Hormone receptor modulators for treating metabolic conditions and disorders
Inventors
Chao, Jianhua • Jain, Rakesh • Hu, Lily • Lewis, Jason Gustaf • Baribault, Helene • Caldwell, Jeremy
Assignees
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Publication Number
US-12209088-B2
Publication Date
2025-01-28
Expiration Date
Abstract
The invention relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L1, A, X1, X2, R1, R2, and R3 are described herein.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, prodrug, or tautomer forms, with defined structural constraints including X1 and X2 such that one is NRx and the other is CH2, linker features L1 and L2, and variable groups A, B, R1, R2, R3, R4, R5, R6a-R6e, R7, R8, and R9. A is selected from (C3-C8) cycloalkyl, (C6-C10) aryl, heterocycloalkyl, or heteroaryl with specified ring-size and heteroatom ranges, and B is a (C6-C10) aryl optionally substituted with one or more R5.
The scaffold further allows ring-forming combinations for R1 and R2, including spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring systems, together with optional substitution patterns. The disclosed examples and enumerated embodiments center on azabicyclo[2.2.1]heptane or related bicyclic cores linked to oxazole, isoxazole, pyrazole, benzothiazole, and aryl or heteroaryl motifs, including carboxylic acid, benzamide, benzoic acid, benzonitrile, ester, sulfonamide, and sulfonyl-carbamoyl forms.
The examples include specific stereochemically defined compounds and salts including hydroiodide and trifluoroacetate forms. The content also describes synthetic preparation and characterization of multiple members of these scaffold families, with reported coupling, deprotection, hydrolysis, ester-to-acid conversion, and related intermediate-to-product sequences, together with characterization by 1H NMR, MS (ES), LCMS, prep-HPLC, and, in some instances, explicit stereochemical assignment.
Claims Coverage
The consolidated claim coverage spans a broad Formula I scaffold claim and independent selected-compound claims. Across these claims, the inventive features are defined by the Formula I core architecture, detailed linker and substituent definitions, and explicit enumerated compound selections with named stereochemistry and functional-group variants.
Formula I compound scaffold with defined X1/X2, L1, and L2
A compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one of X1 or X2 is NRx and the other is CH2; L1 is -(CH2)m(C=O)— or —(CH2)p—; L2 is a bond or —S(O)2—; and A, B, R1, R2, R3, R4, R5, R6a-R6e, R7, R8, and R9 are defined by the stated ring-size, heteroatom, and substituent-class constraints, with m, n, and p limited as stated.
Ring-system scope and optional substitution for A and B
A is (C3-C8) cycloalkyl, (C6-C10) aryl, heterocycloalkyl with one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, or heteroaryl with one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, and B is a (C6-C10) aryl optionally substituted with one or more R5.
R1 and R2 substituent and ring-forming rules
R1 and R2 are each independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, with additional rules allowing R1 and R2 together to form spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, each optionally substituted as stated.
R3 and R4 functional-group definitions
R3 is selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, or cycloalkyl, optionally substituted with halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and OH; R4 is selected from COOR6a, CONR6bR6c, CONH(CH2)nCOOR6a, CONR6bSO2R6d, CONH(CH2)nSO2R6e, CN, heterocycloalkyl, or heteroaryl.
Selected compound groups with explicit stereochemistry
Independent claims select from enumerated groups of specific compounds, including named stereochemically defined azabicyclo[2.2.1]heptane, oxazole, isoxazole, pyrazole, benzothiazole, benzoic acid, benzamide, benzonitrile, ester, sulfonamide, and sulfonyl-carbamoyl variants, each including pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer forms.
The claim coverage is centered on a broad Formula I scaffold with constrained connectivity, ring-system scope, and substituent classes, together with independent claims that expressly select enumerated stereochemically defined compound sets and their pharmaceutically acceptable forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating FXR-involved diseases including liver disease, intestinal disease, kidney disease, autoimmune disorder, and cancer.
FXR ligand binding and FXR activation assays.
In vivo colitis assessment and restoration of epithelial barrier integrity in a DSS mouse model.
In vivo colonic permeability assessment in HFCC diet mice using sucralose urinary excretion.
Preparation and analytical characterization of Formula I compounds and intermediates.
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