Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of trpv1

Patent metadata

Field	Value
Publication number	US-2016376291-A1
Application number	US-201615262202-A
Country	US
Kind code	A1
Filing date	Sep 12, 2016
Priority date	Dec 17, 2007
Publication date	Dec 29, 2016
Grant date	—

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

1 - 20 . (canceled)

21 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by TRPV1 activity, comprising administering to the subject an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I):

wherein:
R 1 is —H; —NR a R b ; a —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 an —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; a —C 2 -4alkyl group substituted with a —OH, —OC 1-4 alkyl, or —NR e R f substituent; or a 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 a —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 14 alkyl, —NR p R q , fluoro, —CO 2 H, 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 c 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 their nitrogen of attachment in —NR e R f form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; and

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, —OC 1-6 alkyl, —CN, —NO 2 , —N(R h )R i , —C(O)N(R h )R i , —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 i ) 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 their 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 , or —SO 2 N(R k )R l ; or a phenyl or 6-membered heteroaryl ring, 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 their 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 n )R o , —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 S, O, or NH;
R 5 is —H, —CH 3 , halo, or —CF 3 ; and
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.

22 . A method according to claim 21 , wherein said agent is selected from the group consisting of:
[2-(2,6-Dichloro-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; (4-tert-Butyl-phenyl)-[2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2-Iodo-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; (3-Chloro-4-trifluoromethyl-phenyl)-[2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-amine; 2-{4-[2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-ylamino]-phenyl}-2-methyl-propionitrile; [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(3-fluoro-4-methanesulfonyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-methanesulfonyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine; 2-(2-Methylbenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2-Methylbenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2-Methylbenzyl)-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2-Chlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2-Chlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2-Chlorobenzyl)-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2,6-Dichlorobenzyl)-N-[2-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2,6-Dichlorobenzyl)-N-[3-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; N-(4-tert-Butylphenyl)-2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine; Methyl 2-(4-{[2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}phenyl)-2-methylpropanoate; 2-(2,4-Dichlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2,6-Dichlorobenzyl)-N-[4-(piperazin-1-ylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(2,4-Dichlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-[2-(Trifluoromethyl)benzyl]-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-[2-(Trifluoromethyl)benzyl]-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-Benzyl-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-Benzyl-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-Benzyl-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine; 2-(4-Chlorobenzyl)-N-[4

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · 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

• A61P25/28

  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

• A61P25/02

  for peripheral neuropathies · CPC title