AZAINDOLES USEFUL AS INHIBITORS OF JAK AND OTHER PROTEIN KINASES
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Abstract
The present invention relates to inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
21 Citations
66 Claims
-
1. A compound of formula (I-E):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 54, 58, 59, 60, 61, 62, 63, 64, 65, 66)
-
2. The compound of claim 1, wherein:
-
a) R1 is T-R′
, wherein T is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units are optionally and independently replaced with —
O—
, —
S—
, —
NR′
—
, —
OCO—
, —
COO—
, —
SO2—
, or —
CO—
, and R′
is hydrogen, C1-C4 alkyl, or an optionally substituted 5- or 6-membered aryl or heteroaryl group;
orb) R1 is —
Si(R′
)3, R′
is hydrogen, C1-C4 alkyl, or an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
-
-
3. The compound of claim 1, wherein R1 is hydrogen, C1-C4 alkyl, —
- COR′
, —
SO2R′
, or —
Si(R′
)3.
- COR′
-
4. The compound of claim 1, wherein R1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), or triethylsilyl (TES).
-
5. The compound of claim 1, wherein R2, R3, and R4 are each independently hydrogen, R′
- , halogen, —
CN, —
NO2, —
N(R′
)2, —
CH2N(R′
)2, —
OR′
, —
CH2OR′
, —
SR′
, —
CH2SR′
, —
COOR′
, —
NR′
COR′
, —
NR′
COCH2R′
, or —
NR′
CO(CH2)2R′
, —
CON(R′
)2, —
SO2N(R′
)2, —
CONR′
(CH2)2N(R′
)2, —
CONR′
(CH2)3N(R′
)2, —
CONR′
(CH2)4N(R′
)2, —
O(CH2)2OR′
, —
O(CH2)3OR′
, —
O(CH2)4OR′
, —
O(CH2)2N(R′
)2, —
O(CH2)3N(R′
)2, or —
O(CH2)4N(R′
)2.
- , halogen, —
-
6. The compound of claim 1, wherein R2, R3, and R4 are each independently —
- Cl, —
Br, —
F, —
CN, —
COOH, —
COOMe, —
NH2, —
N(CH3)2, —
N(Et)2, —
N(iPr)2, —
O(CH2)2OCH3, —
CONH2, —
COOCH3, —
OH, —
CH2OH, —
NHCOCH3, —
SO2NH2, —
SO2N(Me)2, or an optionally substituted group selected from C1-C4alkyl, C1-C4 alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Cl, —
-
7. The compound of claim 1 wherein:
-
a) R2, R3, and R4 are each hydrogen; b) one of R2, R3, or R4 is hydrogen; c) two of R2, R3, or R4 is hydrogen; d) R2 and R4 are both hydrogen, and R3 is halogen, —
CN, —
NO2, or V—
R′
;e) R2 and R4 are both hydrogen, and R3 is an optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; f) R2 and R4 are both hydrogen, and R3 is an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
org) R2 and R4 are both hydrogen, and R3 is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, or oxadiazolyl.
-
-
8. The compound of claim 1, wherein R2, R3, and R4 are each optionally substituted with z occurrences of R6, wherein z is 0-5 and R6 is ═
- O, ═
NR″
, ═
S, halogen, —
CN, —
NO2, or Z—
R″
, wherein Z is a bond or an optionally substituted C1-C6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —
NR″
—
, —
S—
, —
O—
, —
CS—
, —
CO2—
, —
OCO—
, —
CO—
, —
COCO—
, —
CONR″
—
, —
NR″
CO—
, —
NR″
CO2—
, —
SO2NR″
—
, —
NR″
SO2—
, —
CONR″
NR″
—
, —
NR″
CONR″
—
, —
OCONR″
—
, —
NR″
NR″
—
, —
NR″
SO2NR″
—
, —
SO—
, —
SO2—
, —
PO—
, —
PO2—
, or —
POR″
—
, and each occurrence of R″
is independently hydrogen or an optionally substituted C1-C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R″
are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- O, ═
-
9. The compound of claim 8, wherein z is 0, 1, 2, or 3, and each occurrence of R6 is independently hydrogen, R″
- , —
CH2R″
, halogen, —
CN, —
NO2, —
N(R″
)2, —
CH2N(R″
)2, —
OR″
, —
CH2OR″
, —
SR″
, —
CH2SR″
, —
COOR″
, —
NR″
COR″
, —
NR″
COOR″
, —
CON(R″
)2, —
SO2N(R″
)2, —
CONR″
(CH2)2N(R″
)2, —
CONR(CH2)3N(R″
)2, —
CONR″
(CH2)4N(R″
)2, —
O(CH2)2OR″
, —
O(CH2)3OR″
, O(CH2)4OR″
, —
O(CH2)2N(R″
)2, —
O(CH2)3N(R″
)2, —
O(CH2)4N(R″
)2, —
NR″
CH(CH2OH)R″
, —
NR″
CH(CH2CH2OH)R″
, —
NR″
(CH2)R″
, —
NR″
(CH2)2R″
, —
NR″
(CH2)3R″
, —
NR″
(CH2)4R″
, —
NR″
(CH2)N(R″
)2, —
NR″
(CH2)2N(R″
)2, —
NR″
(CH2)3N(R″
)2, —
NR″
(CH2)4N(R″
)2, —
NR″
(CH2)OR″
, —
NR″
(CH2)2OR″
, —
NR″
(CH2)3OR″
, or —
NR″
(CH2)4OR″
.
- , —
-
10. The compound of claim 8, wherein z is 1, 2, or 3 and each occurrence of R6 is independently —
- Cl, —
Br, —
F, —
CN, —
OH, —
NH2, —
CH2OH, C1-C6alkyl, —
O(C1-C6alkyl), —
CH2O(C1-C6alkyl), —
CO(C1-C6alkyl), —
COO(C1-C6 alkyl), —
NHSO2(C1-C6 alkyl), —
SO2NH2, —
CONH2, —
CON(C1-C6 alkyl), —
SO2(C1-C6 alkyl), —
SO2phenyl, phenyl, benzyl, —
N(C1-C6 alkyl)2, or —
S(C1-C6 alkyl), wherein each of the foregoing phenyl, benzyl, and C1-C6alkyl groups is independently and optionally substituted, and wherein each of the foregoing C1-C6alkyl groups is linear, branched, or cyclic.
- Cl, —
-
15. The compound of claim 1, wherein each occurrence of R5 is independently hydrogen, R′
- , —
CH2R′
, halogen, —
CN, —
NO2, —
N(R′
)2, —
CH2N(R′
)2, —
OR′
, —
CH2OR′
, —
SR′
, —
CH2SR′
, —
COOR′
, —
NR′
COR′
, —
NR′
COCH2R′
, —
NR′
CO(CH2)2R′
, —
NR′
COOR′
, —
CON(R′
)2, —
SO2N(R′
)2, —
CONR′
(CH2)2N(R′
)2, —
CONR(CH2)3N(R′
)2, —
CONR′
(CH2)4N(R′
)2, —
O(CH2)2OR′
, —
O(CH2)3OR′
, —
O(CH2)4OR′
, —
O(CH2)2N(R′
)2, —
O(CH2)3N(R′
)2, —
O(CH2)4N(R′
)2, —
NR′
CH(CH2OH)R′
, —
NR′
CH(CH2CH2OH)R′
, —
NR′
(CH2)R′
, —
NR′
(CH2)2R′
, —
NR′
(CH2)3R′
, —
NR′
(CH2)4R′
, —
NR′
(CH2)N(R′
)2, —
NR′
(CH2)2N(R′
)2, —
NR′
(CH2)3N(R′
)2, —
NR′
(CH2)4N(R′
)2, —
NR′
(CH2)OR′
, —
NR′
(CH2)2OR′
, —
NR′
(CH2)3OR′
, or —
NR′
(CH2)4OR′
.
- , —
-
16. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R5 is —
- N(R′
)2, —
NR′
CH(CH2OH)R′
, —
NR′
CH(CH2CH2OH)R′
, —
NR′
(CH2)R′
, —
NR′
(CH2)2R′
, NR′
(CH2)N(R′
)2, or —
NR′
(CH2)2N(R′
)2.
- N(R′
-
17. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R5 is —
- OR′
.
- OR′
-
18. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R5 is —
- NR′
COR′
, —
NR′
COCH2R′
, or —
NR′
CO(CH2)2R′
.
- NR′
-
19. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R5 is an optionally substituted C1-C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
-
20. The compound of claim 1, wherein x is 1 or 2, and each occurrence of R5 is independently halogen, R′
- , —
CN, —
CH2CN, —
(CH2)2CN, —
NO2, —
CH2NO2, —
(CH2)2NO2, —
CON(R′
)2, —
CH2CON(R′
)2, —
(CH2)2CON(R′
)2, —
COOR′
, —
CH2COOR′
, —
(CH2)2COOR′
, —
SO2N(R′
)2, —
CH2SO2N(R′
)2, —
(CH2)2SO2N(R′
)2, —
NR′
SO2R′
, —
CH2NR′
SO2R′
, —
(CH2)2NR′
SO2R′
, —
NR′
CON(R′
)2, —
CH2NR′
CON(R′
)2, —
(CH2)2NR′
CON(R′
)2, —
NR′
SO2N(R′
)2, —
CH2NR′
SO2N(R′
)2, —
(CH2)2NR′
SO2N(R′
)2, —
COCOR′
, —
CH2COCOR′
, —
(CH2)2COCOR′
, —
N(R′
)2, —
CH2N(R′
)2, —
(CH2)2N(R′
)2, —
OR′
, —
CH2OR′
, —
(CH2)2OR′
, —
NR′
COR′
, —
NR′
COCH2R′
, —
NR′
CO(CH2)2R′
, —
CH2NR′
COR′
, or —
(CH2)2NR′
COR′
.
- , —
-
21. The compound of claim 20, wherein R5 is —
- CN, —
CH2CN, —
(CH2)2CN, —
NO2, —
CH2NO2, —
(CH2)2NO2, —
OR′
, —
CH2OR′
, —
CON(R′
)2, —
SO2N(R′
)2, —
N(R′
)2, or R′
.
- CN, —
-
22. The compound of claim 20, wherein each occurrence of R5 is independently hydrogen, halogen, —
- CN, —
CH2CN, —
(CH2)2CN, —
NO2, —
CH2NO2, —
(CH2)2NO2, —
CONH2, —
CON(C1-C4 alkyl), —
SO2NH2, —
SO2N(C1-C4 alkyl), —
NH2, —
N(C1-C4 alkyl), —
OH, —
O(C1-C4 alkyl), —
CH2OH, —
CH2O(C1-C4 alkyl), or an optionally substituted 5- or 6-membered unsaturated ring wherein 0-3 ring carbon atoms is optionally replaced by oxygen, sulfur, or nitrogen.
- CN, —
-
23. The compound of claim 1, wherein R5 is optionally substituted with y occurrences of R7, wherein y is 0-5 and R7 is ═
- O, ═
NR″
, ═
S, halogen, —
CN, —
NO2, or W—
R″
, wherein W is a bond or an optionally substituted C1-C6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —
NR″
—
, —
S—
, —
O—
, —
CS—
, —
CO2—
, —
OCO—
, —
CO—
, —
COCO—
, —
CONR″
—
, —
NR″
CO—
, —
NR″
CO2—
, —
SO2NR″
—
, —
NR″
SO2—
, —
CONR″
NR″
—
, —
NR″
CONR″
—
, —
OCONR″
—
, —
NR″
NR″
—
, —
NR″
SO2NR″
—
, —
SO—
, —
SO2—
, —
PO—
, —
PO2—
, or —
POR″
—
, and each occurrence of R″
is independently hydrogen or an optionally substituted C1-C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R″
, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- O, ═
-
24. The compound of claim 23, wherein y is 0, 1, 2, or 3, and each occurrence of R7 is independently hydrogen, R″
- , —
CH2R″
, halogen, —
CN, —
NO2, —
N(R″
)2, —
CH2N(R″
)2, —
OR″
, —
CH2OR″
, —
SR″
, —
CH2SR″
, —
COOR″
, —
NR″
COR″
, —
NR″
COOR″
, —
CON(R″
)2, —
SO2N(R″
)2, —
CONR″
(CH2)2N(R″
)2, —
CONR(CH2)3N(R″
)2, —
CONR″
(CH2)4N(R″
)2, —
O(CH2)2OR″
, —
O(CH2)3OR″
, —
O(CH2)4OR″
, —
O(CH2)2N(R″
)2, —
O(CH2)3N(R″
)2, —
O(CH2)4N(R″
)2, —
NR″
CH(CH2OH)R″
, —
NR″
CH(CH2CH2OH)R″
, —
NR″
(CH2)R″
, —
NR″
(CH2)2R″
, —
NR″
(CH2)3R″
, —
NR″
(CH2)4R″
, —
NR″
(CH2)N(R″
)2, —
NR″
(CH2)2N(R″
)2, —
NR″
(CH2)3N(R″
)2, —
NR″
(CH2)4N(R″
)2, —
NR″
(CH2)OR″
, —
NR″
(CH2)2OR″
, —
NR″
(CH2)3OR″
, or —
NR″
(CH2)4OR″
.
- , —
-
25. The compound of claim 23, wherein y is 1, 2, or 3 and each occurrence of R7 is independently —
- F, —
Cl, —
Br, —
CN, —
OH, —
NH2, —
CH2OH, C1-C6 alkyl, —
O(C1-C6 alkyl), —
CH2O(C1-C6 alkyl), —
CO(C1-C6 alkyl), —
COO(C1-C6 alkyl), —
NHSO2(C1-C6 alkyl), —
SO2NH2, —
CONH2, —
CON(C1-C6 alkyl), —
SO2(C1-C6 alkyl), —
SO2phenyl, phenyl, benzyl, —
N(C1-C6 alkyl)2, or —
S(C1-C6 alkyl), wherein each of the foregoing phenyl, benzyl, and C1-C6 alkyl groups is independently and optionally substituted, and wherein each of the foregoing C1-C6 alkyl groups is linear, branched, or cyclic.
- F, —
-
26. The compound of claim 1, wherein x is 1, 2, or 3;
- at least one occurrence of R5 is —
N(R′
)2, —
NR′
CH(CH2OH)R′
, —
NR′
CH(CH2CH2OH)R′
, —
NR′
(CH2)R′
, —
NR′
(CH2)2R′
, —
NR′
(CH2)N(R′
)2, —
NR′
(CH2)2N(R′
)2, —
OR′
, —
NR′
COR′
, —
NR′
COCH2R′
, or —
NR′
CO(CH2)2R′
; and
R′
is a C1-C6 aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′
are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′
is optionally substituted with y occurrences of R7, wherein y is 0-5 and R7 is ═
O, ═
NR″
, ═
S, halogen, —
CN, —
NO2, or W—
R″
, wherein W is a bond or an optionally substituted C1-C6 alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —
NR″
—
, —
S—
, —
O—
, —
CS—
, —
CO2—
, —
OCO—
, —
CO—
, —
COCO—
, —
CONR″
, —
NR″
CO—
, —
NR″
CO2—
, —
SO2NR″
, —
NR″
SO2—
, —
CONR″
NR″
—
, —
NR″
CONR″
—
, —
OCONR″
—
, —
NR″
NR″
—
, —
NR″
SO2NR″
—
, —
SO—
, —
SO2—
, —
PO—
, —
PO2—
, or —
POR″
—
, and each occurrence of R″
is independently hydrogen or an optionally substituted C1-C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R″
, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- at least one occurrence of R5 is —
-
27. The compound of claim 26, wherein R′
- is hydrogen, C1-C6 alkyl optionally substituted with 1-3 occurrences of R7, or is a 5-10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with 1-3 occurrences of R7.
-
28. The compound of claim 26, wherein R′
- is hydrogen, C1-C4 alkyl optionally substituted with 1-3 occurrences of R7, or is a ring selected from;
- is hydrogen, C1-C4 alkyl optionally substituted with 1-3 occurrences of R7, or is a ring selected from;
-
29. The compound of claim 1, wherein R5 is —
- N(R′
)2 and the two occurrences of R′
are taken together with the nitrogen atom to which they are bound to form an optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring, wherein, the ring is selected from;
- N(R′
-
32. The compound according to claim 1, wherein R2 and R4 are each independently selected from —
- H, —
Cl, —
Br, —
F, —
CN, —
COOH, —
COOR′
, —
NH2, —
N(CH3)2, —
N(Et)2, —
N(iPr)2, —
NHR′
, —
OR′
, —
SR′
, —
O(CH2)2OCH3, —
CONH2, —
CONHR′
, —
CON(R′
)2, —
OH, —
CH2OH, —
CH2NH2, —
CH2NHR′
, —
CH2N(R′
)2, —
C(R′
)2N(R′
)2, —
NHCOCH3, —
N(R′
)COR′
, —
SO2NH2, —
SO2N(Me)2, or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- H, —
-
33. The compound according to claim 32, wherein R2 and R4 are each hydrogen.
-
34. The compound according to claim 1, wherein R1 is selected from hydrogen, C1-C4 alkyl, —
- COR′
, —
SO2R′
, or —
Si(R′
)3.
- COR′
-
35. The compound according to claim 34, wherein R1 is hydrogen.
-
36. The compound according to claim 1, wherein R3 is selected from —
- H, —
Cl, —
Br, —
F, —
CN, —
COOH, —
COOMe, —
NH2, —
N(R′
)2, —
NO2, —
OR′
, —
CON(R′
)2, —
COOR′
, —
OH, —
SR′
, —
C(R′
)2OR′
, —
N(R′
)COR′
, —
N(R′
)C(O)OR′
, —
SO2NH2, —
SO2N(R′
)2, or an optionally substituted group selected from C1-C4-aliphatic, C1-C4 alkyloxy or —
C≡
C—
C1-C4 aliphatic.
- H, —
-
37. The compound according to claim 36, wherein R3 is selected from —
- H, —
Cl, —
Br, —
CN, —
COOH, —
COOMe, —
CONHR′
, —
CON(Me)2, —
CH2OH, —
NO2, —
NH2 or an optionally substituted C1-C4 aliphatic.
- H, —
-
38. The compound according to claim 37, wherein R3 is selected from —
- Cl, —
Br, —
CN or an optionally substituted C1-C4 aliphatic.
- Cl, —
-
39. The compound according to claim 37, wherein R3 is Cl.
-
40. The compound according to claim 1, wherein R1, R2 and R4 are hydrogen and R3 is selected from —
- Cl, —
Br, —
CN or an optionally substituted C1-C4 aliphatic.
- Cl, —
-
41. The compound according to claim 37, wherein R3 is —
- H, —
OR′
, —
NR′
C(O)R′
, —
NR′
C(O)R′
, —
CON(R′
)2 or —
COOMe.
- H, —
-
42. The compound according to claim 37, wherein R3 is —
- OR′
, —
NR′
C(O)R′
or —
NR′
C(O)OR′
.
- OR′
-
43. The compound according to claim 1, wherein R1, R2 and R4 are hydrogen and R3 is selected from —
- H, —
OR′
, —
NR′
C(O)R′
, —
NR′
C(O)OR′
, —
CON(R′
)2 or —
COOMe.
- H, —
-
54. The compound according to claim 1, wherein R′
- is selected from hydrogen, a C1-C6 aliphatic group optionally substituted with y occurrences of R7, or R′
is a ring selected from;
- is selected from hydrogen, a C1-C6 aliphatic group optionally substituted with y occurrences of R7, or R′
-
58. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
-
59. The composition of claim 58, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s Disease, a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, 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 agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.
-
60. A method of inhibiting JAK-3, ROCK or Aurora kinase activity in a biological sample or a patient, comprising the step of contacting said biological sample or said patient with a compound according to claim 1.
-
61. A method of treating or alleviating a disease or disorder selected from immune responses such as allergic or type I hypersensitivity reactions or asthma;
- autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis;
neurodegenerative disorders;
or solid and hematologic malignancies, comprising administering to a patient in need thereof a compound according to claim 1.
- autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis;
-
62. The method of claim 61, comprising the further step of administering to said patient an additional therapeutic agent.
-
63. The method of claim 61, wherein the disease is an autoimmune disease and is transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis.
-
64. The method of claim 61, wherein the disease is hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, or endothelial dysfunction.
-
65. A method of treating, preventing or lessening the severity of a disease or disorder selected from heart disease, diabetes, Alzheimer'"'"'s disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders, osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases, viral diseases, hyperplasia, reperfusion/ischemia in stroke, heart attacks, organ hypoxia, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, hepatic ischemia, myocardial infarction, congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders comprising administering to a patient in need thereof a compound according to claim 1.
-
66. The method according to claim 65, wherein said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, endometrial, pancreatic, renal, central nervous system, cervical, prostate, or cancer of the gastric tract, CML, AML, APL, acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST).
-
2. The compound of claim 1, wherein:
-
11. (canceled)
-
12. (canceled)
-
13. (canceled)
-
14. (canceled)
-
30. A compound selected from
-
31. (canceled)
- View Dependent Claims (44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55)
-
44. The compound according to claim 31, wherein x is 1, 2, or 3;
- wherein each occurrence of R5 is independently selected from R′
, —
CH2R′
, halogen, —
CN, —
NO2, —
N(R′
)2, —
CH2N(R′
)2, —
OR′
, —
CH2OR′
, —
SR′
, —
CH2SR′
, —
COOR′
, —
NR′
COR′
, —
NR′
COR8R′
, —
NR′
COOR′
, —
CON(R′
)2, —
SO2N(R′
)2, —
CONR′
R8N(R′
)2, —
OR8OR′
, —
OR8N(R′
)2, —
NR′
CH(R9)R′
, —
NR′
CH(R9)C(O)OR′
, —
N(R′
)R8R′
, —
N(R′
)R8R′
, —
N(R′
)R8N(R′
)2, —
N(R′
)R8OR′
, —
NR′
CH(R9)R′
, —
NR′
CH2C(O)N(R′
)2, or —
NR′
CH(R9)C(O)N(R′
)2, wherein R8 is an optionally substituted C1-C4 alkyl and R9 is an optionally substituted C1-C6 aliphatic.
- wherein each occurrence of R5 is independently selected from R′
-
45. The compound according to claim 44, wherein each occurrence of R5 is independently selected from R′
- , —
CH2R′
, halogen, —
CN, —
NO2, —
N(R′
)2, —
CH2N(R′
)2, —
OR′
, —
CH2OR′
, —
SR′
, —
CH2SR′
, —
COOR′
, —
NR′
COR′
, —
NR′
COCH2R′
, —
NR′
CO(CH2)2R′
, —
NR′
COOR′
, —
CON(R′
)2, —
SO2N(R′
)2, —
CONR′
(CH2)2N(R′
)2, —
CONR(CH2)3N(R)2, —
CONR′
(CH2)4N(R′
)2, —
O(CH2)2OR′
, O(CH2)3OR′
, O(CH2)4OR′
, —
O(CH2)2N(R′
)2, —
O(CH2)3N(R′
)2, —
O(CH2)4N(R′
)2, —
NR′
CH(CH2OR9)R′
, —
NR′
CH(CH2CH2OR9)R′
, —
NR′
CH(CH3)R′
, —
NR′
CH(CF3)R′
, —
NR′
CH(CH3)C(O)OR′
, —
NR′
CH(CF3)C(O)OR′
, —
NR′
(CH2)R′
, —
NR′
(CH2)2R′
, —
NR′
(CH2)3R′
, —
NR′
(CH2)4R′
, —
NR(CH2)N(R′
)2, —
NR′
(CH2)2N(R′
)2, —
NR′
(CH2)3N(R′
)2, —
NR′
(CH2)4N(R′
)2, —
NR′
(CH2)OR′
, —
NR′
(CH2)2OR′
, —
NR′
(CH2)3OR′
, —
NR′
(CH2)4OR′
, —
NR′
CH(CH2CH3)R′
, NR′
CH2C(O)N(R′
)2, —
NR′
CH(CH3)C(O)N(R′
)2, —
NR′
CH(CF3)C(O)N(R′
)2, —
NR′
CH(CH2CH3)C(O)N(R′
)2, —
NR′
CH(CH(CH3)2)C(O)N(R′
)2, —
NR′
CH(C(CH3)3)C(O)N(R′
)2, —
NR′
CH(CH2CH(CH3)2)C(O)N(R′
)2, —
NR′
CH(CH2OR9)C(O)N(R′
)2 or —
NR′
CH(CH2CH2N(Me)2)C(O)N(R′
)2.
- , —
-
46. The compound according to claim 44, wherein each occurrence of R5 is independently selected from R′
- , —
CH2R′
, halogen, —
CN, —
NO2, —
N(R′
)2, —
CH2N(R′
)2, —
OR′
, —
CH2OR′
, —
SR′
, —
CH2SR′
, —
COOR′
, —
NR′
COR′
, —
NR′
COCH2R′
, —
NR′
CO(CH2)2R′
, —
NR′
COOR′
, —
CON(R′
)2, —
SO2N(R′
)2, —
CONR′
(CH2)2N(R′
)2, —
CONR(CH2)3N(R′
)2, —
CONR′
(CH2)4N(R′
)2, —
O(CH2)2OR′
, O(CH2)3OR′
, O(CH2)4OR′
, —
O(CH2)2N(R′
)2, —
O(CH2)3N(R′
)2, —
O(CH2)4N(R′
)2, —
NR′
CH(CH2OR9)R′
, —
NR′
CH(CH2CH2OR9)R′
, —
NR′
CH(CH3)R′
, NR′
CH(CF3)R′
, —
NR′
CH(CH3)C(O)OR′
, —
NR′
CH(CF3)C(O)OR′
, —
NR′
(CH2)R′
, —
NR′
(CH2)2R′
, —
NR′
(CH2)3R′
, —
NR′
(CH2)4R′
, —
NR′
(CH2)N(R′
)2, —
NR′
(CH2)2N(R′
)2, —
NR′
(CH2)3N(R′
)2, —
NR′
(CH2)4N(R′
)2, —
NR(CH2)OR′
, —
NR′
(CH2)2OR′
, —
NR(CH2)3OR′
, —
NR′
(CH2)4OR′
, —
NR′
CH(CH2CH3)R′
, —
NR′
CH2C(O)N(R′
)2, —
NR′
CH(CH3)C(O)N(R′
)2, NR′
CH(CF3)C(O)N(R′
)2, —
NR′
CH(CH2CH3)C(O)N(R′
)2, —
NR′
CH(CH(CH3)2)C(O)N(R′
)2, —
NR′
CH(C(CH3)3)C(O)N(R′
)2, —
NR′
CH(CH2CH(CH3)2)C(O)N(R′
)2, —
NR′
CH(CH2OR9)C(O)N(R′
)2 or —
NR′
CH(CH2CH2N(Me)2)C(O)N(R′
)2.
- , —
-
47. The compound according to claim 44, wherein said at least one occurrence of R5 is selected from —
- NHCH2C(O)NHR′
, —
NHCH(CH3)C(O)NHR′
, —
NHCH(CH2CH3)C(O)NHR′
, —
NHCH(CH(CH3)2)C(O)NHR′
, —
NHCH(C(CH3)3)C(O)NHR′
, —
NHCH(CH2CH(CH3)2)C(O)NHR′
, —
NHCH(CH2OH)C(O)NHR′
, —
NHCH(CH2OMe)C(O)NHR′
or —
NHCH(CH2CH2N(Me)2)C(O)NHR′
, wherein R′
is an optionally substituted C1-C4 aliphatic.
- NHCH2C(O)NHR′
-
48. The compound according to claim 44, wherein at least one occurrence of R5 is independently selected from —
- NHR′
, —
NH(CH2)R′
, —
NH(CH2)2R′
, —
NHCH(CH3)R′
, —
NHCH2C(O)NHR′
, —
NHCH(CH3)C(O)NHR′
, —
NHCH(CH2CH3)C(O)NHR′
, —
NHCH(CH(CH3)2)C(O)NHR′
, —
NHCH(C(CH3)3)C(O)NHR′
, —
NHCH(CH2CH(CH3)2)C(O)NHR′
, —
NHCH(CH2OH)C(O)NHR′
, —
NHCH(CH2OMe)C(O)NHR′
or —
NHCH(CH2CH2N(Me)2)C(O)NHR′
, wherein R′
is an optionally substituted phenyl.
- NHR′
-
49. The compound according to claim 44, wherein said at least one occurrence of R5 is —
- NHCH(CH3)R′
, wherein R′
is optionally substituted phenyl.
- NHCH(CH3)R′
-
50. The compound according to claim 44, wherein at least one occurrence of R5 is —
- H, halogen, —
CH3, —
CF3, —
COOH, —
COOMe or —
OR′
, wherein R′
is C1-C4 aliphatic.
- H, halogen, —
-
51. The compound according to claim 44, wherein x is 2 or 3 and at least one occurrence of R5 is —
- F.
-
52. The compound according to claim 44, wherein R1, R2 and R4 are hydrogen and R5 is selected from —
- NHR′
, —
NH(CH2)R′
, —
NH(CH2)2R′
, —
NHCH(CH3)R′
, —
NHCH2C(O)NHR′
, —
NHCH(CH3)C(O)NHR′
, —
NHCH(CH2CH3)C(O)NHR′
, —
NHCH(CH(CH3)2)C(O)NHR′
, —
NHCH(C(CH3)3)C(O)NHR′
, —
NHCH(CH2CH(CH3)2)C(O)NHR′
, —
NHCH(CH2OH)C(O)NHR′
, —
NHCH(CH2OMe)C(O)NHR′
or —
NHCH(CH2CH2N(Me)2)C(O)NHR′
, wherein R′
is an optionally substituted phenyl.
- NHR′
-
53. The compound according to claim 44, wherein R1, R2 and R4 are hydrogen and R5 is selected from —
- NR′
CH(CH2OH)R′
, —
NR′
CH(CH2OMe)R′
, —
NR′
CH(CH2OEt)R′
, —
NR′
CH(CH2OCF3)R′
, —
NR′
CH(CH2CH2OH)R′
, —
NR′
CH(CH2CH2OMe)R′
, —
NR′
CH(CH2CH2OEt)R′
, —
NR′
CH(CH2CH2OCF3)R′
, —
NR′
CH(CH3)C(O)OR′
, —
NR′
CH(CF3)C(O)OR′
, —
NR′
CH(CH3)C(O)N(R′
)2, —
NR′
CH(CF3)C(O)N(R′
)2, —
NR′
CH(CH2CH3)C(O)N(R′
)2, —
NR′
CH(CH2OH)C(O)N(R′
)2, —
NR′
CH(CH2OMe)C(O)N(R′
)2, —
NR′
CH(CH2OEt)C(O)N(R′
)2 or —
NR′
CH(CH2OCF3)C(O)N(R′
)2, wherein R′
is an optionally substituted C1-C4 aliphatic.
- NR′
-
55. The compound according to claim 31, wherein x is 2, 3 or 4 and at least two R5 on adjacent ring members are R′
- , and wherein said two R5 are taken together with the atoms to which they are bound to form an optionally substituted 3-12 membered saturated, partially saturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.
-
44. The compound according to claim 31, wherein x is 1, 2, or 3;
-
56. (canceled)
-
57. (canceled)
Specification
- Resources
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-
Current AssigneeVertex Pharmaceuticals Incorporated
-
Original AssigneeVertex Pharmaceuticals Incorporated
-
InventorsSalituro, Francesco, Farmer, Luc, Bethiel, Randy, Harrington, Edmund, Green, Jeremy, Court, John, Come, Jon, Lauffer, David, Aronov, Alex, Binch, Hayley, Boyall, Dean, Charrier, Jean-Damien, Everitt, Simon, Fraysse, Damien, Mortimore, Michael, Pierard, Francoise, Robinson, Daniel, Wang, Jian, Pinder, Joanne, Wang, Tiansheng, Pierce, Albert
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
-
US Class Current514/214.02
-
CPC Class CodesA61K 31/437 the heterocyclic ring syste...A61K 31/444 containing a six-membered r...A61K 31/496 Non-condensed piperazines c...A61K 31/506 not condensed and containin...A61K 31/5377 not condensed and containin...A61K 31/55 having seven-membered rings...A61K 31/551 having two nitrogen atoms, ...A61K 31/695 Silicon compoundsA61K 45/06 Mixtures of active ingredie...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/08 of the prostateA61P 13/12 of the kidneysA61P 15/00 Drugs for genital or sexual...A61P 15/06 Antiabortive agents; Labour...A61P 15/10 for impotenceA61P 17/00 Drugs for dermatological di...A61P 17/02 : for treating wounds, ulcers...A61P 19/00 : Drugs for skeletal disordersA61P 19/02 : for joint disorders, e.g. a...A61P 19/04 : for non-specific disorders ...A61P 19/08 : for bone diseases, e.g. rac...A61P 19/10 : for osteoporosisA61P 21/00 : Drugs for disorders of the ...A61P 21/02 : Muscle relaxants, e.g. for ...A61P 25/00 : Drugs for disorders of the ...A61P 25/02 : for peripheral neuropathiesA61P 25/04 : Centrally acting analgesics...A61P 25/16 : Anti-Parkinson drugsA61P 25/18 : Antipsychotics, i.e. neurol...A61P 25/28 : for treating neurodegenerat...A61P 27/02 : Ophthalmic agentsA61P 27/06 : Antiglaucoma agents or mioticsA61P 29/00 : Non-central analgesic, anti...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/00 : Antiinfectives, i.e. antibi...A61P 31/12 : AntiviralsA61P 31/18 : for HIVA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 37/00 : Drugs for immunological or ...A61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 7/00 : Drugs for disorders of the ...A61P 7/02 : Antithrombotic agents; Anti...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesC07D 471/04 : Ortho-condensed systemsC07D 519/00 : Heterocyclic compounds cont...C07F 7/0805 : comprising only Si, C or H ...