Bicyclic compounds and their use in the treatment of cancer
Inventors
Bravo, Yalda • BURCH, Jason David • Chen, Austin Chih-Yu • NAGAMIZO, Joe Fred
Assignees
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Publication Number
US-11638704-B2
Publication Date
2023-05-02
Expiration Date
Abstract
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.
Core Innovation
The invention relates to bicyclic/heteroaryl carboxamide therapeutics that are selective EP4 (prostaglandin E2 receptor) antagonists. EP4/PGE2 signaling is described as promoting an immunosuppressive tumor microenvironment via myeloid-derived suppressor cells (MDSCs), type-2 tumor-associated macrophages (TAMs), immature monocytes, and related immunologic effects including IDO/TDO pathways and kynurenine production, as well as effects on Treg cells and cytotoxic Teff cells.
Blocking EP4 is presented as supporting cancer treatment by counteracting the described EP4/PGE2-driven immunosuppressive mechanisms, including induction of IDO/TDO pathways. The disclosure also describes EP4 blockade as being used alone or in combination with other anticancer agents, including anti-CTLA4 and anti-PD-1 or anti-PD-L1 agents and cytotoxic agents.
The invention further relates to a method for the treatment of cancer by administering to a patient in need thereof a compound of Formula Ib. The compound is provided as a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers, with chemical scope defined by Ar, W, X1-X5, R4, Ra, Rb, and n.
Claims Coverage
The claim set includes one independent claim directed to cancer treatment by administering a Formula Ib compound with constrained substituent definitions. Dependent claims further refine the chemical scope, narrow the cancer types, and add an immunotherapy component.
Cancer treatment by administering formula Ib compound
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.
Variable aryl or heteroaryl with limited substitution options
Ar is an aryl or a heteroaryl, optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, heterocycle, aryl, heteroaryl, halogen, CN, ORb, SF5, and C1-C6 haloalkyl.
W defines a selected functional group set
W is selected from C(═O)OR5, C(═O)NHOH, S(═O)2NHRb, S(═O)2NHC(═O)Rb, NHC(═O)NHSO2Rb, 1H-tetrazole, and C(═O)NHS(═O)2Rb.
X1-X5 nitrogen/carbon pattern constraint
X1, X2, X3, X4, and X5 are each independently N or CRa, wherein not more than 2 of X1, X2, X3, X4, and X5 are N.
R4, Ra, and Rb substituent scope
R4 is selected from H, C1-C6 alkyl, halogen and C1-C6 haloalkyl; R5 is selected from H and C1-C6 alkyl; each Ra is independently selected from H, C1-C6 alkyl, halogen, ORb, CN, C3-C6 cycloalkyl, and C1-C6 haloalkyl; and Rb is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl.
Ring index n selection
n is 1, 2, or 3.
Treatment of enumerated cancer types
The method is for treating cancer selected from a listed set of cancer types 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.
Combination with anti-PD-1 or anti-PD-L1 antibody
The method further includes administering an additional agent selected from an anti-PD-1 antibody or an anti-PD-L1 antibody.
The central inventive concept is administering a Formula Ib compound with tightly defined structural substituent constraints, optionally narrowed to specific cancer types and optionally combined with an anti-PD-1 or anti-PD-L1 antibody.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vitro calcium-flux assay using HEK293 EP1-EP4 stably transfected cells, with a PGE2 calcium-flux context and an IC50 activity table.
In vivo CT26 colon tumor mouse xenograft model (Balb/c mice) with example activity data.
Cancer treatment pharmaceutical compositions comprising a carrier and one or more compounds, optionally in combination with anti-PD-1 or anti-PD-L1 antibodies.
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