Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof

a technology of orphan receptor and indazole, which is applied in the field of retinoic acid receptorrelated orphan receptor (ror) regulated diseases and disorders, can solve problems such as relative imbalan

Inactive Publication Date: 2016-01-28
INNOV17
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention describes compounds of formula (I) that are ROR modulators, which can be used to treat ROR-mediated diseases and disorders. These compounds can target specific parts of the immune system and help regulate their activity. The compounds can be in the form of salts and pharmaceutical compositions, and can be used to treat a variety of diseases and disorders such as allergies and autoimmune diseases. The invention is particularly useful for developing new treatments for diseases that have been difficult to target with existing drugs.

Problems solved by technology

Also, in several autoimmune disease models, there is a relative imbalance of increased pathologic TH17 cells over low numbers of protective immunosuppressive CD4+CD25+Foxp3+ regulatory T cells [TReg] (Edwards et al.

Method used

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  • Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof
  • Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof
  • Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1-one

[0317]

[0318]3-Phenylpropanoyl chloride (0.115 g, 0.68 mmol, 1.2 eq) and triethylamine (0.127 mL, 0.90 mmol, 1.66 eq) were added to a stirred solution of 1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole (0.200 g 0.547 mmol, 1.0 eq) in dichloromethane (10 mL) at 0° C. and the mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC, 100% ethyl acetate, Rf=0.5), chilled water was added and the mixture was extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh, elution with 100% of ethyl acetate to obtain 3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1...

example 2

Synthesis of 2-cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone

[0319]

[0320]Using the experimental procedure described in example 1 using 2-cyclohexylacetyl chloride (0.110 g, 0.68 mmol, 1.2 eq), triethylamine (0.126 mL, 0.89 mmol, 1.66 eq) and 1-(piperidin-4-ylmethyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazole (0.20 g, 0.54 mmol, 1.0 eq) in dichloromethane (10 mL), 2-cyclohexyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.150 g, 56%) was obtained as a white solid. LCMS purity: 98.33%; (ES+): m / z 490.60 (M+H+); tr=2.30 min.

example 3

Synthesis of 1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one

[0321]

[0322]To a solution of 3-phenyl-1-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)propan-1-one (0.20 g, 0.40 mmol, 1.0 eq) in MeOH (10 mL) was added p-toluenesulfonic acid (0.471 g, 2.73 mmol, 5.0 eq) at room temperature and the mixture was stirred at for 6 h. After completion of reaction (monitored by TLC, 100% Ethyl acetate Rf=0.40), methanol was removed under reduced pressure, chilled water was added and pH adjusted to 7 with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether to afford 1-(4-((5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)-3-phenylpropan-1-one (0.098 g, 59%) as an off white solid. LC-M...

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Abstract

Provided herein are compounds of the formulas (I) and (II):as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of Retinoic Acid Receptor-Related Orphan Receptor regulated diseases and disorders.

Description

FIELD OF THE INVENTION[0001]The invention relates to Retinoic Acid Receptor-Related Orphan Receptor (ROR) regulated diseases and disorders. More particularly, the invention relates to ROR modulators; compositions comprising a therapeutically effective amount of a ROR modulator; and methods for treating or preventing ROR regulated diseases and disorders. All documents cited to or relied upon below are expressly incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]There are high unmet medical needs in the few established therapies for several autoimmune, inflammatory, metabolic and oncologic diseases. Despite the diverse clinical manifestations of these diseases, Retinoic Acid Receptor-Related Orphan Receptors (RORs) regulate and contribute to the pathogenesis of these diseases through modulation of immune responses and lipid / glucose homeostasis. Only recently has the critical regulatory role of RORs been well-characterized and target validated in severa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D403/14C07D401/14C07D405/14C07D487/08
CPCC07D403/14C07D487/08C07D401/14C07D405/14A61P19/02
Inventor GAWECO, ANDERSONTILLEY, JEFFERSONBLINN, JAMES
Owner INNOV17
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