CXCR3 receptor agonists
Inventors
YEAGER, Adam • Turnbull, Philip • Zhang, Lin • Fan, Junhua • Tamiya, Junko • Steinberg, Marcos • Fowler, Tom • Benelkebir, Hanae • Pasceri, Raffaele • Ieva, Maria • Grant, Kevan • Tran, Yang
Assignees
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Publication Number
US-11040954-B1
Publication Date
2021-06-22
Expiration Date
Abstract
Compounds are provided having the structure of the following Formula I: where R, R1, R2, R3a and R3b are as defined herein. Pharmaceutical compositions comprising such compounds, as well as methods related to their manufacture and use, are also provided.
Core Innovation
The invention relates to a compound having the structure of Formula I, or a stereoisomer, isotope, hydrate, solvate, or pharmaceutically acceptable salt thereof. The compound is defined by variable substituents R, R1, R2, R3a, R3b, R4, R5, R6, R7, R8, and R9 with explicit constraints on permitted identities and substitution counts. The Formula I scaffold allows aryl or heteroaryl groups, nitrogen- or amine-containing moieties, and alternative R2 as —NR8R9, while preserving the defined structural framework.
Within Formula I, R is hydrogen, hydroxy, cyano, halo, or —OS(=O)2R6; R1 is aryl or heteroaryl substituted with 0–4 R4 groups; and R2 is aryl or heteroaryl substituted with 0–3 R5 groups, or alternatively —NR8R9. R3a is hydrogen or alkyl and R3b is a nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen, or R3a and R3b together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon, at least one nitrogen atom and hydrogen.
R4 and R5 are, at each occurrence, selected from cyano, halo, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, heterocyclyl, —S(=O)2R6, —C(=O)R6, —C(=O)OR6, —C(=O)NR6N7, or —NR6R7, with R6 and R7 each being hydrogen or alkyl. R8 is hydrogen or alkyl and R9 is alkyl or aryl substituted with 0–4 R4 groups, or R8 and R9 together with the nitrogen atom form a heterocyclyl substituted with 0–4 R4 groups and optionally substituted with oxo or thioxo. The disclosure also presents pharmaceutical compositions and compounds described as CXCR3 small-molecule agonists, activators, or modulators.
Claims Coverage
The independent claim is directed to a compound having the structure of Formula I, including stereoisomers, isotopes, hydrates, solvates, and pharmaceutically acceptable salts thereof, and a method that agonizes the CXCR3 chemokine receptor of a cell by contacting the cell with a compound of claim 1. The consolidated claim coverage centers on six inventive features.
Formula I compound scaffold with defined substituent variables
A compound having the structure of Formula I, or a stereoisomer, isotope, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3a, R3b, R4, R5, R6, R7, R8, and R9 are defined by the specified allowed identities and substitution counts.
R substitution and aryl or heteroaryl substitution limits
R is hydrogen, hydroxy, cyano, halo, or —OS(=O)2R6; R1 is aryl or heteroaryl substituted with 0–4 R4 groups; and R2 is aryl or heteroaryl substituted with 0–3 R5 groups, or R2 is —NR8R9.
R3a/R3b nitrogen- or amine-containing moiety including cyclic form
R3a is hydrogen or alkyl and R3b is a nitrogen- or amine-containing moiety of carbon with at least one nitrogen atom and hydrogen, or R3a and R3b together with the carbon to which they are attached form a cyclic nitrogen- or amine-containing moiety of carbon with at least one nitrogen atom and hydrogen.
Permitted R4 and R5 substituent classes with R6 and R7 limitations
R4 and R5 are, at each occurrence, cyano, halo, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, heterocyclyl, —S(=O)2R6, —C(=O)R6, —C(=O)OR6, —C(=O)NR6N7, or —NR6R7; and R6 and R7 are hydrogen or alkyl.
R8 and R9 heterocyclyl or substituted alkyl or aryl definition
R8 is hydrogen or alkyl and R9 is alkyl or aryl substituted with 0–4 R4 groups, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0–4 R4 groups and optionally substituted with oxo or thioxo.
CXCR3 agonism by contacting a cell
A method that agonizes the CXCR3 chemokine receptor of a cell by contacting the cell with a compound of claim 1.
Overall, claim coverage is centered on a Formula I scaffold with tightly defined substituent classes and counts for R, R1/R2, R3a/R3b, R4/R5, and R8/R9, including cyclic nitrogen-containing and heterocyclyl options. The claim set also includes a functional use aspect directed to CXCR3 agonism.
Stated Advantages
CXCR3 agonism via induced desensitization is intended to inhibit migration of activated T lymphocytes and NK cells.
The compounds are described for addressing Th1 cell-mediated inflammation.
Documented Applications
Treatment of rheumatoid arthritis.
Treatment of multiple sclerosis.
Treatment of inflammatory bowel disease.
Agonizing the CXCR3 chemokine receptor of a cell by contacting the cell with a compound of claim 1.
Inhibition of migration of activated T lymphocytes and NK cells via CXCR3 agonism via induced desensitization.
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