Immunomodulator compounds

Patent metadata

Field	Value
Publication number	US-11793771-B2
Application number	US-202217838400-A
Country	US
Kind code	B2
Filing date	Jun 13, 2022
Priority date	Jun 27, 2016
Publication date	Oct 24, 2023
Grant date	Oct 24, 2023

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (II):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 6a , R 6b , m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

What is claimed is:

1. A compound of Formula (II)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of halogen, C 5-8 cycloalkyl, C 6-10 aryl and thienyl, wherein the C 6-10 aryl and thienyl are optionally substituted with 1 to 5 R x 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 R b , —OR a , —O—X 1 —OR a , —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 , and —S(O) 2 NR a R b , 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 five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O, and S, wherein the five or six-membered ring is optionally substituted with oxo; each RC is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 1-8 haloalkyl; and optionally when two R x substituents are on adjacent atoms, they are combined to form a fused five, six or seven-membered carbocyclic or heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from halo, oxo, C 1-8 haloalkyl and C 1-8 alkyl;

each R 2a , R 2b and R 2c is independently selected from the group consisting of H, halogen, —CN, —R d , —CO 2 R e , —CONR e R f , —C(O)R e , —OC(O)NR e R f , —NR f C(O)R e , —NR f C(O) 2 R d , —NR e —C(O)NR e R f , —NR e R f , —OR e , —O—X 2 —OR e , —O—X 2 —NR e R f , —O—X 2 —CO 2 R e , —O—X 2 —CONR e R f , —X 2 —OR e , —X 2 —NR e R f , —X 2 —CO 2 R e , —X 2 —CONR e R f , —SF 5 , —S(O) 2 NR e R f , C 6-10 aryl and C 5-10 heteroaryl, wherein each X 2 is a C 1-4 alkylene; each R e and R f 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 five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo; each R d is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;
R 3 is selected from the group consisting of —NR g R h and C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R y ;
each R y is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R j , —CONR j R k , —CONHC 1-6 alkyl-OH, —C(O)R j , —OC(O)NR j R k , —NR j C(O)R k , —NR j C(O) 2 R k , CONOH, PO 3 H 2 , —NR j —C 1-6 alkyl-C(O) 2 R k , —NR 2 C(O)NR j R k , —NR j R k , —OR j , —S(O) 2 NR j R k , —O—C 1-6 alkyl-OR j , —O—C 1-6 alkyl-NR j R k , —O—C 1-6 alkyl-CO 2 R, —O—C 1-6 alkyl-CONR j R k , —C 1-6 alkyl-OR j , C 1-6 alkyl-NR j R k , —C 1-6 alkyl-CO 2 R, —C 1-6 alkyl-CONR j R k , and SF 5 ,
wherein the C 1-6 alkyl portion of R is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, wherein each R j and R k is independently selected from hydrogen, C 1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H, or when attached to the same nitrogen atom R j and R k can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo; each R i is independently selected from the group consisting of —OH, C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl, each of which may be optionally substituted with OH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H;
R g is selected from the group consisting of H, C 1-8 haloalkyl and C 1-8 alkyl;
R h is selected from —C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl-COOH, C 1-8 alkyl-OH,
C 1-8 alkyl-CONH 2 , C 1-8 alkyl-SO 2 NH 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-CONOH,
C 1-8 alkyl-NR h1 R h2 , —C(O)—C 1-8 alkyl, —C(O)—C 1-8 alkyl-OH, —C(O)—C 1-8 alkyl-COOH, C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOH, —C 3-10 cycloalkyl-OH, C 4-8 heterocyclyl, —C 4-8 heterocyclyl-COOH, —C 4-8 heterocyclyl-OH, —C 1-8 alkyl-C 4-8 heterocyclyl, —C 1-8 alkyl-C 3-10 cycloalkyl, C 5-10 heteroaryl, —C 1-8 alkyl-C 5-10 heteroaryl, C 10 carbocyclyl, —C 1-8 alkyl-C 6-10 aryl, —C 1-8 alkyl-(C═O)—C 6-10 aryl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkenyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkynyl, —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-COOH, and —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-OH optionally substituted with CO 2 H; or
R h combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein:
the non-natural amino acids have an alpha carbon substituent selected from the group consisting of C 2-4 hydroxyalkyl, C 1-3 alkyl-guanidinyl, and C 1-4 alkyl-heteroaryl,
the alpha carbon of each natural or non-natural amino acid is optionally further substituted with a methyl group, and
the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O—C 1-6 alkyl, and PO 3 H 2 , wherein
R h1 and R h2 are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 hydroxyalkyl;
the C 1-8 alkyl portions of R h are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO 2 NH 2 , CONH 2 , CONOH, COO—C 1-8 alkyl, PO 3 H 2 and C 5-6 heteroaryl optionally substituted with 1 to 2 C 1-3 alkyl substituents,
the C 10 carbocyclyl, C 5-10 heteroaryl and the C 6-10 aryl portions of R h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) 2 , COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-CONOH, C 1-4 alkyl-PO 3 H 2 , C 1-4 alkyl-COOH, and phenyl and
the C 4-8 heterocyclyl and C 3-10 cycloalkyl portions of R h are optionally substituted with 1 to 4 R w substituents;

each R w substituent is independently selected from C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-COOH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-CONOH, C 1-4 alkyl-PO 3 H, OH, COO—C 1-8 alkyl, COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 and oxo;
R 4 is selected from the group consisting of O—C 1-8 alkyl, O—C 1-8 haloalkyl, O—C 1-8 alkyl-R z , C 6-10 aryl, C 5-10 heteroaryl, —O—C 1-4 alkyl-C 6-10 aryl and —O—C 1-4 alkyl-C 5-10 heteroaryl, wherein the C 6-10 aryl and the C 5-10 heteroaryl are optionally substituted with 1 to 5 R z ;
each R z is independently selected from the group consisting of halogen, —CN, —R m , —CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 3 —OR n , —O—X 3 —NR n R p , —O—X 3 —CO 2 R n , —O—X 3 —CONR n R p , —X 3 —OR n , —X 3 —NR n R p , —X 3 —CO 2 R n , —X 3 —CONR n R p , —SF 5 , —S(O) 2 R n R p , —S(O) 2 NR n R p , and three to seven-membered carbocyclic or four to seven-membered heterocyclic ring, wherein the three to seven-membered carbocyclic or four to seven-membered heterocyclic ring is optionally substituted with 1 to 5 R t ,

Assignees

• Chemocentryx Inc

Inventors

• Lange Christopher
• Malathong Viengkham
• Mcmurtrie Darren J
• Punna Sreenivas
• Singh Rajinder
• Yang Ju
• Zhang Penglie

Classifications

• A61K31/085 Primary

  having an ether linkage to aromatic ring nuclear carbon · CPC title

• A61K31/015

  carbocyclic · CPC title

• A61K31/03

  aromatic · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title