Immunomodulators

Patent metadata

Field	Value
Publication number	US-2016137696-A1
Application number	US-201514938327-A
Country	US
Kind code	A1
Filing date	Nov 11, 2015
Priority date	Nov 14, 2014
Publication date	May 19, 2016
Grant date	—

Abstract

The present disclosure provides compounds which are immunomodulators 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-fluoropyridine, —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 e , 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 independently selected from amino, cyano, methyl, halo, and hydroxy.

2 . A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is

3 . A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
m and w are 1; and R 14 , R 15 , and R 16a are each hydrogen.

4 . A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 16 is —(C(R 17a ) 2 ) 2 —X—R 30 .

5 . A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
each R 17a is hydrogen; X is a chain of between 8 and 46 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three C(O)NH groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO 2 H, —C(O)NH 2 , —CH 2 C(O)NH 2 , and —CH 2 CO 2 H; and R 30 is selected from —CH 3 , —CO 2 H, and —C(O)NH 2 ; provided that when X is all carbon, R 30 is other than —CH 3 .

6 . A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 16 is —C(R 17a ) 2 C(O)N(R 16a )C(R 17a ) 2 —X′—R 31 .

7 . A compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein
each R 17a is selected from hydrogen, —CO 2 H, and —CH 2 CO 2 H; X′ is a chain of between 8 and 48 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three C(O)NH groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO 2 H, —C(O)NH 2 , —CH 2 C(O)NH 2 , and —CH 2 CO 2 H; provided that X′ is other than unsubstituted PEG; and R 30 is selected from —CH 3 , —CO 2 H, and —C(O)NH 2 .

8 . A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 16 is —C(R 17a ) 2 [C(O)N(R 16a )C(R 17a ) 2 ] w′ —X—R 31 .

9 . A compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein
each R 17a is selected from hydrogen, —CO 2 H, and —CH 2 CO 2 H; X is a chain of between 8 and 48 atoms wherein the atoms are selected from carbon and oxygen and wherein the chain may contain one, two, or three C(O)NH groups embedded therein; and wherein the chain is optionally substituted with one or two groups independently selected from —CO 2 H, —C(O)NH 2 , —CH 2 C(O)NH 2 , and —CH 2 CO 2 H; and R 31 is selected from —CH 3 , —CO 2 H, and —C(O)NH 2 .

10 . A compound of claim 3 , or a pharmaceutically accep

Assignees

• Bristol Myers Squibb Co

Inventors

• Gillman Kevin W
• Goodrich Jason
• Boy Kenneth M
• Zhang Yunhui
• Mapelli Claudio
• Poss Michael A
• Sun Li-Qiang
• Zhao Qian
• Mull Eric
• Gillis Eric P
• Scola Paul Michael

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title