Cyclopropylamines as LSD1 inhibitors

• US 10,300,051 B2
• Filed: 10/05/2016
• Issued: 05/28/2019
• Est. Priority Date: 02/13/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, Courter, Joel R., He, Chunhong, Shen, Bo, Wang, Xiaozhao, Yao, Wenqing, Zhang, Fenglei
• Primary Examiner(s): Reese, Heidi
• Application Number:
  US15/285,792
• Publication Number:
  US 20170112816A1
• Time in Patent Office: 965 Days
• Field of Search: None
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4465 only substituted in position 4
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1. A method of treating a disease, wherein said disease is selected from sickle cell disease, leiomyosarcoma, hepatocellular carcinoma, small cell lung cancer, Ewing'"'"'s sarcoma, neuroblastoma, glioblastoma, breast cancer, prostate cancer, ovarian cancer, acute myelogenous leukemia, and myelofibrosis, comprising administering to a patient a therapeutically effective amount of a compound of Formula IIIa:

2. The method of claim 1, wherein q is 0.

3. The method of claim 1, wherein q is 1.

4. The method of claim 1, wherein s is 1.

5. The method of claim 1, wherein n is 0.

6. The method of claim 1, wherein both R⁵ and R⁶ are H.

7. The method of claim 1, wherein both R³ and R⁴ are H.

8. The method of claim 1, wherein R^Z is CN.

9. The method of claim 1, wherein R^Z is OR^a.

10. The method of claim 1, wherein R^Z is methoxy.

11. The method of claim 1, wherein R^Z is ethoxy.

12. The method of claim 1, wherein R^Z is phenoxy substituted by 1 or 2 substituents independently selected from halo and CN.

13. The method of claim 1, wherein R^Z is (pyridinyl)-O—

or (pyrimidinyl)-O—

, of-which is substituted by 1 or 2 substituents independently selected from halo.

14. The method of claim 1, wherein R^Z is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl, 3-carboxyphenyl, 3-[(3 S)-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,

15. The method of claim 1, wherein R^Z is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl,

16. The method of claim 1, wherein R^N is H.

17. The method of claim 1, wherein R^N is R^B.

18. The method of claim 1, wherein each R^B is independently selected from C_1-6 alkyl, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, and S(O)₂R^b2, wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NR^e2)NR^c2R^d2, NR^c2C(═

NR^e2)NR^c2R^d2 NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2 NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c1R^d2.

19. The method of claim 1, wherein R^B is a group of formula:

20. The method of claim 1, wherein the compound has a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula IIIa.

21. The method of claim 1, wherein the compound is selected from:

(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.

22. The method of claim 1, wherein the compound is selected from:

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;

(1 S,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-[(2 S)-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; and

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.

23. The method of claim 1, wherein the compound is selected from:

(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.

24. The method of claim 1, wherein the disease is sickle cell disease.

25. The method of claim 1, wherein the disease is leiomyosarcoma.

26. The method of claim 1, wherein the disease is hepatocellular carcinoma.

27. The method of claim 1, wherein the disease is small cell lung cancer.

28. The method of claim 1, wherein the disease is Ewing'"'"'s carcinoma.

29. The method of claim 1, wherein the disease is neuroblastoma.

30. The method of claim 1, wherein the disease is glioblastoma.

31. The method of claim 1, wherein the disease is breast cancer.

32. The method of claim 1, wherein the disease is prostate cancer.

33. The method of claim 1, wherein the disease is ovarian cancer.

34. The method of claim 1, wherein the disease is acute myelogenous leukemia.

35. The method of claim 1, wherein the disease is myelofibrosis.