Substituted tetrahydropyrans as CCR2 modulators

Patent metadata

Field	Value
Publication number	US-9783540-B2
Application number	US-201615158713-A
Country	US
Kind code	B2
Filing date	May 19, 2016
Priority date	May 21, 2015
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

Compounds are provided that are modulators of the CCR2 receptor. The compounds have the general formula (I):

and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of CCR2 receptors.

First claim

What is claimed is:

1. A compound haying the formula (I)

or a pharmaceutically acceptable salt, stereoisomer or rotamer thereof; wherein
A is C(R 5 )(R 6 ) or N(R 5 );
m and n are each independently 0, 1 or 2, wherein the sum of m and n is less than or equal to 3;
R 1 is selected from the group consisting of aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 5 R x substituents;
R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 4 R x substituents;
or optionally, R 1 and R 2 are combined with the nitrogen atom to which each is attached to form a 6- to 11-membered monocyclic or fused bicyclic heterocyclyl- or heteroaryl ring, wherein the —NR 1 R 2 is optionally further substituted with from 1 to 4 R x substituents;
R 3 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-4 alkyl, each of which is optionally substituted with from 1-3 R y substituents;
R 4 is selected from the group consisting of H, C 1-8 alkyl optionally substituted with 1 to 2 R y and CO 2 H;
R 5 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-8 alkylamino, di-C 1-8 alkylamino, aryl, aryloxy, arylamino, aryl-C 1-4 alkyl, heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl, each of which is optionally substituted with from 1 to 5 R z substituents;
R 6 is selected from the group consisting of H, F, OH, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy groups are optionally substituted with from 1 to 3 R z substituents;
or optionally, R 5 and R 6 are joined to form a spirocyclic 5- or 6-membered cycloalkyl ring which is optionally unsaturated, and has a fused aryl group which is optionally substituted with from 1 to 4 R z substituents;
each R x is independently selected from the group consisting of halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a , —O—X 1 —NR a R b , —O—X 1 —CO 2 R a , —O—X 1 —CONR a R b , —X 1 —OR a ,—X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , —S(O) 2 NR a R b , and 5- or 6-membered aryl or heteroaryl, wherein
each X 1 is a C 1-4 alkylene;
each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo;
each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and
optionally when two R x substituents are on adjacent atoms, are combined to form a fused 5 or 6-membered carbocyclic ring, and wherein the aryl or heteroaryl groups are optionally substituted with 1-3 members selected from halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R y is independently selected from the group consisting of halogen, —CN, —R f , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein
each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S;
each R f is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl;
and each R z is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h ,—X 1 —R j , —X 1 —NR g R h , —X 1 —CONR g R h , —X 1 —NR h C(O)R g , —NHR j , —NHCH 2 R j , and tetrazolyl; wherein
each R g and R h is independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo;
each R i is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl; and
each R j is selected from the group consisting of C 3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.

2. The compound of claim 1 , having the formula (I)

or a pharmaceutically acceptable salt, stereoisomer or rotamer thereof; wherein
A is C(R 5 )(R 6 ) or N(R 5 );
m and n are each independently 0, 1, or 2, wherein the sum of m and n is less than or equal to 3;
R 1 is selected from the group consisting of aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 5 R x substituents;
R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 4 R x substituents;
or optionally, R 1 and R 2 are combined with the nitrogen atom to which each is attached to form a 6- to 11-membered heterocyclyl or heteroaryl ring, optionally substituted with from 1 to 4 R x substituents;
R 3 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-4 alkyl, each of which is optionally substituted with from 1-3 R y substituents;
R 4 is selected from the group consisting of H, C 1-8 alkyl optionally substituted with 1 to 2 R y , and CO 2 H;
R 5 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-8 alkylamino, di-C 1-8 alkylamino, aryl, aryloxy, arylamino, alkyl-C 1-4 , heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4 alkyl, each of which is optionally substituted with from 1 to 5 R z substituents;
R 6 is selected from the group consisting of H, F, OH, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy groups are optionally substituted with from 1 to 3 R z substituents;
or optionally, R 5 and R 6 are joined to form a spirocyclic 5- or 6-membered cycloalkyl ring which is optionally unsaturated, and has a fused aryl group which is optionally substituted with from 1 to 4 R z substituents;
each R x is independently selected from the group consisting of halogen, —CN, —R c

Assignees

• Chemocentryx Inc

Inventors

• Fan Junfa
• Kalisiak Jaroslaw
• Lui Rebecca M
• Mali Venkat Reddy
• Mcmahon Jeffrey P
• Powers Jay P
• Tanaka Hiroko
• Zeng Yibin
• Zhang Penglie

Classifications

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title