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A kind of small molecular compound as jak kinase inhibitor and its use

A technology of small molecular compounds and compounds, applied in anti-inflammatory agents, organic chemistry, digestive system, etc., to achieve good JAK kinase activity and effective effect

Active Publication Date: 2021-11-30
TECHNODERMA MEDICINES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although some studies have reported that JAK1 inhibitors can specifically inhibit Th2 allergic inflammation, there are few reports on the effective inhibition of JAK1 and / or TYK2 inhibitors at the same time. Has broader promise, especially in inflammatory diseases whose pathogenesis involves autoimmune abnormalities
In addition, the pathogenesis of more inflammatory diseases, especially inflammatory skin diseases, may involve multiple JAKs, so it is of great significance to develop potent single or dual inhibitors of JAK1 and Tyk2, especially for topical treatment of skin diseases , strong inhibitors can bring good curative effect while avoiding the side effects caused by systemic drugs, but this will also require strong inhibitory activity to achieve

Method used

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  • A kind of small molecular compound as jak kinase inhibitor and its use
  • A kind of small molecular compound as jak kinase inhibitor and its use
  • A kind of small molecular compound as jak kinase inhibitor and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 The General Method for Synthesizing Compound 1 (TDM-180972)

[0076]

[0077] Step 1: Preparation of compound 1c (4-(2-chloropyrimidin-4-yl)aniline)

[0078] Add compound 1a (2g, 9.129mmol) to the three-necked flask, compound 1b (1.36g, 9.129mmol), tetrakistriphenylphosphine palladium (527g, 0.45mmol), potassium carbonate (2.5g, 18.258mmol), dioxane (20 mL) and water (20 mL), replaced with nitrogen several times, then the mixture was heated to 80° C. and stirred for 45 minutes. After the reaction, the reactant was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=0-60%) to obtain the target compound (compound 1c, 394 mg, yield 21%) as a pale yellow solid. LCMS[M+1] + =206.

[0079]Step 2: Preparation of compound 1e ((S)-N-(4-(2-chloropyrimidin-4-yl)phenyl)-2,2-difluorocyclopropane-1-carboxamide)

[0080] Compound 1c (300mg, 1.459mmol) and compound 1d (187mg, 1.531mmol) were adde...

Embodiment 2

[0084] Example 2 The General Method of Synthetic Compound 2 (TDM-180974)

[0085]

[0086] Step 1: Compound 2 ((S)-5-((4-(4-(4-(2,2-difluorocyclopropane-1-carboxamido)phenyl)pyrimidin-2-yl)amino)- 3-methylpyridoline) preparation

[0087] To a solution of compound 2a (80 mg, 0.258 mmol) in n-butanol (8 mL) was added compound 2b (78 mg, 0.517 mmol) and p-toluenesulfonic acid monohydrate (98 mg, 0.517 mmol), and the mixture was heated to 115° C. and stirred overnight . At the end of the reaction, the mixture was concentrated under reduced pressure, methanol was added to the residue, the solid was collected by filtration, and the solid was purified by preparative HPLC (formic acid) to obtain the white solid target compound TDM-180974 (compound 2, 18.9 mg, yield 10.6%). LCMS[M+H] + = 425.2.

[0088] 1 H NMR (400MHz, DMSO) δ10.73(s, 1H), 10.08(s, 1H), 8.89(d, J=2.2Hz, 1H), 8.60(d, J=5.3Hz, 1H), 8.23(d ,J=2.0Hz,1H),8.18(d,J=8.8Hz,2H),7.90(s,1H),7.79(d,J=8.8Hz,2H),7.49(d,J=5...

Embodiment 3

[0089] Example 3 The General Method of Synthetic Compound 3 (TDM-180977)

[0090]

[0091] Step 1: Preparation of compound 3b (4-amino-N-ethyl-2-methylbenzamide)

[0092] To a solution of compound 3a (1.8 g, 11.91 mmol) in N,N-dimethylformamide (80 mL) was added 2-(7-azabenzotriazole)-N,N,N',N'- Tetramethyluronium hexafluorophosphate (5.4g, 14.289mmol) and N,N-diisopropylethylamine (3.8g, 29.775mmol), the mixture was stirred for 5 minutes, then tetrahydrofuran (2M) of ethylamine was added ( 9 mL, 18 mmol) solution, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove some solvent, water was added to the residue and extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with water (150 mL*3) and saturated brine (150 mL), dried over sodium sulfate, and extracted under reduced pressure The filtrate was concentrated and purified by silica gel chromatography (petroleum ether / ethyl ac...

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Abstract

The present invention provides a small molecular compound, which is a compound represented by the following formula, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, and pharmaceutically Acceptable salt or prodrug, wherein R 1 to R 4 Each is independently selected from C or N; and wherein R is selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. The small molecule compound of the present invention can inhibit JAK kinase, more particularly as a JAK1 / Tyk2 dual inhibitor and a Tyk2 specific inhibitor.

Description

technical field [0001] The present invention belongs to the field of small molecule compounds, in particular, relates to a compound that can be used to prevent or treat autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and systemic lupus erythematosus, etc., or related inflammatory skin diseases such as Small molecule compounds for psoriasis, eczema, vitiligo and alopecia areata, etc. Background technique [0002] JAK (Janus kinase, Janus Kinase) is a family of intracellular non-receptor tyrosine protein kinases, including four members JAK1, JAK2, JAK3 and Tyk2. The JAK-STAT (Signal Transducer and Activator of Transcription proteins) signal transduction pathway is the main pathway for intracellular transduction of signals stimulated by the combination of inflammatory cytokines and receptors. Many evidences show that the JAK-STAT signaling pathway plays an indispensable driving role in the pathogenesis of many diseases, especially autoimmune diseases such ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42C07D401/12C07D401/04C07D401/14A61P37/00A61P29/00A61P17/00A61P19/02A61P19/08A61P1/04A61P1/06A61P37/02A61P9/10A61P3/10A61P9/00A61P17/06A61P17/10A61P31/04A61P17/14
CPCC07D239/42C07D401/12C07D401/04C07D401/14A61P37/00A61P29/00A61P17/00A61P19/02A61P19/08A61P1/04A61P1/06A61P37/02A61P9/10A61P3/10A61P9/00A61P17/06A61P17/10A61P31/04A61P17/14
Inventor 方文奎李冠群蔡雨婷潘翔朱文浩汪杨王增全
Owner TECHNODERMA MEDICINES
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