ARYLCYCLOPROPYLAMINE BASED DEMETHYLASE INHIBITORS OF LSD1 AND THEIR MEDICAL USE

• US 20130231342A1
• Filed: 07/27/2011
• Published: 09/05/2013
• Est. Priority Date: 07/29/2010
• Status: Active Grant

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: Muoz, Alberto Ortega, Fyfe, Matthew Colin Thor, Martinell Pedemonte, Marc, Tirapu Fernandez de la Cuesta, Iigo, Estirate-Martinez, Maria de los ngeles
• Granted Patent: US 9,181,198 B2
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• 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: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 253/07 : with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 : Nitrogen atoms
• CPC Class Codes: C07D 263/48 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 271/07 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 271/113 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/40 : Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 285/08 : 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 285/12 : 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. Thus, in one specific aspect the invention relates to formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX).

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:

2. The compound of claim 1 wherein (A) is an aryl group or a heteroaryl group, wherein said aryl group or said heteroaryl group has n substituents (R3).

3. The compound of claim 1 wherein (A) is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, and further wherein (A) has n substituents (R3).

4. The compound of claim 1 wherein (A) is phenyl or pyridyl, and further wherein said phenyl or said pyridyl has n substituents (R3).

5. The compound of claim 1 wherein (A) has 0 substituents (R3).

6. The compound of claim 1 wherein (B) is —

O—

CH₂-phenyl or phenyl, and further wherein said phenyl or the phenyl moiety comprised in said —

O—

CH₂-phenyl has n substituents (R2).

9. The compound of claim 1 wherein (B) has 0, 1 or 2 substituents (R2).

11. The compound of claim 1 wherein (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl, and further wherein said thiazolyl, said oxadiazolyl, said oxazolyl, said isoxazolyl, said thiadiazolyl, said triazinyl, said pyridazinyl, said pyrazinyl, said pyridinyl or said pyrimidinyl has one substituent (R1).

12. The compound of claim 1 wherein (D) is thiazolyl, oxadiazolyl or pyrimidinyl, and further wherein said thiazolyl, said oxadiazolyl or said pyrimidinyl has one substituent (R1).

13. The compound of claim 1 wherein (D) is oxadiazolyl, wherein said oxadiazolyl has one substituent (R1).

14. The compound of claim 1 wherein (R1) is —

OH, —

O(alkyl), —

NH₂, —

NH(alkyl), —

N(alkyl)(alkyl), amido, —

SO—

NH₂, —

SO—

NH(alkyl), —

SO—

N(alkyl)(alkyl), —

S(O)₂NH₂, —

S(O)₂NH(alkyl), —

S(O)₂N(alkyl)(alkyl), —

C(═

O)NH₂, —

C(═

O)NH(alkyl), —

C(═

O)N(alkyl)(alkyl), -alkylene-C(═

O)NH₂, -alkylene-C(═

O)NH(alkyl), -alkylene-C(═

O)N(alkyl)(alkyl), —

NHC(═

O)-alkyl, —

N(alkyl)-C(═

O)-alkyl, -alkylene-NH₂, -alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl).

15. The compound of claim 1 wherein (R1) is —

OH, —

NH₂, amido, —

S(O)₂NH₂, —

C(═

O)NH₂, —

CH₂—

C(═

O)NH₂, —

NHC(═

O)CH₃, —

NHCH₃, —

N(CH₃)₂ or —

CH₂—

NH₂.

17. The compound of claim 1 wherein (R1) is —

NH₂.

19. The compound of claim 1 wherein (R2) is independently selected from hydroxyl, halo or haloalkyl.

22. The compound of claim 1 wherein the substituents on the cyclopropyl moiety are in trans-configuration.

23. The compound of claim 1 wherein said compound is selected from:

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;

5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine;

5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine;

3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;

3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;

4′

-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

4′

-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;

N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;

4′

-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′

-biphenyl]-3-ol;

5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;

2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;

4-((((trans)-2-(3′

-(trifluoromethyl)-[1,1′

-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;

2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;

3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;

3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;

6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine;

5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;

2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;

6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine;

3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine;

or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of claim 1 wherein said compound is selected from:

4′

-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 22 wherein said compound is an optically active stereoisomer.

26. The compound of claim 22 wherein said compound is the (−

) stereoisomer.

27. The compound of claim 22 wherein said compound is the (+) stereoisomer.

28. The compound of claim 1 wherein said compound is selected from:

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;

(−

) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;

(−

) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;

(−

) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine,

or a pharmaceutically acceptable salt or solvate thereof.

49. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

53. A method of treating or preventing a neurological disease or disorder, the method comprising administering, to a subject in need of such treatment or prevention, the compound of claim 1.

54. The method of claim 53 wherein said compound is selected from:

4′

-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

or a pharmaceutically acceptable salt or solvate thereof.

55. The method of claim 53 wherein said compound is selected from:

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;

(−

) 5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;

(−

) N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;

(−

) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;

(−

) 5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;

or a pharmaceutically acceptable salt or solvate thereof.

56. The method of claim 53 wherein said neurological disease or disorder is selected from depression, Alzheimer'"'"'s disease, Huntington disease, Parkinson'"'"'s disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.

58. A method of treating or preventing cancer, the method comprising administering, to a subject in need of such treatment or prevention, the compound of claim 1.

59. The method of claim 58 wherein said cancer is selected from prostate cancer, breast cancer, lung cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia, lymphoma, or myeloma.

60. The method of claim 59 wherein said leukemia is selected from acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia.

62. A method of treating or preventing a viral infection, the method comprising administering, to a subject in need of such treatment or prevention, the compound of claim 1.

63. The method of claim 62 wherein said viral infection is a herpesvirus infection.

65. The method of claim 62 wherein said viral infection is caused by and/or associated with HIV.

67. A method of treating or preventing viral reactivation after latency, the method comprising administering, to a subject in need of such treatment or prevention, the compound of claim 1.

68. The method of claim 67 wherein the virus that is reactivating is a herpesvirus.

75. A method for enriching an enantiomer of the compound of claim 1, wherein the substituents on the cyclopropyl moiety comprised in said compound are in trans-configuration, the method comprising:

contacting said compound with a chiral recrystallization agent in a solvent; and

isolating the resulting crystallized salt of the chiral recrystallization agent and the compound.

76. The method of claim 75 wherein the chiral recrystallization agent is selected from (S)-(+)-mandelic acid, D-(−

)-tartaric acid, L-(−

)-di-p-toluoyl tartaric acid, or R-(−

)-mandelic acid.

7-8. -8. (canceled)

10. (canceled)

16. (canceled)

18. (canceled)

20-21. -21. (canceled)

29-48. -48. (canceled)

50-52. -52. (canceled)

57. (canceled)

61. (canceled)

64. (canceled)

66. (canceled)

69-74. -74. (canceled)

77-78. -78. (canceled)