LYSINE SPECIFIC DEMETHYLASE-1 INHIBITORS AND THEIR USE

• US 20140213657A1
• Filed: 03/27/2014
• Published: 07/31/2014
• Est. Priority Date: 04/19/2010
• Status: Active Grant

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: MUOZ, Alberto Ortega, CASTRO-PALOMINO LARIA, Julio, FYFE, Matthew Colin Thor
• Granted Patent: US 9,149,447 B2
• Time in Patent Office: Days
• US Class Current: 514/619
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• 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 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/35 containing only non-condensed rings
• CPC Class Codes: C07C 211/40 containing only non-condensed rings
• CPC Class Codes: C07C 211/42 with six-membered aromatic rings being part of the condensed ring systems
• CPC Class Codes: C07C 217/52 having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same 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 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 : the other ring being six-membered, e.g. tetraline

Abstract

The present invention relates to a compound of Formula 1, wherein: (A) is heteroaryl or aryl; each (A′), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (A′) is substituted with 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —CH₂C(=0)NH₂, heteroaryl, cyano, sulfonyl, and sulfinyl; X is 0, 1, 2, or 3; (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B); (Z) is —NH—; (L) is chosen from a single bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—; and (D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents independently chosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy. (A′)X—(A)—(B)—(Z)-(L)-(D) formula (I) The compounds of the invention show activity for inhibiting LSD1, which makes them useful in the treatment or prevention of diseases such as cancer.

Claims

1. A compound of Formula 1

(A′

)_x-(A)-(B)—

(Z)-(L)-(D) 

 

1

wherein;

(A) is heteroaryl or aryl;

each (A′

), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (A′

) is substituted with 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —

CH₂C(═

O)NH₂, heteroaryl, cyano, sulfonyl, and sulfinyl;

X is 0, 1, 2, or 3;

(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);

(Z) is —

NH—

;

(L) is chosen from a single bond, —

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, and —

CH₂CH₂CH₂CH₂—

; and

(D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy;

or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof;

with the proviso that the following compounds are excluded;

N-(2-phenylcyclopropyl)-cyclopentanamine;

10,11-dihydro-N-(2-phenylcyclopropyl)-5H-dibenzo[a,d]cyclohepten-5-amine; and

trans-N-(2-phenylcyclopropyl)-cyclohexanamine.

2. The compound of claim 1, wherein (D) is cycloalkyl having 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy.

3. The compound of claim 1, wherein (L) is a single bond and (D) is benzocycloalkyl having 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy.

4. The compound of any of claims 1-3, wherein (A) is a phenyl group.

5. The compound of any of claims 1-4, wherein X is 1 and (A′

) is an aryl group or an arylalkoxy group, wherein said (A′

) has 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —

CH₂C(═

O)NH₂, heteroaryl, cyano, sulfonyl, and sulfinyl.

6. The compound of any of claims 1-5, wherein X is 1 and (A′

) is a phenyl group having 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —

CH₂C(═

O)NH₂, heteroaryl, cyano, sulfonyl, and sulfinyl.

7. The compound of any of claims 1-5, wherein X is 1 and (A′

) is a benzyloxy group having 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —

CH₂C(═

O)NH₂, heteroaryl, cyano, sulfonyl, and sulfinyl.

8. The compound of any of claims 1-4, wherein X is 0.

9. The compound of any of claims 1-8, wherein (L) is a single bond.

10. The compound of any of claims 1, 2 or 4 to 9, wherein (L) is chosen from —

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, and —

CH₂CH₂CH₂CH₂—

.

11. The compound of any of claims 1-7, wherein the (D) group has 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy.

12. The compound of any of claim 1-3 or 5-11, wherein (A) is a heteroaryl group.

13. The compound of any of claim 1-3 or 5-12, wherein (A) is chosen from pyridyl, pyrimidinyl, and thiophenyl.

14. The compound of claim 1, wherein said compound is chosen from:

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-6-methoxy-2,3-dihydro-1H-inden-1-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-amine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-4,5-dimethoxy-2,3-dihydro-1H-inden-1-amine;

N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-inden-1-amine;

6-methoxy-N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-inden-1-amine;

6-chloro-N-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-inden-1-amine;

N-((trans)-2-phenylcyclopropyl)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine;

7-methoxy-N-((trans)-2-phenylcyclopropyl)-1,2,3,4-tetrahydronaphthalen-1-amine;

N-((trans)-2-(3′

-chlorobiphenyl-4-yl)cyclopropyl)-6-methoxy-2,3-dihydro-1H-inden-1-amine;

N-((trans)-2-(4′

-chlorobiphenyl-4-yl)cyclopropyl)-6-methoxy-2,3-dihydro-1H-inden-1-amine;

6-methoxy-N-((trans)-2-(3′

-methoxybiphenyl-4-yl)cyclopropyl)-2,3-dihydro-1H-inden-1-amine;

N-trans-(2-cyclohexylethyl)-2-phenylcyclopropanamine;

(Trans)-N-(3-cyclohexylpropyl)-2-phenylcyclopropanamine;

(Trans)-N-(2-cycloheptylethyl)-2-phenylcyclopropanamine;

(Trans)-2-(4-(3-bromobenzyloxy)phenyl)-N-(2-cyclohexylethyl)cyclopropanamine;

N-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropyl)-6-methoxy-2,3-dihydro-1H-inden-1-amine;

(Trans)-2-(3′

-chlorobiphenyl-4-yl)-N-(2-cyclohexylethyl)cyclopropanamine;

(Trans)-2-(4′

-chlorobiphenyl-4-yl)-N-(2-cyclohexylethyl)cyclopropanamine;

(Trans)-N-(2-cyclohexylethyl)-2-(3′

-methoxybiphenyl-4-yl)cyclopropanamine;

N-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine; and

1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)cyclopropanecarboxamide;

or a pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical composition comprising the compound of any of claims 1-14 and a pharmaceutically acceptable carrier.

16. A method of treating or preventing a disease or condition, the method comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of the pharmaceutical composition of claim 15.

17. The compound of any of claims 1-14 or the pharmaceutical composition of claim 15 for use in treating or preventing cancer.

18. A method of treating or preventing cancer, the method comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of the pharmaceutical composition of claim 15.

19. The compound of claim 17 or the pharmaceutical composition of claim 17 or the method of claim 18, wherein said cancer is chosen from breast cancer, colorectal cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, and blood cancer.

20. The compound of any of claims 1-14 or the pharmaceutical composition of claim 15 for use in treating or preventing viral infection.

21. A method of treating or preventing viral infection, the method comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of the compound of any of claims 1-14 or the pharmaceutical composition of claim 15.

22. The compound of claim 20 or the pharmaceutical composition of claim 20 or the method of claim 21, wherein said viral infection is a herpesvirus infection.

23. The compound of claim 22 or the pharmaceutical composition of claim 22 or the method of claim 22, wherein said herpesvirus infection is caused by and/or associated with a herpesvirus chosen from HSV-1, HSV-2, and Epstein-Barr virus.

24. The compound of claim 20 or the pharmaceutical composition of claim 20 or the method of claim 21, wherein said viral infection is caused by and/or associated with HIV.

25. The compound of any of claims 1-14 or the pharmaceutical composition of claim 15 for use in treating or preventing viral reactivation after latency.

26. A method of treating or preventing viral reactivation after latency, the method comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of the compound of any of claims 1-14 or the pharmaceutical composition of claim 15.

27. The compound of claim 25 or the pharmaceutical composition of claim 25 or the method of claim 26, wherein the virus that is reactivating is a herpesvirus.

28. The compound of claim 27 or the pharmaceutical composition of claim 27 or the method of claim 27, wherein said herpesvirus is chosen from HSV-1, HSV-2, and Epstein-Barr virus.

29. The compound of claim 25 or the pharmaceutical composition of claim 25 or the method of claim 26, wherein the virus that is reactivating is HIV.

30. A method of inhibiting LSD1 activity, the method comprising administering, to a patient in need of treatment, a therapeutically effective amount of a composition comprising the compound of any of claims 1-14 and a pharmaceutically acceptable carrier in an amount sufficient to inhibit LSD1 activity.

34. The compound of any of claims 1-14, 17, 19, 20, 22 to 25 or 27 to 29 or the pharmaceutical composition of any of claim 15, 17, 19, 20, 22 to 25, 27 to 29 or 32 or the method of any of claim 16, 18, 19, 21 to 24, 26 to 30 or 33, whereby the compound or the pharmaceutical composition is to be administered in combination with an anti-proliferative drug, an anticancer drug, a cytostatic drug, a cytotoxic drug and/or radiotherapy.

35. The method of any of claim 16, 18, 19, 21 to 24, 26 to 30, 33 or 34, wherein said patient is a human.

31. A method for identifying a compound which is a selective inhibitor of LSD1, the method comprising selecting or providing a compound which is a substituted heteroarylcyclopropylamine or a substituted arylcyclopropylamine, and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor, and further wherein the substituted hetero arylcyclopropylamine or the substituted arylcyclopropylamine is defined as follows in Formula 2:

(R3)-(W)-(cyclopropyl)-(NH)-(L′

)-(R4) 

 

2

wherein;

(R3) is present or not present, when present (R3) is chosen from arylalkyl, arylalkoxy, heterocyclylalkyl, and heterocycylalkoxy, wherein said (R3) group has 0, 1, 2, or 3 substituents independently chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

(W) is an aryl or heteroaryl group, wherein said (W) has 0, 1, or 2 substituents chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;

(L′

) is a linker of formula —

(CH₂)_n—

where n is chosen from 0, 1, 2, 3, 4, 5, or 6; and

(R4) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.

32. A pharmaceutical composition comprising a LSD1 selective inhibitor of Formula 2 as defined in claim 31 and a pharmaceutically acceptable carrier.

33. A method of treating or preventing a disease or condition, the method comprising administering, to a patient in need of treatment or prevention, a therapeutically effective amount of the pharmaceutical composition of claim 32.