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US 11,952,434 B2Granted
Immunomodulators
AssigneeBristol-Myers Squibb Company
InventorsKevin W. Gillman, Jason Goodrich, Kenneth M. Boy, Yunhui Zhang, Claudio Mapelli, Michael A. Poss, Paul Michael Scola, David R. Langley, Nicholas A. Meanwell
Life of this patent
Estimating the term…
Abstract
The present disclosure provides compounds which are immunomodulators and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.
Claims6
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;
- R14 and R15 are hydrogen;
- R16a is hydrogen;
- R16 is —(C(R17a)2)2-X-R30,
- 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 —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H;
- R30 is selected from —CO2H, —C(O)NRwRx, and —CH3 wherein Rw and Rx are hydrogen, provided that when X is all carbon, R30 is other than —CH3;
- each R17a is hydrogen,
- each of Rc, Rf, Rh, Ri, Rm, and Rn is hydrogen;
- Ra, Re, Rj, and Rk, are each independently selected from hydrogen and methyl;
- R1 is methyl;
- R1 is phenylC1-C3alkyl wherein the phenyl part is optionally substituted with hydroxyl, halo, or methoxy;
- R2 is C1-C7alkyl and Rb is methyl;
- or, R2 and Rb, together with the atoms to which they are attached, form a piperidine ring;
- R3 is NRxRy(C1-C7alkyl), NRuRvcarbonylC1-C3alkyl, or carboxyC1-C3alkyl;
- R4 and Rd, together with the atoms to which they are attached, form a pyrrolidine ring;
- R5 is hydroxyC1-C3alkyl, imidazolylC1-C3alkyl, or NRxRy(C1-C7alkyl);
- R6 is carboxyC1-C3alkyl, NRuRvcarbonylC1-C3alkyl, NRxRy(C1-C7alkyl), or C1-C7alkyl;
- R7 and Rg, together with the atoms to which they are attached, form a pyrrolidine ring optionally substituted with hydroxy;
- R8 and R10 are benzothienyl or indolylC1-C3alkyl optionally substituted with carboxyC1-C3alkyl;
- R9 is hydroxyC1-C3alkyl, aminoC1-C3alkyl, or C1-C7alkyl;
- R11 is C1-C3alkoxyC1-C3alkyl or C1-C7alkyl;
- R12 is C1-C7alkyl or hydroxyC1-C3alkyl;
- and
- R13 is C1-C7 alkyl, carboxyC1-C3alkyl, or —(CH2)3NHC(NH)NH2.
27 more elements
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;
- R14 and R15 are hydrogen;
- R16a is hydrogen;
- R16 is —(C(R17a)2)2-X-R30,
- 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 —CO2H, —C(O)NH2, —CH2C(O)NH2, and —CH2CO2H;
- R30 is selected from —CO2H, —C(O)NRwRx, and —CH3 wherein Rw and Rx are hydrogen, provided that when X is all carbon, R30 is other than —CH3;
- each R17a is hydrogen,
- each of Rc, Rf, Rh, Ri, Rm, and Rn is hydrogen;
- Ra, Re, Rj, and Rk, are each independently selected from hydrogen and methyl;
- R1 is methyl;
- R1 is phenylC1-C3alkyl wherein the phenyl part is optionally substituted with hydroxyl, halo, or methoxy;
- R2 is C1-C7alkyl and Rb is methyl;
- or, R2 and Rb, together with the atoms to which they are attached, form a piperidine ring;
- R3 is NRxRy(C1-C7alkyl), NRuRvcarbonylC1-C3alkyl, or carboxyC1-C3alkyl;
- R4 and Rd, together with the atoms to which they are attached, form a pyrrolidine ring;
- R5 is hydroxyC1-C3alkyl, imidazolylC1-C3alkyl, or NRxRy(C1-C7alkyl);
- R6 is carboxyC1-C3alkyl, NRuRvcarbonylC1-C3alkyl, NRxRy(C1-C7alkyl), or C1-C7alkyl;
- R7 and Rg, together with the atoms to which they are attached, form a pyrrolidine ring optionally substituted with hydroxy;
- R8 and R10 are benzothienyl or indolylC1-C3alkyl optionally substituted with carboxyC1-C3alkyl;
- R9 is hydroxyC1-C3alkyl, aminoC1-C3alkyl, or C1-C7alkyl;
- R11 is C1-C3alkoxyC1-C3alkyl or C1-C7alkyl;
- R12 is C1-C7alkyl or hydroxyC1-C3alkyl;
- and
- R13 is C1-C7 alkyl, carboxyC1-C3alkyl, or —(CH2)3NHC(NH)NH2.
27 more elements
Dependencies are inferred from the claim text.