Immunomodulators

Patent metadata

Field	Value
Publication number	US-9809625-B2
Application number	US-201615068993-A
Country	US
Kind code	B2
Filing date	Mar 14, 2016
Priority date	Mar 18, 2015
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

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;
m is 1;
w is 0
R 14 and R 15 are hydrogen;
R 16a is selected from hydrogen and C 1 -C 6 alkyl;
R 16 is
—(C(R 17a ) 2 )—C(O)—NR 50 R 51 ;

wherein:
each R 17a is independently selected from hydrogen and C 1 -C 6 alkyl;
one of R 50 and R 51 is selected from hydrogen and C 1 -C 6 alkyl and the other is selected from —(CH 2 ) n′ X, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, and phenyl, wherein the cycloalkyl is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, amino, cyano, and hydroxy, or;
R 50 and R 51 , together with the nitrogen atom to which they are attached, form a four-, five- six- or seven-membered saturated or unsaturated ring optionally containing one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is optionally substituted with one, two, or three groups selected from C 1 -C 6 alkoxy, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxy(C 1 -C 3 alkyl), —NR 70 R 71 , oxo, and phenyl; wherein the phenyl is further optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, cyano, and halo;
n′ is 1-5;
X is selected from —C≡CH,

C 2 -C 6 alkoxymethyl, C 1 -C 6 alkoxycarbonylmethyl, C 1 -C 6 alkylsulfanylmethyl, C 1 -C 6 alkylsulfonylmethyl, azidomethyl, tert-butoxymethyl, C 3 -C 7 cycloalkyl, haloalkoxymethyl, halomethyl, heterocyclyl, hydroxymethyl, isopropoxymethyl, (NR 70 R 71 )methyl, phenyl, phenoxymethyl, and phenylsulfanylmethyl,
one of R 70 and R 71 is selected from hydrogen, C 1 -C 6 alkyl, and hydroxyC 2 -C 6 alkyl and the other is selected from C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfonyl, and hydroxyC 2 -C 6 alkyl;
R c , R f , R h , R i , R m , and R n are hydrogen;
R a , R e , and R j are hydrogen;
R b , R k , and R l are methyl;
R 1 is phenylmethyl wherein the phenyl is substituted with hydroxy;
R 2 is methyl;
R 3 is selected from —CH 2 C(O)NH 2 and —CH 2 CO 2 H;
R 5 is selected from —CH 2 NH 2 , —CH 2 OH, and —CH 2 C(O)NH 2 ;
R 6 is selected from —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 CO 2 H, and (CH 2 ) 2 C(O)NH 2 ;
R 8 and R 10 are —CH 2 (indolyl), wherein the indolyl is optionally substituted with —CH 2 CO 2 H;
R 9 is selected from hydrogen, —(CH 2 ) 2 NH 2 , CH 2 OH, and —CH 2 C(O)NH 2 ;
R 11 and R 12 are —(CH 2 ) 3 CH 3 ;
R 13 is selected from methyl, —CH 2 CH(CH 3 ) 2 , and —(CH 2 ) 2 CO 2 H;
R d and R 4 , together with the atoms to which they are attached, form a pyrollidine ring; and
R g and R 7 , together with the atoms to which they are attached, form a pyrollidine ring, wherein said ring is optionally substituted with one hydroxy group.

2. A compound selected from:

or a pharmaceutically acceptable salt thereof.

Assignees

• Bristol Myers Squibb Co

Inventors

• Boy Kenneth M
• Scola Paul Michael

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title