US 10,882,844 B2Granted

Compounds useful as immunomodulators

AssigneeBristol-Myers Squibb Company

InventorsKap-Sun Yeung, Katharine A. Grant-Young, Li-Qiang Sun, David R. Langley, Denis R. St. Laurent, Paul M. Scola

Life of this patent

Estimating the term…

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.

Claims11

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
m is 0, 1, or 2;
Z is selected from —OCH3 and —O(CH2)nAr;
wherein
n is 1, 2, 3, or 4;
Ar is selected from phenyl and pyridinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4alkoxy, C1-C4alkyl, amido, carboxy, cyano, formyl, halo, haloC1-C4alkyl, haloC1-C4alkoxy, and nitro;
A is selected from —CH2O—, —OCH2—, —(CH2)2—, —CH═CH—, —C(O)NH—, and —NHC(O)—, wherein each group is drawn with its left side attached to R2 and its right side attached to the phenyl ring;
R2 is selected from
wherein
Rm and Rn are independently selected from hydrogen, C1-C3alkyl, and halo;
Y is selected from hydrogen, C1-C3alkoxy, C1-C3alkyl, cyano, and halo;
R5 is a three- to ten-membered monocyclic or bicyclic ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen and containing zero, one, two, or three double bonds, wherein said ring is optionally substituted with one, two, or three groups independently selected from C1-C3alkoxy, C1-C3alkoxyC1-C4alkyl, C1-C4alkoxycarbonyl, C1-C4alkyl, di(C1-C4)alkylamino, amino, aminoC1-C4alkyl, carboxy, carboxyC1-C4alkyl, C3-C4cycloalkyl, and phenyl;
each R3 is independently selected from C1-C4alkyl, cyano, halo, and haloC1-C4alkyl;
R4 is selected from —CH2OH, —CHO and —(CH2)nNRqR8;
wherein
n is 1, 2, 3, or 4;
Rq is selected from hydrogen and C1-C4alkyl;
R8 is selected from hydrogen, C1-C4alkyl, —(CH2)nN(CH3)2,
R9 is selected from hydrogen and C1alkyl;
each R9′ is independently selected from hydrogen and C1-C3alkyl;
and
R10 is selected from hydrogen and C1-C4alkyl;
or
R8 and Rq, together with the nitrogen atom to which they are attached, form a ring which is
wherein
s is 0, 1, or 2;
z is 1, 2, or 3;
and
each R14 is independently selected from C1-C4alkoxycarbonyl, C1-C6alkyl, carboxy, halo, hydroxy, and hydroxyC1-C4alkyl.

26 more elements

A compound selected from

(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-methylpiperidin-4-yl)benzo[d]oxazol-6-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-methylpiperidin-3-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(piperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2-(1-cyclopropylpiperidin-4-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(4-((3-(2-(8-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(pyridin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-methylpyrrolidin-3-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(7-methyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(4-methyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2-(4-(diethylamino)cyclohexyl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2-(1-isopropylpiperidin-4-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(4-((3-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(4-((3-(2-(1-(carboxymethyl)piperidin-4-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(4-((3-(2-(8-oxabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
5-((4-chloro-2-formyl-5-((2-methyl-3-(2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
(R)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid;
5-((4-chloro-2-(hydroxymethyl)-5-((2-methyl-3-(2-(1-methylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
5-((4-chloro-2-4(1,3-dihydroxypropan-2-yl)(methyl)amino)methyl)-5-((2-methyl-3-(2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5 yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
5-((5-((3-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-4-chloro-2-4(1,3-dihydroxypropan-2-yl)amino)methyl)phenoxy)methyl)nicotinonitrile;
5-((4-chloro-2-4(1,3-dihydroxy-2-methylpropan-2-yl)(methyl)amino)methyl)-5-((2-methyl-3-(2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
(S)-1-(4-((3-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
5-((5-((3-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-4-chloro-2-4(1,3-dihydroxy-2-methylpropan-2-yl)amino)methyl)phenoxy)methyl)nicotinonitrile;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
5-((4-chloro-2-4(1,3-dihydroxypropan-2-yl)amino)methyl)-5-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
5-((4-chloro-2-4(1,3-dihydroxy-2-methylpropan-2-yl)amino)methyl)-5-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)-L-serine;
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid;
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)amino)pentanoic acid;
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)amino)-3-methylbutanoic acid;
5-((4-chloro-2-4(1,3-dihydroxypropan-2-yl)(methyl)amino)methyl)-5-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
5-((4-chloro-2-4(1,3-dihydroxy-2-methylpropan-2-yl)(methyl)amino)methyl)-5-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)phenoxy)methyl)nicotinonitrile;
N-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)-N-methyl-L-serine;
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)(methyl)amino)-3-hydroxy-2-methylpropanoic acid;
(S)-2-((5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)(methyl)amino)pentanoic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(2-(1-phenylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid
(S)-1-(5-chloro-2-methoxy-4-((2-methyl-3-(2-(1-phenylpiperidin-4-yl)benzo[d]oxazol-5-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(2-(4-(methoxycarbonyl)cyclohexyl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(4-((3-(2-(4-carboxycyclohexyl)benzo[d]oxazol-5-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(3-(1,2,5,6-tetra-hydropyridin-3-yl)quinoxalin-6-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(4-((3-(3-(8-(tert-butoxycarbonyl)bicyclo[3.2.1]oct-2-en-3-yl)quinoxalin-6-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(2S)-1-(4-((3-(3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)quinoxalin-6-yl)-2-methylbenzyl)-oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid;
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(3-(1,2,3,6-tetrahydropyridin-4-yl)quinoxalin-6-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
and
(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-3-(3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)benzyl)oxy)benzyl)piperidine-2-carboxylic acid;
or a pharmaceutically acceptable salt thereof.

47 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/471,531Filed 19 Dec 2017 · us provisional application
Priority: 20 Dec 2016
Published: US 2019/0352280 A121 Nov 2019
Granted: 5 Jan 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 37/02
Drugs for immunological or allergic disorders: immunomodulators
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links

Family

Application62/436,674Us provisional application · filed 20 Dec 2016
US 2019/0352280 A1Pre-grant publication · published 21 Nov 2019
US 10,882,844 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
m is 0, 1, or 2;
Z is selected from —OCH3 and —O(CH2)nAr;
wherein
n is 1, 2, 3, or 4;
Ar is selected from phenyl and pyridinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C4alkoxy, C1-C4alkyl, amido, carboxy, cyano, formyl, halo, haloC1-C4alkyl, haloC1-C4alkoxy, and nitro;
A is selected from —CH2O—, —OCH2—, —(CH2)2—, —CH═CH—, —C(O)NH—, and —NHC(O)—, wherein each group is drawn with its left side attached to R2 and its right side attached to the phenyl ring;
R2 is selected from
wherein
Rm and Rn are independently selected from hydrogen, C1-C3alkyl, and halo;
Y is selected from hydrogen, C1-C3alkoxy, C1-C3alkyl, cyano, and halo;
R5 is a three- to ten-membered monocyclic or bicyclic ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen and containing zero, one, two, or three double bonds, wherein said ring is optionally substituted with one, two, or three groups independently selected from C1-C3alkoxy, C1-C3alkoxyC1-C4alkyl, C1-C4alkoxycarbonyl, C1-C4alkyl, di(C1-C4)alkylamino, amino, aminoC1-C4alkyl, carboxy, carboxyC1-C4alkyl, C3-C4cycloalkyl, and phenyl;
each R3 is independently selected from C1-C4alkyl, cyano, halo, and haloC1-C4alkyl;
R4 is selected from —CH2OH, —CHO and —(CH2)nNRqR8;
wherein
n is 1, 2, 3, or 4;
Rq is selected from hydrogen and C1-C4alkyl;
R8 is selected from hydrogen, C1-C4alkyl, —(CH2)nN(CH3)2,
R9 is selected from hydrogen and C1alkyl;
each R9′ is independently selected from hydrogen and C1-C3alkyl;
and
R10 is selected from hydrogen and C1-C4alkyl;
or
R8 and Rq, together with the nitrogen atom to which they are attached, form a ring which is
wherein
s is 0, 1, or 2;
z is 1, 2, or 3;
and
each R14 is independently selected from C1-C4alkoxycarbonyl, C1-C6alkyl, carboxy, halo, hydroxy, and hydroxyC1-C4alkyl.

26 more elements

Facts

Application

16/471,531Filed 19 Dec 2017 · us provisional application

Priority

20 Dec 2016

Published

US 2019/0352280 A121 Nov 2019

Granted

5 Jan 2021

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 37/02
Drugs for immunological or allergic disorders: immunomodulators
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links