Bicyclic pyridine, pyrazine, and pyrimidine derivatives as PI3K beta inhibitors
Inventors
Berthelot, Didier Jean-Claude • Mevellec, Laurence Anne • Angibaud, Patrick Rene • Coupa, Sophie • Demestre, Christophe Gabriel Marcel • Meerpoel, Lieven • Mercey, Guillaume Jean Maurice • Meyer, Christophe • Pasquter, Elisabeth Therese Jeanne • Pilatte, Isabelle Noelle Constance • Poncelet, Virginie Sophie • Querolle, Olivier Alexis Georges
Assignees
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Publication Number
US-10894793-B2
Publication Date
2021-01-19
Expiration Date
Abstract
The present invention relates to bicyclic pyridine, pyrazine, and pyrimidine derivatives of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as pI3Kβ inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
Core Innovation
The disclosure relates to compounds of Formula (I), including tautomeric and stereoisomeric forms, N-oxides, salts and solvates, with X1 representing CH, X2 representing N, and Y representing CH2 or NH. The structural scope includes defined substituent classes for R2, R3, Rq, Ar, R4a, and R4b, with Ar being phenyl optionally substituted with one hydroxy, and with Het1, Ring A, and Ring B defined as saturated heterocyclyl rings containing at least one heteroatom selected from O, S, S(=O)p, and N.
The compounds of Formula (I) include enumerated R2, R3, and Rq options such as C1-4 alkyl, halo, OH, NH2, carbonyl-linked Het1, sulfonyl-linked alkyl motifs, CH(OH)-CH2-Rq, and hydroxy- or amino-containing variants, together with optional N-oxide and pharmaceutically acceptable addition salt forms. The aromatic substituent region is further defined by R4a and R4b, including embodiments in which R4a and R4b taken together form structures of Formula (a-1), (a-2), (a-3), (a-4), or (a-5).
The disclosure states pharmacological utility as PI3K kinase inhibition, including PI3Kβ optionally, and identifies treatment and prevention uses for cancer, PTEN-deficient neoplasms, prostate cancer, autoimmune and inflammatory diseases, and other listed conditions. It also includes radiosensitizer and chemosensitizer concepts, combination-therapy concepts, pharmaceutical composition language with a pharmaceutically acceptable carrier, and administration utility in warm-blooded animals.
Claims Coverage
The consolidated claims coverage includes independent claims directed to a compound of Formula (I), including tautomeric or stereoisomeric forms, and to a pharmaceutical composition including a pharmaceutically acceptable carrier. Across the inputs, the inventive features center on a specifically defined heteroatom-containing scaffold with enumerated substituent options, conditional ring formation, and optional N-oxide or pharmaceutically acceptable addition salt forms.
Compound of Formula (I)
A compound of Formula (I), a tautomer or a stereoisomeric form thereof, wherein X1 represents CH; X2 represents N; Y represents CH2 or NH; R2, R3, Rq, Ar, R4a, and R4b are defined by enumerated substituent and ring-forming options; Ar is phenyl optionally substituted with one hydroxy; Het1, Ring A, and Ring B are saturated heterocyclyl rings containing at least one heteroatom selected from O, S, S(=O)p, and N; and the compound includes optional N-oxide or pharmaceutically acceptable addition salt forms.
Specified R2, R3, and Rq substituent patterns
R2, R3, and Rq are defined by multiple C1-4 alkyl and heteroatom-containing options including halo, OH, NH2, carbonyl-linked Het1, CH(OH)-CH2-Rq, sulfonamide- and sulfonyl-linked patterns, and hydroxyl- and amino-containing variants as enumerated.
Y linkage fixed as CH2
The compound of claim 1 is defined such that Y is CH2.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.
The claims are centered on a Formula (I) compound with detailed heteroatom ring and substituent definitions, with dependent scope fixing Y as CH2 and adding a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
Stated Advantages
Inhibits PI3K kinase activity, optionally PI3Kβ.
Intended for treating and/or preventing cancer.
Intended for treating and/or preventing PTEN-deficient neoplasms and prostate cancer.
Intended for treating and/or preventing autoimmune and inflammatory diseases.
Provides radiosensitizer and chemosensitizer concepts.
The compounds are described as active in vivo and may be metabolically converted to active prodrugs.
Enables medicament and combination-therapy utility language.
Documented Applications
Treating and/or preventing cancer.
Treating and/or preventing PTEN-deficient neoplasms and prostate cancer.
Treating and/or preventing autoimmune and inflammatory diseases and other listed conditions.
Use as a radiosensitizer.
Use as a chemosensitizer.
Administration as a pharmaceutical composition to warm-blooded animals.
Example pharmaceutical formulations are described for tablets, suspension, injectable, and ointment.
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