Immunomodulators

Patent metadata

Field	Value
Publication number	US-9861680-B2
Application number	US-201514967960-A
Country	US
Kind code	B2
Filing date	Dec 14, 2015
Priority date	Dec 18, 2014
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration 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:
A is

wherein:
denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
z is 0;
w is 1;
R 14 and R 15 are hydrogen; and
R z is-C(O)NHR 16 ; wherein R 16 is —CHR 17 C(O)NH 2 ; wherein R 17 is selected from hydrogen and —CH 2 OH;
R a , R c , R e , R f , R h , R j , R m , and R n are hydrogen;
R 1 is benzyl optionally substituted with hydroxy;
R 2 is hydrogen or methyl; or, R b and R 2 , together with the atoms to which they are attached, can form a ring as described below;
R 3 is —CH 2 C(O)NH 2 ;
R 4 is hydrogen, or, R 4 and R d , together with the atoms to which they are attached, can form a ring as described below;
R 5 is —(CH 2 )imidazolyl;
R 6 is (CH 2 ) 2 CO 2 H;
R 7 is hydrogen or R 7 and R g , together with the atoms to which they are attached, can form a ring as described below;
R 8 is —(CH 2 )indolyl;
R 9 is —(CH 2 ) 2 NH 2 ;
R 10 is selected from —(CH 2 )indolyl and —(CH 2 )benzothienyl, each optionally substituted with —CH 2 CO 2 H;
R 11 is selected from hydrogen, methyl, and butyl;
R 12 is selected from methyl and butyl;
R 13 is isobutyl;
R b is selected from C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkyl, carboxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, (NR a′ R b′ )C 1 -C 6 alkyl wherein R a′ and R b′ are independently selected from a hydrogen and C 1 -C 6 alkyl, and phenylC 1 -C 6 alkyl wherein the phenyl is optionally substituted with one, two, three, four or five groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano, halo, and nitro; or, R b and R 2 , together with the atoms to which they are attached, form a ring a selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy;
R d is selected from hydrogen, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkyl, carboxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, (NR a′ R b′ )C 1 -C 6 alkyl wherein R a′ and R b′ are independently a selected from hydrogen and C 1 -C 6 alkyl, and phenylC 1 -C 6 alkyl wherein the phenyl is optionally substituted with one, two, three, four or five groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano, halo, and nitro; or, R d and R 4 , together with the atoms to which they are attached, can form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and a tetrahydrothiazole, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl;
R g is selected from hydrogen, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkyl, carboxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, (NR a′ R b′ )C 1 -C 6 alkyl wherein R a′ and R b′ are independently a selected from hydrogen and C 1 -C 6 alkyl, and phenylC 1 -C 6 alkyl wherein the phenyl is optionally substituted with one, two, three, four or five groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano, halo, and nitro; or R g and R 7 , together with the atoms to which they are attached, can form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and a tetrahydrothiazole, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy;
R k is selected from C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkyl, carboxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, (NR a′ R b′ )C 1 -C 6 alkyl wherein R a′ and R b′ are independently selected from hydrogen and C 1 -C 6 alkyl; and phenylC 1 -C 6 alkyl; and
R 1 is C 1 -C 2 alkyl;
provided that at least one of R b , R d , R g , R k , and R l is selected from C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkyl, carboxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, (NR a′ R b′ )C 1 -C 6 alkyl wherein a R a′ and R b′ are independently selected from hydrogen and C 1 -C 6 alkyl, and phenylC 1 -C 6 alkyl wherein the phenyl is optionally substituted with one, two, three, four or five groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano, halo, and nitro.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 17 is hydrogen; and
R 2 is hydrogen or methyl.

3. A compound selected from:

Assignees

• Bristol Myers Squibb Co

Inventors

• Mapelli Claudio
• Allen Martin Patrick
• Scola Paul Michael

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07K7/54 Primary

  with at least one abnormal peptide link in the ring · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title