Immunomodulators

Patent metadata

Field	Value
Publication number	US-9944678-B2
Application number	US-201514971352-A
Country	US
Kind code	B2
Filing date	Dec 16, 2015
Priority date	Dec 19, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 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 i , R j , R m and R n are hydrogen;
R b is hydrogen or methyl;
R d is hydrogen or methyl, or R d and R 4 can form a ring as described below;
R g is hydrogen or methyl, or R g and R 7 can form a ring as described below;
R k and R L are methyl;
each R 20 is independently selected from hydrogen and C 1 -C 6 alkyl;
each R 21 is independently selected from hydrogen and C 1 -C 6 alkyl;
each R 25 is independently selected from hydrogen;
R 1 is benzyl optionally substituted with hydroxy;
R 2 is methyl or, together with the geminal R 20 , forms a cyclopropyl ring;
R 3 is —CH 2 C(O)NH 2 or, together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;
R 4 and R d , together with the atoms to which they are attached, can form a ring 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, hydroxy, and phenyl, or, R 4 , together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;
R 5 is methyl, —CH 2 NH 2 , —(CH 2 )imidazolyl, or, together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;
R 6 is methyl, isobutyl or —(CH 2 )isobutyl;
R 7 is hydrogen, methyl, or R 7 and R g , together with the atoms to which they are attached, can form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and wherein the pyrrolidine and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; or R 7 , together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;
R 8 is —(CH 2 )indolyl;
R 9 is methyl, —CH 2 OH, —(CH 2 ) 2 NH 2 , or, together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;
R 10 is selected from —(CH 2 )indolyl and —(CH 2 )benzothienyl, each optionally substituted with —CH 2 CO 2 H;
R 11 is butyl;
R 12 is butyl; and
R 13 is methyl, isobutyl, —(CH 2 ) 3 NHC(NH)NH 2 , or, together with the geminal R 20 , forms a three- to six-membered carbocyclic ring or a six-membered ring containing an oxygen or a nitrogen atom with a corresponding geminal R 20 group, wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, halo, hydroxy, and amino and wherein the five- and six-membered ring is optionally fused to a phenyl ring;

provided that the compound of formula (I) contains at least one carbon on the backbone of the ring that has four substituents other than hydrogen and is not an alpha-methyl-substituted ring.

2. A compound selected from:

or a pharmaceutically acceptable salt thereof.

Assignees

• Bristol Myers Squibb Co

Inventors

• Sun Li-Qiang
• Zhao Qian
• Gillis Eric P
• Miller Michael Matthew
• Allen Martin Patrick
• Mull Eric
• Scola Paul Michael

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title