Azaindoles useful as inhibitors of JAK and other protein kinases
First Claim
Patent Images
1. A method of inhibiting JAK-3, ROCK, or Aurora kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of formula (I):
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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.
-
Citations
24 Claims
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1. A method of inhibiting JAK-3, ROCK, or Aurora kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
-
2. The method 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, —
-
3. The method 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-C4 alkyl, 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, —
-
4. The method 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.
-
-
5. The method 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, ═
-
6. The method of claim 5, 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″
.
- , —
-
7. The method of claim 5, wherein z is 1, 2, or 3 and each occurrence of R6 is independently —
- F, —
Cl, —
Br, —
CN, —
OH, —
NH2, —
CH2OH, C1-C6 alkyl, —
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, —
-
8. The method of claim 1, wherein compounds have one of formulae I-A, I-B, I-C, I-D, or I-E:
-
9. The method 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′
.
- , —
-
10. The method of claim 1, wherein 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.
-
11. The method 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′
.
- , —
-
12. The method 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, ═
-
13. The method of claim 12, 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″
.
- , —
-
14. The method of claim 1, wherein 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.
- N(R)2, —
-
15. The method of claim 14, 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.
-
16. The method of claim 14, 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;
-
17. The method 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)2 and the two occurrences of R′
-
18. The method of claim 1, wherein R2 and R4 are each independently selected from —
- H, —
F, —
Cl, —
Br, —
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, —
-
19. The method of claim 18, wherein R2 and R4 are each hydrogen.
-
20. The method of claim 1, wherein R3 is selected from —
- H, —
F, —
Cl, —
Br, —
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, —
-
21. The method of 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, —
-
22. The method of 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, —
-
23. The method of claim 1, 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.
-
24. The method of claim 1, wherein the compound of formula I is selected from
-
2. The method of claim 1, wherein R2, R3, and R4 are each independently hydrogen, R′
Specification
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-
Current AssigneeVertex Pharmaceuticals Incorporated
-
Original AssigneeVertex Pharmaceuticals Incorporated
-
InventorsSalituro, Francesco, Farmer, Luc, Bethiel, Randy, Harrington, Edmund, 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, Green, Jeremy
-
Primary Examiner(s)CHANDRAKUMAR, NIZAL S
-
Application NumberUS13/441,287Publication NumberTime in Patent Office487 DaysField of Search435/184, 546/113US Class Current435/184CPC 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 ...