ALK-5 inhibitors and uses thereof
Inventors
Franz, Bettina • Siddiqui-Jain, Adam • Warner, Steven L. • Basireddy, Siva Reddy • Padakanti, Srinivas • Kumar, Naresh
Assignees
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Publication Number
US-11746103-B2
Publication Date
2023-09-05
Expiration Date
Abstract
Provided herein are compounds (e.g., compounds of Formulae (I), (II), (III) and (IV), or of Table 1 or Table 4), and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and kits comprising the same. The compounds provided herein are activin receptor-like kinase (e.g., ALK-5) inhibitors and are, therefore, useful, for example, for treating and/or preventing diseases (e.g., proliferative diseases, such as cancer) in a subject, inhibiting tumor growth in a subject, or inhibiting the activity of an activin receptor-like kinase (e.g., ALK-5) in vitro or in vivo. Also provided herein are methods and synthetic intermediates useful in the preparation of compounds described herein.
Core Innovation
The disclosure provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, defined by specific substituent patterns for R1, R2, R3, R4, and R5. R1 is a C1-C5 alkyl, C3-C5 carbocycle, or halogen, and R2 is an aryl of at least 6 carbon atoms or a nitrogen-containing heteroaryl of at least 6 atoms, optionally substituted with halogens, alkyl, sulfonamide, carbocycle, or heterocycle options, with meta- or para-positioning relative to the amino bond for larger substituents and attachment by a single bond or a methylene or ethylene linker.
The disclosure also includes further formula embodiments, including Formula (II) and Formula (III), with enumerated option sets for substituent variables and additional refinements for selected groups such as R4 and R5. Example compounds are presented to support the scaffold, including compounds built on a pyrimidine-2,4-diamine framework with substituted fused heteroaryl groups and further defined ring systems.
The compounds are framed in a therapeutic-use context involving ALK-5 inhibition and suppression of ALK5/TGF-βR1 signaling. The disclosure further relates to pharmaceutical compositions comprising the compounds and to methods of treating proliferative disease, cancer, and fibrotic disease, including non-small cell lung cancer, as well as methods inhibiting ALK-5 activity in vivo or in vitro by contacting ALK-5 with the claimed compounds.
Claims Coverage
The consolidated claim coverage includes a Formula (I) compound family with constrained substituent patterns and positional rules, additional formula embodiments with enumerated substituent choices, and a functional ALK-5 inhibition claim. The main inventive features are the defined scaffold, meta/para positional restrictions for larger R2 substituents, and the ALK-5 contacting method.
Formula (i) compound scaffold with constrained substituent patterns
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-C5 alkyl, C3-C5 carbocycle, or a halogen; R2 is an aryl of at least 6 carbon atoms or a nitrogen-containing heteroaryl of at least 6 atoms optionally substituted with halogens, optionally hydroxyl- or halogen-substituted C1-C6 alkyl, sulfonamide, carbocycle, or heterocycle options; R3 is H, F, or Cl; R4 is H, a halogen, or a C1-C3 alkyl or cyclopropyl optionally substituted with one or more F; and R5 is H, F, or a C1-C3 alkyl or cyclopropyl optionally substituted with one or more F.
Meta- or para-positioning relative to the amino bond for larger r2 substituents
For alkyl substituents on R2 larger than C3, and for carbocycles larger than cyclopropyl, the relevant group is positioned meta- or para- to the amino bond to the aryl or heteroaryl of R2. The carbocycle and heterocycle options may be attached to R2 by a single bond or a methylene or ethylene linker, with the same positional constraints applied where specified.
ALK-5 activity inhibition by contacting alk-5
A method of inhibiting ALK-5 activity in vivo or in vitro by contacting ALK-5 with a compound of the claimed Formula (I) family or a pharmaceutically acceptable salt thereof.
Compound selection defined by chemical formula or depicted structure
A compound, or a pharmaceutically acceptable salt thereof, selected from an unspecified list and defined in dependent claims by a specific chemical formula or depicted chemical structure.
Overall, the claim coverage centers on a Formula (I) scaffold with defined substituent classes, attachment modes, and meta/para positional restrictions relative to an amino bond, supported by additional formula embodiments and structure-defined compound selection. The claim set also includes a functional claim for inhibiting ALK-5 activity in vivo or in vitro by contacting ALK-5 with the claimed compounds.
Stated Advantages
Suppression of ALK5/TGF-βR1 signaling is described using p-SMAD2 (Ser465/Ser467) readouts.
Inhibition of fibrosis-related fibroblast-to-myofibroblast transformation is described in an IPF FMT context.
Therapeutic effects are described in immune checkpoint combination studies, including combination with immune checkpoint antibodies.
Inhibits ALK-5 activity in vivo or in vitro.
Treating proliferative disease or cancer, including non-small cell lung cancer (NSCLC).
Treating fibrotic disease and inhibiting ALK-5/TGFβ signaling.
Provides pharmaceutical compositions comprising the compounds.
Therapeutic and prophylactic treatment of diseases including cancer and fibrotic or inflammatory diseases such as pulmonary fibrosis and cardiac fibrosis/cardiovascular disease.
TGFβ/ALK-5 pathway modulation.
Inhibition of EMT (epithelial-to-mesenchymal transition).
Tumor growth inhibition.
Metastasis inhibition.
Modulation of the tumor-immune microenvironment, including an antigen presentation pathway.
Combination therapeutic context with PD-1/PD-L1 inhibitors.
Combination therapeutic context with radiation/surgery.
Documented Applications
In vitro and in vivo ALK-5/TGF-β pathway inhibition and associated signaling suppression, including p-SMAD2 (Ser465/Ser467) readouts in an A549 xenograft model context.
Fibrosis-related fibroblast-to-myofibroblast transformation (IPF FMT) assay and related cellular transformation inhibition.
Immune checkpoint combination studies described in combination contexts with anti-PD-1 and anti-PD-L1.
Treg differentiation assessment via FOXP3 in the context of broader pharmacology/functional evaluation.
Cell viability evaluation described in a FOXL2 mutant model (KGN) using a CellTiter-Glo concept.
PK/PD and tolerability evaluations are mentioned as part of the described studies.
Ovarian cancer xenograft (ES-2) survival study context is mentioned.
Treating proliferative disease or cancer, including non-small cell lung cancer (NSCLC).
Treating fibrotic disease described as TGFβ-driven, including association with the TGFβ signaling pathway.
Inhibiting tumor growth.
Inhibiting ALK-5 activity in vivo or in vitro by contacting ALK-5 with the claimed compounds.
Therapeutic and prophylactic treatment of cancer, including solid tumor and hematological cancer.
Therapeutic and prophylactic treatment of pulmonary fibrosis.
Therapeutic and prophylactic treatment of cardiac fibrosis/cardiovascular disease.
Modulation of the TGFβ/ALK-5 pathway, including inhibition of EMT.
Tumor-immune microenvironment modulation, including effects on the antigen presentation pathway.
Combination with PD-1/PD-L1 inhibitors.
Combination with radiation/surgery.
Combination regimens with standard-of-care cancer therapies, including ovarian cancer, pancreatic cancer, prostate cancer, and multiple myeloma therapies.
Combination with fibrosis therapies such as nintedanib, pirfenidone, and oxygen therapy.
Combination with BTK inhibitor therapy, venetoclax, CAR-T therapies, immune checkpoint inhibitors, cytoprotective agents, anti-allergic agents, anti-emetics, analgesics, ER-stress inducers, bromodomain inhibitors, HDAC inhibitors, CDK inhibitors, ATR inhibitors, EGFR pathway inhibitors, and kinase inhibitors.
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