Substituted pyrimidine compounds, compositions and medicinal applications thereof
Inventors
Venkateshappa, Chandregowda • Sivanandhan, Dhanalakshmi • Bakthavatchalam, Rajagopal • Kethiri, Raghava Reddy • Viswanadhan, Vellarkad Narayana • GIRI, SANJEEV
Assignees
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Publication Number
US-10273224-B2
Publication Date
2019-04-30
Expiration Date
Abstract
The present disclosure relates to pyrimidine compounds of formula (I), their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to process of preparation of these pyrimidine compounds, and to pharmaceutical compositions containing them. The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders mediated by epidermal growth factor receptor (EGFR) family kinases.
Core Innovation
The invention relates to compounds represented by Formula I, including stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The compounds are defined by selected ring-A and ring-B structural options, together with variable substituent selections such as W, X, Y, Z, R1, R2, R7, R8, R9, R10, R11, Ra and Ra', as well as integers q, n, and p. Ring A is selected from aryl, heteroaryl, cycloalkyl, cycloaryl, and heterocycloaryl, and ring B is selected from specified 5-membered mono- and bicyclic N/O/S-containing heterocycles with optional substitution.
The structural definition further specifies linkage elements and heteroatom-containing groups through W, X, Y, and Z, with X selected from C(O), S(O)2, or S(O), Y selected from O, NR, or S, and Z absent or O. Ring-B substitution is optionally present by 1 to 4 substituents selected independently from hydrogen, halogen, cyano, CF3, C1-6 alkyl, substituted amino substituents, and other listed groups, and in some embodiments R7 and R8 are taken together to form a cycloalkyl or heterocycloalkyl ring. The claim set also specifies that a particular compound is excluded.
The document frames the intended medicinal use as inhibition of EGFR T790M, including covalent irreversible inhibition and covalent reversible inhibition, and as treatment of diseases or conditions associated with epidermal growth factor receptor (EGFR) family kinases. The compounds are described as being used to treat cancers and related conditions, including non-small cell lung cancer, small cell lung cancer, prostate cancer, head and neck cancer, and breast cancer. The disclosure also includes pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier.
Claims Coverage
The consolidated claim coverage centers on Formula I compounds with defined ring selections and substituent parameter constraints, together with dependent claims that add therapeutic use and formulation coverage. The inventive features comprise one broad Formula I scaffold claim, parameterized structural refinements, explicit EGFR-family-kinase-associated treatment claims, specified cancer indications, and pharmaceutical composition coverage.
Substituted pyrimidine compound of Formula I
A compound represented by Formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof, with ring A selected from aryl, heteroaryl, cycloalkyl, cycloaryl, or heterocycloaryl and ring B selected from specified 5-membered mono- and bicyclic N/O/S-containing heterocycles with optional substitution.
Parameterized substituent and linkage constraints within Formula I
The Formula I structure is further constrained by selectable substituent parameters including W, X, Y, Z, R1, R2, R7, R8, R9, R10, R11, Ra and Ra', and integer constraints q, n, and p, with X selected from C(O), S(O)2, or S(O), Y selected from O, NR, or S, Z absent or O, and in some embodiments R7 and R8 taken together to form a cycloalkyl or heterocycloalkyl ring, while excluding a specified compound.
EGFR T790M-associated disease treatment
A compound of Formula I is provided for treating a disease associated with epidermal growth factor receptor (EGFR) family kinases, including EGFR T790M-associated disease and covalent irreversible or covalent reversible inhibition.
Treatment of specified cancer indications associated with EGFR-family kinase activity
A compound defined by Formula I is provided for treating diseases or conditions associated with non-small cell lung cancer, small cell lung cancer, prostate cancer, head and neck cancer, or breast cancer.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, formulated with a pharmaceutically acceptable carrier, optionally with one or more other pharmaceutical compositions.
Across the consolidated claim coverage, the inventive core is a Formula I substituted scaffold with defined ring selections and parameterized substituent constraints, further tied to therapeutic use for EGFR-family-kinase-associated disease and specified cancer indications, and optionally provided as a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease associated with epidermal growth factor receptor (EGFR) family kinases, including EGFR T790M-associated disease.
Treating diseases or conditions associated with non-small cell lung cancer, small cell lung cancer, prostate cancer, head and neck cancer, or breast cancer.
A pharmaceutical composition containing the compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, optionally together with one or more other pharmaceutical compositions.
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