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Publication Number
US-10570138-B2
Publication Date
2020-02-25
Expiration Date
Abstract
The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.
Core Innovation
The disclosure describes substituted pyrazolo[1,5-a]pyrimidine and related fused heterocyclic derivatives, together with specific intermediates and exemplified compounds. The structures include pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a][1,3,5]triazine, imidazo-fused, purine-like, and carbazole-containing systems, with substituents such as 5-fluoro-3-pyridyl, indole-derived side chains, and fluorinated aryl groups. The patent text also presents compound series through formulae IX-a, IX-b, IX-c and X-a through X-i, supported by named examples and characterized materials.
The disclosure further defines the compound space through variable substituent frameworks, including X as N or CH and substituents R_x, R_y, and R_z selected from halogen, cyano, nitro, OR, SR, N(R)2, and multiple carbonyl- and sulfur-containing groups. The claimed frameworks also include linkage rules in which two substituents on the same carbon form O or S, as well as ring-closure options when two R groups on the same nitrogen are taken together. The examples and claims are tied to pharmaceutically acceptable salts, including hydrochloride salts, and to specific stereochemical variants in some embodiments.
The examples describe preparation and characterization of multiple compounds and intermediates, with reported yields, purities, and analytical data such as 1H NMR and ES-LCMS. The partial content references purification and analytical confirmation for representative compounds across the disclosed series, including chiral variants and enantiomerically enriched products. The overall disclosure supports a defined chemical space of substituted fused heterocyclic compounds grounded in exemplified preparations and structural formula claims.
Claims Coverage
The claim coverage centers on compound families defined by structural formula sets, including formulae IX-a, IX-b, IX-c and formulae X-a through X-i, plus additional independent claims broadly directed to a compound or a pharmaceutically acceptable salt. The main inventive coverage is the constrained substituent framework, including variable X, R_x, R_y, and R_z, the O/S fusion rules, the ring-closure rules for R groups, and the integer parameters p, m, and n. In addition, dependent claim coverage includes pharmaceutical compositions comprising the claimed compound or salt with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Formula-defined compound selection
A compound selected from formulae IX-a, IX-b, and IX-c, or from formulae X-a through X-i, or a pharmaceutically acceptable salt thereof, wherein X is N or CH.
Defined substituent framework for Rx, Ry, and Rz
Each of R_x, R_y, and R_z is independently selected from R, halogen, cyano, nitro, OR, SR, N(R)2, N(R)C(O)R, C(O)N(R)2, C(O)N(R)OR, N(R)C(O)N(R)2, N(R)C(O)OR, OC(O)N(R)2, N(R)SO2R, SO2RN(R)2, C(O)R, C(O)OR, OC(O)R, S(O)R, or SO2R.
O or S linkage formation on the same carbon
Two R_x on the same carbon, or two R_y on the same carbon, are taken together to form O or S.
Ring-closure rules for R groups
Each R is independently hydrogen, deuterium, or an optionally substituted group selected from defined aliphatic, carbocyclic, heterocyclic, heteroaromatic, and bicyclic ring types, with additional ring formation when two R groups on the same nitrogen are taken together with intervening atoms to form a 4-7 membered ring having 1-2 heteroatoms in addition to the nitrogen.
Parameter constraints for p, m, and n
Each p is independently 0, 1, or 2 as valency will allow, and each of m and n is independently 1, 2, 3, 4, or 5.
Pharmaceutical composition with carrier, adjuvant, or vehicle
A pharmaceutical composition comprising the claimed compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
The claims primarily cover structurally defined fused heterocyclic compounds selected from specified formula sets, with tightly constrained substituent definitions, O/S fusion rules, ring-closure rules, and index ranges. Additional claim scope includes pharmaceutically acceptable salts, generic compound claims in the provided claim summaries, and pharmaceutical compositions containing the claimed compound or salt.
Stated Advantages
Broad therapeutic utility for inflammatory, autoimmune, ocular/nasal, pulmonary, metabolic and other conditions.
Use for viral infections and cancer.
Combination therapy approaches with anti-cancer/chemotherapeutic agents and immuno-oncology agents.
AHR target engagement, AHR-related modulation, and in vivo anti-tumor efficacy are described.
Inhibits AHR in a biological sample or patient.
Documented Applications
Therapeutic treatment of inflammatory, autoimmune, ocular/nasal, pulmonary, metabolic and other conditions.
Treatment or use in viral infections.
Treatment or use in cancer, including anti-tumor efficacy described with AHR antagonist I-70 alone or with anti-PD-1.
Combination therapy in cancer with immuno-oncology agents, including checkpoint inhibitors and other listed immuno-oncology modalities.
In vivo and in vitro assays for AHR inhibition and general treatment indications tied to AHR-mediated disorders.
Use in a patient and in a biological sample to inhibit AHR.
Oral administration and parenteral administration.
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