub.4) 8.39 (d, 1H), 8.11 (d,
1H), 7.87 (d, 1 H), 7.41-7.36 (m, 1 H), 7.24 (dd, 1 H), 7.14 (d, 1
H), 7.13 (s, 1H), 6.86 (d, 1 H), 6.79 (d, 1 H), 5.62 (s, 1 H), 3.77
(s, 3 H) 113 396.40 (methanol-d.sub.4) 8.31 (d, J = 5.4 Hz, 1 H),
8.10 (dd, J = 4.8 Hz, 1 H), 7.98 (s, 1 H), 7.80 (d, J = 0.9 Hz, 1
H) 7.70 (dd, J = 2.3, 8.5 Hz, 1 H), 7.61 (d, J = 5.5 Hz, 1 H),
7.48-7.36 (m, 3 H), 7.25 (d, J = 8.5 Hz, 1 H) 114 398.40
(methanol-d.sub.4) 8.39 (d, J = 5.9 Hz, 1 H), 8.10 (d, J = 7.2 Hz,
1 H), 7.87 (d, J = 6.4 Hz, 1 H), 7.37-7.07 (m, 6 H), 6.90 (d, J =
8.4 Hz, 1 H), 5.67 (s, 1 H) 115 351.30 (methanol-d.sub.4) 8.90 (s,
1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.30 (s, 1H), 7.18 (dd, 1H), 7.16
(d, 1H), 6.81 (d, 2H), 5.65 (s, 1H) 116 333.30 (methanol-d.sub.4)
8.91 (s, 1H), 8.10 (d, J = 8.3 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H),
7.24 (s, 1 H), 7.20-7.18 (m, 2 H), 7.00 (d, J = 12.0 Hz, 1 H), 6.91
(d, J = 8.3 Hz, 1 H), 6.86 (t, J = 8.5 Hz, 1 H), 5.62 (s, 1 H) 117
347.30 (methanol-d.sub.4) 9.03 (s, 1 H), 8.72 (d, 1H), 7.41 (dd,
1H), 7.19 (d, 1H), 7.08 (d, 1H), 7.07 (dd, 1H), 6.99 (d, 1H), 6.92
(d, 1H), 6.85 (dd, 1H), 5.63 (s, 1H), 4.30 (s, 3 H) 118 333.30
(methanol-d.sub.4) 8.94 (s, 1 H), 8.07 (dd, 1 H), 7.49 (ddd, 1H),
7.33 (s, 1H), 7.21 (dd, 1H), 7.20 (d, 1H), 6.78 (dd, 1H), 6.57 (dd,
1H), 6.45 (dd, 1H), 5.94 (s, 1H) 119 364.30 120 365.30
(DMSO-d.sub.6) 12.00 (s, H), 11.96 (s, H), 9.20 (s, H), 8.36 (d, J
= 5.7 Hz, H), 8.18 (s, H), 8.00 (d, J = 7.8 Hz, H), 7.72 (d, J =
8.4 Hz, H), 7.65 (s, H), 7.61 (d, J = 5.6 Hz, 2H), 7.53 (s, H),
7.34 (d, J = 8.5 Hz, 2H), 7.22-7.17 (m, H), 7.09 (d, J = 8.0 Hz,
H), 5.75 (s, H). 121 376.30 (DMSO-d.sub.6) 11.82 (s, H), 10.14 (s,
H), 8.33 (d, J = 5.5 Hz, H), 8.16 (s, H), 7.97 (d, J = 8.1 Hz, H),
7.79 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 5.7 Hz, H), 7.45-7.41 (m,
2H), 7.19-7.16 (m, H), 7.04 (d, J = 8.0 Hz, H), 7.00-6.97 (m, H),
5.74 (s, H), 3.14 (s, 3H). 122 315.20 123 391.30 (DMSO-d.sub.6)
11.89 (s, H), 9.66 (s, H), 8.35 (d, J = 5.6 Hz, H), 8.00 (d, J =
7.9 Hz, 2H), 7.59 (d, J = 5.6 Hz, 2H), 7.23-7.21 (m, H), 7.17 (d, J
= 8.3 Hz, H), 7.12 (s, H), 7.09 (d, J = 8.4 Hz, H), 7.03 (s, H),
5.61 (s, H), 3.17 (s, 3H). 124 332.20 (DMSO-d.sub.6) 11.92 (s, H),
11.87 (s, H), 8.32 (d, J = 5.7 Hz, H), 7.98 (d, J = 8.0 Hz, H),
7.56 (d, J = 5.6 Hz, H), 7.36 (s, H), 7.25-7.22 (m, H), 7.09 (d, J
= 7.9 Hz, H), 7.02 (t, J = 7.5 Hz, H), 6.43 (s, H), 5.81 (s, H),
2.23 (s, 3H), 1.91 (s, 3H) 125 342.40 (methanol-d.sub.4) 8.41 (d, J
= 5.8 Hz, 1 H), 7.76-7.72 (m, 1 H), 7.67- 7.65 (m, 2 H), 7.44 (d, =
8.5 Hz, 2 H), 7.42-7.38 (m, 2 H), 7.12 (d, J = 1.0 Hz, 1 H), 6.81
(d, J = 8.5 Hz, 2 H), 5.25 (s, 1 H) 126 356.10 127 360.10 128
342.40 (methanol-d.sub.4) 8.53 (d, J = 6.1 Hz, 1 H), 8.21 (d, J =
7.8 Hz, 1 H), 8.03 (d, J = 6.3 Hz, 1 H), 7.67-7.27 (m, 8 H), 6.04
(s, 1 H) 129 370.10 (methanol-d.sub.4) 8.39 (d, H), 7.77-7.64 (m,
3H), 7.53 (d, H), 7.37 (d, H), 7.28 (m, 2H), 6.96 (d, H), 6.76 (s,
H), 5.95 (s, H), 4.88 (s, H), 4.72 (s, H), 3.87 (s, 3H), 2.21 (s,
3H). 130 418.40 (methanol-d.sub.4) 8.25 (d, 1 H), 7.83 (d, 1 H),
7.41 (d, 1 H), 7.37-6.85 (m, 7 H), 4.27-4.15 (m, 2 H), 3.74 (s, 3
H), 1.15 (t, 3 H) 131 438.10 (DMSO-d.sub.6) 11.90 (s, H), 8.35 (d,
J = 5.6 Hz, H), 7.98 (d, J = 7.9 Hz, H), 7.71-7.57 (m, H),
7.51-7.46 (m, 2H), 7.39-7.32 (m, 2H), 7.22- 7.15 (m, 2H), 7.10-7.07
(m, 2H), 7.03-7.00 (m, H), 6.85 (d, J = 6.6 Hz, 2H), 6.78 (d, J =
7.6 Hz, H), 5.66 (s, H). 132 418.10 (DMSO-d.sub.6) 11.92 (s, H),
8.37 (d, J = 5.6 Hz, H), 8.00 (d, J = 7.8 Hz, H), 7.61 (d, J = 5.5
Hz, H), 7.39 (d, J = 7.3 Hz, 2H), 7.30-6.95 (m, 8H), 6.73 (s, 2H),
6.04 (s, H), 2.30 (s, 3H), 2.12 (s, 2H). 133 328.10 (DMSO-d.sub.6)
11.99 (s, H), 8.39 (m, H), 8.08 (d, H), 7.68 (d, H), 7.36-
7.09 (m, 3H), 6.92-6.73 (m, 2H), 6.65 (s, H), 6.50 (s, H), 2.35 (s,
3H). 134 382.10 135 328.10 (DMSO-d.sub.6) 11.96 (s, H), 8.37 (d, J
= 5.6 Hz, H), 8.02 (d, J = 7.9 Hz, H), 7.64 (dd, J = 5.7, 16.8 Hz,
H), 7.26-7.22 (m, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.66 (s, H), 3.69
(s, 3H). 136 366.10 (DMSO-d.sub.6) 11.91 (s, H), 8.35 (d, J = 5.6
Hz, H), 7.98 (d, J = 8.1 Hz, H), 7.61-7.57 (m, 3H), 7.38 (d, J =
8.0 Hz, 2H), 7.22-7.14 (m, 2H), 6.99 (t, J = 7.5 Hz, 2H), 6.86 (s,
br, H), 5.75 (s, H). 137 312.10 (DMSO-d.sub.6) 12.04 (s, H), 8.38
(d, J = 5.7 Hz, H), 8.03 (t, J = 8.0 Hz, H), 7.64 (d, J = 5.8 Hz,
H), 7.33-6.99 (9H), 5.68 (s, H), 2.23 (s, 3H). 138 330.40 139
359.40 140 328.40 141 340.40 142 358.40 143 415.40 144 356.40 145
356.40 146 356.40 147 390.40 148 358.10 149 378.10 150 360.30
(methanol-d.sub.4) 8.39 (d, 1H), 7.71 (dd, 1H), 7.64 (d, 1H), 7.65
(d, 1H), 7.58 (d, 1H), 7.41 (dd, 1H), 7.33 (d, 1H), 7.13 (d, 1H),
7.06 (s, 1H), 6.91 (dd, 1H), 5.27 (s, 1H) 151 401.40
(methanol-d.sub.4) 8.93 (s, 1 H), 8.02 (d, 1 H), 7.55 (dd, 1H),
7.43 (d, 1H), 7.40 (s, 1H), 7.22 (dd, 1H), 7.18 (d, 2H), 6.86 (d,
2H), 4.23 (q, 2H), 3.65 (s, 3 H), 1.14 (t, 3H) 152 403.90 153
375.90 154 328.00 155 261.00 156 294.00 157 413.10 158 342.90
(methanol-d.sub.4) 8.92 (s, 1H); 7.88 (d, 1H); 7.80 (dd, 1H); 7.72
(dd, 1H); 7.50 (d, 1H); 7.42 (d, 2H); 7.20 (s, 1H); 6.82 (d, 2H);
5.15 (s, 1H) 159 357.00 (methanol-d.sub.4) 8.90 (s, 1H); 7.88 (d,
1H); 7.82 (dd, 1H); 7.75 (dd, 1H); 7.62 (d, 1H); 7.42 (d, 2H); 7.15
(s, 1H); 7.78 (d, 2H); 5.22 (s, 1H); 3.15 (s, 3H) 160 361.30
(DMSO-d.sub.6) 12.35 ppm (bs, 0.5H), 12.1 (bs, 0.5H), 8.9 (s,
0.5H), 8.85 (s, 0.5H), 7.9 (dd, 0.5H), 7.8 (s, 0.5H), 7.5 to 7.65
(m, 3H), 7.3 (dd, 0.5H), 7.1 to 7.2 (m, 2H), 6.85 to 6.95 (m,
1.5H), 6.7 (dd, 0.5H), 6.5 (t, 0.5H), 6.25 to 6.4 (m, 1H), 5.1 (s,
0.5H), 5.05 (s, 0.5H). 161 341.30 (DMSO-d.sub.6) 12.3 ppm (bs,
0.63H), 12.1 (bs, 0.37H), 9.55 (s, 0.37H), 9.35 (s, 0.63H), 8.9 (s,
1H), 7.9 (dd, 0.37H), 7.75 (d, 0.63H), 7.6 (m, 1H), 7.5 (t, 2H),
7.3 (dd, 0.37H), 7.0 to 7.2 (m, 2H), 6.9 (s, 0.37H), 6.5 to 6.7 (m,
2.25H), 5.15 (s, 1H), 2.35 (s, 1.13H), 2.0 (s, 1.9H). 162 465.30
(DMSO-d.sub.6, 300 MHz) 12.75 (s, 1H), 8.46 (d, J = 11 Hz, 1H),
8.06 (d, J = 12.5 Hz, 1H), 7.82 (d, J = 11 Hz, 1H), 7.41 (m, 6H),
7.30 (m, 2H), 7.19 (m, 2H), 7.11 (m, 2H), 6.93 (d, J = 14 Hz, 1H),
5.89 (s, 1H), 3.31 (br s, 3H).
Example 8
JAK-3 Inhibition Assay
[0167] Compounds were screened for their ability to inhibit JAK
using the assay shown below. Reactions were carried out in a kinase
buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM
MgCl.sub.2, 25 mM NaCl, and 0.01% BSA.
[0168] Substrate concentrations in the assay were 5 .mu.M ATP (200
.mu.Ci/.mu.mole ATP) and 1 .mu.M poly(Glu).sub.4Tyr. Reactions were
carried out at 25.degree. C. and 1 nM JAK-3.
[0169] To each well of a 96 well polycarbonate plate was added 1.5
.mu.l, of a candidate JAK-3 inhibitor along with 50 .mu.L of kinase
buffer containing 2 .mu.M poly(Glu).sub.4Tyr and 10 .mu.M ATP. This
was then mixed and 50 .mu.L, of kinase buffer containing 2 nM JAK-3
enzyme was added to start the reaction. After 20 minutes at room
temperature (25.degree. C.), the reaction was stopped with 50
.mu.l, of 20% trichloroacetic acid (TCA) that also contained 0.4 mM
ATP. The entire contents of each well were then transferred to a 96
well glass fiber filter plate using a TomTek Cell Harvester. After
washing, 60 .mu.L of scintillation fluid was added and .sup.33P
incorporation detected on a Perkin Elmer TopCount. After removing
the mean background values for all of the data points, the data
were fit using Prism software to obtain a K, value (app).
Example 9
JAK-2 Inhibition Assay
[0170] The JAK-2 assays were performed as described above in
Example 8 except that JAK-2 enzyme was used, the final
poly(Glu).sub.4Tyr concentration was 15 .mu.M, and final ATP
concentration was 12 .mu.M. Selected results are presented in Table
1.
[0171] All publications and patents cited in this specification are
herein incorporated by reference as if each individual publication
or patent were specifically and individually indicated to be
incorporated by reference. Although the foregoing invention has
been described in some detail by way of illustration and example
for purposes of clarity of understanding, it will be readily
apparent to those of ordinary skill in the art in light of the
teachings of this invention that certain changes and modifications
may be made thereto without departing from the spirit or scope of
the appended claims.
* * * * *