Fused tricyclic ring derivatives as SRC homology-2 phosphate inhibitors
Inventors
Fu, Jiping • Lou, Yan • HE, Yigang
Assignees
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Publication Number
US-12264167-B2
Publication Date
2025-04-01
Expiration Date
Abstract
The present disclosure provides certain fused tricyclic ring derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Core Innovation
The disclosure describes compounds of Formula (I), Formula (IA), Formula (IB), Formula (IC), and related scaffold families, including pharmaceutically acceptable salts, optical isomers, racemates, tautomers, cis/trans geometric isomers, hydrates, and isotopically labeled compounds. The compounds are defined by extensive substituent variables and ring-system options, including heteroaryl, aralkyl, heterocyclyl, sulfur-containing linkages, amino, aminoalkyl, alkyl, halo, alkoxy, hydroxy, cyano, and thioether-linked features.
The invention relates to a method of making a compound of Formula (IC), including pharmaceutically acceptable salts, by reacting a compound of Formula 1-a with a compound of Formula 1-d, or reacting a compound of Formula 1-c with a compound of Formula 1-e. The reacting step is transition metal-catalyzed, with the transition metal being palladium, and the bidentate phosphine Xantphos used in the process; the metal is potassium or sodium, and X1 is bromine or iodine.
The document further includes embodiments of complex fused heteroaromatic and spirocyclic compounds, including pyrazine/pyrido-oxazine/spirooxane products, tetrahydropyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine cores, and stereochemical variants. It also presents synthetic examples, intermediate structures, characterization data, and late-stage functional-group diversification in the synthetic context.
Claims Coverage
The consolidated claim coverage includes multiple independent claim records centered on a method of making a compound of Formula (IC). Across the provided items, the inventive features focus on reacting specified Formula 1-a/1-d or Formula 1-c/1-e partners, optionally forming pharmaceutically acceptable salts, and defining the Formula (IC) scaffold through extensive substituent and ring-forming limitations; recurring dependent refinements specify transition-metal-catalyzed conditions, palladium, Xantphos, potassium or sodium, and bromine or iodine for X1.
Method of making a compound of Formula (IC) by reacting defined precursors
Reacting a compound of Formula 1-a with a compound of Formula 1-d, or reacting a compound of Formula 1-c with a compound of Formula 1-e, to obtain a compound of Formula (IC), optionally a pharmaceutically acceptable salt thereof.
Formula (IC) scaffold with extensive substituent definitions
Defining Formula (IC) with variable structural components including A, E, Z, L, Z1, R1-R6, and related groups, with selections such as bonds, CH2, O, NH, S, S(O), and S(O)2, together with broad substituent classes and ring-system constraints.
Ring of formula (c) formed by substituent combinations
Allowing R11 and R12, or related substituent pairs, together with the attached carbon atom to form a ring of formula (c), with additional constraints involving e, k, q, R17, R18, and R19.
Transition-metal-catalyzed reacting step
Characterizing the reacting step as transition metal-catalyzed, with further refinement to palladium and the bidentate phosphine Xantphos in the dependent claim coverage.
Potassium or sodium metal component
Specifying the metal used as potassium or sodium, with X1 defined as bromine or iodine in the dependent claim coverage.
Selection of a Formula (IC) compound from a group
Selecting the compound of Formula (IC) from a specified group of compounds, as recited in one independent claim record.
Overall, the claims center on making Formula (IC) compounds by specified precursor reactions, with broad structural scope over the Formula (IC) scaffold and repeated dependent refinements for transition-metal-catalyzed conditions, palladium with Xantphos, potassium or sodium, and bromine or iodine. The independent claim set also includes a selection limitation for a Formula (IC) compound from a specified group.
Stated Advantages
The compounds are stated to function as Src Homology-2 phosphatase (SHP2) inhibitors.
The disclosure states therapeutic use for SHP2-related diseases, including cancers and immune/inflammatory disorders.
Defines pharmaceutically acceptable salt forms including acid addition salts, metal-ion salts, and organic base salts.
Provides multiple compound forms for assays, including optical isomers, racemates, tautomers, geometric isomers, hydrates, and isotopically labeled compounds.
Supports therapeutic-context terminology including treating, patient, disease/disorder/condition, combination therapy, and therapeutically effective amount.
Documented Applications
Therapeutic application of SHP2 inhibition for diseases and cancers including Noonan syndrome (NS), Leopard syndrome, juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and multiple solid tumors.
Treatment of SHP2-related diseases, including cancers and immune/inflammatory disorders.
Use against specific cancer types listed in the disclosure, including lung, stomach, liver, colon, kidney, breast, pancreas, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, and acute myeloid leukemia.
Treatment of Noonan syndrome and Leopard syndrome.
Assays using the defined compound forms, including optical isomers, racemates, tautomers/geometric isomers, hydrates, and isotopically labeled compounds.
Therapeutic contexts described using treatment-related terminology involving SHP2.
Pharmaceutical formulation examples containing a compound of Formula (I), including tablet formulation, capsule formulation, injectable formulation, inhalation composition, topical gel, ophthalmic solution, and nasal spray solution.
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