CYCLOPROPYLAMINES AS LSD1 INHIBITORS

• US 20170121302A1
• Filed: 10/07/2016
• Published: 05/04/2017
• 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, Konkol, Leah C., Qian, Ding-Quan, Shen, Bo, Yao, Wenqing, Zhang, Fenglei
• Granted Patent: US 9,994,546 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• 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 211/58 attached in position 4
• CPC Class Codes: C07D 211/98 Nitrogen atom
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

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 compound of Formula I:

2. The compound of claim 1, 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.

3. The compound of claim 1 having Formula II:

4. The compound of claim 1 having Formula IIIa or IIIb:

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, having Formula IVa or IVb:

6. The compound of claim 1 having Formula Va or Vb:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 0.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is halo.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is F.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both R⁵ and R⁶ are H.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is monocyclic C_3-7 cycloalkyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is monocyclic 4-7 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, or piperidinyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopropyl, cyclohexyl, azetidinyl, or piperidinyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, or S(O)₂R^b3, wherein said C_1-6 alkyl, C_6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═

NR^e3)NR^c3R^d3, NR^c3C(═

NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_1-4 alkyl optionally substituted by CN, C(O)NR^c3R^d3, OR^a3, or C(O)OR^a3.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_1-4 alkyl optionally substituted by CN, C(O)NR^c3R^d3, or C(O)OR^a3.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is —

CH₂—

CN, —

CH₂—

C(═

O)OH, —

CH₂—

C(═

O)NH(CH₃), —

CH_2—

C(═

O)N(CH₃)₂, or —

CH₂CH₂OH.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R³ is independently selected from C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, C_3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, 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^c2R^d2.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R³ is independently selected from C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, S(O)₂R^b2, and S(O)₂NR^c2R^d2, wherein said C_1-6 alkyl, C_6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, 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^c2R^d2.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R³ is independently selected from C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, and S(O)₂R^b2, wherein said C_1-6 alkyl, C_6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, 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^c2R^d2.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is H, C_1-4 alkyl, or C_6-10 aryl-C_1-4 alkyl-, wherein said C_1-4 alkyl and C_6-10 aryl-C_1-4 alkyl- are each optionally substituted by halo or OR^a4.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_1-4 alkyl substituted by methoxy.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is C_6-10 aryl-C_1-4 alkyl- substituted by fluoro.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is H, methyl, methoxymethyl, or 4-fluorophenylmethyl.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Z is H.

32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

34. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 2.

35. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

36. 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.

37. The compound of claim 1 selected from:

(1-{4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}cyclobutyl)acetonitrile;

(1-Methyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

(3-{4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

(1-Benzyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

3-(3-(Cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)propanoic acid;

(1-Acetyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

(1-Benzoyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

Methyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidine-1-carboxylate;

(1-(Methylsulfonyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile;

2-(3-(Cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)nicotinonitrile;

3-Cyano-4-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)benzoic acid;

2-(3-(Cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)benzonitrile;

4-(3-(Cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)benzonitrile;

[1-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)cyclobutyl]acetonitrile;

(1′

-(Ethylsulfonyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3′

-biazetidin-3′

-yl)acetonitrile;

[4-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile;

[1-Methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile;

[1-Acetyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile;

[1-(4-Fluorobenzoyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile;

[1-(Methylsulfonyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile;

[4-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-1-(phenylsulfonyl)piperidin-4-yl]acetonitrile;

Ethyl 4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxylate;

4-(Cyanomethyl)-N,N-dimethyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide;

4-(Cyanomethyl)-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide;

4-(Cyanomethyl)-N-(4-fluorophenyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide;

(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1,3′

-biazetidin-3′

-yl)acetonitrile;

4-(3′

-(Cyanomethyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3′

-biazetidin-1′

-yl)-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

N-{[1-(1-Methylpiperidin-4-yl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine;

Trans-2-phenyl-N-{[1-(1-phenylpiperidin-4-yl)azetidin-3-yl]methyl}cyclopropanamine;

1-Phenyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)cyclohexanecarbonitrile;

[1-(Ethylsulfonyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetonitrile;

[3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

2-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]nicotinonitrile;

4-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]-2,5-difluoro-N-isopropylbenzamide;

{3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[3-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}acetonitrile;

{3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}acetonitrile;

2-Chloro-6-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]benzonitrile;

2-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]benzonitrile;

4-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]benzonitrile;

Methyl 3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxylate;

3-(Cyanomethyl)-N-(2,4-difluorophenyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide;

N-(3-Chloro-2-fluorophenyl)-3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide;

[1-(3,5-Difluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-Benzoyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(2-Fluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(3-Fluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(4-Fluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-Methyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetic acid;

N-Methyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3-yl)acetamide; and

N,N-Dimethyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3-yl)acetamide,

or a pharmaceutically acceptable salt of any of the aforementioned.

38. The compound of claim 1 selected from:

{1-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetic acid;

{1-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetic acid;

{1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetic acid;

N,N-dimethyl-2-{1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetamide;

N-methyl-2-{1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetamide;

[1-(methylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide;

3-(cyanomethyl)-N-methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide;

3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide;

[1-methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid;

[1-ethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid;

N,N-dimethyl-2-[1-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetamide;

N-methyl-2-[1-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetamide;

2-[1-(ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]-N,N-dimethylacetamide;

2-[1-(ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]-N-methylacetamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

39. The compound of claim 1 selected from:

[1-(1-methyl-1H-pyrazol-4-yl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(2-hydroxyethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(3-hydroxycyclobutyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(cis-4-hydroxycyclohexyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(isothiazol-5-ylcarbonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(morpholin-4-ylcarbonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-(trans-4-hydroxycyclohexyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(1-hydroxycyclopentyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(1-hydroxycyclopropyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(1-methyl-1H-pyrazol-5-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(3-hydroxyazetidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(4-hydroxypiperidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(4-methoxypiperidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(cis-4-hydroxycyclohexyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[1-[(trans-4-hydroxycyclohexyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(4-hydroxycyclohexyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(methylsulfonyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1H-pyrazol-4-ylcarbonyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrazin-2-ylcarbonyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydrofuran-3-yl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]acetonitrile;

{1-[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetic acid;

2-(3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(tetrahydrofuran-2-carbonyl)azetidin-3-yl)acetonitrile;

2-(3-(cyanomethyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidin-1-yl)-N,N-dimethylacetamide;

2-[1-(ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]ethanol;

2-[1-(methylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]ethanol;

2-[3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]acetamide;

2-[3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]-N-methylacetamide;

3-(cyanomethyl)-3-(4-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide;

3-[2-(dimethylamino)-2-oxoethyl]-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxamide;

methyl 3-[2-(dimethylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate;

methyl 3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate;

N,N-dimethyl-2-(1-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidin-3-yl)acetamide;

N,N-dimethyl-3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxamide;

N-methyl-2-[1-(methylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetamide;

tetrahydrofuran-3-yl 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1H-pyrazol-5-ylcarbonyl)azetidin-3-yl]acetonitrile;

{3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3R)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl}acetonitrile;

{3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3S)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl}acetonitrile;

{3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile;

{3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyridin-2-ylacetyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]acetonitrile;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]acetonitrile;

N,N-dimethyl-2-[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]acetamide;

N-methyl-2-[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]acetamide;

2-[1-(cyclopropylmethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]-N,N-dimethylacetamide;

2-[1-(cyclopropylmethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]-N-methylacetamide;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrimidin-2-ylmethyl)azetidin-3-yl]acetic acid;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrimidin-5-ylmethyl)azetidin-3-yl]acetic acid;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4-ylmethyl)azetidin-3-yl]acetic acid;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5-ylmethyl)azetidin-3-yl]acetic acid;

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-2-ylmethyl)azetidin-3-yl]acetic acid; and

[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(3,3,3-trifluoropropyl)azetidin-3-yl]acetic acid,

or a pharmaceutically acceptable salt of any of the aforementioned.

40. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

41. A method of inhibiting LSD1 comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with said LSD1.

42. 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.

43. The method of claim 42 wherein said cancer is a hematological cancer.

44. The method of claim 43 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.

45. The method of claim 43 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.

46. 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.