Compounds useful as immunomodulators

Patent metadata

Field	Value
Publication number	US-10745382-B2
Application number	US-201615290167-A
Country	US
Kind code	B2
Filing date	Oct 11, 2016
Priority date	Oct 15, 2015
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
m is 0, 1, or 2;
Z is —OR 1 ; wherein
R 1 is selected from hydrogen, C 3 -C 6 alkenyl, haloC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, —(CH 2 ) n X, and —(CH 2 ) n Ar;
n is 1, 2, 3, or 4;
X is selected from —CH 3 , —CF 3 , C 1 -C 4 alkoxy, —N(CH 3 ) 2 , C 3 -C 6 cycloalkyl optionally substituted with one or two halo groups, —CN, —CO 2 R g , —C(O)NH 2 , —C(O)N(CH 3 ) 2 ,

 morpholinyl, tetrahydropyranyl, pyrrolidonyl optionally substituted with a hydroxy group, and piperidinyl optionally substituted with one or two groups independently selected from C 1 -C 4 alkyl, carboxy, hydroxy, and C 1 -C 4 alkoxycarbonyl;
R g is selected from hydrogen and C 1 -C 4 alkyl; and
Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, and quinolinyl; wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, amido, amidoC 1 -C 4 alkyl, —(CH 2 ) q CO 2 C 1 -C 4 alkyl, —(CH 2 ) q OH, carboxy, cyano, formyl, halo, haloC 1 -C 4 alkyl, haloC 1 -C 4 alkoxy, nitro, phenyl optionally substituted with one cyano group, phenyloxy optionally substituted with one halo group, phenylcarbonyl, pyrrole, and tetrahydropyran, wherein q is 0, 1, 2, 3, or 4;

A is selected from —CH 2 O—, —OCH 2 —, —(CH 2 ) 2 —, —CH═CH—, —C(O)NH—, and —NHC(O)—, wherein each group is drawn with its left side attached to R 2 and its right side attached to the phenyl ring;
R 2 is selected from

 wherein
R m is selected from hydrogen, C 1 -C 3 alkyl, —C≡C-Ph, halo, haloC 1 -C 3 alkyl, and

R n is selected from hydrogen, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and

Y is selected from hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, and halo;
R 5 is selected from hydrogen, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, and

R L is selected from hydrogen, C 1 -C 3 alkyl, cyano, halo, and haloC 1 -C 3 alkyl;
R 6 and R 50 are selected from hydrogen, —(CH 2 )NR c R d , —C(O)NR c R d , —NHC(O)(CH 2 ) t NR c R d , —O—(CH 2 ) n C(O)NR c R d , —O—(CH 2 ) n NR c R d , hydroxyC 1 -C 6 alkoxy wherein the C 1 -C 6 alkoxy is optionally substituted with one or two additional hydroxy groups,

n is 1, 2, 3, or 4;
t is 0, 1, 2, 3, or 4;
w is 1, 2, 3, 4;
z is 1, 2, or 3;
R 80 is hydrogen or C 1 -C 3 alkyl;
each R z is independently selected from C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkylamido, C 1 -C 4 alkylamino, C 1 -C 4 alkylcarbonyl, amido, carboxy, carboxyC 1 -C 4 alkyl, di(C 1 -C 4 alkyl)amido, di(C 1 -C 4 alkyl)amino, halo, haloC 1 -C 4 alkoxy, haloC 1 -C 4 alkyl, hydroxy, hydroxyC 1 -C 4 alkyl, morpholinyl, —NR c R d , (NR c R d )C 1 -C 4 alkyl, —NR e R f (NR e R f )C 1 -C 4 alkyl, oxo, phenyl, and phenylC 1 -C 4 alkyl, wherein the phenyl and the phenyl part of the phenylC 1 -C 4 alkyl are optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkyl and halo;
R c and R d are independently selected from hydrogen, C 2 -C 4 alkenylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 4 alkylcarbonyl, amidoC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, arylC 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, (C 3 -C 10 cycloalkyl)C 1 -C 4 alkyl, haloC 1 -C 4 alkylcarbonyl, heterocyclylC 1 -C 4 alkyl, heterocyclylC 1 -C 4 alkylcarbonyl, hydroxyC 1 -C 6 alkyl, and hydroxyC 1 -C 4 alkylcarbonyl, wherein the alkyl part of the amidoC 1 -C 4 alkyl, the aminoC 1 -C 4 alkyl, the arylC 1 -C 4 alkyl, the (C 3 -C 10 cycloalkyl)C 1 -C 4 alkyl, the heterocyclylC 1 -C 4 alkyl and the heterocyclylC 1 -C 4 alkylcarbonyl is optionally substituted with one or two groups independently selected from carboxy and hydroxy; wherein the alkyl part of the hydroxyC 1 -C 4 alkyl and the hydroxyC 1 -C 4 alkylcarbonyl is optionally substituted with one or two groups independently selected from carboxy and hydroxy; and wherein the aryl part of the arylC 1 -C 4 alkyl, the C 3 -C 10 cycloalkyl, the cycloalkyl part of the (C 3 -C 10 cycloalkyl)C 1 -C 4 alkyl and the heterocyclyl part of the heterocyclylC 1 -C 4 alkyl and the heterocyclylC 1 -C 4 alkylcarbonyl are each optionally substituted with one, two, or three groups independently selected from C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkyl, and halo;
R e and R f , together with the atom to which they are attached, form a ring selected from morpholine and

Q is selected from S, S(O) 2 , O, and NR p ; wherein R p is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylamidoC 1 -C 4 alkyl, C 1 -C 4 alkylaminoC 1 -C 4 alkyl, amidoC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, di(C 1 -C 4 alkyl)amidoC 1 -C 4 alkyl, di(C 1 -C 4 alkyl)aminoC 1 -C 3 alkyl, hydroxyC 1 -C 4 alkyl, pyridinyl, and phenyl optionally substituted with methoxy;

provided that one of R 5 , R 6 , and R 50 is other than hydrogen; and
R 7 is hydrogen or

 wherein n, z, t, and R z are as defined above in R 6 ; provided that one of R L and R 7 is other than hydrogen;

each R 3 is independently selected from C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyano, halo, and haloC 1 -C 4 alkyl; and
R 4 is selected from —(CH 2 ) p CHO, —(CH 2 ) p CO 2 H, —(CH 2 ) n OH, —C(O)NR 100 R 101 , —CH(CH 3 )NR q R 8 , and —(CH 2 ) n NR q R 8 ; wherein
R 100 and R 101 are selected from hydrogen, C 1 -C 6 alkyl, and hydroxy(C 1 -C 6 alkyl) optionally substituted with an additional hydroxy group; or, R 100 and R 101 , together with the nitrogen atom to which they are attached, form a six-membered ring optionally substituted with a carboxy group;

p is 0, 1, 2, or 3;
n is 1, 2, 3, or 4;
R q is selected from hydrogen, C 1 -C 4 alkyl, benzyl, (C 3 -C 6 cycloalkyl)C 1 -C 3 alkyl, haloC 1 -C 4 alkyl, hydroxyC 1 -C 6 alkyl optionally substituted with a second hydroxy group, and pyridinyl(C 1 -C 3 alkyl) optionally substituted with a cyano group; and
R 8 is selected from hydrogen, C 1 -C 4 alkyl, —(CH 2 ) n N(CH 3 ) 2 , carboxyC 2 -C 6 alkenyl, carboxyC 1 -C 6 alkyl, and hydroxyC 1 -C 6 alkyl, wherein the alkyl part of the carboxyC 1 -C 6 alkyl and the hydroxyC 1 -C 6 alkyl is optionally substituted with one hydroxy or phenyl group wherein the phenyl group is further optionally substituted with a hydroxy group;

Assignees

• Bristol Myers Squibb Co

Inventors

• Yeung Kap-Sun
• Connolly Timothy P
• Frennesson David B
• Grant-Young Katharine A
• Hewawasam Piyasena
• Langley David R
• Meng Zhaoxing
• Mull Eric
• Parcella Kyle E
• Saulnier Mark George
• Sun Li-Qiang
• Wang Alan Xiangdong
• Xu Ningning
• Zhu Juliang
• Scola Paul Michael

Classifications

• C07D471/08

  Bridged systems · CPC title

• C07D417/12

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

• C07D491/08

  Bridged systems · CPC title

• C07D403/12

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

• C07D401/12

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