Immunomodulators
The present disclosure provides compounds which are immunomodulators and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.
1. A method of enhancing, stimulating, and/or increasing an immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
A is
wherein:
denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
m is 1;
w is 0;
R 14 and R 15 are hydrogen;
R 16a is hydrogen;
R 16 is —(C(R 17a ) 2 ) 2 -X-R 30 ,
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;
R 30 is selected from —CO 2 H, —C(O)NR w R x , and —CH 3 wherein R w and R x are hydrogen, provided that when X is all carbon, R 30 is other than —CH 3 ;
each R 17a is hydrogen,
each of R c , R f , R h , R i , R m , and R n is hydrogen;
R a , R e , R j , and R k , are each independently selected from hydrogen and methyl;
R 1 is methyl;
R 1 is phenylC 1 -C 3 alkyl wherein the phenyl part is optionally substituted with hydroxyl, halo, or methoxy;
R 2 is C 1 -C 7 alkyl and R b is methyl; or, R 2 and R b , together with the atoms to which they are attached, form a piperidine ring;
R 3 is NR x R y (C 1 -C 7 alkyl), NR u R v carbonylC 1 -C 3 alkyl, or carboxyC 1 -C 3 alkyl;
R 4 and R d , together with the atoms to which they are attached, form a pyrrolidine ring;
R 5 is hydroxyC 1 -C 3 alkyl, imidazolylC 1 -C 3 alkyl, or NR x R y (C 1 -C 7 alkyl);
R 6 is carboxyC 1 -C 3 alkyl, NR u R v carbonylC 1 -C 3 alkyl, NR x R y (C 1 -C 7 alkyl), or C 1 -C 7 alkyl;
R 7 and R g , together with the atoms to which they are attached, form a pyrrolidine ring optionally substituted with hydroxy;
R 8 and R 10 are benzothienyl or indolylC 1 -C 3 alkyl optionally substituted with carboxyC 1 -C 3 alkyl;
R 9 is hydroxyC 1 -C 3 alkyl, aminoC 1 -C 3 alkyl, or C 1 -C 7 alkyl;
R 11 is C 1 -C 3 alkoxyC 1 -C 3 alkyl or C 1 -C 7 alkyl;
R 12 is C 1 -C 7 alkyl or hydroxyC 1 -C 3 alkyl; and
R 13 is C 1 -C 7 alkyl, carboxyC 1 -C 3 alkyl, or —(CH 2 ) 3 NHC(NH)NH 2 .
2. The method of claim 1 , further comprising administering an additional agent prior to, after, or simultaneously with the compound of formula (I), or a therapeutically acceptable salt thereof.
3. The method of claim 2 , wherein the additional agent is an antimicrobial agent, an antiviral agent, a cytotoxic agent, and/or an immune response modifier.
4. The method of claim 1 , wherein the compound of formula (I) is selected from:
or a pharmaceutically acceptable salt thereof.
5. A method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is
wherein:
denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;
m is 1;
w is 0;
R 14 and R 15 are hydrogen;
R 16a is hydrogen;
R 16 is —(C(R 17a ) 2 ) 2 -X-R 30 ,
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;
R 30 is selected from —CO 2 H, —C(O)NR w R x , and —CH 3 wherein R w and R x are hydrogen, provided that when X is all carbon, R 30 is other than —CH 3 ;
each R 17a is hydrogen,
each of R c , R f , R h , R i , R m , and R n is hydrogen;
R a , R e , R j , and R k , are each independently selected from hydrogen and methyl;
R 1 is methyl;
R 1 is phenylC 1 -C 3 alkyl wherein the phenyl part is optionally substituted with hydroxyl, halo, or methoxy;
R 2 is C 1 -C 7 alkyl and R b is methyl; or, R 2 and R b , together with the atoms to which they are attached, form a piperidine ring;
R 3 is NR x R y (C 1 -C 7 alkyl), NR u R v carbonylC 1 -C 3 alkyl, or carboxyC 1 -C 3 alkyl;
R 4 and R d , together with the atoms to which they are attached, form a pyrrolidine ring;
R 5 is hydroxyC 1 -C 3 alkyl, imidazolylC 1 -C 3 alkyl, or NR x R y (C 1 -C 7 alkyl);
R 6 is carboxyC 1 -C 3 alkyl, NR u R v carbonylC 1 -C 3 alkyl, NR x R y (C 1 -C 7 alkyl), or C 1 -C 7 alkyl;
R 7 and R g , together with the atoms to which they are attached, form a pyrrolidine ring optionally substituted with hydroxy;
R 8 and R 10 are benzothienyl or indolylC 1 -C 3 alkyl optionally substituted with carboxyC 1 -C 3 alkyl;
R 9 is hydroxyC 1 -C 3 alkyl, aminoC 1 -C 3 alkyl, or C 1 -C 7 alkyl;
R 11 is C 1 -C 3 alkoxyC 1 -C 3 alkyl or C 1 -C 7 alkyl;
R 12 is C 1 -C 7 alkyl or hydroxyC 1 -C 3 alkyl; and
R 13 is C 1 -C 7 alkyl, carboxyC 1 -C 3 alkyl, or —(CH 2 ) 3 NHC(NH)NH 2 .
6. The method of claim 5 , wherein the compound of formula (I) is selected from:
or a pharmaceutically acceptable salt thereof.