Compounds useful as immunomodulators

Patent metadata

Field	Value
Publication number	US-9850225-B2
Application number	US-201514681772-A
Country	US
Kind code	B2
Filing date	Apr 8, 2015
Priority date	Apr 14, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

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;
R 1 is selected from hydrogen, —(CH 2 ) n X and —(CH 2 ) n Ar; wherein
n is 1, 2, 3, or 4;
X is selected from —CH 3 , —CF 3 , CN, —CO 2 R 4 , —C(O)NH 2 , OR 4 , and pyrrolidonyl;
R 4 is H or C 1 -C 3 alkyl;
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 alkyl)carbonyl, (C 1 -C 4 alkyl)sulfonyl, amido, aminocarbonyl, aminocarbonyl(C 1 -C 3 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; and wherein q is 0, 1, 2, 3, or 4;

R 2 is selected from

wherein Y is selected from cyano, chloro, and methyl;
R q is selected from hydrogen, C 1 -C 3 alkyl, and benzyl;
R 3 is selected from

wherein R z is selected from C 1 -C 3 alkyl, C 1 -C 3 alkylsulfonylC 1 -C 3 alkyl, C 1 -C 3 alkylsulfoxylC 1 -C 3 alkyl, amidoC 1 -C 3 alkyl, aminoC 1 -C 4 alkyl, carboxyC 1 -C 3 alkyl, cyanoC 1 -C 3 alkyl, dimethylamidoC 1 -C 3 alkyl, dimethylaminoC 1 -C 4 alkyl, haloC 1 -C 3 alkyl, hydroxyC 1 -C 3 alkyl, C 1 -C 3 alkylsulfanylC 1 -C 3 alkyl, pyridinylC 1 -C 3 alkyl, tetrazolylC 1 -C 3 alkyl, imidazolylC 1 -C 3 alkyl wherein the imidazole is optionally substituted with methyl or a benzyl group, phenylC 1 -C 3 alkyl wherein the phenyl is optionally substituted with cyano, methyl, or hydroxy, thiazolylC 1 -C 3 alkyl;
R 6 is selected from hydrogen, benzyl, and methyl;
each R 6′ is independently selected from hydrogen and methyl;
R 7 is selected from hydrogen, C 1 -C 3 alkyl, and benzyl;
o is 1 or 2;
X is CH or N;
p is 0 or 1;
R a is hydroxy; and
R b is selected from hydrogen, benzyl, and methyl; or

R 3 and R q , together with the nitrogen atom to which they are attached, form a ring selected from

s is 0 or 1;
z is 1, 2, or 3; and
R 8 is selected from hydroxy and —NHSO 2 R 11 ;
R 9 is selected from hydrogen and —CO 2 H;
R 10 is selected from halo and hydroxy;
R 11 is selected from trifluoromethyl, cyclopropyl, C 1 -C 3 alkyl, dimethylamino, and imidazolyl substituted with a methyl group;
Q is selected from CH 2 , S, O, and NCH 3 ; and

R 5 is selected from C 2 -C 4 alkenyl, C 1 -C 4 alkyl, cyano, methoxy, halo, and trifluoromethyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is

 and
R 3 is

5. A compound selected from
N-(2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)ethyl)acetamide;
(R)-2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxy-2-methylpropanoic acid;
(R)-2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxypropanoic acid;
(S)-4-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxybutanoic acid;
(S)-1-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzyl)piperidine-2-carboxylic acid;
N-(2-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)ethyl)acetamide;
(S)-4-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxybutanoic acid;
(R)-2-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxypropanoic acid;
(R)-2-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxy-2-methylpropanoic acid;
(S)-1-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzyl)piperidine-2-carboxylic acid;
(S)-2-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyloxy)-6-methylbenzylamino)-3-hydroxy-2-methylpropanoic acid;
(S)-4-(2-(3-cyanobenzyloxy)-4-((2-methylbiphenyl-3-yl)methoxy)benzylamino)-3-hydroxybutanoic acid;
(2S,3S)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid;
(2R,3R)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid;
2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid;
(2R,3S)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid;
(R)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid;
2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid;
(S)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid;
(S)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid;
2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-2-(hydroxymethyl)-3-methylbutanoic acid;
(S)-3-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-4-hydroxybutanoic acid;
(R)-3-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-4-hydroxybutanoic acid;
(R)-2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid;
N-(2-((2-(benzyloxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)ethyl)acetamide;
N-(2-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2-((3-methylbenzyl)oxy)benzyl)amino)ethyl)acetamide;
N-(2-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2-(2,2,2-trifluoroethoxyl)benzyl)amino)ethyl)acetamide;
N-(2-((4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2-propoxybenzyl)amino)ethyl)acetamide;
N-(2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)ethyl)acetamide;
N-(2-((2-((4-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)ethyl)acetamide;
N-(2-((2

Assignees

• Bristol Myers Squibb Co

Inventors

• Chupak Louis S
• Ding Min
• Martin Scott W
• Zheng Xiaofan
• Hewawasam Piyasena
• Connolly Timothy P
• Xu Ningning
• Yeung Kap-Sun
• Zhu Juliang
• Langley David R
• Scola Paul Michael

Classifications

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• C07D413/12

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

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title