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Publication Number
US-10501460-B2
Publication Date
2019-12-10
Expiration Date
Abstract
Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.
Core Innovation
A method is disclosed for treating a subject suffering from a disease or condition mediated by a bromodomain by administering to the subject in need thereof an effective amount of a compound of formula (III). The compound is provided as a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof, and the disclosed structural framework includes variable groups and substitution rules.
The disease or condition mediated by a bromodomain includes breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma. The compound of formula (III) is defined by variable substituents including Y1 as N, R1 as H or selected from deuterated and substituted alkyl, aryl, aryl-alkyl, heteroaryl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl groups, and R3 with optional substitution by 1 to 3 Rj groups.
The structure further includes R2 as H and a linkage group L selected from C(R6)(R7), C(O), S(O), S, P(O)(Ra), CH=C(Rb), CH(Rb), or Si(Rc)(Rc), with constraints on R6 and R7. The document also describes bromodomain-targeting small-molecule compounds on related heteroaromatic scaffolds, including isoxazole, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-b]pyridine, and pyrazoles.
Claims Coverage
The provided claim coverage centers on independent method claims for treating bromodomain-mediated disease by administering an effective amount of a compound of formula (III), with dependent claims narrowing the allowed structural variables, linkage group L, disease subset, and in some items adding a chemotherapeutic agent. Across the inputs, the recurring inventive features are the therapeutic administration method, the defined formula (III) scaffold, and the specified disease scope.
Bromodomain-mediated disease treatment by administering formula (III) compounds
A method for treating a subject suffering from a disease or condition mediated by a bromodomain by administering to the subject in need thereof an effective amount of a compound of formula (III), including pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof, for breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma.
Defined bromodomain-compound scaffold with substituent variables
The compound of formula (III) is defined by extensive variable substituent rules, including Y1 as N, R1 and R3 selected from deuterated and non-deuterated alkyl, aryl, aryl-alkyl, heteroaryl, heteroalkyl, heterocycloalkyl, alkenyl, or alkynyl groups, and optional substitution of R3 by 1 to 3 Rj groups from an enumerated functional group set.
Linkage group L selection and constraints
The compound of formula (III) defines L as one of the specified linkage groups including C(R6)(R7), C(O), S(O), S, P(O)(Ra), CH=C(Rb), CH(Rb), or Si(Rc)(Rc), with R6 as H or D and R7 selected from an enumerated set including halogen, OH, C1-6 alkyl, aryl, C3-6 cycloalkyl, heterocycloalkyl, heteroaryl, C1-6 haloalkyl, ORd, C(O)NRdRd, and SO2Rd, optionally substituted by Rh groups.
Combination therapy with a chemotherapeutic agent
The method is further refined by administering a chemotherapeutic agent in addition to the bromodomain-mediated disease treatment.
The claims collectively cover bromodomain-mediated disease treatment by administering an effective amount of a structurally defined formula (III) compound, with dependent claim coverage tightening substituent definitions and the linkage group L, narrowing disease subsets, and in some instances adding a chemotherapeutic agent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a subject suffering from a disease or condition mediated by a bromodomain, including breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, and uveal melanoma.
Example preparation and compound examples for bromodomain-relevant isoxazole and pyrrolo[2,3-b]pyridine or pyrrolo[3,2-b]pyridine compounds.
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