Triaryl compounds for treatment of PD-L1 diseases

Patent metadata

Field	Value
Publication number	US-11266643-B2
Application number	US-202016874212-A
Country	US
Kind code	B2
Filing date	May 14, 2020
Priority date	May 15, 2019
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I)including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1a, R1b, R1c, R1d, R2a, R2b, R3, R3a, R4, R6, R7, R8, A, Z, X1 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, prodrug or bioisostere thereof, wherein:
R 1a , R 1b , R 1c and R 1d are each independently selected from the group consisting of H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and CN;
X 1 is C 1-3 alkylene, optionally substituted with one or two C 1-2 alkyl or CO 2 H;
R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, —Y, —X 2 —C(O) 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —CONR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a and —X 2 —Y wherein each X 2 is C 1-6 alkylene and any C 1-8 alkyl or C 1-6 alkylene, is optionally further substituted with one or two members independently 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 each Y is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl and 5- to 6-membered heteroaryl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, SO 3 H and CO 2 H;
or R 1a and R 2b are combined to form a 4- to 10-membered ring or spirocyclic ring, optionally having one or two additional ring vertices selected from O, N or S;
wherein the ring formed by combining R 2a and R 2b , is substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 3 —C(O) 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —CONR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and X 3 —SO 3 R a ; wherein X 3 is a bond or C 1-6 alkylene;

R 3 and R 4 are each independently selected from the group consisting of F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 and CF 3 ;
the subscript n is 0, 1, 2 or 3;
each R 3a is independently selected from the group consisting of H, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 2-3 alkenyl and CN;
R 6 , R 7 and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 and CF 3 ;
A is a member selected from the group consisting of —N(R a )—, —C(═O)N(R a )—, —S(O)N(R a )—, and —S(O) 2 N(R a )—;
Z is selected from the group consisting of:
i) a monocyclic, bicyclic, or spirocyclic non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with up to four R a and/or R b ;
ii) a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and
iii) a fused bicyclic heteroaryl ring, optionally substituted with one to three R c ;

wherein when A is —N(R a )—, then Z is a fused bicyclic heteroaryl ring optionally substituted with one to three R c ;
each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, C 1-6 alkylene-SO 3 H;
each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is optionally further substituted with one or two members independently selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl and CO 2 H;
and R a and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, optionally substituted with halogen, OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H;
each R c is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1 - 6 haloalkyl, —Y 1 , —X 4 —C(O) 2 R a , —O—X 4 —C(O) 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —CONR a R b , —O—X 4 —CONR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —C(O) 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl; and optionally two R c on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

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

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

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having formula (Id):

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the group R 1a is OCH 3 and R 1b is F.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—, and Z is selected from the group consisting of:
i) a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with up to four R a and/or R b ; and
ii) a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a non-aromatic heterocyclic ring having a formula selected from the group consisting of:

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and said heterocyclic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with up to four R a and/or R b .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —N(R a )—, and Z is a fused bicyclic heteroaryl ring, optionally substituted with one to three R c .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a fused bicyclic heteroaryl ring having a formula selected from the group consisting of:

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are each H.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, optionally

Assignees

• Chemocentryx Inc

Inventors

• Fan Pingchen
• Lange Christopher
• Mali Venkat Reddy
• Mcmurtrie Darren J
• Malathong Viengkham
• Punna Sreenivas
• Singh Rajinder
• Yang Ju
• Zeng Yibin
• Zhang Penglie

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D239/36

  as doubly bound oxygen atom or as unsubstituted hydroxy radical · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title