Cyanoindazole compounds and uses thereof
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Abstract
Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.
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Citations
21 Claims
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1. A compound of Formula IIb2:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 21)
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2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl;
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
orR1 is selected from pyridin-4-yl and pyrimidin-4-yl;
wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R15.
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10;
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3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl;
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R10;
orR1 is selected from pyridin-4-yl and pyrimidin-4-yl;
wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1 or 2 substituents independently selected from R15.
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R10;
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4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl;
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R10;
orR1 is pyridin-4-yl;
wherein said pyridin-4-yl is optionally substituted with 1 or 2 substituents independently selected from R15.
- wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R10;
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5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl and pyrazolyl;
- wherein said phenyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R10.
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6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyridin-2-yl and pyridin-3-yl, wherein said pyridin-2-yl and pyridin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R10;
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R1 is selected from pyridin-4-yl;
wherein said pyridin-4-yl is optionally substituted with R15.
- or
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7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1 wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R11.
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8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, halo, ORa1, C(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, and S(O)2Rb1;
- wherein said C1-6 alkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, and C6-10 aryl-C1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R11.
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9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, C6-10 aryl-C1-3 alkylene, halo, ORa1, C(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, and S(O)2Rb1;
- wherein said C1-6 alkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, C3-10 cycloalkyl-C1-3 alkylene, 4-10 membered heterocycloalkyl-C1-3 alkylene, and C6-10 aryl-C1-3 alkylene are each optionally substituted with 1 or 2 substituents independently selected from R11.
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10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, halo, ORa1, C(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, and S(O)2Rb1;
- wherein said C1-6 alkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, and C6-10 aryl, are each optionally substituted with 1 or 2 substituents independently selected from R11.
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11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R15 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halo, D, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, and OC(O)NRc1Rd1;
- wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11.
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12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R15 is C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from R11.
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13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R11 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halo, D, CN, OR, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3 NRc3C(O)ORa3, NRc3S(O)Rb3, NRc3S(O)2Rb3, and NRc3S(O)2NRc3Rd3;
- wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl, are each optionally substituted with 1, 2, or 3 substituents independently selected from R12.
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14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R11 is independently selected from C1-6 alkyl, halo, CN, ORa3, C(O)Rb3, and NRc3Rd3;
- wherein said C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R12.
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15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted with 1 or 2 substituents independently selected from:
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CH3, —
CH2CH3, —
OCH3, cyclopropyl, —
CH2CF3, 2-chlorophenyl, —
CH(CH3)2, —
CH2OH, —
C(O)NHCH3, —
C(O)N(CH3)2, —
NHC(O)CH3, —
CF3, —
CH2CN, —
F, —
SO2CH3, —
C(CH3)2CN, 1-cyanocyclopropyl, —
C(O)NHCH(CH3)2, —
Cl, —
SO2CH(CH3)2, 4-methylpiperazin-1-yl, morpholinyl, 4-acetylpiperazin-1-yl, tetrahydro-2H-pyran-4-yl, —
C(CH3)2OH, 3-fluoropyrrolidin-1-yl, 4-hydroxypiperidin-1-yl, —
NHCH(CH3)CH2CH3, 3-(hydroxymethyl)azetidin-1-yl, and 3-(dimethylamino)pyrrolidin-1-yl.
- —
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16. The compound of claim 1 selected from:
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3-(1-Ethyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile; 3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile; 3-(1-(2-Chlorophenyl)-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(hydroxymethyl)phenyl)-1H-indazole-6-carbonitrile; 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-N-methylbenzamide; 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-N,N-dimethylbenzamide; N-(4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl) phenyl)-1H-indazol-3-yl)phenyl)acetamide; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-p-tolyl-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(3-methoxyphenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-methoxyphenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carbonitrile; 3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 3-(4-(Cyanomethyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-2-fluoro-N-methylbenzamide; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-1H-indazole-6-carbonitrile; 3-(4-(2-Cyanopropan-2-yl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile; 3-(4-(1-Cyanocyclopropyl) phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl) phenyl)-1H-indazole-6-carbonitrile; 4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-2-fluoro-N,N-dimethylbenzamide; 3-Chloro-4-(6-cyano-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazol-3-yl)-N-isopropylbenzamide; 3-(3-Fluoro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile; 3-(2-Chloro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(isopropylsulfonyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-morpholinopyridin-3-yl)-1H-indazole-6-carbonitrile; N-(5-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)pyridin-2-yl)acetamide; 3-(6-(4-Acetylpiperazin-1-yl)pyridin-3-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methylpyridin-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-methylpyridin-3-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methoxypyrimidin-5-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(oxazol-5-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isothiazol-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isoxazol-4-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methyloxazol-5-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile; 3-(6-(((R)-sec-Butyl)amino)pyridin-3-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(3-(hydroxymethyl)azetidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(6-(4-hydroxypiperidin-1-yl)pyridin-2-yl)-1H-indazole-6-carbonitrile; 5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-6-carbonitrile; and 3-(6-((S)-3-(Dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
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20. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
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21. A method of inhibiting HPK1 activity, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt thereof.
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2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl;
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17. A compound of Formula IIb2:
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18. A compound of Formula IIb2:
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19. A compound of Formula IIb2:
Specification
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Current AssigneeIncyte Corporation
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Original AssigneeIncyte Corporation
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InventorsVechorkin, Oleg, Atasoylu, Onur, Ye, Hai Fen, Liu, Kai, Zhang, Ke, Yao, Wenqing
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Primary Examiner(s)Rahmani, Niloofar
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Application NumberUS16/125,084Publication NumberTime in Patent Office690 DaysField of Search5483611US Class CurrentCPC Class CodesA61K 31/416 condensed with carbocyclic ...A61K 31/454 containing a five-membered ...A61P 35/00 Antineoplastic agentsC07D 231/56 Benzopyrazoles; Hydrogenate...C07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...C07D 403/04 directly linked by a ring-m...C07D 405/10 linked by a carbon chain co...C07D 405/14 containing three or more he...C07D 413/04 directly linked by a ring-m...C07D 417/04 directly linked by a ring-m...