TGF-β inhibitors
Inventors
Gelman, Marina • Kinsella, Todd • Bhamidipati, Somasekhar • Darwish, Ihab • Singh, Rajinder • Yu, Jiaxin
Assignees
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Publication Number
US-12227508-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Disclosed are pyrazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, X, Z, m, p, and R2 are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.
Core Innovation
The invention relates to compounds having the structure of formula (I), including pharmaceutically acceptable salts, prodrugs, N-oxides, solvates, and hydrates. The compounds are defined by variable structural parameters including m, p, X, A, n, Y, and a fused bicyclic ring Z, together with specified optional substitution patterns on Ar, Het, Cak, Hca, and alkyl.
A core structural aspect is the definition of Z as a fused bicyclic ring, with ring A selected as Ar or a 5- or 6-membered Het. Z is optionally substituted by one or two RZ groups selected from defined substituent classes, with optional further substitution by RZ2 groups and additional defined substituent sets for R1, R2, Rb, and related variables.
The Y ring is defined as a 5- to 9-membered Hca optionally substituted by halo or C1-C6 alkyl. Representative structures and example compounds instantiate the formula (I) scaffold with different fused heteroaryl or bicyclic ring systems and pendant aromatic substituents, including indazole, benzimidazole, benzo[d]thiazole, imidazo[1,2-a]pyridine, quinoline, quinoxaline, pyrazolo[5,1-b]oxazine, pyrazolo[5,1-b][1,3]oxazole, pyrrolo[1,2-b]pyrazole, dihydropyrazolo[5,1-b]oxazole, and triazolo[1,5-a]pyridine based compounds.
Claims Coverage
The consolidated claim coverage includes two inventive feature groups centered on the formula (I) compound class and a therapeutic method claim.
Formula (I) compound class
A compound having the structure of formula (I), or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, with structural parameters m, p, X, A, n, Y, and Z defined by the claim.
Fused bicyclic ring Z with optional RZ and RZ2 substitution
Z is a fused bicyclic ring in which ring A is Ar or a 5- or 6-membered Het, and Z is optionally substituted by one or two RZ groups with further optional substitution by RZ2 groups and defined substituent sets for R1, R2, Rb, and related variables.
TGF-β receptor superfamily-mediated disease treatment
A method for treating a disease or condition mediated by or involving a member of the TGF-β receptor superfamily by administering an effective inhibitory amount of a compound according to claim 1 to a subject in need thereof.
Overall, the claim coverage centers on a formula (I) compound class with a fused bicyclic Z ring, broad substituent variability, and pharmaceutically acceptable forms, together with a therapeutic method directed to TGF-β receptor superfamily-mediated disease or condition treatment.
Stated Advantages
Blocks TGF-β superfamily activity, including GDF-8/myostatin, TGF-β1/2/3, activin, and nodal.
Treats and prevents diseases involving TGF-β signaling.
Inhibition of TGF-β cytokine signaling and kinase activity associated with TGF-β receptor superfamily targets.
Pharmaceutical composition and medicament embodiments are stated for the kinase inhibitor compounds.
Therapeutic applicability is stated for pulmonary hypertension, fibrosis, cancers, inflammatory disorders, wound healing, arthritis, and osteoporosis.
Documented Applications
Blocking TGF-β superfamily activity in vitro and in vivo for study.
Treatment and prevention of diseases involving TGF-β signaling, including oncology, fibrotic disorders, muscle and adipose tissue disorders, bone degenerative diseases, neuromuscular disorders, and diabetes.
Inhibition of TGF-β superfamily/cytokine signaling, including GDF-8 signaling and TGF-β signaling, for kinase targets such as ACVR1, ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, BMPR1A, BMPR1B, BMPR2, and TGFBR1.
Therapeutic use in cancer treatment, including combination therapy with chemotherapeutic agents and checkpoint/immuno-oncology agents such as PD-1, PD-L1, and CTLA-4 antibodies.
Treatment of a disease or condition mediated by or involving a member of the TGF-β receptor superfamily by administering an effective inhibitory amount of a compound according to claim 1 to a subject in need thereof.
Pulmonary hypertension.
Fibrosis, including idiopathic pulmonary fibrosis, kidney fibrosis, and liver fibrosis.
Cancers.
Inflammatory disorders.
Wound healing.
Arthritis.
Osteoporosis.
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