Triaryl compounds for treatment of PD-L1 diseases
Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 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.
1 . A compound of Formula (Id):
or a pharmaceutically acceptable salt, prodrug or bioisostere thereof, wherein:
R 1a is OCH 3 ;
R 1b is F;
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, C 1-4 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 2a 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 ;
A is a member selected from the group consisting of —N(R a )—, and —C(═O)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 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 .
3 . 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:
4 . 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 heteroaryl ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.
5 . 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 .
6 . 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 .
7 . 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:
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are each H.
9 . 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 having one or two additional ring vertices selected from O, N or S; wherein said ring or spirocyclic ring 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 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 , and —X 2 —SO 3 R a ; wherein X 2 is a bond or C 1-6 alkylene.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a is H or C 1-8 alkyl; and R 2b is —Y or —X 2 —Y.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.
15 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof wherein Y is selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl, 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, C 1-4 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.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )— and Z is a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with R a and/or R b .
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )— and Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c .
18 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
19 . A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 1 having the formula
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.