Heterocyclic compounds and uses thereof
Inventors
Zhang, Jiazhong • BUELL, JOHN • Chan, Katrina • Ibrahim, Prabha N. • Lin, Jack • Pham, Phuongly • Shi, Songyuan • Spevak, Wayne • Wu, Guoxian • Wu, Jeffrey
Assignees
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Publication Number
US-10519177-B2
Publication Date
2019-12-31
Expiration Date
Abstract
Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.
Core Innovation
The invention relates to 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 (Va), including a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. The treated disease or condition is selected from breast cancer, midline carcinomas, acute myeloid leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma.
The compound of formula (Va) is defined by extensive structural constraints on substituents R1, R2, R3, R4, R5, R6, R7, Rj, Rk, and R11, with the wavy line indicating the point of attachment to the rest of molecule. In the disclosed framework, R2, R4, and R6 are H, R7 is H, —OH, C1-6 alkyl, deuterated C1-6 alkyl, aryl, cycloalkyl, or heterocycloalkyl, and R1 is heteroaryl optionally substituted with from 1-3 Rj groups, with ring-forming options also defined for selected substituent groups.
The structural scope further defines R3 and R5, including deuterated and non-deuterated alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl options for R3 and optional substitution of R5 with from 1 to 2 R11 groups selected from D, halogen, C1-6 alkyl, deuterated C1-6 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, and —CN. The document also discloses multiple example compounds within pyrrolo[3,2-b]pyridine / isoxazole and related heteroaromatic scaffolds, with substituted sulfonyl, aryl, heteroaryl, deuterated, fluorinated, and sulfur-containing variants.
Claims Coverage
The consolidated independent claim coverage includes five independent method claims. Across these claims, the core inventive coverage is bromodomain-mediated treatment by administering an effective amount of a compound of formula (Va), with claim variants distinguished mainly by the permitted definitions of R1, R3, R5, R7, and associated substituent or ring-forming options.
Bromodomain-mediated treatment by administering formula (Va) compound
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 (Va), including a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof.
Specified cancer indications
The disease or condition is breast cancer, midline carcinomas, acute myeloid leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma.
Core structural constraints for formula (Va)
In formula (Va), R2 is H, R4 is H, and R6 is H; R7 is H, —OH, C1-6 alkyl, deuterated C1-6 alkyl, aryl, cycloalkyl, or heterocycloalkyl; R1 is heteroaryl optionally substituted with from 1-3 Rj groups; and R5 is optionally substituted with from 1 to 2 R11 groups selected from D, halogen, C1-6 alkyl, deuterated C1-6 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, and —CN, with the wavy line indicating the point of attachment to the rest of molecule.
R3 defined as deuterated or non-deuterated alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
In one independent claim variant, R3 is deuterated C1-6 alkyl, C1-6 alkyl, aryl, heteroaryl, C3-8 cycloalkyl, or heterocycloalkyl, each optionally substituted with from 1-3 substituents selected from the recited functional group set.
R3 defined as aryl or heteroaryl with optional substitution
In other independent claim variants, R3 is aryl or heteroaryl optionally substituted with from 1-3 substituents or from 1-5 substituents independently selected from the recited functional group sets.
Formula (Va) treatment with limited form variants in a simplified claim
A method for treating a subject suffering from a disease or condition mediated by a bromodomain by administering an effective amount of a compound of formula (shown), or a pharmaceutically acceptable salt, a solvate, or a deuterated analog thereof.
The independent claims collectively cover bromodomain-mediated therapeutic methods for the listed cancers by administering effective amounts of formula (Va) compounds and variants. The principal distinctions among claim variants lie in the defined substituent scopes, especially the permitted forms of R3 and the associated substitution patterns for R1, R5, R7, and related groups.
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 myeloid leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, and uveal melanoma.
The document includes exemplified bromodomain-targeted compounds within the formula (Va) framework, including pyrrolo[3,2-b]pyridine–isoxazole analogs and related benzoic acid, amide, sulfonamide, phosphonic acid, and boronic acid variants.
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