Substituted tetrahydropyrans as CCR2 modulators

Patent metadata

Field	Value
Publication number	US-12054484-B2
Application number	US-202117357427-A
Country	US
Kind code	B2
Filing date	Jun 24, 2021
Priority date	May 21, 2015
Publication date	Aug 6, 2024
Grant date	Aug 6, 2024

Abstract

Compounds are provided that are modulators of the CCR2 receptor. The compounds have the general formula (Ia1′):

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

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound having the formula (Ia1′):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is aryl-C 1-4 alkylene, heteroaryl-C 1-4 alkylene, aryl, or heteroaryl;
wherein the heteroaryl or heteroaryl portion of heteroaryl-C 1-4 alkylene has 1, 2, or 3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein the aryl portion of aryl-C 1-4 alkylene, heteroaryl portion of heteroaryl-C 1-4 alkylene, aryl, or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected RX substituents;

R 2 is H, C 1-8 alkyl, C 3-8 cycloalkyl-C 1-4 alkylene, aryl-C 1-4 alkylene, heteroaryl-C 1-4 alkylene, C 3-8 cycloalkyl, aryl, or heteroaryl;
wherein the heteroaryl or heteroaryl portion of heteroaryl-C 1-4 alkylene has 1, 2, or 3 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein the aryl portion of aryl-C 1-4 alkylene, heteroaryl portion of heteroaryl-C 1-4 alkylene, aryl, or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected RX substituents; or

R 1 and R 2 together with the nitrogen atom to which they are attached, form a monocyclic 6- to 11-membered heterocyclyl, a fused bicyclic 6- to 11-membered heterocyclyl, a monocyclic 6- to 11-membered heteroaryl, or a fused bicyclic 6- to 11-membered heteroaryl;
wherein the monocyclic 6- to 11-membered heterocyclyl, fused bicyclic 6- to 11-membered heterocyclyl, monocyclic 6- to 11-membered heteroaryl, or fused bicyclic 6- to 11-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected RX substituents;

each R x is independently halogen, —CN, —R c , —X 1 C(O)NR a R b , —X 1 C(O)OR a , —X 1 NR a R b , —X 1 OR a , —C(O)R a , —C(O)NR a R b , —C(O)OR a , —NR a R b , —NR b C(O)R a , —NR a C(O)NR a R b , —NR b C(O)OR e , —OR a , —OX 1 C(O)NR a R b , —OX 1 C(O)OR a , —OX 1 NR a R b , —OX 1 OR a , —OC(O)NR a R b , —SF 5 , —S(O) 2 NR a R b , phenyl, or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, OH, C 1-4 alkoxy, and C 1-4 haloalkoxy; or
two vicinal R x , together with the carbon atoms to which they are attached, form a fused 5- or 6-membered carbocyclyl;
each R a is independently H, C 1-8 alkyl, or C 1-8 haloalkyl;
each R b is independently H, C 1-8 alkyl, or C 1-8 haloalkyl; or
each R a and R b , together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein each 5- or 6-membered heterocyclyl is optionally and independently substituted with 1 oxo substituent;

each R c is independently C 1-8 alkyl, C 1-8 haloalkyl, or C 3-6 cycloalkyl;
R 3 is H, C 1-8 alkyl, C 3-8 cycloalkyl-C 1-4 alkylene, or C 3-8 cycloalkyl, wherein the C 1-8 alkyl, C 3-8 cycloalkyl portion of C 3-8 cycloalkyl-C 1-4 alkylene, or C 3-8 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected Ry substituents;
R 4 is H, C 1-8 alkyl, or C(O)OH, wherein the C 1-8 alkyl is optionally substituted with 1 or 2 independently selected R y substituents;
each R y is independently halogen, —CN, —R f , —C(O)R d , —C(O)NR d R e , —C(O)OR d , —NR d R e , —NR e C(O)R d , —NR d C(O)NR d R e , —NR e C(O)OR f , —OR d , —OC(O)NR d R e , or —S(O) 2 NR d R e ;
each R d is independently H, C 1-8 alkyl, or C 1-8 haloalkyl;
each R e is independently H, C 1-8 alkyl, or C 1-8 haloalkyl; or
each R d and R e , together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

each R f is independently C 1-8 alkyl, C 1-8 haloalkyl, or C 3-6 cycloalkyl;
each R z is independently halogen, —CN, —R i , —X 1 C(O)NR g R h , —X 1 NR g R h , —X 1 NR h C(O)R g , —C(O)R g , —C(O)NR g R h , —C(O)OR g , —NR g R h , —NHCH 2 R j , —NR h C(O)R g , —NR g C(O)NR g R h , —NR h C(O)OR i , —NH(pyrrolinyl), —NH(tetrahydrofuranyl), —NH(piperidinyl), —NH(tetrahydropyranyl), —NH(morpholinyl), —OR g , —OC(O)NR g R h , —S(O) 2 NR g R h , or tetrazolyl;
each R g is independently H, C 1-8 alkyl, Cis haloalkyl, or C 3-6 cycloalkyl;
each R h is independently H, C 1-8 alkyl, Cis haloalkyl, or C 3-6 cycloalkyl; or
each R g and R h , together with the nitrogen atom to which they are attached, independently forms a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;
wherein each 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl independently has 0, 1, or 2 additional ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and
wherein each 5- or 6-membered heterocyclyl is optionally and independently substituted with 1 or 2 oxo substituents;

each R i is independently C 1-8 alkyl, C 1-8 haloalkyl, or C 3-6 cycloalkyl;
each R j is independently C 3-6 cycloalkyl, pyrrolinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, or morpholinyl;
each X 1 is independently C 1-4 alkylene;
m is 1;
n is 1; and
q is 1, 2, 3, 4, or 5.

2. The pharmaceutical composition of claim 1 , wherein R 1 and R 2 , together with the nitrogen atom to which they are attached, form a fused bicyclic 6- to 11-membered heterocyclyl or a fused bicyclic 6- to 11-membered heteroaryl selected from the group consisting of:

3. The pharmaceutical composition of claim 1 , wherein R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 (cyclopropyl), CH 2 (cyclobutyl), cyclopropyl, or cyclobutyl.

4. The pharmaceutical composition of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a pharmaceutically acc

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

• A61P35/00

  Antineoplastic agents · CPC title