Compounds useful as immunomodulators

Patent metadata

Field	Value
Publication number	US-9872852-B2
Application number	US-201414915782-A
Country	US
Kind code	B2
Filing date	Sep 2, 2014
Priority date	Sep 4, 2013
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

Disclosed are compounds of Formula (I): (I). Also disclosed are methods of using such compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of virological diseases or disorders and cancer.

First claim

What is claimed is:

1. A compound of Formula (I):

or salts thereof, wherein:
Ring B is phenyl or thienyl;
Ring A is:

wherein A″ is CH or N, and wherein one of R 1 and R 2 is Q and the other of R 1 and R 2 is R b ;
R 3 is H or —CH 2 C(O)OH;
R 4 is —NHCH 2 CH 2 NHC(O)CH 3 ;
Q is:
(i)

wherein R y is —OH, —CH 3 , —CH 2 OH, —C(O)OH, —CH 2 C(O)OH, or —C(O)NHCH 2 CH 2 OH, —C(O)NH 2 , —NHC(O)CH 3 , and R z is —OH, —CH 3 , —OCH 3 , —OC(O)CH 3 , or —CH 2 CH═CH 2 and R h is —CH 3 or —C(O)CH 3 ;
(ii) —CH 2 NH—R x wherein R x is cyclobutyl, —(CH 2 )cyclobutyl optionally substituted with two fluorine atoms, cyclopropyl, hydroxycyclopentyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxytetrahydrofuranyl, N-methyl piperidinyl, N-ethyl piperidinyl, hydroxytetrahydrothienyl, or

(iii) —CH 2 NR a —CR a R a —(CH 2 ) n —R x wherein R x is hydrogen, azetidinonyl, cyclohexyl, hydroxyphenyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinyl, imidazolyl, N-methylimidazolyl, —C(O)(morpholinyl), piperazinyl optionally substituted with a methyl, phenyl, alkoxyphenyl, hydroxyphenyl, pyridinyl, pyrimidinyl, or —C(O)OC(CH 3 ) 3 group, pyrrolidinyl, pyridinyl, thiomorpholine dioxide, or methyl triazolyl; or
(iv) —CHR a —NR a —CR a R a —(CHR a ) n —R x wherein R x is —OH, —OCH 3 , —C(O)OH, —OPh, —CH(CO 2 H)—NHC(O)CH 3 , —O(CH 2 ) 2 O(CH 2 ) 2 OH, —O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 OH, —O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 CO 2 H—O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 CO 2 H, —C(O)CH 3 , —C(O)NR a R a , —C(O)NR q R q , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)Ph, —C(O)NH(CH 2 ) 2 -imidazolyl, NHC(O)OCH 2 Ph, —N(CH 3 )S(O) 2 CH 3 , —NHC(O)CH═CH 2 , —NHC(O)CH═CHC(O)CH 2 CH 3 , —NHS(O) 2 CH 3 , or

each R a is independently H, —CH(OH)CH 3 , OH, —(CH 2 ) 2 OH, —CH 2 OH, —(CH 2 ) 2 NH 2 , —CH 2 CH 3 , or —CH 3 ; or, two R a groups on the same carbon atom can form a four, five-, or six-membered carbocyclic ring, an N-methylpiperidinyl ring, or a pyranyl ring;
each R b is independently H, F, Cl, Br, —CF 3 , —CN, CH 3 , or —OCH 3 ;
each R c is independently —OCH 3 , —OH, —OCH 2 CH 3 , —O(CH 2 )OCH 3 , —OCH 2 CH═CH 2 , —O(CH 2 ) 2 CH 3 , —O(CH 2 ) 2 -morpholinyl, or F;
or two R c attached to adjacent carbon atoms form —O—(CH 2 ) v —O—, wherein v is 1 or 2;
each R q is selected from hydrogen, —CH 2 C(O)NHCH 2 CO 2 H, —(CH 2 )C(O)NHCH(CO 2 H)CH 2 CH(CH 3 ) 2 , —CH(Bn)-C(O)NHCH(CO 2 H)(CH 2 ) 3 NHC(NH)NH 2 ;
m is zero or 1;
n is zero, 1, 2, or 3;
each p is independently zero or 1; and
q is zero, 1, or 2.

2. The compound according to claim 1 or salts thereof, wherein Ring A is:

3. The compound according to claim 2 or salts thereof, wherein Q is:

4. The compound according to claim 2 or salts thereof, wherein Q is: —CH 2 NH—R x wherein R x is cyclobutyl, —(CH 2 )cyclobutyl optionally substituted with two fluorine atoms, cyclopropyl, hydroxycyclopentyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxytetrahydrofuranyl, N-methyl piperidinyl, N-ethyl piperidinyl, hydroxytetrahydrothienyl, or

5. The compound according to claim 2 or salts thereof, wherein Q is: —CH 2 NR a —CR a R a —(CH 2 ) n —R x wherein R x is hydrogen, azetidinonyl, cyclohexyl, hydroxyphenyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinyl, imidazolyl, N-methylimidazolyl, —C(O)(morpholinyl), piperazinyl optionally substituted with a methyl, phenyl, alkoxyphenyl, hydroxyphenyl, pyridinyl, pyrimidinyl, or —C(O)OC(CH 3 ) 3 group, pyrrolidinyl, pyridinyl, thiomorpholine dioxide, or methyl triazolyl.

6. The compound according to claim 2 or salts thereof, wherein Q is —CHR a —NR a —CR a R a —(CHR a ) n —R x wherein R x is —OH, —OCH 3 , —C(O)OH, —OPh, —CH(CO 2 H)—NHC(O)CH 3 , —O(CH 2 ) 2 O(CH 2 ) 2 OH, —O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 OH, —O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 CO 2 H—O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 CO 2 H, —C(O)CH 3 , —C(O)NR a R a , —C(O)NR q R q , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)Ph, —C(O)NH(CH2)2-imidazolyl, NHC(O)OCH 2 Ph, —N(CH 3 )S(O) 2 CH 3 , —NHC(O)CH═CH 2 , —NHC(O)CH═CHC(O)CH 2 CH 3 , —NHS(O) 2 CH 3 , or

7. The compound according to claim 1 selected from: (S)-1-(2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (1); 1-(4-((2′-fluoro-2-methylbiphenyl-3-yl)methoxy)benzyl)azetidine (3); N-{2-[({3-bromo-2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (4); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) [2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine (5); N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}-N-methylmethanesulfonamide (6); 1-({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (7); 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-(morpholin-4-yl)ethan-1-one (8); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[2-(4-methylpiperazin-1-yl)ethyl]amine (9); 1-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}piperidin-2-one (10); 1-{3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}pyrrolidin-2-one (11); 4-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}piperazin-2-one (12); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[2-(morpholin-4-yl)ethyl]amine (13); 1-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (14); 2-[methyl({3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetic acid (15); N-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1-ethylpiperidin-3-amine (16); 1-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}pyrrolidin-2-one (17); (2S,4R)-4-(acetyloxy)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (18); N-(2-hydroxyethyl)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) piperidine-4-carboxamide (19); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[1-(5-methyl-4H-1,2,4-triazol-3-yl)ethyl]amine (20); N-{2-[({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (21); (2S,4R)-1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-4-methoxypyrrolidine-2-carboxylic acid (22); N-{3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}acetamide (23); (1R,2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol (24); N-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1-methylpiperidin-3-amine (25); (2S)-1-({2-methoxy-3-methyl-4-[(2-methyl-3-phenylpheny

Assignees

• Bristol Myers Squibb Co

Inventors

• Chupak Louis S
• Zheng Xiaofan

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title