Agonists of stimulator of interferon genes sting

A technology of interferon and agonist, which is applied in the field of agonist of interferon gene stimulator STING, which can solve the problem that the physiological correlation needs to be fully characterized

Pending Publication Date: 2020-11-20
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

STING has also been found to directly bind cytosolic DNA, although the physiologi

Method used

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  • Agonists of stimulator of interferon genes sting
  • Agonists of stimulator of interferon genes sting
  • Agonists of stimulator of interferon genes sting

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] Scheme 2: Synthesis of compound 1:

[0170]

[0171] 2-(6-(1H-imidazol-1-yl)pyridazin-3-amido)benzoic acid methyl ester, 1: Intermediate A (190 mg, 1 mmol), 2-aminobenzoic acid methyl ester (166 mg, 1.1 mmol), HATU (456 mg, 1.2 mmol) and DIPEA (0.52 mL, 3 mmol) were dissolved in DMF (5 mL) and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the resulting crude material was purified by silica gel column chromatography using 2% to 5% MeOH in DCM to obtain Compound 1 (226 mg) as an off-white solid. LC-MS(ESI+): m / z 324.27[M+H] + .

[0172] Option 3

[0173]

[0174] a Reagents and conditions: a) Thionyl chloride, reflux, 3 hours; ethyl 2-aminocyclohex-1-ene-1-carboxylate, DIPEA, acetonitrile, rt, 30 minutes

[0175] 2-(6-(1H-imidazol-1-yl)pyridazine-3-amido)cyclohex-1-ene-1-carboxylic acid ethyl ester: 6-(1H-imidazol-1-yl)pyridazine -3-Carboxylic acid (19 mg, 0.1 mmol) was dissolved in...

Embodiment 2-L

[0180] Scheme 5: Synthesis of Compound 2-Li

[0181]

[0182] Lithium 2-(6-(1H-imidazol-1-yl)pyridazin-3-amido)-5-methoxybenzoate, 2-Li: Preparation of 2 by using the method followed for compound 1 (Scheme C) -(6-(1H-Imidazol-1-yl)pyridazin-3-amido)-5-methoxybenzoic acid methyl ester. The resulting ester (20 mg, 0.057 mmol) was dissolved in DMSO (0.8 mL), then aq. 0.1 M LiOH (0.68 mL, 1.2 mmol) was added, followed by stirring at room temperature until the reaction was complete (about 3 hours). The reaction was monitored by LCMS. Then, the reaction mixture was acidified by dropwise addition of 1M HCl to generate the desired acid. The obtained precipitate was isolated and washed with water to afford acid 2 as an off-white solid. LC-MS(ESI+): m / z 340.4[M+H] + . Acid 2 (10.2 mg, 0.03 mmol) was additionally suspended in 2.5 mL of water (0.25 mL / mg) and sonicated for 20 minutes to prepare a homogeneous suspension. After this time, 1 M LiOH (30 μL, 0.03 mmol) was added to ob...

Embodiment 6-L

[0186]

[0187] Lithium 2-(6-(1H-imidazol-1-yl)pyridazin-3-amido)-4,5-difluorobenzoate, 6-Li: The method followed by using compound 2-Li (Scheme D ) to prepare compound 6-Li. LC-MS(ESI+): m / z 346.1[M+H] + .

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Abstract

The invention provides compounds having STimulator of INterferon Genes (STING) agonistic bioactivity that can be used in the treatment of tumors in patients afflicted therewith. The compounds are of formula (I): as defined herein. Compounds for practice of a method of the invention can be delivered via oral delivery for systemic exposure, as well as delivered intratumorally. Antitumor therapy using a compound of formula (I) can further comprise administration of an effective dose of an immune-checkpoint targeting drug.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 633,409, filed February 21, 2018, the disclosure of which is incorporated herein by reference in its entirety. Background technique [0003] The cGAS-STING signaling pathway plays a key role in the innate immune response mounted by mammalian host cells to eliminate a variety of DNA and RNA viruses. STING (Stimulator of Interferon Gene, Stimulator of Interferon Gene) is an endoplasmic reticulum (ER) resident signaling protein partially localized to the mitochondria-associated membrane, which is expressed in both immune and non-immune cell types. Express widely. STING translocates to The perinuclear region, where it rapidly induces the production of type I interferon (IFN) and pro-inflammatory cytokines in a TBK1- / IRF3-dependent manner. STING has also been found to directly bind cytosolic DNA, although the physiological relevance of direct DN...

Claims

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Application Information

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IPC IPC(8): A61K31/497C07D403/04C07D403/14
CPCA61K31/497C07D403/04C07D403/14A61K45/06A61P35/00A61K31/536A61K31/517C07D413/14C07D401/14C07D405/14C07D471/04C07D498/04C07D493/08A61K2300/00A61K31/501A61K31/506A61K47/6803A61K9/127A61K2039/505A61K9/0019A61K9/0053A61K31/5365
Inventor 卢克·L·莱森艾米丽·N·陈阿纳博·查特吉马诺伊·库马尔阿纳·玛丽亚·加莫·阿尔拜罗迈克·彼得拉西彼得·舒尔茨于晨光田宫淳子威廉·韦尼尔阿尼尔·古普塔拉姆库马尔·莫杜库里
Owner THE SCRIPPS RES INST
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