CYCLOPROPYLAMINES AS LSD1 INHIBITORS
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Abstract
The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
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Citations
51 Claims
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1. A compound of Formula I:
- View Dependent Claims (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)
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3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring B is monocyclic 4-7 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.
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4. The compound of claim 1 or 2 having Formula II:
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5. The compound of claim 1 or 2 having Formula IIIa:
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6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 0.
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7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1.
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8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein s is 1.
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9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.
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10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.
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11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both R5 and R6 are H.
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12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both R3 and R4 are H.
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13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is CN, ORB, or Cy1.
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14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is CN.
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15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is ORB.
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16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is ORa and Ra is selected from C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, and C3-10 cycloalkyl-C1-4 alkyl-, each of which is optionally substituted with halo or CN.
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17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is methoxy.
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18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is ethoxy.
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19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is phenoxy substituted by 1 or 2 substituents independently selected from halo and CN.
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20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is (C6-10 aryl-C1-4 alkyl)-O—
- .
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21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is (pyridinyl)-O—
- or (pyrimidinyl)-O—
, of which is substituted by 1 or 2 substituents independently selected from halo.
- or (pyrimidinyl)-O—
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22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is (C3-10 cycloalkyl-C1-4 alkyl)-O—
- .
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23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is (C3-10 cycloalkyl)-O—
- .
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24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is Cy1.
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25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is phenyl substituted by 1 or 2 substituents independently selected from Cy2, halo, CN, C1-6 alkoxy, —
- C(O)NRc3Rd3, —
C(O)ORa3, (4-10 membered heterocycloalkyl)-O—
, and C1-4 cyanoalkyl.
- C(O)NRc3Rd3, —
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26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is phenyl substituted by 1 or 2 substituents independently selected from Cy2, halo, and C1-4 cyanoalkyl.
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27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is phenyl substituted by 1 or 2 halo.
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28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is pyridinyl substituted by 1 or 2 substituents independently selected from halo and C1-6 alkoxy.
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29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl, 3-carboxyphenyl, 3-[(3S)-tetrahydrofuran-3-yloxy]phenyl, 3-(tetrahydropyran-4-yloxy)phenyl, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, benzyloxy, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 3-cyanophenyl, 2-cyanophenoxy, (5-fluoropyridin-2-yl)oxy, (5-fluoropyrimidin-2-yl)oxy, 3-cyanophenoxy, 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, ethoxy, cyclobutylmethoxy, cyclohexyloxy, 4-methoxyphenyl, 3-(aminocarbonyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl,
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30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RZ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl,
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31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RN is H.
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32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RN is RB.
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33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each RB is independently selected from C1-6 alkyl, 4-10 membered heterocycloalkyl, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, and S(O)2Rb2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRe2)NRc2Rd2, NRc2C(═
NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O) ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc1Rd2.
- NRe2)NRc2Rd2, NRc2C(═
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34. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each RB is independently selected from C1-6 alkyl, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, and S(O)2Rb2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRe2)NRc2Rd2, NRc2C(═
NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc1Rd2.
- NRe2)NRc2Rd2, NRc2C(═
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35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RB is a group of formula:
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36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.
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37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.
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38. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula I.
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39. The compound of claim 1 selected from:
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(1-Acetyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile; Methyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate; 4-(Cyanomethyl)-N,N-dimethyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}-piperidine-1-carboxamide; (1-(Methylsulfonyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile; (1-Methyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile; (4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile; and [4-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1-(pyridin-3-ylmethyl)piperidin-4-yl]acetonitrile, or a pharmaceutically acceptable salt of any of the aforementioned.
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40. The compound of claim 1 selected from:
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3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N-methylpropanamide; 3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N,N-dimethylpropanamide; (1R,2S)—
N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;(1S,2R)—
N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]acetic acid; (1R,2S)—
N-{[1-[(2S)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;(1R,2S)—
N-{[1-[(2R)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;3-[4-(2-fluorobenzyl)-4({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(3-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(2,4-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(2,3-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(3,4-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; (1R,2S)—
N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N,N-dimethylpropanamide; 3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N-methylpropanamide; 3-[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}-methyl)piperidin-1-yl]propanoic acid; 3-[4-[4-(1-cyanocyclopropyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[3-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; or a pharmaceutically acceptable salt of any of the aforementioned.
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41. The compound of claim 1 selected from:
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(1R,2S)—
N-{[4-(methoxymethyl)-1-(morpholin-4-ylacetyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;(1R,2S)—
N-{[4-(methoxymethyl)-1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;3-(4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-{3-[(3R)-tetrahydrofuran-3-yloxy]benzyl}piperidin-1-yl)propanoic acid 3-[4-(3-ethoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(3-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(4-cyano-2-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(4-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-2,2-dimethylpropanoic acid; 3-[4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(4-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(6-methoxypyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl) piperidin-1-yl]propanoic acid; 3-[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-[4-{[(5-fluoropyrimidin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; 3-{[1-(2-cyanoethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid; 3-{[1-(cyclopropylmethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid; 3-{[1-[(dimethylamino)acetyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzamide; 3-{[1-[(dimethylamino)acetyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzonitrile; 3-{[1-ethyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid; 3-{[1-isopropyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid; 3-{[1-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid; 3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(pyridin-2-ylmethyl)piperidin-4-yl]methyl}benzoic acid; 3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]methyl}benzoic acid; 3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]methyl}benzoic acid; and 3-{4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-[3-(tetrahydro-2H-pyran-4-yloxy)benzyl]piperidin-1-yl}propanoic acid; or a pharmaceutically acceptable salt of any of the aforementioned.
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42. 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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43. A method of inhibiting LSD1 comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with said LSD1.
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44. A method of inhibiting LSD1 comprising contacting a pharmaceutical composition of claim 42 with said LSD1.
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45. 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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46. The method of claim 45, wherein said cancer is a hematological cancer.
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47. The method of claim 46, 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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48. The method of claim 45, 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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49. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of claim 42 wherein said disease is cancer.
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50. 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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51. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of claim 42 wherein said disease is a viral disease or a beta-globinopathy.
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3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring B is monocyclic 4-7 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.
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2. A compound of Formula I:
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, He, Chunhong, Qian, Ding-Quan, Wang, Xiaozhao, Yao, Wenqing, Zhang, Fenglei, Courter, Joel R., Shen, Bo
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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 CodesA61K 31/445 Non condensed piperidines, ...A61K 31/4465 only substituted in position 4A61K 31/4525 containing a five-membered ...A61K 31/453 containing a six-membered r...A61K 31/454 containing a five-membered ...A61K 31/4545 containing a six-membered r...A61K 31/506 not condensed and containin...A61K 31/5377 not condensed and containin...A61P 31/12 AntiviralsA61P 35/00 Antineoplastic agentsC07D 211/14 with hydrocarbon or substit...C07D 211/26 with hydrocarbon radicals, ...C07D 211/34 with hydrocarbon radicals, ...C07D 211/96 Sulfur atomC07D 401/06 linked by a carbon chain co...C07D 401/10 linked by a carbon chain co...C07D 401/12 linked by a chain containin...C07D 405/04 directly linked by a ring-m...C07D 405/12 linked by a chain containin...C07D 413/06 linked by a carbon chain co...