Immunomodulator compounds

Patent metadata

Field	Value
Publication number	US-10919852-B2
Application number	US-201816047545-A
Country	US
Kind code	B2
Filing date	Jul 27, 2018
Priority date	Jul 28, 2017
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

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

including stereoisomers and pharmaceutically acceptable salts thereof, wherein Z, L, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , 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 (I)

or a pharmaceutically acceptable salt thereof wherein:

each of R 1a , R 1b , R 1c , R 1d is independently selected from the group consisting of H, halogen, CF 3 , CN, C 1-4 alkyl and —O—C 1-4 alkyl, wherein the C 1-4 alkyl and —O—C 1-4 alkyl are optionally further substituted with halogen, hydroxyl, methoxy or ethoxy;
L is a linking group selected from the group consisting of:

wherein each of the subscripts q is independently 1, 2, 3 or 4, and L is optionally further substituted with one or two members selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl and —CO 2 H;
Z is piperidinyl optionally substituted with from 1 to 4 groups independently selected from halogen, CN, hydroxy, oxo, C 1-4 alkyl, —NH 2 , —NHC 1-3 alkyl, —N(C 1-3 alkyl) 2 , —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, —OC(O)(C 1-4 alkyl), —CO 2 (C 1-4 alkyl) and —CO 2 H;
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 , —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 , —X 2 —OR, —X 2 —NR e R f , —X 2 —CO 2 R e , —SF 5 , and —S(O) 2 NR e R f , 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, 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 ;
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 hydroxyalkyl, C 1-8 alkyl-CO 2 R j , C 1-8 alkyl—CONR j R k , and C 1-8 alkyl-CONHSO 2 R j , C 1-8 alkyl-SO 2 NR j R k , C 1-8 alkyl-SO 3 R j , C 1-8 alkyl—B(OH) 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, C 1-8 alkyl-NR h1 R h2 , —C(O)R j , C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOR j , —C 3-10 cycloalkyl-OR j , C 1-8 alkyl—C 6-10 aryl, —C 1-8 alkyl C═O)C 6-10 aryl, —CO 2 —C 1-8 alkyl-O 2 C—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkenyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkynyl, —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-COOR j , and —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-OR j optionally substituted with 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 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H; or
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 , C(O)NHOH, COO—C 1-8 alkyl, and PO 3 H 2 ,
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 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, C 1-4 alkyl-OH, C 1-4 alkly-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-C(O)NHOH, C 1-4 alkyl- PO 3 H 2 , C 1-4 alkyl-COOH, and phenyl and the 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-C(O)NHOH, C 1-4 alkyl-PO 3 H, OH, COO—C 1-8 alkyl, COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 and oxo;
R 4 is selected from the group consisting of —O—C 1-4 alkyl-pyridyl optionally substituted with 1 to 5 R 4a ;
each R 4a is independently selected from the group consisting of halogen, —CN, —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 n , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , —S(O) 2 R n R p , —S(O) 2 NR n R p , and C 3-7 cycloalkyl, wherein the cycloalkyl ring is optionally substituted with 1 to 5 R t , wherein each R t is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, —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 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , and —S(O) 2 NR n R p ;

wherein each X 4 is a C 1-6 alkylene; each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl; and optionally when two R 4a substituents are on adjacent atoms, they are combined to form a fused five or six-membered carbocyclic ring optionally substituted with oxo;
n is 0, 1, 2 or 3;
each R 5 is independently selected from the group consisting of halogen, —CN, —R q , —CO 2 R r , —CONR r R s , —C(O)R r , —OC(O)NR r R s , —NR r C(O)R s , —NR r C(O) 2 R q , —NR—C(O)NR r R s , —NR r R s , —OR r , —O—X 5 —OR r , —O—X 5 —NR r R s , —O—X 5 —CO 2 R r , —O—X 5 —CONR r R s , —X 5 —OR r , —X 5 —NR r R s , —X 5 —CO 2 R r , —X 5 —CONR r R s , —SF 5 , —S(O) 2 NR r R s , wherein each X 5 is a C 1-4 alkylene; each R r and R s is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R q is independently selected from the group consisting of C 1-8 alkyl, and C 1-8 haloalkyl;
R 6a is selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;
m is 0, 1, 2, 3 or 4;
each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, and NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having the formula (Ia)

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having the formula (Ib)

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having formula (Ia1) or (Ia2):

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein each of R 2a , R 2b , and R 2c independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, and C 1-4 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 3 is selected from the group consisting of:

Assignees

• Chemocentryx Inc

Inventors

• Lange Christopher
• Malathong Viengkham
• Mali Venkat Reddy
• Mcmahon Jeffrey
• Mcmurtrie Darren J
• Punna Sreenivas
• Roth Howard S
• Singh Rajinder
• Wang Yu
• Yang Ju
• Zhang Penglie

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title