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Pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, preparation method of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, pharmaceutical compositions and application of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof and pharmaceutical compositions

A five-membered heterocycle and compound technology, applied in the field of chemistry and medicine, can solve problems such as poor membrane permeability and metabolic instability

Active Publication Date: 2021-06-25
YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the STING agonists reported so far are cyclic dinucleotide analogues, but the defects of in vivo metabolic instability, poor membrane permeability, and intratumoral administration only greatly limit the application of STING agonists. The research and development of STING small molecule agonists is of great significance

Method used

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  • Pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, preparation method of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, pharmaceutical compositions and application of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof and pharmaceutical compositions
  • Pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, preparation method of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, pharmaceutical compositions and application of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof and pharmaceutical compositions
  • Pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, preparation method of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof, pharmaceutical compositions and application of pyrimido five-membered heterocyclic compounds or pharmaceutically acceptable salts and isomers thereof and pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0525] Example 1: Synthesis of Compound S1

[0526] 2-(2-Amino-6-(propylamino)-9H-purin-9-yl)-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)carboxamide (S1 )

[0527]

[0528] Step 1: Synthesis of Compound 2

[0529] Raw material 1 (6.8 g, 40 mmol) was weighed and dissolved in anhydrous tetrahydrofuran, Boc anhydride (38 mL, 160 mmol) was added at 0° C., DMAP (492 mg, 4 mmol) was added, and the reaction was carried out overnight at room temperature. The next day, spin off tetrahydrofuran under reduced pressure, add EA (300mL) to redissolve, wash with 1M hydrochloric acid solution (25mL×2), wash with water (30mL) once, wash once with saturated brine (30mL), dry with anhydrous sodium sulfate, filter, The solvent was evaporated to dryness to give a yellow oil. The yellow oil was dissolved in methanol (300 mL) and saturated NaHCO was added 3 The solution (200 mL) was heated to 50° C. for 1 h, transferred to room temperature, and reacted overnight. The next day, after the reaction wa...

Embodiment 2

[0540] Example 2: Synthesis of Compound S132

[0541] N-(2-(2-Amino-6-(pyrrol-1-yl)-9H-purin-9-yl)ethyl)-1-ethyl-3-methyl-1H-pyrazole-5-methyl Amide (S132)

[0542]

[0543] Step 1: Synthesis of Compound 7

[0544] Compound 2 (200 mg, 0.54 mmol) was weighed and dissolved in 1,4-dioxane, tetrahydropyrrole (44 mg, 0.60 mmol) and TEA (0.15 mL, 1.08 mmol) were added, and the temperature was raised to 60 °C and stirred for 3 h. . Stop the reaction, spin off 1,4-dioxane, add 10 mL of DCM to dissolve, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent to dryness, make sand, and purify by column chromatography (DCM:MeOH=60 : 1 to 30: 1) to obtain compound 7 (163 mg, 75%). 1 H NMR (300 MHz, Chloroform-d) δ: 7.99 (d, J=1.8 Hz, 1H), 3.84-3.77 (m, 2H), 2.09-2.01 (m, 2H), 1.48 (s, 9H).

[0545] Step 2: Synthesis of Compound 8

[0546] Weigh compound 7 (163 mg, 0.4 mmol) and dissolve it in anhydrous THF (5 mL), add N-CBZ-eth...

Embodiment 3

[0553] Example 3: Synthesis of Compound 147

[0554] N-(2-(2-Amino-6-(cyclopropylamino)-9H-purin-9-yl)ethyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide ( S147)

[0555]

[0556] Step 1: Synthesis of Compound 11

[0557] Compound 2 (200 mg, 0.54 mmol) was weighed and dissolved in 1,4-dioxane, cyclopropylamine (34.2 mg, 0.60 mmol) and TEA (0.15 mL, 1.08 mmol) were added, the temperature was raised to 60 °C and the reaction was stirred for 3 h . Stop the reaction, spin off 1,4-dioxane, add 10 mL of DCM to dissolve, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent to dryness, make sand, and purify by column chromatography (DCM:MeOH=60 : 1 to 30: 1) to obtain compound 10 (166 mg, 79%). 1 H NMR (300 MHz, Chloroform-d) δ: 7.98 (d, J=1.8 Hz, 1H), 6.19 (d, J=9.5 Hz, 1H), 3.03 (m, 1H), 1.48 (s, 18H), 0.70 -0.55(m, 4H).

[0558] Step 2: Synthesis of Compound 12

[0559] Compound 11 (156 mg, 0.40 mmol) was weighed and d...

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Abstract

The invention discloses pyrimido five-membered heterocyclic compounds with structures as shown in a general formula I in the specification or pharmaceutically acceptable salts thereof. The pyrimido five-membered heterocyclic compounds or the pharmaceutically acceptable salts thereof overcome the defects that a STING micromolecule agonist is lacked, and a nucleotide STING agonist is poor in druggability and the like in the prior art. The pyrimido five-membered heterocyclic compounds disclosed by the invention have very good excitation activity on STING, and show good treatment effect on tumors and infectious diseases.

Description

technical field [0001] The present invention relates to the field of chemical medicine, in particular to pyrimido five-membered heterocyclic compounds or their pharmaceutically acceptable salts, isomers and their preparation methods, pharmaceutical compositions and uses. Background technique [0002] Innate immunity is the first line of defense against invading pathogens and tissue damage. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) from pathogens or damage-associated molecular patterns (DAMPs) from the body itself, initiating a cascade In response, the expression of genes such as interferons (IFNs), chemokines and inflammatory factors is induced. This innate immune response not only suppresses the proliferation and spread of pathogens at an early stage, but also induces an acquired immune response to eventually clear the infection. Additionally, this innate immune response monitors tumor initiation and invasion. At presen...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02A61P37/02A61P31/12A61P31/16A61P31/18A61P31/22
CPCC07D487/04A61P35/00A61P35/02A61P37/02A61P31/12A61P31/16A61P31/18A61P31/22Y02P20/55Y02A50/30
Inventor 蒋晟何朝勇张阔军
Owner YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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