Bicyclic compounds and their use in the treatment of cancer
The present disclosure is directed to novel compounds of Formula I and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g. controlling, alleviating, or slowing the progression of) of cancer, including glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. The compounds of the disclosure are selective antagonists of the EP4 receptor and useful treatment of various diseases that may be ameliorated with blockade of PGE2-mediated signaling.
1. A method for the treatment of cancer comprising administering to a patient in need thereof a compound of Formula Ib:
or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein:
Ar is an aryl or a heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocycle, aryl, heteroaryl, halogen, CN, OR b , SF 5 , and C 1 -C 6 haloalkyl;
W is selected from C(═O)OR 5 , C(═O)NHOH, S(═O) 2 NHR b , S(═O) 2 NHC(═O)R b , NHC(═O)NHSO 2 R b , 1H-tetrazole, and C(═O)NHS(═O) 2 R b ;
X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CR a , wherein not more than 2 of X 1 , X 2 , X 3 , X 4 , and X 5 are N;
R 4 is selected from H, C 1 -C 6 alkyl, halogen and C 1 -C 6 haloalkyl;
R 5 is selected from H and C 1 -C 6 alkyl;
each R a is independently selected from H, C 1 -C 6 alkyl, halogen, OR b , CN, C 3 -C 6 cycloalkyl, and C 1 -C 6 haloalkyl;
R b is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 haloalkyl; and
n is 1, 2, or 3.
2. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein Ar is aryl optionally substituted with 1 to 3 substituents independently selected from halogen, CN, C 1 -C 6 alkyl, SF 5 , C 1 -C 6 haloalkyl, heterocycle, aryl, heteroaryl, and OR b ; wherein R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl.
3. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein one of X 1 , X 2 , X 3 , X 4 , and X 5 is N, and the others are each independently C—R a .
4. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein W is selected from C(═O)OR 5 , S(═O) 2 NHR b , S(═O) 2 NHC(═O)R b , NHC(═O)NHSO 2 R b , and 1H-tetrazole.
5. The method of claim 4 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein W is CO 2 H.
6. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein n is 1.
7. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein R 4 is selected from H, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
8. The method of claim 7 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein R 4 is H.
9. The method of claim 1 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein each R a is independently selected from H, C 1 -C 6 alkyl, halogen, OR b , CN, and C 1 -C 6 haloalkyl.
10. The method of claim 9 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein each R a is independently selected from H, halogen, OR b , and CN.
11. The method of claim 1 , wherein the compound has the Formula Id:
or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein
each X 1 , X 2 , X 3 , X 4 , and X 5 is independently C—R a , or one of X 1 , X 2 , X 3 , X 4 , and X 5 is N, and the others are each independently C—R a ;
each R a is independently selected from H and halogen;
R d is selected from CN, C 1 -C 3 alkyl, SF 5 , C 1 -C 3 haloalkyl, heterocycle, aryl, heteroaryl, and OR b wherein R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl.
12. The method of claim 11 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein one of X 1 , X 2 , X 3 , X 4 , and X 5 is C—R a ; the others are CH; and R a is halogen.
13. The method of claim 11 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein R d is selected from heterocycle, aryl, and heteroaryl.
14. The method of claim 13 , or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers thereof, wherein R d is aryl.
15. The method of claim 1 , wherein the compound of Formula Ib is selected from:
or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof.
16. The method of claim 1 , wherein said cancer is selected from glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.
17. The method of claim 1 , wherein said cancer is selected from colon cancer, bladder cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer.
18. The method of claim 1 , the method further comprises administering an additional agent selected from an anti-PD-1 antibody and an anti-PD-L1 antibody.