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

Patent metadata

Field	Value
Publication number	US-9308236-B2
Application number	US-201414201977-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 15, 2013
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

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;

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 , R e , 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 e can form a ring with the corresponding vicinal R group and the atoms to which it is attached 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 b is methyl or, R b and R 2 , together with the atoms to which they are attached, 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, and hydroxy;
R d is methyl or, R d and R 4 , together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl;
R g is methyl or, R g and R 7 , together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two 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, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy; and
R l is methyl or, R l and R 12 , together with the atoms to which they are attached, form a ring selected from azetidine and pyrollidine, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R d and R 4 , together with the atoms to which they are attached, form a ring selected from azetidine, pyrollidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy;
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 or two 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; and
R k is methyl.

3. The compound of claim 2 , or a therapeutically acceptable salt thereof, wherein R 8 is selected from
azaindolylC 1 -C 3 alkyl, benzothiazolylC 1 -C 3 alkyl, benzothienylC 1 -C 3 alkyl, benzyloxyC 1 -C 3 alkyl, diphenylmethyl, furanylC 1 -C 3 alkyl, imidazolylC 1 -C 3 alkyl, naphthylC 1 -C 3 alkyl, pyridinylC 1 -C 3 alkyl, thiazolylC 1 -C 3 alkyl, thienylC 1 -C 3 alkyl; and
indolylC 1 -C 3 alkyl, wherein the indolyl part is optionally substituted with one group selected from C 1 -C 3 alkyl, cyano, halo, and hydroxy.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 8 is 3-indolylC 1 -C 3 alkyl optionally substituted with one group selected from C 1 -C 3 alkyl, halo, hydroxy, or cyano.

5. A method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one macrocyclic peptide of claim 1 .

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P31/14

  for RNA viruses · CPC title