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-11066405-B2
Publication Date
2021-07-20
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 disclosure relates to selective EP4 receptor antagonists defined by a bicyclic/heteroaryl carboxamide scaffold, including compounds of Formula I, Formula Ib, and subclasses Ia–Id, with extensive structural variable definitions. The permitted chemical structures include pharmaceutically acceptable salts, solvates, solvate of the salt, hydrates, a single stereoisomer, a mixture of stereoisomers, and a racemic mixture of stereoisomers.
The invention specifies enumerated definitions for structural elements including Ar, W, X1–X5, Y, Z, and substituent variables R1–R8, thereby defining the allowed compounds. Named structural motifs include bicyclo[1.1.1]pentane, spiro[3.3]heptane, indole, pyridine, and indazole derivatives, together with indole-7-carboxamides bearing a bicyclo[1.1.1]pentane scaffold and benzylic substituents.
The disclosure frames the approach as antagonism of the EP4 receptor signaling pathway for anticancer treatment, including blocking PGE2-mediated EP4 signaling and discussing tumor-associated immune components such as myeloid-derived suppressor cells, type-2 tumor-associated macrophages, IDO/TDO, and tumor volume in a murine colon cancer model.
Claims Coverage
The consolidated claim coverage centers on broad independent claims for compounds of Formula Ib, with enumerated structural limits on Ar, W, X1–X5, R4, R5, Ra, Rb, and n, plus pharmaceutically acceptable and stereochemical forms. The main inventive features are the constrained Formula Ib structure, functional-group selection for W, and the substitution-pattern constraint on X1–X5.
Formula Ib selective scaffold with defined variable constraints
A compound of Formula Ib, including pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate forms, and stereochemical variants, wherein Ar is an aryl or heteroaryl optionally substituted with 1 to 3 substituents; W is selected from enumerated functional-group types; X1–X5 are each independently N or CRa with not more than 2 of X1–X5 being N; R4 and R5 have enumerated alkyl/halogen and haloalkyl/halogen classes; Ra and Rb are independently selected from enumerated substituent classes; and n is 1, 2 or 3.
Functional-group refinement of W in Formula Ib variants
Within Formula Ib, 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.
Substitution-pattern constraint on X1–X5
In Formula Ib, X1, X2, X3, X4, and X5 are each independently N or CRa, with no more than 2 of X1–X5 being N.
Pharmaceutical composition comprising the Formula Ib compound
A pharmaceutical composition containing the Formula Ib compound together with a pharmaceutically acceptable carrier.
The claim coverage is anchored on the Formula Ib compound class with defined allowable substituent identities, functional-group choices for W, and a constraint on the number of N atoms within X1–X5, together with specified pharmaceutically acceptable and stereochemical forms. Dependent claims further refine W selection, and include a pharmaceutical composition.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer.
Cancer treatment using the compounds in combination with anti–PD-1/PD-L1 antibodies.
Functional calcium-flux assay evaluation on EP receptor subtypes, including EP4 Ca2+ flux IC50 data.
In vivo CT26 colon tumor mouse treatment example [procedural detail omitted for safety].
Prevention and treatment of multiple cancers by blocking PGE2-mediated EP4 signaling.
Prevention and treatment of glioblastoma.
Prevention and treatment of prostate cancer.
Combination therapy with anti–PD-1 antibody or anti–PD-L1 antibody, or other anticancer agents.
Tumor volume effect in a murine colon cancer model.
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