Imidazopyridines and imidazopyrazines as LSD1 inhibitors
First Claim
Patent Images
1. A method of inhibiting lysine specific demethylase-1 activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:
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Abstract
The present invention is directed to imidazo[1,5-a]pyridine and imidazo[1,5-a]pyrazine derivatives of Formula I, or a pharmaceutically acceptable salt thereof, which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
79 Citations
65 Claims
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1. A method of inhibiting lysine specific demethylase-1 activity in a patient, comprising administering to the patient a therapeutically effective amount of 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, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65)
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2. The method of claim 1, wherein the patient has cancer.
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3. The method of claim 2, wherein the cancer is a sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin cancer.
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4. The method of claim 2, wherein the cancer is a hematological cancer.
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5. The method of claim 4, wherein the hematological cancer is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis, polycythemia vera, essential thrombocytosis, myelodysplasia syndrome, and multiple myeloma.
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6. The method of claim 1, wherein:
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Ring A is C6-10 aryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA; R1 is ORa1 or Cy1; R3 is H; R4 is H; each RA is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; RX is H; each Ra1 is independently selected from C1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy5; and each Re5, Re6, and Re8 is independently selected from H, C1-4 alkyl, and CN.
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7. The method of claim 1, wherein:
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Ring A is C6-10 aryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA; R1 is ORa1; R3 is H; R4 is H; each RA is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; RX is H; each Cy4 and Cy5 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy; each Ra1 is independently selected from C1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy5; and each Re5, Re6, and Re8 is independently selected from H, C1-4 alkyl, and CN.
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8. The method of claim 1, wherein:
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X is CRX; Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from RA; Ring B is phenyl;
5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
C3-7 cycloalkyl;
or 4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
wherein said phenyl, 5-10 membered heteroaryl, C3-7 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from RB;R1 is ORa1; R3 is H; R4 is H; each RA is independently selected from halo, CN, and NO2; each RB is independently selected from Cy4, halo, C1-6 alkyl, ═
O, and C(O)ORa5, wherein said C1-6 alkyl is optionally substituted by Cy4;RX is H; each Cy4 is independently selected from C3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy; each Cy5 is independently selected from 4-7 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from RCy; each RCY is selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, S(O)2Rb6, and S(O)2NRc6Rd6, wherein said C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1 or 2 substituents independently selected from halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, S(O)2Rb6, and S(O)2NRc6Rd6; each Ra1 is independently selected from C1-3 alkyl optionally substituted with 1 or 2 substituents independently selected from Cy5; and each Ra5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, halo, CN, ORa8, SRa8, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8, NRc8C(O)Rb8, NRc8C(O)NRc8Rd8, NRc8C(O)ORa8, C(═
NRe8)NRc8Rd8, NRc8C(═
NRe8)NRc8Rd8, S(O)Rb8, S(O)NRc8Rd8, S(O)2Rb8, NRc8S(O)2Rb8, NRc8S(O)2NRc8Rd8, and S(O)2NRc8Rd8;or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C1-6 haloalkyl, halo, CN, ORa8, SRa8, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8, NRc8C(O)Rb8, NRc8C(O)NRc8Rd8, NRc8C(O)ORa8, C(═
NRe8)NRc8Rd8, NRc8C(═
NRe8)NRc8Rd8, S(O)Rb8, S(O)NRc8Rd8, S(O)2Rb8, NRc8S(O)2Rb8, NRc8S(O)2NRc8Rd8, and S(O)2NRc8Rd8, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, ORa8, SRa8, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8, NRc8C(O)Rb8, NRc8C(O)NRc8Rd8, NRc8C(O)ORa8, C(═
NRe8)NRc8Rd8, NRc8C(═
NRe8)NRc8Rd8, S(O)Rb8, S(O)NRc8Rd8, S(O)2Rb8, NRc8S(O)2Rb8, NRc8S(O)2NRc8Rd8, and S(O)2NRc8Rd8.
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9. The method of claim 1, wherein X is N.
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10. The method of claim 1, wherein X is CRX.
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11. The method of claim 1, wherein Ring A is C6-10 aryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA.
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12. The method of claim 1, wherein Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from RA.
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13. The method of claim 1, wherein Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from halo, CN, and NO2.
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14. The method of claim 1, wherein Ring B is phenyl;
- 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
C3-7 cycloalkyl;
or 4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
wherein said phenyl, 5-10 membered heteroaryl, C3-7 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from RB.
- 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
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15. The method of claim 1, wherein Ring B is phenyl, pyrazolyl, cyclohexenyl, dihydropyridinyl, 1H-indazolyl, 2,3-dihydro-1H-indolyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1,3-benzoxazolyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-benzimidazolyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-benzimidazolyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, quinolinyl, 1,3-benzothiazolyl, pyridinyl, 1,5-naphthyridinyl, quinoxalinyl, 2,3-dihydrooxazolo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, furo[3,2-b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-1H-indenyl, 1,4-dihydro-2H-3,1-benzoxazinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-dihydro-1H-isoindolyl, imidazo[4,5-b]pyridinyl, or pyrimidinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, halo, C1-6 alkyl, C1-6 haloalkyl, ═
- O, CN, ORa5, NRc5C(O)ORa5, NRc5Rd5, C(O)NRc5Rd5, and C(O)ORa5, wherein said C1-6 alkyl is optionally substituted by 5-6 membered heterocycloalkyl, CN, ORa5, NRc5C(O)ORa5, or NRc5C(O)NRc5Rd5.
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16. The method of claim 1, wherein Ring B is phenyl, pyrazolyl, cyclohexenyl, dihydropyridinyl, 1H-indazolyl, 2,3-dihydro-1H-indolyl, 3,4-dihydro-2H-1,4-benzoxazinyl, or 2,3-dihydro-1,4-benzodioxinyl, each optionally substituted by 1, 2, or 3 substituents independently selected from C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, halo, C1-6 alkyl, ═
- O, and C(O)ORa5, wherein said C1-6 alkyl is optionally substituted by 5-6 membered heterocycloalkyl.
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17. The method of claim 1, wherein group:
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18. The method of claim 1, wherein R1 is ORa1 or Cy1.
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19. The method of claim 1, wherein R1 is ORa1 or 4-10 membered heterocycloalkyl.
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20. The method of claim 1, wherein R1 is ORa1.
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21. The method of claim 1, wherein R1 is (i) C1-6 alkyl substituted with NRc1Rd1 or (ii) NRc1Rd1, wherein Rc1 is H and Rd1 is substituted with NRc8Rd8;
- or Rc1 and Rd1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group substituted with NRc8Rd8.
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22. The method of claim 1, wherein R1 is independently selected from pyrrolidinylmethoxy optionally substituted by methyl;
- piperidinylmethoxy optionally substituted by methyl, ethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-hydroxypropyl, 2-methoxyethyl, or 2-hydroxy-2-methylpropyl;
4-(dimethylamino)piperidinyl; and
3-(dimethylamino)pyrrolidinyl.
- piperidinylmethoxy optionally substituted by methyl, ethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-hydroxypropyl, 2-methoxyethyl, or 2-hydroxy-2-methylpropyl;
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23. The method of claim 1, wherein R1 is 3-piperidinylmethoxy, 3-pyrrolidinylmethoxy, 1-piperidinyl, or 1-pyrrolidinyl, each of which is optionally substituted with a member selected from methyl, ethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-hydroxypropyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl and 4-(dimethylamino).
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24. The method of claim 1, wherein R1 is 3-piperidinylmethoxy, 3-pyrrolidinylmethoxy, 1-piperidinyl, 1-pyrrolidinyl, 1-methylpiperidin-3-yl-methoxy, 1-(2-hydoxyethyl)piperidin-3-yl, 1-(2-cyanoethyl)piperidin-3-yl, 1-(2-hydoxypropyl)piperidin-3-yl, 1-(2-methoxyethyl)piperidin-3-yl, 1-(2-hydoxy-2-methylpropyl)piperidin-3-yl, 4-(dimethylamino)piperidin-1-yl, 1-ethylpiperidin-3-yl-methoxy, or 3-(dimethylamino)pyrrolidin-1-yl.
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25. The method of claim 1, wherein R1 is pyrrolidinylmethoxy optionally substituted by methyl.
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26. The method of claim 1, wherein R3 is H.
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27. The method of claim 1, wherein R4 is H.
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28. The method of claim 1, wherein each RA is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, or 3, substituents independently selected from halo, C1-6 haloalkyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4.
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29. The method of claim 1, wherein each RA is independently selected from halo, CN, and NO2.
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30. The method of claim 1, wherein RA is CN.
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31. The method of claim 1, wherein each RB is independently selected from Cy4, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ═
- O, ORa5, NRc5C(O)ORa5, NRc5Rd5, C(O)NRc5Rd5, and C(O)ORa5, wherein said C1-6 alkyl is optionally substituted by Cy4, CN, ORa5, NRc5C(O)ORa5, or NRc5C(O)NRc5Rd5.
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32. The method of claim 1, wherein each RB is independently selected from Cy4, halo, C1-6 alkyl, ═
- O, and C(O)ORa5, wherein said C1-6 alkyl is optionally substituted by Cy4.
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33. The method of claim 1, wherein each RB is independently selected from C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, halo, C1-4 alkyl wherein said C1-4 alkyl is optionally substituted by CN, OH, N(C1-4 alkyl)C(O)O(C1-4 alkyl), —
- O—
(C1-4 alkyl) or N(C1-4 alkyl)C(O)N(C1-4 alkyl)2;
C1-6 haloalkyl, ═
O, C(O)O(C1-4 alkyl), OH, C1-4 alkoxy, N(C1-4 alkyl)C(O)O(C1-4 alkyl), CN, NH2, NH(C1-4 alkyl), C(O)NH(C1-4 alkyl), and (5-6 membered heterocycloalkyl)-C1-4 alkyl- wherein said (5-6 membered heterocycloalkyl)-C1-4 alkyl- is optionally substituted by C1-4 alkyl.
- O—
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34. The method of claim 1, wherein each RB is independently selected from C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, halo, C1-4 alkyl, ═
- O, C(O)O(C1-4 alkyl), and (5-6 membered heterocycloalkyl)-C1-4 alkyl- wherein said (5-6 membered heterocycloalkyl)-C1-4 alkyl- is optionally substituted by C1-4 alkyl.
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35. The method of claim 1, wherein each RB is independently selected from cyclobutyl, morpholino, chloro, fluoro, methyl, ethyl, 2-propyl, cyclopropyl, difluoromethyl, ═
- O, t-butoxycarbonyl, morpholinomethyl, morpholinoethyl, hydroxymethyl, methoxy, —
N(CH3)C(O)O(CH3), —
CH2—
N(CH3)C(O)O(CH3), 2-oxopyrrolidinyl, CN, NH2, OH, 1-hydroxy-1-methylethyl, dimethylamino, —
CH2—
N(CH3)C(O)N(CH3)2, difluoromethoxy, ethoxy, methoxymethyl, 1-hydroxyethyl, 1-cyano-1-methylethyl, C(O)NH(CH3) and 4-methyl-piperazinylmethyl.
- O, t-butoxycarbonyl, morpholinomethyl, morpholinoethyl, hydroxymethyl, methoxy, —
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36. The method of claim 1, wherein each RB is independently selected from cyclobutyl, morpholino, chloro, fluoro, methyl, ethyl, ═
- O, t-butoxycarbonyl, morpholinomethyl, morpholinoethyl, and 4-methyl-piperazinylmethyl.
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37. The method of claim 1, wherein RX is H.
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38. The method of claim 1, wherein each Cy1, Cy3, Cy4, and Cy5 is independently selected from phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy.
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39. The method of claim 1, wherein each Cy4 is independently selected from C3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy.
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40. The method of claim 1, wherein each Cy4 is independently selected from cyclobutyl, morpholino, 2-oxopyrrolidinyl and piperazinyl, each of which is optionally substituted with C1-4 alkyl.
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41. The method of claim 1, wherein each Cy4 is independently selected from cyclobutyl, morpholino, and piperazinyl, each of which is optionally substituted with C1-4 alkyl.
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42. The method of claim 1, wherein each Cy5 is independently selected from 4-10 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from RCy.
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43. The method of claim 1, wherein each Cy5 is independently selected from pyrrolidinyl and piperidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy.
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44. The method of claim 1, wherein each RCy is independently selected from C1-4 alkyl, oxo, and NRc6Rd6, wherein said C1-4 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN and ORa6.
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45. The method of claim 4, wherein each Ra1 is independently selected from C1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy5.
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46. The method of claim 4, wherein each Ra1 is independently selected from C1-3 alkyl optionally substituted with 1 or 2 substituents independently selected from Cy5.
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47. The method of claim 1, wherein each Ra1 is independently selected from (pyrrolidinyl)methyl which is optionally substituted on the pyrrolidinyl moiety by a methyl group-;
- and (piperidinyl)methyl- which is optionally substituted on the piperidinyl moiety by methyl, ethyl, 2-hydroxyethyl, 2-cyanoethyl, 2-hydroxypropyl, 2-methoxyethyl, or 2-hydroxy-2-methylpropyl.
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48. The method of claim 1, wherein each Ra1 is independently selected from (pyrrolidinyl)methyl- which is optionally substituted on the pyrrolidinyl moiety by a methyl group.
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49. The method of claim 1, wherein the compound is a compound having Formula IIa:
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50. The method of claim 1, wherein the compound is a compound having Formula IIb:
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51. The method of claim 1, wherein the compound is a compound having Formula IIIa:
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52. The method of claim 1, wherein the compound is a compound having Formula IIIb:
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53. The method of claim 1, wherein the compound is a compound having Formula IVa:
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54. The method of claim 1, wherein the compound is a compound having Formula IVb:
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55. The method of claim 1, wherein the compound is a compound having Formula Va:
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56. The method of claim 1, wherein the compound is a compound having Formula Vb:
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57. The method of claim 1, wherein the compound is a compound having Formula VIa or Formula VIb:
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58. The method of claim 1, wherein the compound is a compound having Formula VIIa or Formula VIIb:
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59. The method of claim 1, wherein the compound is a compound having Formula VIIIa or Formula VIIIb:
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60. The method of claim 1, wherein the compound is a compound having Formula IXa or Formula IXb:
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61. The method of claim 1, wherein the compound is a compound having Formula Xa or Formula Xb
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62. The method of claim 1, wherein the compound is a compound having Formula XIa or XIb
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63. The method of claim 1, wherein the compound is selected from:
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4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 6-(4-fluorophenyl)-5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridine; 5-(4-methylphenyl)-6-(4-nitrophenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridine; 2-fluoro-4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 3-fluoro-4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(4-chlorophenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(1-cyclobutyl-1H-pyrazol-4-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(2-fluoro-4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(4-ethylcyclohex-1-en-1-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; tert-butyl 4-{6-(4-cyanophenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-5-yl}-3,6-dihydropyridine-1(2H)-carboxylate; 4-{5-(1-methyl-1H-indazol-5-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo-[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(4-morpholin-4-ylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo-[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-(2,3-dihydro-1,4-benzodioxin-6-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-[4-(morpholin-4-ylmethyl)phenyl]-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-[4-(2-morpholin-4-ylethyl)phenyl]-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-{5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo-[1,5-a]pyridin-6-yl})benzonitrile; and 4-(5-(4-methylphenyl)-8-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt of any of the aforementioned.
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64. The method of claim 1, wherein the compound is selected from:
-
4-(5-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1-methyl-1H-indazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(5-(1-methyl-1H-benzimidazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(8-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-quinolin-6-ylimidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1,3-dimethyl-1H-indazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(1,3-benzothiazol-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; (R)-4-(5-(benzo[d]thiazol-5-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(2-methyl-1,3-benzothiazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 2-fluoro-4-[8-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-(2-cyanoethyl)piperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-(2-hydroxypropyl)piperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-(2-methoxyethyl)piperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(5-[3-(hydroxymethyl)-4-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-(5-fluoro-6-methoxypyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(5-[4-(hydroxymethyl)-3-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; Methyl [4-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy)}imidazo[1,5-a]pyrazin-5-yl)phenyl]methylcarbamate; 4-(5-[3,5-difluoro-4-(hydroxymethyl)phenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; methyl [4-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy)}imidazo[1,5-a]pyrazin-5-yl)-2-fluorobenzyl]methylcarbamate; methyl [5-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo [1,5-a]pyrazin-5-yl)pyridin-2-yl]methylcarbamate; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(6-methoxypyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1,5-naphthyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; (R)-4-(8-((1-methylpiperidin-3-yl)methoxy)-5-(quinoxalin-6-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3-methyl-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(8-((1-methylpiperidin-3-yl)methoxy)-5-(1,5-naphthyridin-3-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(furo[3,2-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(1-methyl-2-oxoindolin-5-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(8-((1-ethylpiperidin-3-yl)methoxy)-5-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-8-((1-ethylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)-8-((1-ethylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(5-amino-6-methoxypyridin-3-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(5-fluoro-6-methoxypyridin-3-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(8-((1-methylpiperidin-3-yl)methoxy)-5-(6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(6-methoxypyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3,5-difluoro-4-(hydroxymethyl)phenyl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; Methyl [5-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-5-yl)pyridin-2-yl]methylcarbamate; 4-(5-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5-hydroxy-6-methylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[4-(1-hydroxy-1-methylethyl)phenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5-fluoro-6-morpholin-4-ylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[4-(hydroxymethyl)-3-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[6-(dimethylamino)pyridin-3-yl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5,6-dimethylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; N-[4-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-5-yl)-2-fluorobenzyl]-N,N′
,N′
-trimethylurea;4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-1H-benzimidazol-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(8-(4-(dimethylamino)piperidin-1-yl)-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(5-(5,6-dimethylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; (R)-methyl (4-(6-(4-cyanophenyl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyrazin-5-yl)-2-fluorophenyl)(methyl)carbamate; 4-(5-(5-fluoro-6-methylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(5,6-dimethylpyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(5-fluoro-6-methoxypyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-[3-(hydroxymethyl)-4-methylphenyl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-[2-(hydroxymethyl)-4-methylphenyl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(6-methoxy-5-methylpyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; methyl (4-{6-(4-cyanophenyl)-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-5-yl}-2-fluorophenyl)methylcarbamate; methyl (4-(6-(4-cyanophenyl)-8-(4-(dimethylamino)piperidin-1-yl)imidazo[1,5-a]pyrazin-5-yl)phenyl)(methyl)carbamate; methyl (5-(6-(4-cyanophenyl)-8-(4-(dimethylamino)piperidin-1-yl)imidazo[1,5-a]pyrazin-5-yl)pyridin-2-yl)(methyl)carbamate; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(5-fluoro-6-methylpyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-{5-[6-(difluoromethoxy)pyridin-3-yl]-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-6-yl)}benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(6-ethoxypyridin-3-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-1H-indazol-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(5-(2-hydroxy-2,3-dihydro-1H-inden-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 2-fluoro-4-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(8-(4-(dimethylamino)piperidin-1-yl)-5-(quinoxalin-6-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-(8-(4-(dimethylamino)piperidin-1-yl)-5-(furo[3,2-b]pyridin-6-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(4-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-5-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; (S)-4-(8-(3-(dimethylamino)pyrrolidin-1l-yl)-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-[(3 S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; (R)-4-(8-((1-ethylpiperidin-3-yl)methoxy)-5-(1-methyl-2-oxoindolin-5-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-8-((1-(2-methoxyethyl)piperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(3-ethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-yl)-8-{[(3R)-1-(2-hydroxypropyl)piperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(furo[3,2-b]pyridin-6-yl)-8-(((3R)-1-(2-hydroxypropyl)piperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(8-(((3R)-1-(2-hydroxypropyl)piperidin-3-yl)methoxy)-5-(quinoxalin-6-yl)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-furo[3,2-b]pyridin-6-yl-8-{[(3R)-1-(2-methoxyethyl)piperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)-8-((1-(2-methoxyethyl)piperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[4-(1-hydroxyethyl)phenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[3,5-difluoro-4-(1-hydroxyethyl)phenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-[8-{[(3R)-1-methylpiperidin-3-yl]methoxy}-5-(6-methylpyridin-3-yl)imidazo[1,5-a]pyridin-6-yl]benzonitrile; 4-(5-[3-fluoro-4-(1-hydroxyethyl)-5-methylphenyl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5-fluoro-6-methylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-{8-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-5-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]imidazo[1,5-a]pyridin-6-yl}benzonitrile; 4-(5-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]-8-{[(3R)-1-(2-methoxyethyl)piperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5,6-dimethylpyridin-3-yl)-8-{[(3R)-1-(2-methoxyethyl)piperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(5,6-dimethylpyridin-3-yl)-8-{[(3R)-1-ethylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-[6-(1-cyano-1-methylethyl)pyridin-3-yl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(6-ethylpyridin-3-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(1-cyclobutyl-1H-pyrazol-4-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; and 5-(6-(4-cyanophenyl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-5-yl)-N-methylpyridine-2-carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned.
-
-
65. The method of claim 1, wherein the compound is selected from:
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4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(2-hydroxy-2,3-dihydro-1H-inden-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(8-(4-(dimethylamino)piperidin-1-yl)-5-(7-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-{5-(1-cyclobutyl-1H-pyrazol-4-yl)-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-6-yl)}benzonitrile; 4-{5-[5-(difluoromethyl)-6-methylpyridin-3-yl]-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 5-{6-(4-cyanophenyl)-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-5-yl}-N-methylpyridine-2-carboxamide; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-[5-(hydroxymethyl)-6-methylpyridin-3-yl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-{5-[2-(difluoromethyl)-1-methyl-1H-benzimidazol-5-yl]-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-quinolin-3-ylimidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-quinolin-6-ylimidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-[8-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-5-(6-methylpyridin-3-yl)imidazo[1,5-a]pyridin-6-yl]benzonitrile; 4-(5-[5-(methoxymethyl)-6-methylpyridin-3-yl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 5-{6-(4-cyanophenyl)-8-[4-(dimethylamino)piperidin-1-yl]imidazo[1,5-a]pyrazin-5-yl}-2-methoxynicotinonitrile; 4-{8-[4-(dimethylamino)piperidin-1-yl]-5-[4-(hydroxymethyl)-3-methylphenyl]imidazo[1,5-a]pyrazin-6-yl}benzonitrile; 4-[8-[4-(dimethylamino)piperidin-1-yl]-5-(2-methoxypyrimidin-5-yl)imidazo[1,5-a]pyrazin-6-yl]benzonitrile; 4-(5-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(1,2-dimethyl-1H-benzimidazol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; 4-(5-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-8-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3-isopropyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(3-cyclopropyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; (R)-4-(5-(2-isopropyl-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; and (R)-4-(5-(2-cyclopropyl-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-8-((1-methylpiperidin-3-yl)methoxy)imidazo[1,5-a]pyridin-6-yl)benzonitrile; or a pharmaceutically acceptable salt of any of the aforementioned.
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2. The method of claim 1, wherein the patient has cancer.
Specification
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Current AssigneeIncyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
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Original AssigneeIncyte Corporation
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InventorsWu, Liangxing, Konkol, Leah C., Lajkiewicz, Neil, Lu, Liang, Xu, Meizhong, Yao, Wenqing, Yu, Zhiyong, Zhang, Colin, He, Chunhong
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Primary Examiner(s)Willis, Douglas M
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Application NumberUS15/610,015Publication NumberTime in Patent Office440 DaysField of Search544349, 546121US Class CurrentCPC Class CodesA61P 35/00 Antineoplastic agentsC07D 471/04 Ortho-condensed systemsC07D 487/04 Ortho-condensed systemsC07D 519/00 Heterocyclic compounds cont...