Spiroheterocyclic compound as well as preparation method and application thereof

A spiro-heterocycle, compound technology, applied in the direction of drug combination, organic chemistry, digestive system, etc., to achieve the effect of inhibiting production

Pending Publication Date: 2022-05-06
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, patent applications CN107522634, WO2012158784, WO2018145653, etc. have disclosed some RORγt small molecule modulators, but there are no related products on the market. This field still needs to develop new RORγt small molecule modulators with better activity and higher safety

Method used

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  • Spiroheterocyclic compound as well as preparation method and application thereof
  • Spiroheterocyclic compound as well as preparation method and application thereof
  • Spiroheterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0351] Preparation example 1 (preparation of key intermediate)

[0352]

[0353] first step:

[0354] Compound 1-a (20g, 85.822mmol, 1.00equiv) and trifluoromethyltrimethylsilane (TMSCF 3 , 61.02g, 429.111mmol, 5.00equiv) in tetrahydrofuran (200mL) was added tetrabutylammonium fluoride (54.15g, 171.644mmol, 2.00equiv) and stirred overnight at room temperature. After the reaction was monitored by LCMS until the reaction was complete, it was quenched by adding 1N HCl at 0°C. The reaction solution was extracted with ethyl acetate, anhydrous Na 2 SO 4 (sodium sulfate) dry. The reaction solution was concentrated and separated by column chromatography (EA / PE, 15%-30%) to obtain light yellow oily compound 1-b (11.80 g, 34.602 mmol, 40.32% yield). LCMS:(ESI,m / z):[M-1] - = 338.75. 1 H NMR (300MHz, chloroform-d) δ7.66 (dd, J = 8.6, 7.0Hz, 1H), 7.52 (dd, J = 9.6, 2.2Hz, 1H), 7.45–7.33 (m, 1H), 3.56 ( s, 1H).

[0355] Step two:

[0356] Add 4-(4,4,5,5-tetramethyl- 1,3,2-Diox...

preparation example 2

[0357] Preparation example 2 (preparation of key intermediate)

[0358]

[0359] first step:

[0360] At 0°C, 2 mL of sodium nitrite (NaNO 2 ) (293 mg, 4.24 mmol, 1.1 equiv) in water, followed by the dropwise addition of HCl (6M, 2 mL, 11.58 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred for an additional 1 hour at 0°C. Additional KI (673mg, 4.05mmol, 1.05eq) was added at 0°C and then stirred overnight at room temperature. The completion of the reaction was monitored by LCMS, and water (30 mL) was added to dilute the reaction, and extracted with ethyl acetate (3×15 mL). The organic phases were combined, washed with saturated brine and concentrated to dryness, and the residue was separated by column chromatography (EA / PE, 10%-50%) to obtain compound 2-b (912mg, 2.46mmol, 63.87% yield), yellow oil liquid. LCMS:(ESI,m / z):[M-1] - = 368.9.

[0361] Step two:

[0362] To compound 2-b (23.00g, 62.16mmol, 1equiv) in 1,4-dioxane solution (300mL), add diboronic aci...

preparation example 3

[0363] Preparation example 3 (preparation of key intermediate)

[0364]

[0365] (4-formylphenyl)boronic acid (2.43g, 16.215mmol, 1.2 eqiv), tetrakistriphenylphosphine palladium (1.56 g, 1.351 mmol, 0.10 eqiv) and potassium carbonate (5.6 g, 40.537 mmol, 3.00 eqiv). The reaction mixture was stirred overnight at 80 °C under nitrogen protection. The completion of the reaction was monitored by LCMS, the solvent was removed in vacuo, and the residue was separated by column chromatography (EA / PE, 0%-40%) to obtain a crude product, which was purified by n-hexane to obtain compound 3 (2.491g, 7.153mmol, 52.94% yield rate), a yellow solid. LCMS:(ESI,m / z):[M-1] - =347.00. 1 H NMR (400MHz, DMSO-d 6 )δ10.07(s,1H),8.84(s,1H),8.02(d,J=8.3Hz,2H),7.99–7.88(m,4H),7.82(d,J=8.3Hz,2H). 19 F NMR (377MHz, DMSO-d 6 ) δ-73.89.

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PUM

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Abstract

The invention provides a spiro heterocyclic compound, and a preparation method and application thereof. The spiroheterocyclic compound is shown as a formula I in the specification. The compound has inhibitory activity on ROR [gamma] t and can effectively inhibit ROR [gamma] t protein receptors, so that differentiation of Th17 cells is regulated and controlled, generation of IL-17 is inhibited, and related autoimmune diseases mediated by ROR [gamma] t are treated.

Description

technical field [0001] The invention relates to a spiroheterocyclic compound, its preparation method and application. Background technique [0002] Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs) belong to the nuclear receptor superfamily of ligand-dependent transcription factors, and play important roles in reproductive development, circadian rhythm regulation, metabolic disorders, inflammation and immune It plays an important role in a series of physiological and pathological processes such as system regulation. RORs mainly include three members: RORα, RORβ and RORγ. RORα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood. RORβ is mainly distributed in the central nervous system, including the brain, retina and pineal gland. RORγ is highly expressed in the thymus, and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20C07D491/22C07D519/00A61K31/438A61K31/527A61K31/439A61K31/444A61K31/506A61K31/4545A61K31/5386A61P17/06A61P25/28A61P19/02A61P1/00A61P19/08A61P37/06A61P11/00A61P29/00
CPCC07D491/20C07D491/22C07D519/00A61P17/06A61P25/28A61P19/02A61P1/00A61P19/08A61P37/06A61P11/00A61P29/00A61K31/444A61K31/438A61K31/439A61K31/4545A61K31/506A61K31/527A61K31/5386A61P17/00
Inventor 王倩张冰宾石辰舒思杰霍国永向志军夏广新吴国胜梁涛赵永新李令文柯樱
Owner SHANGAI PHARMA GRP CO LTD
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