Immunomodulators

Patent metadata

Field	Value
Publication number	US-10143746-B2
Application number	US-201715446298-A
Country	US
Kind code	B2
Filing date	Mar 1, 2017
Priority date	Mar 4, 2016
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The present disclosure provides novel macrocyclic compounds 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;
R a and R j are each independently selected from hydrogen and methyl;
R c , R f , R h , R i , R m , and R n are hydrogen;
R 1 , R 8 , and R 10 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain;
R 3 and R 6 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain, or, R 3 and R 6 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
R 9 and R 13 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain, or, R 9 and R 13 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
R 7 is selected from a natural amino acid side chain and an unnatural amino acid side chain; or R 7 and R 16 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group; or R 7 and R g can form a ring as described below;

provided that at least one of R 3 and R 6 ; R 9 and R 13 , and R 7 and R 16 form a bridge;
R 5 is a natural amino acid side chain or an unnatural amino acid side chain, or, R 3 and R 5 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group; or R 5 and R e can form a ring as described below;
R 2 , R 4 , 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 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 e is hydrogen or methyl, or, R e and R 5 , 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 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;
R k is hydrogen or 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 to four 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. 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
z is 0;
w is 1;
R 14 and R 15 are hydrogen; and
R z is —C(O)NHR 16 .

4. A compound of claim 3 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;
R 3 is —CH 2 C(O)NH 2 or R 3 and R 6 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group, or R 3 and R 5 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group,
R 4 and R d , together with the atoms to which they are attached, form a pyrrolidine ring;
R 5 is selected from C 1 -C 7 alkyl and —CH 2 (imidazolyl) optionally substituted with CF 3 C(O)—, or R 3 and R 5 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
R 6 is selected from C 1 -C 7 alkyl and —(CH 2 ) 2 C(O)NH 2 , or R 3 and R 6 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
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 or R 7 and R 16 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
R 8 is —(CH 2 )indolyl;
R 9 is selected from hydroxymethyl and —CH 2 CH 2 CO 2 H or R 9 and R 13 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group;
R 10 is selected from —(CH 2 )indolyl and —(CH 2 )benzothienyl, each optionally substituted with —CH 2 CO 2 H;
R 11 is C 1 -C 7 alkyl;
R 12 is C 1 -C 7 alkyl; and
R 13 is selected from C 1 -C 7 alkyl and —(CH 2 ) 3 NHC(NH)NH 2 or R 9 and R 13 together form a bridge containing between 2 and 7 carbon atoms, optionally one double bond, and optionally one —C(O)NH— or —NHC(O)— group.

5. A compound selected from:
Example 1400; Example 1401; Example 1402; Example 1403; Example 1404; Example 1405; Example 1500; Example 1501; Example 1502; Example 1503; Example 1504; Example 1505; Example 1506; Example 1507; Example 1508; Example 5001; Example 5002; Example 5003; Example 5004; Example 5005; Example 5006; Example 5007; Example 5008; Example 7155; Example 7156; Example 105

Assignees

• Bristol Myers Squibb Co

Inventors

• Allen Martin Patrick
• Gillis Eric P
• Langley David R
• Miller Michael Matthew
• Mull Eric
• Sun Li-Qiang
• Yeung Kap-Sun
• Grant-Young Katharine A
• Meanwell Nicholas A
• Scola Paul Michael

Classifications

• C07K7/56

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

• C07K7/08 Primary

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• A61K2039/55516

  Proteins; Peptides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P43/00

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