Compounds and methods for EP300 or CBP modulation and indications therefor
Inventors
Spevak, Wayne • BUELL, JOHN • Guo, Zuojun • Inagaki, Hiroaki • Jin, Yongil • Pham, Phuongly • Shi, Songyuan • Walleshauser, Jack • Wu, Jeffrey • Wu, Guoxian • Zhang, Chao • Zhang, Jiazhong • Zhang, Ying
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11446287-B2
Publication Date
2022-09-20
Expiration Date
Abstract
Disclosed are compounds of Formula I:or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein A1, A2, A3, A4, R4, X1, X2, and X3 are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.
Core Innovation
The disclosure relates to compounds of Formula I, including pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, deuterated analogs, and in some descriptions prodrugs and hydrates. The compounds are defined by substituent variables A1-A4, X1-X3, L, R1-R14, G1-G2, J1-J2, and L2, with alternative structural arrangements and conditional provisions that restrict L for particular combinations of A1, A2, A3, A4, X1, X2, and X3. The scaffold includes extensive optional substitution patterns and ring-system definitions, together with allowed linker options such as a bond, CH2-CH2, and C(O).
The disclosure also presents specific heteroaromatic and cyclic embodiments, including substituted pyrrolo[2,3-b]pyridine and pyrrolo[3,2-b]pyridine cores bearing isoxazole substituents and substituted benzoic acid, benzonitrile, benzoate, picolinic acid, and related motifs. The examples include chiral small-molecule structures, enumerated compounds such as P-0001 through P-0449 and P-0145 through P-0170, and specific substituent variations including fluoro, chloro, difluoro, trifluoromethoxy, methoxy, dimethoxy, diethoxy, cyano, hydroxy, cyclobutylmethyl, tetrahydro-2H-pyran, and triazole-substituted groups. Biological evaluation is described using Alphascreen binding assays measuring inhibition of bromodomain interactions for EP300-BD, BRD4-BD12, and CBP-BD.
The patent also frames the compounds as modulators of EP300/CBP, where EP300 and CBP are described in connection with histone acetyltransferase activity. Therapeutic context is provided for diseases and conditions mediated by EP300 or CBP, including explicit mention of acute myeloid leukemia, multiple myeloma, prostate cancer, small-cell lung cancer, non-small cell lung cancer, bladder cancer, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, breast cancer, Alzheimer's disease, and Parkinson's disease. The disclosure includes pharmaceutical compositions and treatment methods.
Claims Coverage
The consolidated claims coverage includes one broad independent Formula I compound claim and, in the supplied material, a separate selection claim to specified P-structures. The independent compound claim centers on a structurally parameterized Formula I scaffold with extensive substituent definitions, while additional claim language narrows ring and functional-group selections and includes therapeutic method coverage for EP300/CBP-mediated disease or condition.
Formula I compound scaffold with variable A/X/L framework
A compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, deuterated analog, prodrug, or hydrate thereof, wherein A1-A4, X1-X3, L, and L2 are defined by allowed structural options and conditional relationships, including cases where L is a bond.
Defined ring and substituent options for R1 through R8
R1 is selected from phenyl, 5-9 membered heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, with optional substitution by G1 and G2 groups; R2, R3, and R4 are restricted to the listed allowed groups; R5 is defined according to whether it is attached to carbon or nitrogen, with optional -L2-J1 and J2 substitution; R6 is a five membered heteroaryl containing at least one nitrogen atom, optionally substituted with R8 groups; and R7 is H, halo, or C1-C6 alkyl.
Functional-group definitions for G1, G2, J1, and J2
G1 and G2 are independently selected from defined functional-group and substituent classes, and J1 and J2 are each selected from specified sets of functional groups and substituents, with attachment-dependent exclusions when these groups are attached to nitrogen.
Selected P-structures
A compound selected from specified structures P-0001 through P-0449, or a pharmaceutically acceptable salt thereof.
EP300/CBP therapeutic method
A method for treating a disease or condition mediated by EP300 or CBP by administering an effective amount of a compound as defined in claim 1 to a subject.
Combination with additional therapeutic agents
The method further includes one or more additional therapeutic agents selected from epigenetic modulators, including DNA methyltransferase, histone/protein methyltransferase, histone demethylase, histone deacetylase inhibitors, histone acetyltransferase, other chromatin remodelers, and a BRD4 inhibitor.
The consolidated claim coverage centers on a broad Formula I compound family defined by interconnected scaffold variables and extensive substituent selections, with additional narrowing for ring systems and functional groups. The provided claim set also includes therapeutic method coverage for EP300/CBP-mediated disease or condition and a separate selection claim covering enumerated P-structures.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A method for treating a disease or condition mediated by EP300 or CBP by administering an effective amount of a compound as defined in claim 1 to a subject.
Combination therapy for such treatment that further includes one or more additional therapeutic agents selected from epigenetic modulators, including DNA methyltransferase, histone/protein methyltransferase, histone demethylase, histone deacetylase inhibitors, histone acetyltransferase, other chromatin remodelers, and a BRD4 inhibitor.
Treatment regimens using EP300/CBP modulators for acute myeloid leukemia, multiple myeloma, prostate cancer, small-cell lung cancer, non-small cell lung cancer, bladder cancer, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, breast cancer, Alzheimer's disease, and Parkinson's disease.
Interested in licensing this patent?