Adenosine 2A receptor modulators for use in the treatment of cancer

1 . A method for preventing resistance to anti-cancer immunotherapy and/or treating a cancer in a subject suffering from a cancer or at risk of suffering from resistance to anti-cancer immunotherapy, said method comprising administering a compound of Formula (I) or a pharmaceutical formulation thereof to a subject in need thereof, wherein Formula (I) is:

wherein R 1 is selected from a phenyl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl and five or six membered heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl; R 2 is selected from H and halogen; R 3 is selected from H, CN and optionally substituted C 1 -C 6 alkyl; R 4 is OR, where R is an optionally substituted C 1 -C 6 alkyl or a C 1 -C 6 hydroxyalkyl; SR, where R is an optionally substituted C 1 -C 6 alkyl; XR(R′); an optionally substituted phenyl; or an optionally substituted five or six membered heteroaryl, wherein X is selected from O, S, N and R and R′ are independently an optionally substituted C 1 -C 6 alkyl, or XRR′ form together an optionally substituted four to six membered heterocyclic alkyl, wherein the term “substituted” refers to groups substituted with from 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, amino (—NH 2 , —NH—, —N—), amide (—NHC(O)—), carbonyl (—C(O)—), alkoxycarbonyl (—C(O)O—), carboxylic acid, ether (—O—), thioether (—S—), sulfoxide (—S(O)—), sulfone (—S(O) 2 —), and C 1 -C 6 alkyl, wherein said cancer is a solid tumor cancer.

2 . A method for eliciting or increasing an immune response to immunotherapy, said method comprising administering an effective amount of one or more compound of Formula (I) or a pharmaceutical formulation thereof in combination with one or more of treatment selected from adoptive cell therapy, Chimeric Antigen Receptor T cell (CAR-T) therapy, tumor infiltrating lymphocyte (TIL) therapy, anti-cancer vaccine therapy or immunomodulating therapy comprising administering immune checkpoint inhibitors, bispecific T cell engagers, or nanobodies that bind to a single or multiple drug targets, wherein Formula (I) is:

wherein R 1 is selected from a phenyl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl and a five or six membered heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl; R 2 is selected from H and halogen; R 3 is selected from H, CN and optionally substituted C 1 -C 6 alkyl; R 4 is OR, where R is an optionally substituted C 1 -C 6 alkyl or a C 1 -C 6 hydroxyalkyl; SR, where R is an optionally substituted C 1 -C 6 alkyl; XR(R′); an optionally substituted phenyl; or an optionally substituted five or six membered heteroaryl, wherein X is selected from O, S, or N and R and R′ are independently an optionally substituted C 1 -C 6 alkyl, or XRR′ form together an optionally substituted four to six membered heterocyclic alkyl.

3 . The method according to claim 1 , wherein R 1 is phenyl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl.

4 . The method according to claim 1 , wherein R 1 is selected from phenyl, halogeno phenyl or a C 1 -C 6 alkyl phenyl.

5 . The method according to claim 1 , wherein R 1 is a five or six membered heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl.

6 . The method according to claim 1 , wherein R 1 is an optionally substituted five or six membered heteroaryl selected from optionally substituted pyridinyl, optionally substituted thiophenyl, optionally substituted pyrazolyl and optionally substituted tetrazolyl, wherein optionally substituted refers to an optional substitution by one or more halogen, cyano, hydroxy or C 1 -C 6 alkyl.

7 . The method according to claim 1 , wherein R 2 is H.

8 . The method according to claim 1 , wherein R 3 is CN.

9 . The method according to claim 1 , wherein R 4 is XR(R′), X is selected from O, S, or N and R and R′ are independently an optionally substituted C 1 -C 6 alkyl, or XRR′ form together an optionally substituted four to six membered heterocyclic alkyl.

10 . The method according to claim 1 , wherein R 4 is a group OR wherein R is an optionally substituted C 1 -C 6 alkyl.

11 . The method according to claim 1 , wherein R 4 is a group SR wherein R is an optionally substituted C 1 -C 6 alkyl.

12 . The method according to claim 1 , wherein R 4 is selected from pyridine, pyrrolidine and azetidine.

13 . The method according to claim 1 , wherein R 4 is optionally substituted pyridine.

14 . The method according to claim 1 , wherein said compound is selected from the group consisting of:

4-([1,1′-biphenyl]-3-yl)-2-amino-6-(azetidin-1-yl)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(2′-fluoro-[1,1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3′-fluoro-[1,1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3′-fluoro-[1,1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(2′-methyl-[1,1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3′-methyl-[1,1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(4′-methyl-[1, 1′-biphenyl]-3-yl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-6-(piperidin-1-yl)-4-(3-(pyridin-2-yl)phenyl)pyridine-3,5-dicarbonitrile;

2-amino-6-(piperidin-1-yl)-4-(3-(pyridin-3-yl)phenyl)pyridine-3,5-dicarbonitrile;

2-amino-6-(piperidin-1-yl)-4-(3-(pyridin-4-yl)phenyl)pyridine-3,5-dicarbonitrile;

2-amino-6-(piperidin-1-yl)-4-(3-(thiophen-2-yl)phenyl)pyridine-3,5-dicarbonitrile;

2-amino-6-(piperidin-1-yl)-4-(3-(thiophen-3-yl)phenyl)pyridine-3,5-dicarbonitrile;

4-(3-(1H-pyrazol-5-yl)phenyl)-2-amino-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

4-(3-(1H-tetrazol-5-yl)phenyl)-2-amino-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(diethylamino)pyridine-3, 5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-morpholinopyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(bis(2-hydroxyethyl)amino) pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(4-methylpiperazin-1-yl)pyridine-3,5-dicarbonitrile;

4-([1,1′-biphenyl]-3-yl)-2-amino-6-((2-hydroxyethyl)amino) pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(diisopropylamino)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(benzylamino)pyridine-3,5-dicarbonitrile;

4-([1,1′-biphenyl]-3-yl)-2-amino-6-(benzylthio)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-methoxypyridine-3,5-dicarbonitrile;

4-([1,1′-biphenyl]-3-yl)-2-amino-6-ethoxypyridine-3,5-dicarbonitrile;

4-([1,1′-biphenyl]-3-yl)-2-amino-6-(2-hydroxyethoxy)pyridine-3,5-dicarbonitrile;

4-([1, 1′-biphenyl]-3-yl)-2-amino-6-(benzyloxy)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-(3-fluoropyridin-2-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-(6-fluoropyridin-2-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-(4-fluoropyridin-2-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-(5-fluoropyridin-3-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-(2-fluoropyridin-3-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(2-fluoro-5-(pyridin-3-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(2-fluoro-3-(pyridin-3-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile;

2-amino-4-(3-fluoro-5-(pyridin-3-yl)phenyl)-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile; and

4-(3-(1,3,4-oxadiazol-2-yl)phenyl)-2-amino-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile.

15 . The method according to claim 1 , wherein said compound is administered in combination with one or more of treatment selected from adoptive cell therapy, CAR-T therapy, TIL therapy, anti-cancer vaccine therapy, tumor specific antibodies, immunomodulating therapy, an anti-cancer immunotherapeutic agent, and immune checkpoint inhibitors.

16 . The method according to claim 1 , wherein said cancer is selected from lung cancer, breast cancer, ovarian cancer, cervical cancer, uterus cancer, head and neck cancer, melanoma, cancers of the digestive system, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal carcinoma, kidney cancer, prostate cancer, gastric cancer, bronchus cancer, pancreatic cancer, urinary bladder cancer, hepatic cancer and brain cancer.