1,3-dihydroxy-phenyl derivatives useful as immunomodulators

Patent metadata

Field	Value
Publication number	US-10590105-B2
Application number	US-201716315800-A
Country	US
Kind code	B2
Filing date	Jul 5, 2017
Priority date	Jul 8, 2016
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

Abstract

The present disclosure generally relates to compounds of formula (I), wherein R2 is a phenyl or pyridinyl moiety, 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 —(CH 2 ) n Ar; wherein
n is 1, 2, 3, or 4;
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;

R 2 is selected from

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

R 5 is phenyl or a monocyclic or bicyclic fully-unsaturated heterocycle containing five to ten atoms wherein one to four of those atoms are independently selected from nitrogen, oxygen and sulfur; and wherein the phenyl and the monocyclic or bicyclic group is optionally substituted with one, two, three, four, or five substituents independently selected from C 1 -C 3 alkyl, cyano, formyl, halo, haloC 1 -C 3 alkoxy, haloC 1 -C 3 alkyl, hydroxy, oxo, -L-(CH 2 ) m′ NR c R d , -L-(CH 2 ) m′ OH,

wherein
L is selected from a bond, —CH 2 , —NHC(O)—, —C(O)NH—, and —O—; provided that L is —CH 2 — when it is attached to the parent molecular moiety through a nitrogen atom in the heterocycle;
m′ is 1, 2, 3, or 4; provided that when m′ is 1, L is a bond that is attached to the parent molecular moiety through a carbon atom;
t is 0, 1, 2, or 3;
z is 1, 2, or 3;
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, cyano, 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, —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, phenyl, and phenylC 1 -C 4 alkyl; wherein R e and R f , together with the atom to which they are attached, form a ring selected from morpholine and

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, heteroarylC 1 -C 4 alkyl, and hydroxyC 1 -C 4 alkyl; 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, and the heteroarylC 1 -C 4 alkyl 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 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 heteroaryl part of the heteroarylC 1 -C 4 alkyl 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;
Q is selected from S, 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 when R 2 is

then R 5 is other than phenyl; and
R 6 is hydrogen, or, R 5 and R 6 , together with the atoms to which they are attached, form a five- or six-membered unsaturated ring containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with one or two substituents independently selected from C 1 -C 3 alkyl, cyano, formyl, halo, haloC 1 -C 3 alkyl, hydroxy, oxo, -L-(CH 2 ) n NR c R d , -L-(CH 2 ) n OH;
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 —(CH 2 ) n′ NR q R 8 , wherein
n′ is 1, 2, 3, or 4;
R q is selected from hydrogen, C 1 -C 4 alkyl, and benzyl; and
R 8 is selected from

wherein
s is 0, 1, or 2;
z is 1, 2, or 3;
R j 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, and C 1 -C 3 alkylsulfanylC 1 -C 3 alkyl;
R w is —CO 2 H or —CONH 2 ,
R 9 is selected from hydrogen, benzyl, and methyl;
each R 9′ is independently selected from hydrogen, ethyl, and methyl;
R 10 is selected from hydrogen, C 1 -C 3 alkyl, and benzyl; and
R 11 is selected from C 2 -C 4 alkenyl and C 1 -C 4 alkyl;

or
R 8 and R q , together with the nitrogen atom to which they are attached, form a ring selected from

wherein
s is 0, 1, or 2;
z is 1, 2, or 3;
Q′ is selected from CHR 13′ , S, O, —N(CH 2 ) 2 OH, and NCH 3 ;
R 12 is selected from hydrogen, —CO 2 H, hydroxyC 1 -C 4 alkyl,

and —C(O)NHSO 2 R 16 ; wherein R 16 is selected from trifluoromethyl, cyclopropyl, C 1 -C 4 alkyl, dimethylamino, 4-methylpiperazinyl, and imidazolyl substituted with a methyl group;
R 13 is selected from hydrogen, hydroxyC 1 -C 4 alkyl, and —CO 2 H;
R 13′ is selected from hydrogen, hydroxyC 1 -C 3 alkyl, and —CO 2 H; and
R 14 is selected from C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkyl, carboxy, halo, hydroxy, hydroxyC 1 -C 4 alkyl, and —NR c′ R d′ ; wherein R c ′ and R d ′ are independently selected from hydrogen, C 1 -C 4 alkoxycarbonyl, and C 1 -C 4 alkylcarbonyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —(CH 2 ) n Ar wherein n is 1 and Ar is pyridinyl optionally substituted with cyano.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 3 is halo.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from

wherein
R n is hydrogen;
Y is methyl;
R 5 is phenyl or a monocyclic or bicyclic fully-unsaturated heterocycle containing five to ten atoms wherein one to four of those atoms are independently selected from nitrogen, oxygen and sulfur; and wherein the phenyl and

Assignees

• Bristol Myers Squibb Co
• Bristol Meyers Squibb Co

Inventors

• Yeung Kap-Sun
• Grant-Young Katharine A
• Zhu Juliang
• Saulnier Mark G
• Frennesson David B
• Meng Zhaoxing
• Scola Paul Michael

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/22

  for herpes viruses · CPC title