Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
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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.
84 Citations
63 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)
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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)2NR4Rd4, 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)NR4Rd4, C(O)ORa4, NRc4Rd4 NRc4C(O)Rb4S(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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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)NR4Rd4, 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)NR4Rd4, C(O)ORa4, NRc4Rd4 NRc4C(O)Rb4S(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 Res, R6, 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)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, SRa5, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8 NRc8C(O)Rb8, NRc8C(O)NRc8Rd8, NRc8C(O)ORa5, 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 R5 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)ORa5, 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, 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 RX is H.
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8. 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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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 RA.
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10. 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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11. 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;
C3-7 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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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, 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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13. 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, 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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14. 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)NR4Rd4, 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)NR4Rd4, C(O)ORa4, NRc4Rd4 NRc4C(O)Rb4S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4.
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15. 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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16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RA is CN.
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17. 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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18. 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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19. 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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20. 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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21. 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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22. 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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23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1 or Cy1.
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24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1 or 4-10 membered heterocycloalkyl.
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25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1.
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26. 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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27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from pyrrolidinylmethoxy optinally 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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28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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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29. 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-hydroxy-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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30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is pyrrolidinylmethoxy optionally substituted by methyl.
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31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
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32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
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33. 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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34. 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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35. 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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36. 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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37. 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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38. 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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39. 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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40. 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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41. 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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42. 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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43. 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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44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein group:
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45. The compound of claim 1 having Formula IIa:
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46. The compound of claim 1, having Formula IIb:
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47. The compound of claim 1, having Formula IIIa:
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48. The compound of claim 1 having Formula IIIb:
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49. The compound of claim 1, having Formula IVa:
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50. The compound of claim 1 having Formula IVb:
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51. The compound of claim 1, having Formula Va:
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52. The compound of claim 1 having Formula Vb:
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53. The compound of claim 1, having Formula VIa or Formula VIb:
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54. The compound of claim 1, having Formula VIIa or Formula VIIb:
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55. The compound of claim 1, having Formula VIIIa or Formula VIIIb:
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56. The compound of claim 1, having Formula IXa or Formula IXb:
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57. The compound of claim 1, having Formula Xa or Formula Xb
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58. The compound of claim 1, having Formula XIa or Formula XIb
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59. The compound of claim 1 selected from:
-
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:
-
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-(l-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-[(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.
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61. The 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-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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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 comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with said lysine specific demethylase-1.
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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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InventorsXu, Meizhong, Zhang, Colin, He, Chunhong, Wu, Liangxing, Konkol, Leah C., Lu, Liang, Yao, Wenqing, Lajkiewicz, Neil, Yu, Zhiyong
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Primary Examiner(s)Willis, Douglas M
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Application NumberUS14/795,536Publication NumberTime in Patent Office726 DaysField of Search514249, 514303, 544350, 546119US Class CurrentCPC Class CodesA61P 35/00 Antineoplastic agentsC07D 471/04 Ortho-condensed systemsC07D 487/04 Ortho-condensed systemsC07D 519/00 Heterocyclic compounds cont...