LYSINE SPECIFIC DEMETHYLASE-1 INHIBITORS AND THEIR USE

• US 20120283266A1
• Filed: 04/19/2010
• Published: 11/08/2012
• Est. Priority Date: 09/25/2009
• Status: Active Grant

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: Ortega Muñoz, Alberto, Castro-Palomino Laria, Julio, Fyfe, Matthew Colin Thor
• Granted Patent: US 8,859,555 B2
• Time in Patent Office: Days
• US Class Current: 514/252.12
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/095 Sulfur, selenium, or tellurium compounds, e.g. thiols
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/40 containing only non-condensed rings
• CPC Class Codes: C07C 217/08 the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 323/25 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members

Abstract

The invention relates to a compound of Formula (I): (A′)_x-(A)-(B)-(Z)-(L)-(D), 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, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, amido, 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 —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—; and (D) is chosen from —N(—R1)—R2, —O—R3, and —S—R3, wherein: R1 and R2 are mutually linked to form a heterocyclic ring together with the nitrogen atom that R1 and R2 are attached to, wherein said heterocyclic ring has 0, 1, 2, or 3 substituents independently chosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, halo, cyano, alkoxy, haloalkyl, and haloalkoxy, or R1 and R2 are independently chosen from —H, alkyl, cycloalkyl, haloalkyl, and heterocyclyl, wherein the sum of substituents on R1 and R2 together is 0, 1, 2, or 3, and the substituents are independently chosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro; and R3 is chosen from —H, alkyl, cycloalkyl, haloalkyl, and heterocyclyl, wherein R3 has 0, 1, 2, or 3 substituents independently chosen from —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro; or an enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof. The compounds of the invention show inhibitory LSD1 activity, which makes them useful in the treatment or prevention of diseases such as cancer.

Claims

1. A compound of Formula I:

(A′

)_x-(A)-(B)-(Z)-(L)-(D) 

 

I

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, aryl, arylalkoxy, alkyl, alkoxy, cyano, sulfonyl, amido, 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 —

CH₂CH₂—

, —

CH₂CH₂C₂—

, and —

CH₂CH₂CH₂C₂—

; and

(D) is chosen from —

N(—

R1)-R2, —

O—

R3, and —

S—

R3, wherein;

R1 and R2 are mutually linked to form a heterocyclic ring together with the nitrogen atom that R1 and R2 are attached to, wherein said heterocyclic ring has 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C(alkyl)(C₁-C₆ alkyl), alkyl, halo, cyano, alkoxy, haloalkyl, and haloalkoxy, or

R1 and R2 are independently chosen from —

H, alkyl, cycloalkyl, haloalkyl, and heterocyclyl, wherein the sum of substituents on R1 and R2 together is 0, 1, 2, or 3, and the substituents are independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro; and

R3 is chosen from —

H, alkyl, cycloalkyl, haloalkyl, and heterocyclyl, wherein R3 has 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro;

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

with the proviso that the following compounds are excluded;

N1-[(trans)-2-phenylcyclopropyl]-N2-undecyl-rel-1,2-ethanediamine;

N1-[(trans)-2-phenylcyclopropyl]-N2-tricyclo[3.3.1.13,7]dec-2-yl-rel-1,2-ethanediamine;

N1-cyclooctyl-N2-[(trans)-2-phenylcyclopropyl]-rel-1,2-ethanediamine;

N1,N1-dimethyl-N2-(2-phenylcyclopropyl)-1,3-propanediamine;

N1,N1-dimethyl-N2-(2-phenylcyclopropyl)-1,2-ethanediamine; and

trans-1-phenyl-2-[(2-hydroxyethyl)amino]cyclopropane.

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is aryl.

3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is phenyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X is 1 or 2;

5. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X is 1 and (A′

) is chosen from aryl and arylalkoxy, wherein said aryl or said arylalkoxy has 0 or 1 substituent chosen from halo and haloalkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt or solvate thereof, wherein (A′

) is chosen from phenyl, benzyloxy, and phenethyloxy, wherein said phenyl, said benzyloxy, or said phenethyloxy has 0 or 1 substituent chosen from halo and haloalkyl.

7. The compound of claim 5 or a pharmaceutically acceptable salt or solvate thereof wherein the (A′

) group is in the para position with respect to the cyclopropyl ring (B).

8. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (D) is —

N(—

R1)-R2, and further wherein R1 and R2 are mutually linked to form a heterocyclic ring together with the nitrogen atom that R1 and R2 are attached to, wherein said heterocyclic ring has 0.1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

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

10. The compound of claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein said heterocyclic ring is a 4, 5, or 6 membered heterocyclic ring which is saturated.

11. The compound of claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein said heterocyclic ring is chosen from azetidinyl, pyrrolidinyl, piperidinyl, and morpholino.

13. The compound of claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein said heterocyclic ring has 0 or 1 substituent chosen from —

NH₂, —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and alkyl.

14. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (D) is —

N(—

R1)-R2, and further wherein R1 and R2 are independently chosen from —

H, alkyl, cycloalkyl, and haloalkyl, wherein the sum of substituents on R1 and R2 together is 0, 1, 2, or 3, and the substituents are independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro.

17. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (D) is chosen from —

O—

R3 and —

S—

R3, and further wherein R3 is chosen from alkyl, cycloalkyl, and haloalkyl, wherein R3 has 0, 1, 2, or 3 substituents independently chosen from —

NH₂, —

NH(C₁-C₆ alkyl), —

N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and fluoro.

18. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is heteroaryl.

19. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is a heteroaryl chosen from pyridyl, pyrimidinyl, and thiophenyl.

21. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (I) is —

CH₂CH₂—

.

22. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein (A) and (Z) are in the trans orientation with respect to the cyclopropyl ring (B).

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

N1-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropyl)-N2-cyclopropylethane-1,2-diamine;

N1-((trans)-2-(3′

-chlorobiphenyl-4-yl)cyclopropyl)-N2-cyclopropylethane-1,2-diamine;

N1-cyclopropyl-N2-((trans)-2-(4-phenethoxyphenyl)cyclopropyl)ethane-1,2-diamine;

N1,N1-diethyl-N2-((trans)-2-(4-(3-fluorobenzyloxy)phenyl)cyclopropyl)ethane-1,2-diamine;

(trans)-2-(4-bromophenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)cyclopropanamine;

N1-((trans)-2-(terphenyl-4-yl)cyclopropyl)-N2-cyclopropylethane-1,2-diamine;

(trans)-N-(2-(piperidin-1-yl)ethyl)-2-(3′

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

N1,N1-diethyl-N2-((trans)-2-(3′

-(trifluoromethyl)biphenyl-4-yl)cyclopropyl)ethane-1 2-diamine;

(trans)-N-(2-(piperazin-1-yl)ethyl)-2-(3′

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

(S)-1-(2-((trans)-2-(3′

-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(3′

-chlorobiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4′

-chlorobiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(3′

-methoxybiphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

(R)-1-(2-((trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylamino)ethyl)pyrrolidin-3-amine; and

(R)-1-(2-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine;

or pharmaceutically acceptable salt or solvate thereof.

31. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

33. A method of treating or preventing an LSD1-mediated disease or condition comprising administering, to a subject in need of treatment or prevention, a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

34. A method of treating or preventing cancer comprising administering, to a subject in need of treatment or prevention, a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

35. The method of claim 34, wherein said cancer is chosen from brain cancer, colorectal cancer, breast cancer, lung cancer, prostate cancer, skin cancer, testicular cancer, and blood cancer.

36. The method of claim 34, whereby said compound or said pharmaceutically acceptable salt or solvate thereof is to be administered in combination with an anti-proliferative drug, an anticancer drug, a cytostatic drug, a cytotoxic drug and/or radiotherapy.

38. The method of claim 33, wherein said subject is a human.

9. (canceled)

12. (canceled)

15. (canceled)

16. (canceled)

20. (canceled)

23-26. -26. (canceled)

28-30. -30. (canceled)

32. (canceled)

37. (canceled)