Substituted pyrroline kinase inhibitors
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Abstract
The present invention is directed to novel substituted pyrroline compounds useful as kinase inhibitors and methods for treating or ameliorating a kinase mediated disorder.
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Citations
30 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)
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2. The compound of claim 1 wherein Ra is selected from the group consisting of thienyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl, furanyl, thiazolyl and pyrazolyl.
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3. The compound of claim 1 wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
C(O)—
(C1-4)alkyl-R9, —
C(O)-aryl-R8, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
NH(aryl-R8), —
C(O)—
N(C1-4alkyl-R9)2, —
SO2-(C1-4)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6;
wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom.
- C1-4alkyl-R5, —
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4. The compound of claim 1 wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, -aryl-R6 and -heteroaryl-R6;
wherein heteroaryl is attached to the azaindole nitrogen atom in the one position via a heteroaryl ring carbon atom.
- C1-4alkyl-R5, -aryl-R6 and -heteroaryl-R6;
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5. The compound of claim 1 wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5 and -naphthyl-R5.
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6. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
O-aryl-R6, —
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, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R5 and -heteroaryl-R6.
- O—
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7. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
O-aryl-R6, —
N—
R7, hydroxy and -heteroaryl-R6.
- O—
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8. The compound of claim 1 wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
O-aryl-R6, —
N—
R7, hydroxy, -imidazolyl-R6, -triazolyl-R6 and -tetrazolyl-R6.
- O—
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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 the group consisting of hydrogen, —
- C1-4alkyl, —
C2-4alkenyl, —
C2-4alkynyl, —
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(C1-4)alkyl)2, —
SO2-(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
(C1-4)alkyl-N—
R7, —
(C1-4)alkyl-(halo)1-3, —
(C1-4)alkyl-OH, -aryl-R8, —
(C1-4)alkyl-aryl-R8 and —
(C1-4)alkyl-heteroaryl-R8;with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from the group consisting of —
C1-4alkoxy, —
(C1-4)alkoxy-(halo)1-3, —
SH, —
S—
(C1-4)alkyl, —
N—
R7, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R3.
- C1-4alkyl, —
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10. The compound of claim 1 wherein R7 is 2 substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C2-4alkenyl, —
C2-4alkynyl, —
(C1-4)alkyl-OH, —
(C1-4)alkyl-O—
(C1-4)alkyl, —
(C1-4)alkyl-NH2, —
(C1-4)alkyl-NH(C1-4alkyl), —
(C1-4)alkyl-N(C1-4alkyl)2, —
(C1-4)alkyl-S—
(C1-4)alkyl, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl), —
C(O)—
N(C1-4alkyl)2, —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
C(N)—
NH2, -cycloalkyl-R8, —
(C1-4)alkyl-heterocyclyl-R8, -aryl-R3, —
(C1-4)alkyl-aryl-R8 and —
(C1-4)alkyl-heteroaryl-R8.
- C1-4alkyl, —
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11. The compound of claim 1 wherein R7 is 2 substituents independently selected from the group consisting of of hydrogen, —
- C1-4alkyl, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
C(O)—
O—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl) and —
SO2—
N(C1-4alkyl)2.
- C1-4alkyl, —
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12. The compound of claim 1 wherein R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
(C1-4)alkyl-(halo)1-3 and —
(C1-4)alkyl-OH;with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from the group consisting of —
C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halo, —
(C1-4)alkoxy-(halo)1-3, hydroxy and nitro.
- C1-4alkyl, —
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13. The compound of claim 1 wherein R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy and nitro.
- C1-4alkoxy, —
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14. The compound of claim 1 wherein R6, R8 and R9 are hydrogen.
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15. The compound of claim 1 wherein R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of 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 and —
(C1-4)alkyl-N—
R7;with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
C1-4alkoxy-R5, —
N—
R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -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 the group consisting of hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, -cycloalkyl-R6, -aryl-R6 and —
(C1-4)alkyl-N—
R7;with the proviso that, when R2 is attached to a nitrogen atom, a quaternium salt is not formed; and
, with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
C1-4alkoxy-R5, —
N—
R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -heteroaryl-R6.
- 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 the group consisting of hydrogen, —
- C1-4alkyl-R5 and -aryl-R6;
with the proviso that when R2 is attached to a nitrogen atom, a quaternium salt is not formed; and
, with the proviso that when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
N—
R7, halogen, hydroxy and -heteroaryl-R6.
- C1-4alkyl-R5 and -aryl-R6;
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18. The compound of claim 1 wherein R3 is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of 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—
(C1-8)alkyl-R9, —
SO2-aryl-R8, —
N—
R7, —
(C1-4)alkyl-N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8and -heteroaryl-R8.
- C1-4alkyl-R10, —
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19. The compound of claim 1 wherein R3 is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
CO2H, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halogen, hydroxy and nitro.
- C1-4alkyl-R10, —
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20. The compound of claim 1 wherein R3 is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, halogen and hydroxy.
- C1-4alkyl-R10, —
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21. The compound of claim 1 wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of 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-R3, —
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, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8.
- C1-4alkyl-R10, —
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22. The compound of claim 1 wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
CO2H, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.
- C1-4alkyl-R10, —
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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 the group consisting of hydrogen, C1-4alkyl-R10, C1-4alkoxy-R10, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, halogen and hydroxy.
- NH2, —
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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 the group consisting of hydrogen, C1-4alkyl-R10, C1-4alkoxy-R10, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, chlorine, fluorine and hydroxy.
- NH2, —
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25. The compound of claim 1 wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- NH2, —
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26. The compound of claim 1 wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen and (halo)1-3.
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27. The compound of claim 1 wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen and (fluoro)3.
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28. The compound of claim 1 wherein the compound of Formula (I) is a compound selected from Formula (Ia):
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29. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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30. A method for preparing a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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2. The compound of claim 1 wherein Ra is selected from the group consisting of thienyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl, furanyl, thiazolyl and pyrazolyl.
Specification
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Current AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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Original AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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InventorsYe, Hong, Maryanoff, Bruce E., Kuo, Gee-Hong, O'Neill, David, Zhang, Han-Cheng, McComsey, David F., Shen, Lan
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Primary Examiner(s)Shameem; Golam M
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Application NumberUS11/435,999Publication NumberTime in Patent Office1,077 DaysField of Search546/112, 546/268.1, 546/268.4, 546/113, 514/299, 514/300, 514/279US Class Current514/300CPC Class CodesA61P 11/06 AntiasthmaticsA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 17/14 for baldness or alopeciaA61P 19/02 for joint disorders, e.g. a...A61P 25/00 Drugs for disorders of the ...A61P 25/04 Centrally acting analgesics...A61P 25/08 Antiepileptics; Anticonvuls...A61P 25/18 Antipsychotics, i.e. neurol...A61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/18 for HIVA61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/06 Immunosuppressants, e.g. dr...A61P 39/00 General protective or antin...A61P 43/00 Drugs for specific purposes...A61P 7/02 Antithrombotic agents; Anti...A61P 7/10 : Antioedematous agents; Diur...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 systems