Cd73 inhibitor and a2a/a2b adenosine receptor inhibitor combination therapy

A method for treating a cancer in a human subject in need thereof, comprising administering to the human subject an effective amount of an inhibitor of human CD73 and an inhibitor of A2A adenosine receptor and/or A2B adenosine receptor, wherein:

• (1) the inhibitor of human CD73 comprises:
• (a) an antibody that binds to human CD73 at an epitope within amino acids 40-52 of SEQ ID NO:
• 70;
• (b) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody that has a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:25;
• or
• (c) an antibody that binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO:70;
• (d) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody that has a heavy chain comprising the amino acid sequence of SEQ ID NO:30 and a light chain comprising the amino acid sequence of SEQ ID NO:31;
• (e) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody that has a heavy chain comprising the amino acid sequence of SEQ ID NO:33 and a light chain comprising the amino acid sequence of SEQ ID NO:31;
• (f) an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179;
• or
• (g) an inhibitor selected from the group consisting of CB-708 and AB680;
• and
• (2) the inhibitor of A2A adenosine receptor and/or A2B adenosine receptor (A2A/A2B) comprises a compound of:
• (a) Formula (I):
• or a pharmaceutically acceptable salt thereof, wherein
• Cy1 is phenyl which is substituted by 1 or 2 substituents independently selected from halo and CN;
• Cy2 is 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl of Cy2 are each optionally substituted with 1, 2, or 3 groups each independently selected from C1-3 alkyl, C1-3 alkoxy, NH2, NH(C1-3 alkyl) and N(C1-3 alkyl)2;
• R2 is selected from phenyl-C1-3 alkyl-, C3-7 cycloalkyl-C1-3 alkyl-, (5-7 membered heteroaryl)-C1-3 alkyl-, (4-7 membered heterocycloalkyl)-C1-3 alkyl-, and ORa2, wherein the phenyl-C1-3 alkyl-, C3-7 cycloalkyl-C1-3 alkyl-, (5-7 membered heteroaryl)-C1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C1-3 alkyl- of R2 are each optionally substituted with 1, 2, or 3 independently selected RC substituents;
• Ra2 is (5-7 membered heteroaryl)-C1-3 alkyl- optionally substituted with 1 or 2 independently selected RC substituents;
• each RC is independently selected from halo, C1-6 alkyl, C6 aryl, 5-7 membered heteroaryl, (4-7 membered heterocycloalkyl)-C1-3 alkyl-, ORa4, and NRc4Rd4;
• and
• each Ra4, Rc4, and Rd4 are independently selected from H and C1-6 alkyl;
• (b) Formula (II):
• or a pharmaceutically acceptable salt thereof, wherein
• R2 is selected from H and CN;
• Cy1 is phenyl which is substituted by 1 or 2 substituents independently selected from halo and CN;
• L is C1-3 alkylene, wherein said alkylene is optionally substituted with 1, 2, or 3 independently selected R8D substituents;
• Cy4 is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, wherein the phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8D and R8;
• each R8 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, (5-6 membered heteroaryl)-C1-3 alkyl, and (4-7 membered heterocycloalkyl)-C1-3 alkyl, wherein the C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl, (5-6 membered heteroaryl)-C1-3 alkyl, and (4-7 membered heterocycloalkyl)-C1-3 alkyl of R8 are each optionally substituted with 1, 2, or 3 independently selected R8A substituents;
• each R8A is independently selected from halo, C1-6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, ORa81, and NRc81Rd81, wherein the C1-3 alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R8A are each optionally substituted with 1, 2, or 3 independently selected R8B substituents;
• each Ra81, Rc81, and Rd81 is independently selected from H, C1-6 alkyl, and 4-7 membered heterocycloalkyl, wherein the C1-6 alkyl and 4-7 membered heterocycloalkyl of Ra81, Rc81, and Rd81 are each optionally substituted with 1, 2, or 3 independently selected R8B substituents;
• each R8B is independently selected from halo and C1-3 alkyl;
• and
• each R8D is independently selected from OH, CN, halo, C1-6 alkyl, and C1-6 haloalkyl;
• (c) Formula (III):
• or a pharmaceutically acceptable salt thereof, wherein
• Cy1 is phenyl which is substituted by 1 or 2 substituents independently selected from halo and CN;
• R2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R2 are each optionally substituted with 1, 2, or 3 independently selected R2A substituents;
• each R2A is independently selected from D, halo, C1-6 alkyl, and C1-6 haloalkyl;
• R4 is selected from phenyl-C1-3 alkyl-, C3-7 cycloalkyl-C1-3 alkyl-, (5-6 membered heteroaryl)-C1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C13 alkyl wherein the phenyl-C1-3 alkyl-, C3-7 cycloalkyl-C1-3 alkyl-, (5-6 membered heteroaryl)-C1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C1-3 alkyl- of R4 are each optionally substituted with 1, 2, or 3 independently selected R4A substituents;
• each R4A is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa41, and NRc41Rd41;
• and
• each Ra41, Rc41, and Rd41 is independently selected from H and C1-6 alkyl;
• or
• (d) Formula (IV):
• or a pharmaceutically acceptable salt thereof, wherein
• Cy1 is phenyl which is substituted by 1 or 2 substituents independently selected from halo and CN;
• Cy2 is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy2 are each optionally substituted with 1, 2, or 3 independently selected R6 substituents;
• each R6 is independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl;
• R2 is phenyl-C1-3 alkyl- or (5-6 membered heteroaryl)-C1-3 alkyl-, wherein the phenyl-C1-3 alkyl- and (5-6 membered heteroaryl)-C1-3 alkyl- of R2 are each optionally substituted with 1, 2, or 3 independently selected R2A substituents;
• and
• each R2A is independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl,
• or a pharmaceutically acceptable salt thereof.