SUBSTITUTED PYRROLINES AS KINASE INHIBITORS
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Abstract
The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
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Citations
36 Claims
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1. 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, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)
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2. The compound of claim 1 wherein R is selected from phenyl, naphthyl, thienyl or benzothienyl.
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3. The compound of claim 1 wherein R1 is selected from hydrogen, —
- C1-6alkyl-R5, —
C2-6alkenyl-R5, —
C2-6alkynyl-R5, -aryl-R6 or -heteroaryl-R6;
wherein a heteroaryl ring carbon atom forms the point of attachment to the indole nitrogen atom.
- C1-6alkyl-R5, —
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4. The compound of claim 1 wherein R1 is selected from hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-6alkynyl-R5, -phenyl-R6, -naphthyl-R6, -pyridinyl-R6, -pyrimidinyl-R6, -quinolinyl-R6 or -benzothienyl-R6;
wherein a pyridinyl, pyrimidinyl, quinolinyl or benzothienyl ring carbon atom forms the point of attachment to the indole nitrogen atom.
- C1-4alkyl-R5, —
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5. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from hydrogen, —
- O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-OH, —
O—
(C1-4)alkyl-O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-NH2, —
O—
(C1-4)alkyl-NH(C1-4alkyl), —
O—
(C1-4)alkyl-N(C1-4alkyl)2, —
O—
(C1-4)alkyl-S—
(C1-4)alkyl, —
O—
(C1-4)alkyl-SO2—
(C1-4)alkyl, —
O—
(C1-4)alkyl-SO2—
NH2, —
O—
(C1-4)alkyl-SO2—
NH(C1-4alkyl), —
O—
(C1-4)alkyl-SO2—
N(C1-4alkyl)2, —
O—
C(O)H, —
O—
C(O)—
(C1-4)alkyl, —
O—
C(O)—
NH2, —
O—
C(O)—
NH(C1-4alkyl), —
O—
C(O)—
N(C1-4alkyl)2, —
O—
(C1-4)alkyl-C(O)H, —
O—
(C1-4)alkyl-C(O)—
(C1-4)alkyl, —
O—
(C1-4)alkyl-CO2H, —
O—
(C1-4)alkyl-C(O)—
O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-C(O)—
NH2, —
O—
(C1-4)alkyl-C(O)—
NH(C1-4alkyl), —
O—
(C1-4)alkyl-C(O)—
N(C1-4alkyl)2, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
CO2H, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(NH)—
NH2, —
C(O)—
NH(C1-4alkyl), —
C(O)—
N(C1-4alkyl)2, —
SH, —
S—
(C1-4)alkyl, —
S—
(C1-4)alkyl-S—
(C1-4)alkyl, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-OH, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-NH2, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-NH(C1-4alkyl), —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-N(C1-4alkyl)2, —
S—
(C1-4)alkyl-NH(C1-4alkyl), —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
N—
R7, —
(C1-4)alkyl-N—
R7, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, —
(C1-4)alkyl-cycloalkyl-R6, -heterocyclyl-R6, —
(C1-4)alkyl-heterocyclyl-R6, -aryl-R6, —
(C1-4)alkyl-aryl-R6, -heteroaryl-R6 or —
(C1-4)alkyl-heteroaryl-R6.
- O—
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6. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from hydrogen, —
- O—
(C1-4)alkyl, —
C(O)H, —
N—
R7, —
(C1-4)alkyl-N—
R7, hydroxy, -heterocyclyl-R6 or —
(C1-4)alkyl-heterocyclyl-R6.
- O—
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7. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from hydrogen, —
- O—
(C1-4)alkyl, —
C(O)H, —
N—
R7, —
(C1-4)alkyl-N—
R7, hydroxy, -pyrrolidinyl-R6, -morpholinyl-R6, -thiazolidinyl-R6, —
(C1-4)alkyl-piperidinyl-R6 or -piperazinyl-R6.
- O—
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8. The compound of claim 1 wherein R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —
- C1-4alkyl, —
(C1-4)alkyl-(halo)1-3 or —
(C1-4)alkyl-OH;with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from —
C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halo, —
(C1-4)alkoxy-(halo)1-3, hydroxy or nitro.
- C1-4alkyl, —
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9. The compound of claim 1 wherein R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen or —
- C1-4alkyl;
with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from halo.
- C1-4alkyl;
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10. The compound of claim 1 wherein R7 is 2 substituents independently selected from hydrogen, —
- C1-6alkyl, —
C2-6alkenyl, —
C2-6alkynyl, —
(C1-4)alkyl-OH, —
(C1-4)alkyl-O—
(C1-4)alkyl, —
(C1-4)alkyl-NH2, —
(C1-4)alkyl-NH(C1-6alkyl), —
(C1-4)alkyl-N(C1-6alkyl)2, —
(C1-4)alkyl-S—
(C1-4)alkyl, —
C(O)—
(C1-4)alkyl, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(O)—
NH(C1-6alkyl), —
C(O)—
N(C1-6alkyl)2, —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-6alkyl), —
SO2—
N(C1-6alkyl)2, —
C(N)—
NH2, -cycloalkyl-R8, —
(C1-4)alkyl-heterocyclyl-R8, -aryl-R8, —
(C1-4)alkyl-aryl-R8 or —
(C1-4)alkyl-heteroaryl-R8.
- C1-6alkyl, —
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11. The compound of claim 1 wherein R7 is 2 substituents independently selected from hydrogen, —
- C1-6alkyl, —
C2-6alkenyl, —
C2-6alkynyl, —
(C1-4)alkyl-OH, —
(C1-4)alkyl-N(C1-6alkyl)2 or —
(C1-4)alkyl-heteroaryl-R8.
- C1-6alkyl, —
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12. The compound of claim 1 wherein R7 is 2 substituents independently selected from hydrogen, —
- C1-6alkyl, —
C2-6alkenyl, —
C2-6alkynyl, —
(C1-4)alkyl-OH, —
(C1-4)alkyl-N(C1-6alkyl)2 or —
(C1-4)alkyl-furyl-R8.
- C1-6alkyl, —
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13. The compound of claim 1 wherein R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —
- C1-4alkyl, —
(C1-4)alkyl-(halo)1-3 or —
(C1-4)alkyl-OH;with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from —
C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halo, —
(C1-4)alkoxy-(halo)1-3, hydroxy or nitro.
- C1-4alkyl, —
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14. The compound of claim 1 wherein R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen or —
- C1-4alkyl.
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15. The compound of claim 1 wherein R2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
C(O)H, —
C(O)—
(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)—
NH(aryl-R8), —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -aryl-R6 or —
(C1-4)alkyl-N—
R7;with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from —
C1-4alkoxy-R5, —
N—
R7, cyano, halogen, hydroxy, nitro, oxo (wherein oxo is attached to a saturated carbon atom), -heterocyclyl-R6 or -heteroaryl-R6.
- C1-4alkyl-R5, —
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16. The compound of claim 1 wherein R2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —
- C1-4alkyl-R5;
with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from —
C1-4alkoxy-R5, halogen or hydroxy.
- C1-4alkyl-R5;
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17. The compound of claim 1 wherein R2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —
- C1-4alkyl-R5;
with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from —
C1-4alkoxy-R5, bromine, iodine or hydroxy.
- C1-4alkyl-R5;
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18. The compound of claim 1 wherein R9 is 1 to 2 substituents independently selected from hydrogen, —
- C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy or nitro.
- C1-4alkoxy, —
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19. The compound of claim 1 wherein R9 is hydrogen.
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20. The compound of claim 1 wherein R3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
C(O)—
(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, —
N—
R7, —
(C1-4)alkyl-N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 or -heteroaryl-R8.
- C1-4alkyl-R10, —
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21. The compound of claim 1 wherein R3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen or halogen.
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22. The compound of claim 1 wherein R3 is hydrogen.
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23. The compound of claim 1 wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
C(O)-(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SH, —
S—
(C1-4)alkyl-R10, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl-R9), —
SO2—
N(C1-4alkyl-R9)2, —
N—
R7, —
(C1-4)alkyl-N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 or -heteroaryl-R8.
- C1-4alkyl-R10, —
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24. The compound of claim 1 wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —
- C1-4alkyl-R10 or halogen.
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25. The compound of claim 1 wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —
- C1-4alkyl-R10 or chlorine.
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26. The compound of claim 1 wherein R10 is 1 to 2 substituents independently selected from hydrogen, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro or oxo.
- NH2, —
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27. The compound of claim 1 wherein R10 is hydrogen.
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28. The compound of claim 1 wherein R11 is selected from hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, -aryl-R8, -heteroaryl-R8 or halogen.
- C1-4alkyl-R10, —
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29. The compound of claim 1 wherein R11 is hydrogen.
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30. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ia):
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31. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ib):
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32. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ic):
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33. The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Id):
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34. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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35. A composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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36. A method for preparing a composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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2. The compound of claim 1 wherein R is selected from phenyl, naphthyl, thienyl or benzothienyl.
Specification
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Current AssigneeBruce Conway, Bruce E. Maryanoff, David F. Mccomsey, Han-Cheng Zhang, Hong Ye, Keith Demarest, Kimberly White, Leonard R. Hecker
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Original AssigneeBruce Conway, Bruce E. Maryanoff, David F. Mccomsey, Han-Cheng Zhang, Hong Ye, Keith Demarest, Kimberly White, Leonard R. Hecker
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InventorsConway, Bruce, Hecker, Leonard R., Ye, Hong, Demarest, Keith, Maryanoff, Bruce E., Zhang, Han-Cheng, White, Kimberly, McComsey, David F.
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Application NumberUS12/787,034Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/235.200CPC Class CodesA61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 17/14 for baldness or alopeciaA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/04 Centrally acting analgesics...A61P 25/18 Antipsychotics, i.e. neurol...A61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 43/00 Drugs for specific purposes...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 401/14 : containing three or more he...C07D 403/04 : directly linked by a ring-m...C07D 403/14 : containing three or more he...C07D 405/14 : containing three or more he...C07D 409/14 : containing three or more he...C07D 417/14 : containing three or more he...