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Publication Number
US-12071428-B2
Publication Date
2024-08-27
Expiration Date
Abstract
Disclosed herein are compounds and methods of treating diseases and/or conditions associated with FGFR inhibition.
Core Innovation
The disclosed subject matter relates to substituted compounds of formula (I) and related variants, including pharmaceutically acceptable salts thereof. The compounds include indazole-based small-molecule compounds with constrained structural options such as spirocycloalkyl, spiroheterocycloalkyl, bridged bicyclic rings, cycloalkyl rings, and heteroaryl-linked scaffolds with variable substituents and stereochemical forms.
The disclosure presents multiple specific example compounds and analytical characterization data, including LCMS m/z and 1H NMR, for numbered example series spanning indazole/heteroaryl ether scaffolds and related substituted compounds. The examples include pyridyl, pyridazinyl, nicotinonitrile, methoxy, fluoro, chloro, methylsulfonyl, sulfonamide-containing, and nitrile-containing variants, as well as stereodefined forms such as (1R), (1S), (2R), and (2S) compounds.
The subject matter further connects the defined compounds to pharmaceutical and therapeutic use aspects, including pharmaceutical compositions with a pharmaceutically acceptable excipient and treatment of developmental disorders including achondroplasia and related conditions. The disclosure also references cancer treatment, including FGFR-mutant cancer, and frames the compounds as FGFR kinase inhibitor candidates.
Claims Coverage
The consolidated claim coverage centers on a compound, or a pharmaceutically acceptable salt thereof, defined by the described indazole-based chemical structure scope. Across the input items, the recurring inventive themes are the defined compound/salt forms, a pharmaceutical composition including a pharmaceutically acceptable excipient, and therapeutic methods for developmental disorders and cancer, with some items also identifying FGFR-mutant cancer as a narrower indication.
Indazole compound defined by formula scope
A compound, or a pharmaceutically acceptable salt thereof, defined by the chemical formula scope including formulas (I), (IA), (IB), IA-5/IA-6/IA-7, and IB-1/IB-2, with variable substituent definitions and representative structure images.
Pharmaceutically acceptable salt of a defined compound
The compound is specified as a pharmaceutically acceptable salt tied to particular chemical structures shown in embedded images.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition including the compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Treatment of developmental disorders including achondroplasia
A method for treating developmental disorders, including achondroplasia and related conditions, by administering the compound or a pharmaceutically acceptable salt thereof to a subject in need.
Treatment of cancer by administering the compound
A method for treating cancer in a subject by administering the compound or a pharmaceutically acceptable salt thereof, with cancer restricted to a specified list of cancer types.
Treatment of FGFR-mutant cancer
The cancer-treatment method is further applied to an FGFR-mutant cancer.
The claim coverage is directed to a defined indazole-based compound scaffold and its pharmaceutically acceptable salts, with dependent coverage for a pharmaceutical composition and therapeutic methods. The methods include treatment of developmental disorders such as achondroplasia and treatment of a specified list of cancers, with some claim coverage further narrowed to FGFR-mutant cancer.
Stated Advantages
Selectivity.
Improved efficacy/PK/property profiles.
CNS penetrance.
Documented Applications
Treatment of developmental disorders, including achondroplasia and related conditions.
Treatment of cancer, including urothelial carcinoma, breast carcinoma, endometrial adenocarcinoma, ovarian carcinoma, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung carcinoma, pancreatic exocrine carcinoma, oral cancer, prostate cancer, bladder cancer, colorectal carcinoma, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasms, head and neck (squamous) carcinoma, melanoma, leiomyosarcoma, and sarcomas.
Treatment of FGFR-mutant cancer.
Diagnosis/identification of FGFR-associated disease using assay-based testing concepts, including kit-based testing, liquid biopsy, break apart FISH, circulating tumor DNA, next generation sequencing, and immunohistochemistry.
Analytical characterization of example compounds using LCMS and 1H NMR.
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