IMIDAZOPYRIDINES AND IMIDAZOPYRAZINES AS LSD1 INHIBITORS
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Accused Products
Abstract
The present invention is directed to imidazo[1,5-a]pyridine and imidazo[1,5-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
31 Citations
68 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, 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, 66, 67, 68)
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2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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; each Re5, Re6, and Re8 is independently selected from H, C1-4 alkyl, and CN.
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3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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)ORa8, 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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5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.
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6. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, wherein X is CRX.
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7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-10 aryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from RA.
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8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from RA.
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9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted by 1 or 2 substituents independently selected from halo, CN, and NO2.
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10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl;
- 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;
C3-7cycloalkyl;
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, C3-7cycloalkyl, 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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11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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, each optionally substituted by 1, 2, or 3 substituents independently selected from C3-7cycloalkyl, 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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13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1 or Cy1.
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14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1 or 4-10 membered heterocycloalkyl.
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15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1.
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16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is 3-piperidinylmethoxy, 3-pyrrolidinylmethoxy or 1-piperidinyl, 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 or 4-(dimethylamino).
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19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is 3-piperidinylmethoxy, 3-pyrrolidinylmethoxy, 1-piperidinyl, 1-pyrrolidinyl, 1-methylpiperidin-3-yl-methoxy, 1-(2-hydroxyethyl)piperidin-3-yl, 1-(2-cyanoethyl)piperidin-3-yl, 1-(2-hydroxypropyl)piperidin-3-yl, 1-(2-methoxyethyl)piperidin-3-yl, 1-(2-hydoxy-2-methylpropyl)piperidin-3-yl, 4-(dimethylamino)piperidin-1-yl, or 1-ethylpiperidin-3-yl-methoxy, 3-(dimethylamino)pyrrolidin-1-yl.
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20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is pyrrolidinylmethoxy optionally substituted by methyl.
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21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
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22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
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23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each RA is independently selected from halo, CN, and NO2.
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25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RA is CN.
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26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RX is H.
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33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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34. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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38. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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40. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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41. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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42. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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43. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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44. The compound of claim 1 having Formula IIa:
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45. The compound of claim 1, having Formula IIb:
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46. The compound of claim 1, having Formula IIIa:
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47. The compound of claim 1 having Formula IIIb:
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48. The compound of claim 1, having Formula IVa:
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49. The compound of claim 1 having Formula IVb:
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50. The compound of claim 1, having Formula Va:
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51. The compound of claim 1 having Formula Vb:
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52. The compound of claim 1, having Formula VIa or VIb:
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53. The compound of claim 1, having Formula VIIa or VIIb:
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54. The compound of claim 1, having Formula VIIIa or VIIIb:
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55. The compound of claim 1, having Formula IXa or IXb:
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56. The compound of claim 1, having Formula Xa or Xb
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57. The compound of claim 1, having Formula XIa or XIb
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58. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein group:
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59. The compound of claim 1 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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60. The compound of claim 1 selected from:
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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-cyano ethyl)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-fluoro phenyl)(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-1-yl)-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)imidazo[1,5-a]pyrazin-6-yl)benzonitrile; 4-[8-[(3S)-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]dioxin[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]dioxin[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.
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61. A compound of claim 1 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-cyclo butyl-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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62. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
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63. A method of inhibiting lysine specific demethylase-1 (LSD1) comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with said LSD1.
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64. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disease is cancer.
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65. The method of claim 64 wherein said cancer is a hematological cancer.
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66. The method of claim 65 wherein said hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), or multiple myeloma.
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67. The method of claim 64 wherein said 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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68. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disease is a viral disease or a beta-globinopathy.
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2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
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., Lu, Liang, Xu, Meizhong, Yao, Wenqing, Zhang, Colin, He, Chunhong, Lajkiewicz, Neil, Yu, Zhiyong
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current1/1
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CPC Class CodesA61P 35/00 Antineoplastic agentsC07D 471/04 Ortho-condensed systemsC07D 487/04 Ortho-condensed systemsC07D 519/00 Heterocyclic compounds cont...