Immunomodulators

Patent metadata

Field	Value
Publication number	US-10450347-B2
Application number	US-201715465218-A
Country	US
Kind code	B2
Filing date	Mar 21, 2017
Priority date	Feb 4, 2015
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

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 selected from a bond,

wherein:
denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
z is 0, 1, or 2;
w is 1 or 2;
n is 0 or 1;
m is 1 or 2;
m′ is 0 or 1;
p is 0, 1, or 2;
R x is selected from hydrogen, amino, hydroxy, and methyl;
R 14 and R 15 are independently selected from hydrogen and methyl; and
R z is selected from hydrogen and —C(O)NHR 16 ; wherein 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 v is hydrogen or a natural amino acid side chain;
Q is selected from

wherein R b is defined below, and a five- or six-membered ring containing one, two, or three double bonds and either optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen and sulfur or optionally containing four nitrogen atoms, wherein the ring is optionally substituted with one, two, three, or four substituents independently selected from C 1 -C 6 alkoxycarbonyl, C 1 -C 3 alkyl, amino, C 1 -C 3 alkylamino, carboxy, C 1 -C 3 dialkylamino, halo, and haloC 1 -C 3 alkyl;
U is selected from

wherein R k is defined below, and a five- or six-membered ring containing one, two, or three double bonds and either optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally containing four nitrogen atoms, wherein the ring is optionally substituted with one, two, three, or four substituents independently selected from C 1 -C 6 alkoxycarbonyl, C 1 -C 3 alkyl, amino, C 1 -C 3 alkylamino, carboxy, C 1 -C 3 dialkylamino, halo, and haloC 1 -C 3 alkyl;
provided that at least one of Q and U is a five- or six-membered ring containing one, two, or three double bonds and either containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur or containing four nitrogen atoms;
R c , R f , R h , R i , R m , and R n are hydrogen;
R a , R e , R j , and R k , 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 and R k can each form a ring with the corresponding vicinal R group and the atoms to which they are 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 hydrogen or methyl, 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 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 hydrogen or methyl 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 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; 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. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from

and a five-membered ring containing one or two double-bonds and containing one, two, three, or four nitrogen atoms; and
U is selected from

and a five-membered ring containing one or two double-bonds and containing one, two, three, or four nitrogen atoms.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein A is

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
z is 0 and 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 .

5. A compound of claim 4 wherein
R 1 is phenylC 1 -C 3 alkyl wherein the phenyl is optionally substituted with hydroxy;
R 2 is C 1 -C 7 alkyl or, R b and R 2 , together with the atoms to which they are attached, form a morpholine or piperidine ring;
R 3 is selected from —CH 2 CO 2 H and —CH 2 C(O)NH 2 ;
R 4 and R d , together with the atoms to which they are attached, form a pyrrolidine ring;
R 5 is selected from —CH 2 NH 2 and —CH 2 (imidazolyl);
R 6 is selected from C 1 -C 7 alkyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 CO 2 H;
R 7 is hydrogen or R 7 and R g , together with the atoms to which they are attached, form a pyrroldine ring optionally substituted with a hydroxy group;
R 8 is —(CH 2 )indolyl;
R 9 is selected from aminomethyl, hydroxymethyl, —CH 2 CH 2 NH 2 , and CH 2 CH 2 CH 2 CH 2 NH 2 ;
R 10 is selected from —(CH 2 )indolyl, —(CH 2 )naphthyl, and —(CH 2 )benzothienyl, each optionally substituted with —CH 2 CO 2 H;
R 11 is C 1 -C 7 alkyl; and
R 12 is C 1 -C 7 alkyl.

6. A compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein:
A is selected from a bond,

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)NH2;

wherein R 17 is selected from hydrogen and —CH 2 OH and wherein R 18 is selected from hydr

Assignees

• Bristol Myers Squibb Co

Inventors

• Miller Michael Matthew
• Allen Martin Patrick
• Li Ling
• Mapelli Claudio
• Poirier Maude A
• Sun Li-Qiang
• Zhao Qian
• Mull Eric
• Gillis Eric P
• Scola Paul Michael

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/20

  for DNA viruses · CPC title