HETEROARYL-BIPHENYL AMINES FOR THE 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 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 - 31 . (canceled)
32 . A process for preparing a compound of formula (II),
or a pharmaceutically acceptable salt thereof,
wherein:
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 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR 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 a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and 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 unsubstituted or 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 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;
or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;
wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 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 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR 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 H, 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 ;
Z is selected from the group consisting of
unsubstituted or 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, and 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 unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 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, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and
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 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR 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 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is independently 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;
the process comprising:
(a) converting the compound having formula (2e1) to a compound having formula (2f1) with a borate reagent and a first catalyst;
(b) contacting a compound having formula (2f1) with a compound having formula (2g1) and a second catalyst, under Suzuki-type conditions to produce a compound having formula (2h1);
(c) reductively aminating the compound having formula (2h1) with HN(R 2a )(R 2b ) and a hydride reagent to provide the compound having formula (II),
wherein in the above formulae (2j1), (2k1), (2h1), and (II), each R′ is independently selected from the group consisting of H and C 1 -C 6 alkyl;
X is a member selected from the group consisting of Br and Cl;
X′ is a member selected from the group consisting of I, Br and Cl;
the ring bearing R S is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine and pyrazine; and
R s has 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and CN.
33 . A process for preparing a compound of formula (II),
or a pharmaceutically acceptable salt thereof,
wherein:
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 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR 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 a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and 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 unsubstituted or 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 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;
or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;
wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 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 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR 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 H, 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 ;
Z is selected from the group consisting of
unsubstituted or 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, and 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 unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 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, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and
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 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR 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 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y i is independently 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;
the process comprising:
(a) contacting a compound having formula (2e1) with a compound having formula (2g′1) and a catalyst, under Suzuki-type conditions to produce a compound having formula (2h1);
(b) reductively aminating the compound having formula (2h1) with HN(R 2a )(R 2b ) and a hydride reagent to provide the compound having formula (II),
wherein in the above formulae (2e1), (2g′1), (2h1), and (II), each R′ is independently selected from the group consisting of H and C 1 -C 6 alkyl;
X is a member selected from the group consisting of I, Br and Cl;
the ring bearing R S is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine and pyrazine; and
R s has 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and CN.
34 . A process for preparing a compound of formula (II),
or a pharmaceutically acceptable salt thereof,
wherein:
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 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR 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 a C 1-6 alkylene, and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, and 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 unsubstituted or 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 , C(O)NH 2 , —C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H, and CO 2 H;
or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N, and S;
wherein the 4- to 9-membered ring or spirocyclic ring formed by combining R 2a and R 2b is unsubstituted or substituted with 1 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 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR 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 H, 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 ;
Z is selected from the group consisting of
unsubstituted or 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, and 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 unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 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, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, or —CO 2 H; and
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 —CO 2 R a , —O—X 4 —CO 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —C(O)NR a R b , —O—X 4 —C(O)NR 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 —CO 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y i is independently 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;
the process comprising:
(a) contacting a compound having formula (2j1) with a compound having formula (2k1) and a first catalyst, under Suzuki-type conditions to produce a compound having formula (2h1);
(b) reductively aminating the compound having formula (2h1) with HN(R 2a )(R 2b ) and a hydride reagent to provide the compound having formula (II),
wherein in the above formulae (2j1), (2k1), (2h1), and (II), each R and R′ is independently selected from the group consisting of H and C 1 -C 6 alkyl;
X is a member selected from the group consisting of I, Br and Cl;
the ring bearing R s is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine and pyrazine; and
R s has 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and CN.
35 . The method of claim 32 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
36 . The method of claim 32 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
37 . The method of claim 33 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
38 . The method of claim 33 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
39 . The method of claim 34 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
40 . The method of claim 34 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.