CYCLOPROPYLAMINE DERIVATIVES USEFUL AS LSD1 INHIBITORS

• US 20130197013A1
• Filed: 07/27/2011
• Published: 08/01/2013
• Est. Priority Date: 07/29/2010
• Status: Active Grant

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Alberto Ortega Munoz, Maria De Los Angeles Estiarte-Martinez
• Inventors: Pedemonte, Marc Martinell, Fyfe, Mathew Colin Thor, Muoz, Alberto Ortega, Laria, Julio Castro-Palomino, Estiarte-Martnez, Maria de los ngeles, Vidal, Nuria Valls
• Granted Patent: US 9,006,449 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 211/40 containing only non-condensed rings
• CPC Class Codes: C07C 215/64 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 255/53 containing cyano groups and hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/09 the carbon skeleton being further substituted by at least two halogen atoms
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/42 having hetero atoms attached to the substituent nitrogen atom nitro radicals C07D213/26
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/57 Nitriles
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 239/26 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings

Abstract

The invention relates to cyclopropylamine compounds, in particular the compounds of Formula (I), and their use in therapy, including e.g. in the treatment or prevention of cancer, a neurological disease or condition, or viral infection.

Claims

1. A compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

2. The compound of claim 1 wherein said compound is a compound of Formula (II) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

3. The compound of claim 1 wherein said compound is a compound of Formula (III) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

4. The compound of claim 1 wherein (G) is a heterocyclyl.

6. The compound of claim 1 wherein (G) is phenyl.

9. The compound of claim 1 wherein E is —

X³═

X⁴—

, and X¹, X², X³ and X⁴ are independently C(R2) or N.

10. The compound of claim 1 wherein E is —

X³═

X⁴—

, and X¹, X², X³ and X⁴ are independently C(R2).

13. The compound of claim 1 wherein E is —

S—

, and X¹ and X² are independently C(R2) or N.

21. The compound of claim 1 wherein each (R1) is independently chosen from alkyl, aryl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, heterocycle, sulfonyl, sulfonamide, hydroxyl, or alkoxy.

22. The compound of claim 1 wherein each (R1) is independently chosen from —

CF₃, —

F, —

Cl, —

CN, —

CH₃, —

OH, —

OCH₃, —

C(═

O)NH₂, —

NH—

CO—

CH₃, —

NH—

SO₂—

CH₃, —

NH—

SO₂—

CH₂—

CH₃, —

NH—

SO₂—

CH(CH₃)—

CH₃, —

NH—

SO₂—

(C₆H₅), —

NH—

SO₂—

(C₆H₄)—

CN, —

NHSO₂CF₃, or —

S(═

O)₂NHCH₃.

29. The compound of claim 1 wherein said compound is a compound of Formula (IV) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

30. The compound of claim 29 wherein E is —

S—

or —

X³═

X⁴—

.

38. The compound of claim 29 wherein (G) is an aryl or heterocyclyl.

42. The compound of claim 29 wherein each (R1) is independently chosen from alkyl, aryl, amino, amido, nitro, halo, haloalkyl, cyano, heterocyclyl, sulfonyl, sulfonamide, hydroxyl, or alkoxy.

43. The compound of claim 1 wherein said compound is a compound of Formula (V) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

47. The compound of claim 43 wherein (G) is an aryl or heterocyclyl.

51. The compound of claim 43 wherein each (R1) is independently chosen from alkyl, aryl, amino, amido, nitro, halo, haloalkyl, cyano, heterocyclyl, sulfonyl, sulfonamide, hydroxyl, or alkoxy.

52. The compound of claim 1, wherein said compound is:

(trans)-2-(3′

-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine;

(trans)-2-(terphenyl-4-yl)cyclopropanamine;

4′

-((trans)-2-aminocyclopropyl)biphenyl-4-ol;

4′

-((trans)-2-aminocyclopropyl)biphenyl-3-ol;

(trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(3,5-dichlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-chlorophenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile;

(Trans)-2-(6-p-tolylpyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-m-tolylpyridin-3-yl)cyclopropanamine;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide;

2-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol;

(Trans)-2-(6-(3-methoxy-4-methylphenyl)pyridin-3-yl)cyclopropanamine;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4-difluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4,6-trifluorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenol;

(Trans)-2-(6-(2-fluoro-3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(5-chlorothiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(5-methylthiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(1H-indol-6-yl)pyridin-3-yl)cyclopropanamine;

(Trans)-2-(6-(benzo[b]thiophen-5-yl)pyridin-3-yl)cyclopropanamine;

3-(5-((trans)-2-aminocyclopropyl)-3-methylpyridin-2-yl)phenol;

(trans)-2-(6-(3-chlorophenyl)-5-methylpyridin-3-yl)cyclopropanamine;

(trans)-2-(5-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(4-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine,

(trans)-2-(6-(3-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine,

(trans)-2-(6-(2-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3-methoxy-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-methylphenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-chlorophenol;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenol;

(trans)-2-(6-(2-fluoro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(2-chloro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)acetamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)methanesulfonamide;

(trans)-2-(6-(benzo[b]thiophen-2-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(benzo[b]thiophen-3-yl)pyridin-3-yl)cyclopropanamine;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)thiophene-2-carbonitrile;

(trans)-2-(6-(4-methylthiophen-3-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

4-(3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)phenol;

4-(3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)benzamide;

(trans)-2-(2-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-hydroxybenzonitrile;

(trans)-2-(6-(3,4-difluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,3-difluorophenol;

(trans)-2-(6-(3-chloro-4-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine;

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-3-chloro-2-fluorophenol;

(trans)-2-(6-(1H-indazol-6-yl)pyridin-3-yl)cyclopropanamine;

(trans)-2-(6-(9H-carbazol-2-yl)pyridin-3-yl)cyclopropanamine;

6-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)indolin-2-one;

6-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzofuran-2(3H)-one;

4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)pyridin-2(1H)-one;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)benzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)propane-2-sulfonamide;

4′

-((trans)-2-aminocyclopropyl)-4-fluorobiphenyl-3-ol;

4′

-((trans)-2-aminocyclopropyl)-5-chlorobiphenyl-3-ol;

4′

-((trans)-2-aminocyclopropyl)-5-chloro-4-fluorobiphenyl-3-ol;

N-(4′

-((trans)-2-aminocyclopropyl)biphenyl-3-yl)benzenesulfonamide;

N-(4′

-((trans)-2-aminocyclopropyl)biphenyl-3-yl)propane-2-sulfonamide;

N-(4′

-((trans)-2-aminocyclopropyl)biphenyl-3-yl)methanesulfonamide;

N-(2-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)methanesulfonamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-methoxybenzonitrile;

N-(4′

-((trans)-2-aminocyclopropyl)biphenyl-2-yl)methanesulfonamide;

4′

-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-carbonitrile;

N-(4′

-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-yl)methanesulfonamide;

4′

-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-carbonitrile;

N-(4′

-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-yl)methanesulfonamide;

3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxybenzonitrile;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxyphenyl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide;

3-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

(Trans)-2-(5-(3-methoxyphenyl)pyridin-2-yl)cyclopropanamine;

4-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

2-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol;

2-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

4-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol;

2-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol;

4-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol;

2-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

2-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol;

3-(5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol;

4-(5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-methoxyphenyl)methanesulfonamide;

N-(4′

-((trans)-2-aminocyclopropyl)-5-chloro-[1,1′

-biphenyl]-3-yl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenyl)methanesulfonamide;

N-(4′

-((trans)-2-aminocyclopropyl)-4-fluoro-[1,1′

-biphenyl]-3-yl)methanesulfonamide;

N-(5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenyl)methanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)ethanesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-4-cyanobenzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-3-cyanobenzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-2-cyanobenzenesulfonamide;

N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)-4-cyanobenzenesulfonamide;

N-(4′

-((trans)-2-aminocyclopropyl)-[1,1′

-biphenyl]-3-yl)-1,1,1-trifluoromethanesulfonamide;

4′

-((trans)-2-aminocyclopropyl)-6-hydroxy-[1,1′

-biphenyl]-3-carbonitrile;

4′

-((trans)-2-aminocyclopropyl)-[1,1′

-biphenyl]-2-ol,

4′

-((trans)-2-aminocyclopropyl)-3′

-methoxy-[1,1′

-biphenyl]-3-ol;

N-(3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamide;

or

a pharmaceutically acceptable salt or solvate thereof.

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

79. A method of treating or preventing depression, Alzheimer disease, Huntington disease, Parkinson disease, or Dementia with Lewy Bodies, the method comprising administering, to a subject in need of such treatment or prevention, the compound of claim 1.

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

84. A method of modulating histone methylation levels in a mammalian cell, the method comprising administering the compound of claim 1.

5. (canceled)

7-8. -8. (canceled)

11-12. -12. (canceled)

14-20. -20. (canceled)

23-28. -28. (canceled)

31-37. -37. (canceled)

39-41. -41. (canceled)

44-46. -46. (canceled)

48-50. -50. (canceled)

53-68. -68. (canceled)

69. A pharmaceutical composition comprising a compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

70-71. -71. (canceled)

72. A method of treating or preventing cancer, the method comprising administering, to a subject in need of such treatment or prevention, a compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

73. The method of claim 72 wherein said cancer is chosen from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia, or lymphoma.

74-77. -77. (canceled)

81-83. -83. (canceled)

85-89. -89. (canceled)