Tetrahydro-pyrimidoazepines as modulators of TRPV1

Patent metadata

Field	Value
Publication number	US-9422293-B2
Application number	US-201414157671-A
Country	US
Kind code	B2
Filing date	Jan 17, 2014
Priority date	Mar 21, 2006
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

Certain tetrahydro-pyrimidoazepine compounds are described, which are useful as TRPV1 modulators. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by TRPV1. Thus, the compounds may be administered to treat, e.g., pain, itch, cough, asthma, or inflammatory bowel disease.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
R 1 is NR a R b;
R a and R b taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl or bridged bicyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-4 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , halo, —CO 2 H, and benzyl substituents;
where R p and R q are each independently —H or —C 1-6 alkyl; or R p and R q taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

R 2 is —H or —C 1-6 alkyl;
R 3 is a phenyl group unsubstituted or substituted with one, two, or three R g substituents;
where each R g substituent is —C 1-6 alkyl; —C 1-4 alkyl-OH unsubstituted or substituted with —CF 3 ; saturated monocyclic cycloalkyl; —OH; —OC 1-6 alkyl; phenoxy; —CN; —NO 2 ; —N(R h )R i ; —C 1-4 alkyl-N(R h )R i ; —C(O)N(R h )R i ; —N(R h )C(O)R i ; —N(R h )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 CF 3 ; —SO 2 N(R h )R i ; —SCF 3 ; halo; —CF 3 ; —OCF 3 ; —CO 2 H; —CO 2 C 1-6 alkyl; —C(R j )(R x )—CN; —C(R j )(R x )—OH; —C(R j )(R x )—CO 2 C 1-6 alkyl; —C(R j )(R x )—CO 2 H; —C(R j )(R x )—C(O)N(R h )R i ;phenyl; or monocyclic heteroaryl;
where R h and R i are each independently —H or —C 1-6 alkyl; or R h and R i (when both are present) taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group;
R j is independently —H, —C 1-6 alkyl, or —CF 3 ;
R x is —H or —C 1-6 alkyl; or R j and R x taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring;

and
Ar is a pyridyl, group unsubstituted or substituted with one, two, or three R k substituents;
where each R k substituent is independently —C 1-6 alkyl, —C 1-2 alkyl -OH, —OH, —OC 1-6 alkyl, phenoxy, —CN, —NO 2 , —N(R 1 )R m , —C(O)N(R 1 )R m , —N(R 1 )C(O)R m , —N(R 1 )SO 2 C 1-6 alkyl, —N(R 1 ) SO 2 CF 3 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R 1 )R m , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, or —CO 2 C 1-6 alkyl;
where R 1 and R m are each independently —H, —C 1-6 alkyl, saturated monocyclic cycloalkyl, or —CF 3 ;

or a pharmaceutically acceptable salt of such compound.

2. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein R a and R b taken together with their nitrogen of attachment form an aziridinyl, pyrrolidinyl, piperidinyl, 2-oxo-piperidin-1-yl, piperazinyl, oxo-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholin-4-yl, 1,1-dioxo-λ 6 - [1,2 ]thiazinan-2-yl, azepanyl, 1,4-oxazepanyl, or 7-azabicyclo[2.2.1]hept-7-yl group unsubstituted or substituted with a -C 1-6 alkyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, fluoro, —OH, or —CO 2 H substituent.

3. A compound, pharmaceutically or pharmaceutically acceptable salt as defined in claim 1 , wherein R 2 is —H.

4. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein Ar is 2-pyridyl substituted with —CF 3 , —NO 2 , or —N(R 1 )R m .

5. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein Ar is 2-pyridyl substituted with —CF 3 .

6. A compound selected from the group consisting of:
[2-Isopropyl-7-(3-methyl-quinoxalin-2 -yl)-6,7,8,9-tetrahydro -5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine
[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
(4-tert-Butyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-amine;
N 4 -(3-Chloro-4-trifluoromethyl-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;
(4-Bromo-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-amine;
(4-tert-Butyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-4-yl]-amine;
N 4 -(4-tert-Butyl-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepine-2,4-diamine;
N 2 ,N 2 -Dimethyl-N 4 -(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;
N 4 -(4-Chloro-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepine-2,4-diamine;
N 4 -(4-Trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepine-2,4-diamine;
[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin -4-yl]-(4-trifluoromethyl-phenyl)-amine;
1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperidine-4-carboxylic acid;
1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperidin-4-ol;
[2-(4-Isopropyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
4-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperazin-2-one;
(R)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol;
[2-(4-Methyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
(S)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol;
[2-Piperazin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
[2-Thiomorpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
[2-(4-Benzyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
[2-Pyrrolidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;
2-{4-[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol; and
2-{4-[2-Azepan-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;
and pharmaceutically acceptable salts thereof.

7. A compound selected from the group consisting of:
1-[4-({2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone;
N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;
N,N-Dimethyl-4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide;
N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;
N-[4-(Methylsulfanyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Allison Brett D
• Branstetter Bryan James
• Breitenbucher J Guy
• Hack Michael D
• Hawryluk Natalie A
• Lebsack Alec D
• Mcclure Kelly J
• Merit Jeffrey E

Classifications

• A61P39/02

  Antidotes · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title