Immunomodulators acting as antagonists of PD-1

Patent metadata

Field	Value
Publication number	US-11066445-B2
Application number	US-201816624989-A
Country	US
Kind code	B2
Filing date	Jun 21, 2018
Priority date	Jun 23, 2017
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

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

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;
m is 1 or 2;
m′ is 0 or 1;
w 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;
R 16a is selected from hydrogen and C 1 -C 6 alkyl;
R 16 is selected from
—(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;

wherein:
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 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 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 10 is indolylC 1 -C 3 alkyl, wherein the indolyl part is optionally substituted with one group selected from C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylC 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, 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, cyano, 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, —NR p R q , (NR p R q )C 1 -C 3 alkyl, and tetrazolylC 1 -C 3 alkyl, or with two 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; or
R 10 is azaindolylC 1 -C 3 alkyl wherein the azaindolyl part of the azaindolylC 1 -C 3 alkyl is substituted with one or two other groups independently 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; or
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 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 , toge

Assignees

• Bristol Myers Squibb Co

Inventors

• Gillman Kevin W
• Goodrich Jason
• Sun Li-Qiang
• Mull Eric
• Langley David R
• Scola Paul Michael

Classifications

• C07K7/56 Primary

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title