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Pyridazine compound

A compound, pyridazine-based technology, applied in the field of TYK2 inhibitor, prevention or treatment of related diseases, can solve problems such as no observed toxicity performance

Pending Publication Date: 2021-12-10
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

BMS-986165, a highly selective inhibitor of TYK2 currently developed by BMS, has shown efficacy close to that of antibodies in a phase II clinical trial of psoriasis (for reference, see Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med.2018 Oct; 379(14):1313-1321), and the patient tolerated it well, and no toxicity related to JAK1 / 2 was observed

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Synthesis Example 1 001 Compound embodiment

[0096] 6- (cyclopropyl-carboxamido) -4 - ((2-methoxyimino-amine) ethyl) phenyl) amino) -N- methyl-pyridazine-3-carboxamide

[0097]

[0098] Synthetic route and specific synthetic steps:

[0099]

[0100] First step: 1- (2-methoxy-3-nitrophenyl) ethane-1-ketone 001-B synthesis

[0101] 001-A (3.0 g, 16.5 mmol) was dissolved in DMF (30.0 mL), and potassium carbonate (4.56 g, 33.0 mmol) was sequentially added, iodide (5.85 g, 41.25 mmol). The mixture was stirred for 12 hours, and the white solid was precipitated, filtered, collected, and ethyl acetate (30.0 mL) was added, and twice was washed with deionized water, and the brine was washed once. Thick, silica gel column chromatography was separated from 001-B (3.08 g, yield: 96%).

[0102] LCMS: RT: 1.797min; MS M / Z (ESI): 196.4 [M + H].

[0103] 1 H NMR (400MHz, CDCL 3 Δ7.93 (DD, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.82 (DD, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.30 (T, J = 8.0 Hz, 1H), 3.9...

Embodiment 2

[0124] Example 2 Synthesis of Compound 002

[0125] (E) -6 - ((5- (1- (hydroxyimine) ethyl) pyridin-2-yl) amino) -4 - ((2-methoxy-3- (1-methyl-1H- 1,2,4-triazole-3-yl) phenyl) amino) -N-methyl pyridazine-3-formamide

[0126]

[0127] Synthetic route and specific synthetic steps:

[0128]

[0129] Step 1: Starting materials 002-a synthesis

[0130] Starting materials and methods of Scheme 002-a of Ref. Highly Selective Inhibition ofTyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery ofthe Allosteric Inhibitor BMS-986165, J Med Chem.2019 Oct 24; 62 (20) : 8973-8995.

[0131] Step 2: 6 - ((5-acetylpyridine-2-yl) amino) -4 - ((2-methoxy-3- (1-methyl-1H-1,2,4-triazole-3 - Synthesis of Base) Phenyl) amino) -N-methylpyridazine-3-formamide 002-C

[0132] 002-A (65.0 mg, 0.48 mmol), 002-b (150.0 mg, 0.40 mmol), Pd at room temperature 2 (DBA) 3(37.0 mg, 0.04 mmol), xantphos (23.0 mg, 0.04 mmol) and cesium carbonate (261.0 mg, 0.80 mmol) were added to 1,4-dioxane...

Embodiment 3

[0138] Example 3 Synthesis of Compound 003

[0139] (E) -4 - ((2-methoxy-3- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) amino) -6 - ((5-) 1-methoxyamino) ethyl) pyridin-2-yl) amino) -N-methyl pyridazine-3-formamide

[0140]

[0141] Synthetic route and specific synthetic steps:

[0142]

[0143] 002-C (50 mg, 0.11 mmol), methoxy amine hydrochloride (18.5 mg, 0.22 mmol) and sodium acetate (36.0 mg, 0.44 mmol) were added to ethanol / water (3.0 ml / 6.0 mL). In the mixture, heated to 80 ° C for 18 hours, and the reaction solution was cooled to room temperature concentration. The crude product was dissolved in DMF (5.0 mL) by preparing liquid chromatography (0.1% ammonia water) purified from 003 (5.91 mg, yield 11%).

[0144] LCMS: RT: 4.60min; MS M / Z (ESI): 503.2 [M + H].

[0145] 1 H NMR (400 MHz, DMSO-D6) δ 11.01 (S, 1H), 10.36 (S, 1H), 9.16 (D, J = 4.8 Hz, 1H), 8.57 (S, 1H), 8.44 (D, J = 2.0Hz, 1H), 8.11 (S, 1H), 8.00 (DD, J 1 = 8.8Hz, J 2 = 2.0Hz, 1H), 7.70 (D, J = 8.8 Hz, 1H...

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Abstract

The invention provides a pyridazine compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the pyridazine compound or the pharmaceutically acceptable salt, and application of the pyridazine compound, the pharmaceutically acceptable salt or the pharmaceutical composition as a TYK2 inhibitor in prevention or treatment of related diseases.

Description

Technical field [0001] The present invention relates to a new type of pyridazine compound or a pharmaceutically acceptable salt thereof, comprising a pharmaceutical composition thereof and a use of TYK2 inhibitors in preventing or treating related diseases. Background technique [0002] TYK2 is one of the non-acceptable tyrosine kinase JAK family members. Janus kinase (JAK) consists of four family members, namely JAK1, JAK2, JAK3, and TYK2. When the cytokine receptor is bonded to cytokine, the downstream signal path is activated by phosphorylated STAT protein, and the transcription and expression of the associated gene is achieved, and the signal is transduced from the cell membrane to the nucleus. JAK-mediated signal transduction pathway, an important role in the proliferation, differentiation, apoptosis, and immune responses such as cytokine-dependent modified cells, is a hot target for treating inflammatory diseases, autoimmune diseases and cancer point. [0003] In recent yea...

Claims

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Application Information

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IPC IPC(8): C07D237/24C07D401/14C07D403/12A61K31/501A61P29/00A61P37/06A61P35/00
CPCC07D237/24C07D401/14C07D403/12A61P29/00A61P37/06A61P35/00
Inventor 张国宝陈家隽周峰古鹏陈平唐任宏任晋生
Owner JIANGSU SIMCERE PHARMA
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