Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1

Patent metadata

Field	Value
Publication number	US-9440978-B2
Application number	US-201314133848-A
Country	US
Kind code	B2
Filing date	Dec 19, 2013
Priority date	Dec 17, 2007
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Certain TRPV1-modulating imidazolo-, oxazolo-, and thiazolopyrimdine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.

First claim

What is claimed is:

1. A compound selected from the group consisting of:
(a) compounds of Formula (I):

wherein:
R 1 is —H; —NR a R b ; —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, or —SO 2 —C 1-6 alkyl group unsubstituted or substituted with —OH, —OC 1-4 alkyl, or —NR c R d substituent;
where R a and R b are each independently —H; —C 1-6 alkyl; —C 2-4 alkyl group substituted with —OH, —OC 1-4 alkyl, or —NR e R f substituent; or saturated monocyclic cycloalkyl, —C 1 alkyl-(saturated monocyclic cycloalkyl), —C 1 alkyl-(carbon-linked, saturated monocyclic heterocycloalkyl), benzyl, or —C 1 alkyl-(monocyclic heteroaryl) group, each unsubstituted or substituted with —C 1-6 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , or fluoro substituent;
or R a and R b taken together with the nitrogen of attachment in —NR a R b form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-2 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , fluoro, —CO 2 H, oxo, dioxo and monocyclic cycloalkyl substituents;
where R c and R d are each independently —H or —C 1-6 alkyl;
or R c and R d taken together with the nitrogen of attachment in —NR e R d form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;

R e and R f are each independently —H or —C 1-6 alkyl;
or R e and R f taken together with the nitrogen of attachment in —NR e R f form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;

R p and R q are each independently —H or —C 1-6 alkyl;
or R p and R q taken together with the nitrogen of attachment in —NR p R q form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;

R 2 is:
1) a phenyl group unsubstituted or substituted with one, two, or three R g substituents;
where each R g substituent is —C 1-6 alkyl, —OH, —CN, —NO 2 , —N(R h )R i , —C(O)N(R h )R i , —C(O)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) 2 —CN, —C(R j ) 2 —CO 2 C 1-4 alkyl, —C(R j ) 2 —CO 2 H, —C(R j ) 2 —CON(R h )R i , —C(R j ) 2 —CH 2 N(R h )R i , or —C(R j ) 2 —OH;
or two adjacent R g substituents taken together form —OC 1-2 alkylO—, —C 2-6 alkylO-, or —C 2-6 alkylN(R h )—;
where R h and R i are each independently —H or —C 1-6 alkyl;
or R h and R i taken together with the nitrogen of attachment in —NR h R i form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;

where each R j is independently —H, —C 1-6 alkyl, or —CF 3 ;
or both R j substituents taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring; or

2) a thiadiazolyl or six-membered monocyclic heteroaryl ring, each substituted with —CF 3 or tert-butyl;

R 3 is —H, —CH 3 , —CF 3 , halo, —CN, —COC 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R k )R l , —CH 2 N(R k )R l , —S(O) 0-2 —C 1-6 alkyl, —S—Si(C 1-6 alkyl) 3 , —SO 2 CF 3 , —SO 2 N(R k ) R l , a phenyl or 6-membered heteroaryl ring, wherein said phenyl and said 6-membered heteroaryl ring are each unsubstituted or substituted
with —OH, —CH 2 N(R k )R l , —C(O)N(R k )R l , —SO 2 N(R k )R l , or —CO 2 H;
where R k and R l are each independently —H or —C 1-6 alkyl; or R k and R l taken together with the nitrogen of attachment in —NR k R l form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;

R 4 is —H, —CF 3 , halo, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R a )R 6 , —C 1-4 alkyl-OH, —C 1-4 alkyl-N(R n )R o , —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , or —SO 2 N(R n )R o ;
where R n and R o are each independently —H or —C 1-6 alkyl;

X is NH;
R 5 is —H, —CH 3 , halo, or —CF 3 ;
R 6 and R 7 are each independently —H or methyl; or R 6 and R 7 taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring;
and (b) pharmaceutically acceptable salts of the compounds of Formula (I).

2. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 1 is —H, methyl, —OC 1-4 alkyl, —SC 1-4 alkyl, or —SO 2 —C 1-6 alkyl;
and (b) pharmaceutically acceptable salts of said compounds.

3. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 1 is —H;
and (b) pharmaceutically acceptable salts of said compounds.

4. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 1 is —NR a R b ;
and (b) pharmaceutically acceptable salts of said compounds.

5. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 1 is isopropylamino, isobutylamino, diisopropylamino, 2-hydroxy-1-methyl-ethylamino, 2-morpholin-4-yl-ethyl, 2-pyrrolidin-1-yl-ethyl, cyclopropylmethylamino, azetidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, 2-isopropyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, piperidinyl, 4-pyrrolidin-1-yl-piperidin-1-yl, piperazinyl, 4-methyl-piperazinyl, 4-isopropyl-piperazinyl, 4-isobutyl-piperazinyl, 4-cyclopentyl-piperazinyl, or morpholinyl;
and (b) pharmaceutically acceptable salts of said compounds.

6. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R a and R b are each independently —H; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl; an ethyl or propyl group substituted with an —OH or —NR e R f substituent; or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopentylmethyl, pyridylmethyl, pyrrolidinylmethyl, or piperidinylmethyl group, each unsubstituted or substituted with a methyl, methoxy, or fluoro substituent;
and (b) pharmaceutically acceptable salts of said compounds.

7. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R a and R b taken together with the nitrogen of attachment form an azetidinyl, pyrrolidinyl, piperidinyl, 2-oxo-piperidin-1-yl, piperazinyl, oxo-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholin-4-yl, or azepanyl group, each unsubstituted or substituted with a —C 1-4 alkyl, —OH, —CH 2 —OC 1-2 alkyl, —CO 2 H, or monocyclic cycloalkyl substituent;
and (b) pharmaceutically acceptable salts of said compounds.

8. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 2 is a phenyl group unsubstituted or substituted with one or two R g substituents;
and (b) pharmaceutically acceptable salts of said compounds.

9. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein R 2 is a thiadiazolyl, pyridinyl, or pyrazinyl ring substituted with —CF 3 or tert-butyl;
and (b) pharmaceutically acceptable salts of said compounds.

10. A compound as defined in claim 1 selected from the group consisting of:
(a) the compounds of Formula (I) wherein each R g substituent is independently methyl, isopropyl, tert-butyl, —OCH 3 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 NH 2 , —SO 2 (morpholinyl), —SO 2 (piperazinyl), fluoro, chloro, —CF 3 , —OCF 3 , —CO 2 CH 3 , —C(CH 3 ) 2 —CN, —C(CH 3 ) 2 —CO 2 CH 3 , —C(CH 3 ) 2 —CONH 2 , or —C(CH 3 ) 2 —OH; or two adjacent R g subst

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Branstetter Bryan James
• Breitenbucher J Guy
• Lebsack Alec D
• Liu Jing
• Rech Jason C
• Xiao Wei

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/04

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