Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor

Patent metadata

Field	Value
Publication number	US-9732087-B2
Application number	US-201414460217-A
Country	US
Kind code	B2
Filing date	Aug 14, 2014
Priority date	Jun 12, 2008
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

Diamino-pyridine, pyrimidine and pyridazine compounds which may be used as H 4 receptor modulators, and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H 4 receptor activity, such as allergy, asthma, autoimmune diseases, and pruritis.

First claim

What is claimed is:

1. A chemical entity selected from the compounds of Formula (I)

wherein
Z is N;
Y is CH;
R 1 is:
a) —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SCH 3 , or C 1-8 alkyl, each independently unsubstituted or substituted with —OH or —CF 3 ;
b) —(CH 2 ) 0-2 —Ar 1 , —CHR 2 —Ar 1 , or —(CH 2 ) 0-2 —Ar 2 , each of said Ar 1 and Ar 2 independently unsubstituted or substituted with halo, —CH 3 , or —OCH 3 ;
Ar 1 is a 6-membered aromatic carbocyclic ring;
Ar 2 is a 5 to 6-membered heteroaromatic ring containing N, S or O; or
c) cycloalkyl, —(CH 2 )-(monocyclic cycloalkyl), —(CH 2 )-(bridged polycyclic cycloalkyl) 0-1 , —(CHR 2 )-(monocyclic cycloalkyl), —(CH 2 )-(fused cycloalkyl), —(CH 2 )-(bridged monocyclic cycloalkyl), —(CH 2 ) 0-1 -tetrahydrofuranyl, or —(CH 2 ) 0-1 -tetrahydropyranyl, each of said cycloalkyl independently unsubstituted or substituted with one, two, or three C 1-4 alkyl substituents;

R 2 is —C 1-4 alkyl;

is selected from the group consisting of:

where R a and R b are each independently H or C 1-3 alkyl;
and pharmaceutically acceptable salts of compounds of Formula (I).

2. A chemical entity of claim 1 , wherein R a is H.

3. A chemical entity of claim 1 , wherein R b is H or methyl.

4. A chemical entity of claim 1 , wherein R 2 is methyl.

5. A chemical entity selected from the group consisting of:
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopropylmethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2,2-dimethylpropyl)pyrimidin-2-amine;
1-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2-methylpropan-2-ol;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclobutylpyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[bicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(tetrahydrofuran-2-ylmethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(1-methylethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopropylpyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyrimidin-2-amine;
Butyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
Bicyclo[2.2.1]hept-2-yl[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
Cyclopentyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
(2,2-Dimethyl-propyl)-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
Cyclopropylmethyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
Isopropyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
(4-Fluoro-benzyl)-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
Cyclopropyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
[4-(3R)-(3-Methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-(tetrahydro-furan-2-ylmethyl)-amine;
(2-Methoxy-ethyl)-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine;
[4-(3R)-(3-Methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R)-1-cyclohexylethyl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(cyclopropylmethyl)pyrimidin-2-amine;
1-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2-methylpropan-2-ol;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2,2-dimethylpropyl)pyrimidin-2-amine;
2-Methyl-1-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-2-ol;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyl)pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyrimidin-2-amine;
N-(Cyclopentylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R, 2S, 4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyrimidin-2-amine;
3-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol;
N-Cyclopropyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-bicyclo[2.2.1]hept-2-ylpyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4,4,4-trifluorobutyl)pyrimidin-2-amine;
3-({4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol;
3-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol;
3-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol;
2,2-Dimethyl-3-({4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyrimidin-2-amine;
N-Bicyclo[2.2.1]hept-2-yl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
3-({4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol;
2,2-Dimethyl-3-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(4-methylbenzyl)pyrimidin-2-amine;
N-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyrimidin-2-amine;
N-(4-Methoxybenzyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-benzylpyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methoxybenzyl)pyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methylbenzyl)pyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(3S,5S,7S)-tricyclo[3.3.1.1.3.7]dec-1-ylmethyl]pyrimidin-2-amine;
4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine;
N-(Cyclohexylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
N-Cyclohexyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-butylpyrimidin-2-amine;
4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclohexylmethyl)pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine;
4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyl)pyrimidin-2-amine;
4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyrimidin-2-amine;
N-Cyclopentyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;
4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Cai Hui
• Chavez Frank
• Dunford Paul J
• Greenspan Andrew J
• Meduna Steven P
• Quiroz Jorge A
• Savall Brad M
• Tays Kevin L
• Thurmond Robin L
• Wei Jianmei
• Wolin Ronald L
• Zhang Xiaohu

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/06

  Antianaemics · CPC title