Cyclopropylamines as LSD1 inhibitors

Patent metadata

Field	Value
Publication number	US-9346840-B2
Application number	US-201414475762-A
Country	US
Kind code	B2
Filing date	Sep 3, 2014
Priority date	Mar 25, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

This invention relates to the use of cyclopropylamine derivatives for the modulation, notably the inhibition of the activity of Lysine-specific demethylase 1 (LSD1). Suitably, the present invention relates to the use of cyclopropylamines in the treatment of cancer.

First claim

The invention claimed is:

1. A compound of Formula (IV) or Formula (V):

wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, —NHSO 2 Me, —NHSO 2 Ph, arylalkoxy, C 3 -C 7 cycloalkyl, —NHC(O)R a , 1-methyl-1H-pyrazol-4-yl, hydroxyl, C 1 -C 4 alkoxy, halogen, amino, substituted amino, and —C(O)OR a ;
R 3 is selected from the group consisting of aryl, heteroaryl —SO 2 R a , —NHC(O)R a , —CH 2 C(O)OR a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , amino, substituted amino, arylalkyl, and heteroarylalkyl;
each R a is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl;
R b is hydrogen or C 1 -C 3 alkyl; or
R a and R b together form a 5- or 6-membered heterocycloalkyl ring;
R 4 is H;
W is —(CH 2 ) 1-4 or —CH(R c )(CH 2 ) 0-3 , in which R c is —CN or C 1 -C 4 alkyl;
X is N;
Z is (CH 2 ) q , wherein q is 0-2, and wherein when q is 0, Z represents a bond; and
m is 0-3;
or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is F, Cl, C 1 -C 4 alkoxy, or C 1 -C 4 alkyl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 0.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is selected from the group consisting of aryl, arylalkyl, heteoaryl, and heteroarylalkyl, wherein any said aryl or heteroaryl are each optionally substituted with one, two, or three groups selected from the group consisting of —COOH, C 1 -C 4 alkoxy, —C(O)OC 1 -C 4 alkyl, C 1 -C 4 alkyl, halogen, —CN, tetrazolyl, —NHSO 2 Me, —SO 2 Me, —C(O)NHSO 2 Me, and —OCH 2 COOH.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is selected from the group consisting of —SO 2 R a , —C(O)OR a , —C(O)R a , —C(O)NR a R b , arylalkyl, and heteroarylalkyl, wherein R a is phenyl, phenylmethyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl; and R b is hydrogen or C 1 -C 3 alkyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is represented by Formula (VI):

wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, —NHSO 2 Me, —NHSO 2 Ph, arylalkoxy, C 3 -C 7 cycloalkyl, —NHC(O)R a , 1-methyl-1H-pyrazol-4-yl, hydroxyl, C 1 -C 4 alkoxy, halogen, amino, substituted amino, and —C(O)OR a ;
each R a is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl;
W is —(CH 2 ) 1-4 or —CH(R c )(CH 2 ) 0-3 , in which R c is —CN or C 1 -C 4 alkyl;
s is 1 or 2;
m is 0 or 1; and
each R 5 is independently selected from the group consisting of: —COOH, C 1 -C 4 alkoxy, —C(O)OC 1 -C 4 alkyl, C 1 -C 4 alkyl, halogen, CN, tetrazolyl, —NHSO 2 Me, —SO 2 Me, —C(O)NHSO 2 Me, and —OCH 2 COOH.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is represented by Formula (VII):

wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, —NHSO 2 Me, —NHSO 2 Ph, arylalkoxy, C 3 -C 7 cycloalkyl, —NHC(O)R a , 1-methyl-1H-pyrazol-4-yl, hydroxyl, C 1 -C 4 alkoxy, halogen, amino, substituted amino, and —C(O)OR a ;
each R a is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl;
W is —(CH 2 ) 1-4 or —CH(R c )(CH 2 ) 0-3 , in which R c is —CN or C 1 -C 4 alkyl;
s is 1 or 2;
m is 0 or 1; and
each R 5 is independently selected from the group consisting of: —COOH, C 1 -C 4 alkoxy, —C(O)OC 1 -C 4 alkyl, C 1 -C 4 alkyl, halogen, CN, tetrazolyl, —NHSO 2 Me, —SO 2 Me, —C(O)NHSO 2 Me, and —OCH 2 COOH.

8. The compound or pharmaceutically acceptable salt thereof according to claim 6 , wherein s is 1 and R 5 is —COOH.

9. The compound or pharmaceutically acceptable salt thereof according to claim 7 , wherein s is 1 and R 5 is —COOH.

10. A compound which is:
1,1-Dimethylethyl 4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;
1,1-Dimethylethyl 4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;
1,1-Dimethylethyl 4-({[(1S,2R)-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate;
[trans-2-Phenylcyclopropyl]{[1-(phenylmethyl)-4-piperidinyl]methyl}amine;
N-Phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide;
Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone;
1-(4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanone;
Benzyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate;
1,1-Dimethylethyl 4-({[trans-2-phenylcyclopropyl]amino}methyl)hexahydro-1H-azepine-1-carboxylate
2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetic acid;
4-{[(3R)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoic acid;
4-{[(3S)-3-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-pyrrolidinyl]methyl}benzoic acid;
4-{3-[4-({[(1R,2S)-2-Phenylcyclopropyl]amino}methyl)-1-piperidinyl]propyl}benzoic acid;
trans-2-Phenyl-N-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)cyclopropanamine;
trans-N-((1-(2-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
trans-N-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
trans-N-((1-(4-Fluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
trans-N-((1-(2,4-Difluorobenzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
Ethyl 4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate;
trans-N-((1-(4-(Methylsulfonyl)benzyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
2-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzonitrile;
trans-2-Phenyl-N-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)cyclopropanamine;
trans-N-((1-((5-Methylisoxazol-3-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
trans-N-((1-((1H-Pyrazol-4-yl)methyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine;
N-(4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)acetamide;
4-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol;
5-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzo[c][1,2]oxaborol-1(3H)-ol;
(4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)phenyl)boronic acid;
2-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
3-((4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(4-Bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(4-Chlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(3,4-Dichlorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(4-(Trifluoromethyl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(3,4-Dimethoxyphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid;
4-((4-(((trans-2-(4-Acetamidophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Johnson Neil W
• Kasparec Jiri
• Rouse Meagan B
• Tian Xinrong
• Miller William Henry
• Suarez Dominic

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07C211/35

  containing only non-condensed rings · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title