Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions

Patent metadata

Field	Value
Publication number	US-9850283-B2
Application number	US-201615009575-A
Country	US
Kind code	B2
Filing date	Jan 28, 2016
Priority date	Mar 15, 2013
Publication date	Dec 26, 2017
Grant date	Dec 26, 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 method of treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more macrocyclic peptides 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;

n is 0 or 1;
R 14 and R 15 are independently selected from hydrogen and methyl; and
R 16 is selected from hydrogen, —CHR 17 C(O)NH 2 ,

—CHR 17 C(O)NHCHR 18 C(O)NH 2 , and
—CHR 17 C(O)NHCHR 18 C(O)NHCH 2 C(O)NH 2 ;
wherein R 17 is selected from hydrogen and CH 2 OH and wherein R 18 is selected from hydrogen and methyl;
R c , R f , R h , R i , R m , and R n are hydrogen;
R a and R j are each independently selected from hydrogen and methyl;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain or form a ring with the corresponding vicinal R group as described below;
R b is methyl or, R b and R 2 , together with the atoms to which they are attached, form a ring selected from azetidine, pyrolidine, 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 methyl or R d and R 4 , together with the atoms to which they are attached, can form a ring selected from azetidine, pyrolidine, 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;
R e is hydrogen or methyl, or Re and R5, together with the atoms to which they are attached, form a ring selected from azetidine, pyrolidine, 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 g is methyl or R g and R 7 , together with the atoms to which they are attached, can form a ring selected from azetidine, pyrolidine, 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;
R k is methyl or R k and R 11 , together with the atoms to which they are attached, selected from azetidine, pyrolidine, 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; and
R 1 is methyl or, R 1 and R 12 , together with the atoms to which they are attached, form a ring selected from azetidine and pyrolidine, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy.

Assignees

• Bristol Myers Squibb Co

Inventors

• Miller Michael Matthew
• Mapelli Claudio
• Allen Martin Patrick
• Bowsher Michael S
• Boy Kenneth M
• Gillis Eric P
• Langley David R
• Mull Eric
• Poirier Maude A
• Sanghvi Nishith
• Sun Li-Qiang
• Tenney Daniel J
• Yeung Kap-Sun
• Zhu Juliang
• Reid Patrick C
• Scola Paul Michael

Classifications

• A61P31/22

  for herpes viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P31/04

  Antibacterial agents · CPC title