Pyrimidine tricyclic enone derivatives for inhibition of ROR-gamma and other uses
Inventors
Jiang, Xin • Bender, Christopher F. • Visnick, Melean • HOTEMA, Martha R. • SHELDON, Zachary S. • Lee, Chitase • Caprathe, Bradley William • Bolton, Gary • Kornberg, Brian
Assignees
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Publication Number
US-11292781-B2
Publication Date
2022-04-05
Expiration Date
Abstract
Disclosed herein are compounds of the formulas: as well as analogs thereof, wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to inhibit RORγ and/or reduce the expression of IL-17. Also provided are methods of administering compounds and composition provided herein to a patient in need thereof, for example, for the treatment or prevention of diseases or disorders associated with inflammation or autoimmune disorders.
Core Innovation
The disclosed subject matter describes compounds defined by a specified structural formula with variable bonding patterns and multiple Markush substituents, including R1, Ra, R2, R2′, R3, R4, R4′/R4″, X2, p, n, R5, Y1, A1, Y2, A2, A3, Re, and Rd. The scaffold includes a parameter a that is 0, 1, or 2, and pharmaceutically acceptable salts are included within the scope.
The structural definition permits the bond between carbon atoms 1 and 2 to be a single bond, an epoxidized double bond, or a double bond, and the bond between carbon atoms 4 and 5 to be a single bond or a double bond. A conditional constraint states that when carbon atoms 4 and 5 form a double bond, R2′ is absent and the hydrogen atom at carbon atom 5 is absent.
The disclosed scaffold includes cyano, heteroaryl, substituted heteroaryl, CF3, and C(O)Ra substitution space, together with heteroaryl, aryl, cycloalkyl, heterocycloalkyl, and amido substituent options and connection variables through X2, Y1/A1, Y2/A2, and A3Rd. The examples are within a polycyclic scaffold containing a nitrile, a lactam-like carbonyl, a fused ring system with multiple nitrogen atoms, and pendant aromatic or heteroaromatic substituents.
Claims Coverage
The consolidated material includes one independent claim directed to a compound of a specified formula and pharmaceutically acceptable salts thereof. The inventive features are the variable bond states in the fused core, the parameter a, the Markush-defined substituent framework for R1, R2/R2′, R3, R4/R4′, X2/p/n, and R5, together with the conditional absence rule for R2′ when carbon atoms 4 and 5 form a double bond.
Fused core bonding-defined structural formula
The compound is defined by a structural formula in which the bond between carbon atoms 1 and 2 is a single bond, an epoxidized double bond, or a double bond, and the bond between carbon atoms 4 and 5 is a single bond or a double bond.
Parameter a controls the core
The compound has a parameter a equal to 0, 1, or 2.
R1 selection including cyano, substituted heteroaryl, CF3, and C(O)Ra
R1 is cyano, heteroaryl (C≤8), substituted heteroaryl (C≤8), CF3, or C(O)Ra, wherein Ra is hydroxy, amino, alkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), alkylsulfonylamino (C≤8), or a substituted version of these groups.
R2 and R2′ substituent classes with a conditional absence rule
R2 is hydrogen or one of multiple substituent types including alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or acyl, or substituted versions, and R2′ is absent, hydrogen, or a corresponding set of substituent options; when the bond between carbon atoms 4 and 5 is a double bond, R2′ is absent and the hydrogen atom at carbon atom 5 is absent.
R3, R4, and R5 substitution patterns with linkage options
R3 is alkyl (C≤12), alkenyl (C≤12), aryl (C≤12), aralkyl (C≤12), or substituted versions. R4 includes amino, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amido, and substituted versions, or an X2-(CH2)p-R4″ option where X2 is arenediyl, substituted arenediyl, heterocycloalkanediyl, substituted heterocycloalkanediyl, heteroarenediyl, or substituted heteroarenediyl, and p is 0, 1, 2, 3, or 4. R5 is selected from amino, hydroxy, isopropoxy, OS(O)2C6H4CH3, alkyl, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, acyl, acyloxy, alkylamino, dialkylamino, alkylsulfonylamino, or substituted versions, or OY1-A1, Y2-C(O)NRc-A2, or A3Rd.
Pharmaceutically acceptable salts
The compound is also provided as pharmaceutically acceptable salts thereof.
The independent claim broadly covers a structurally defined compound family with selectable bond orders and Markush-defined substituent sets for multiple positions, including an explicit proviso that removes R2′ and the hydrogen at carbon atom 5 when carbon atoms 4 and 5 form a double bond. The scope also expressly includes pharmaceutically acceptable salts.
Stated Advantages
Inhibits RORγ.
Reduces IL-17 expression.
Provides anti-inflammatory and antioxidant properties.
Documented Applications
Evaluating compound activity using an AREc32 luciferase reporter assay for Nrf2 activation.
Evaluating compound activity using a GAL4-RORγ inverse agonist assay for RORγ inhibition with a cell viability readout.
Evaluating compound activity using an IL-17A release inhibition assay in differentiated primary human CD4+ T cells with HTRF detection and viability readout.
Treatment or management of inflammatory/autoimmune and IL-17-associated disorders, including those involving Th17 cells and IL-17 expression.
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