Cyclopropylamines as LSD1 inhibitors

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:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl;

R Z is CN, OR a , 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, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 3-cyanophenyl, 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, 4-methoxyphenyl, 3-(aminocarbonyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl,

each R 1 is independently selected from halo or C 1-6 alkyl;

R N is H or R B ;

each R B is independently selected from C 1-6 alkyl, 4-10 membered heterocycloalkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and S(O) 2 R 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 c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c1 R d2 ;

R 3 and R 4 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;

R 5 and R 6 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;

each Cy is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

R a is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, and C 3-10 cycloalkyl-C 1-4 alkyl-, each of which is optionally substituted with halo or CN;

each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and Cy, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

or any R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group;

each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, or 2 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

each R e2 and R e4 is independently selected from H, C 1-4 alkyl, and CN;

n is 0, 1, 2, or 3;

q is 0, 1, or 2; and

s is 1, 2, 3, or 4.

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 R 5 and R 6 are H.

7. The method of claim 1 , wherein both R 3 and R 4 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 c2 R d2 , C(O)OR a2 , and S(O) 2 R 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 c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c1 R 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.