Immunomodulators

Patent metadata

Field	Value
Publication number	US-10358463-B2
Application number	US-201715475227-A
Country	US
Kind code	B2
Filing date	Mar 31, 2017
Priority date	Apr 5, 2016
Publication date	Jul 23, 2019
Grant date	Jul 23, 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;
denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
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 10 is —(CH 2 ) n Q′, wherein n is 1-3 and Q′ is a five, six-fused saturated or unsaturated ring system containing one, two, three, or four nitrogen atoms, wherein said ring system is optionally substituted with one, two, or three groups selected from C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylC 1 -C 3 alkyl, C 1 -C 3 alkyl, (C 1 -C 6 alkyl)S(O) 2 NHC(O)C 1 -C 3 alkyl, arylS(O) 2 NHC(O)C 1 -C 3 alkyl, arylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, carboxy, carboxyC 1 -C 3 alkyl, cyano, C 3 -C 6 cycloalkylS(O) 2 NHC(O)C 1 -C 3 alkyl, C 3 -C 6 cycloalkylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkoxy, haloC 1 -C 3 alkyl, heteroarylS(O) 2 NHC(O)C 1 -C 3 alkyl, heteroarylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, hydroxy, —NR p R q , (NR p R q )C 1 -C 3 alkyl, tetrazolyl, tetrazolylC 1 -C 3 alkyl, and phenyl, wherein the phenyl is further optionally substituted by one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, and halo; provided Q′ is other than azaindolyl or indolyl; or
R 10 is —(CH 2 ) n Z′, wherein n is 1-3 and Z′ is a six, six-fused saturated or unsaturated ring system containing one, two, three or four nitrogen atoms, wherein said ring system is optionally substituted with one, two, or three groups selected from C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylC 1 -C 3 alkyl, C 1 -C 3 alkyl, (C 1 -C 6 alkyl)S(O) 2 NHC(O)C 1 -C 3 alkyl, arylS(O) 2 NHC(O)C 1 -C 3 alkyl, arylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, carboxy, carboxyC 1 -C 3 alkyl, cyano, C 3 -C 6 cycloalkylS(O) 2 NHC(O)C 1 -C 3 alkyl, C 3 -C 6 cycloalkylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkoxy, haloC 1 -C 3 alkyl, heteroarylS(O) 2 NHC(O)C 1 -C 3 alkyl, heteroarylC 1 -C 3 alkylS(O) 2 NHC(O)C 1 -C 3 alkyl, hydroxy, —NR p R q , (NR p R q )C 1 -C 3 alkyl, tetrazolyl, tetrazolylC 1 -C 3 alkyl, and phenyl, wherein the phenyl is further optionally substituted by one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, and halo;
R p and R q are independently selected from hydrogen and C 1 -C 6 alkyl;
R 13 is selected from a natural amino acid side chain, an unnatural amino acid side chain, and —(C(R 17a ) 2 ) 2 —X—R 30 ; —C(R 17a ) 2 C(O)N(R 16a )C(R 17a ) 2 —X′—R 31 ; —C(R 17a ) 2 [C(O)N(R 16a )C(R 17a ) 2 ] w′ —X—R 31 ; —(C(R 17a )(R 17 )C(O)NR 16a ) n′ —H; and —(C(R 17a )(R 17 )C(O)NR 16a ) m′ —C(R 17a )(R 17 )—CO 2 H;
w′ is 2 or 3;
n′ is 1-6;
m′ is 0-5;
X is a chain of between 1 and 172 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, three, or four groups selected from —NHC(O)NH—, and —C(O)NH— embedded therein; and wherein the chain is optionally substituted with one to six groups independently selected from —CO 2 H, —C(O)NH 2 , —CH 2 C(O)NH 2 , and —(CH 2 )CO 2 H;
X′ is a chain of between 1 and 172 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, three, or four groups selected from —NHC(O)NH—, and —C(O)NH— embedded therein; and wherein the chain is optionally substituted with one to six groups independently selected from —CO 2 H, —C(O)NH 2 , and —CH 2 CO 2 H, provided that X′ is other than unsubstituted PEG;
R 30 is selected from —CO 2 H, —C(O)NR w R x , and —CH 3 wherein R w and R x are independently selected from hydrogen and C 1 -C 6 alkyl, provided that when X is all carbon, R 30 is other than —CH 3 ;
R 31 is —CO 2 H, —C(O)NR w R x , —CH 3 , alexa-5-SDP, and biotin;
each R 17a is independently selected from hydrogen, C 1 -C 6 alkyl, —CH 2 OH, —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H,
each R 17 is independently selected from hydrogen, —CH 3 , (CH 2 ) z N 3 , —(CH 2 ) z NH 2 , —X—R 31 , —(CH 2 ) z CO 2 H, —CH 2 OH, CH 2 C≡CH, and —(CH 2 ) z -triazolyl-X—R 35 , wherein z is 1-6 and R 35 is selected from —CO 2 H, —C(O)NR w R x , CH 3 , biotin, -2-fluropyridine, —C(O)—(CH 2 ) 2 —C(O)O-vitamin E, —C(O)O-vitamin E; and

provided at least one R 17 is other than hydrogen, —CH 3 , or —CH 2 OH;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12 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 independently selected from amino, cyano, methyl, halo, and hydroxy; and wherein
each unnatural amino acid side chain is independently selected from:
C 2 -C 7 alkenyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 6 alkoxycarbonylC 1 -C 3 alkyl, C 1

Assignees

• Bristol Myers Squibb Co

Inventors

• Miller Michael Matthew
• Allen Martin Patrick
• Li Ling
• Bowsher Michael S
• Gillis Eric P
• Mull Eric
• Zhao Qian
• Sun Li-Qiang
• Langley David R
• Scola Paul Michael

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/04

  Antibacterial agents · CPC title