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Polyheterocyclic modulators of STING (stimulators of interferon gene)

A technology of heterocyclic and heteroaromatic rings, applied in the field of polyheterocyclic regulators of STING (interferon gene stimulator)

Pending Publication Date: 2022-07-08
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nonetheless, to date, few effective STING activators have been developed or entered the clinic

Method used

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  • Polyheterocyclic modulators of STING (stimulators of interferon gene)
  • Polyheterocyclic modulators of STING (stimulators of interferon gene)
  • Polyheterocyclic modulators of STING (stimulators of interferon gene)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment G01

[0867] Example G01: Preparation of 4-[4-(1-ethyl-3-methyl-1 according to Scheme G H -pyrazol-5-yl)-1 H -Imidazol-2-yl]-1-methyl-1 H -Indazole-6-carboxamide.

[0868] Scenario G:

[0869]

[0870] Step 1: Synthesis of 6-bromo-1-methyl-1H-indazole-4-carboxylic acid 2-(1-ethyl-3-methyl-1 H - Pyrazol-5-yl)-2-oxoethyl ester (G-1).

[0871] To 6-bromo-1-methyl-1 under nitrogen H -Indazole-4-carboxylic acid (Int-HG-13) (280 mg, 1.10 mmol) and 2-bromo-1-(1-ethyl-3-methyl-1 H To a suspension of -pyrazol-5-yl)ethan-1-one (Int-TG-07) (279 mg, 1.21 mmol) was added DIPEA (0.50 mL, 3.00 mmol). The yellow solution was stirred at 25°C for 17 hours. LCMS analysis indicated complete consumption of starting material. The solution was concentrated in vacuo to provide the title compound (G-1), which was used in the next step without further purification. 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.48 (s, 1H), 8.18 (s, 1H), 8.05(d, J = 1.5 Hz, 1H), 6.98 (s, 1H), 5.57 (s, 2H), 4.50 (q, J ...

Embodiment H01

[0880] Example H01: Preparation of 4-[4-(1-ethyl-3-methyl-1 according to Scheme H H -Pyrazol-5-yl)-1,3-thiazol-2-yl]-1-methyl-1 H -Indazole-6-carboxamide.

[0881] Scenario H:

[0882]

[0883] Step 1: Synthesis of 6-bromo-4-[4-(1-ethyl-3-methyl-1 H -Pyrazol-5-yl)-1,3-thiazol-2-yl]-1-methyl-1 H -Indazole (H-1).

[0884] to 6-bromo-1-methyl-1 H -Indazole-4-carbothioamide (Int-HG-14) (93.5 mg, 0.346 mmol) in MeOH (3.0 mL) to a suspension of 2-bromo-1-(1-ethyl-3- methyl-1 H - Pyrazol-5-yl)ethan-1-one (Int-TG-07) (105 mg, 0.454 mmol). The reaction was heated at 80 °C for 14 h. LCMS analysis indicated consumption of starting material and formation of product mass. The reaction was concentrated in vacuo to provide a white solid. The solid was triturated with DCM (5.0 mL) and then dried under vacuum to afford the title compound (H-1) (65 mg, 47% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 ) δ = 8.57 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 1.3 Hz, 1H)...

Embodiment J01

[0889] Example J01: Preparation of 4-[3-(1-ethyl-3-methyl-1 according to Scheme J H -pyrazol-5-yl)-1-methyl-1 H -1,2,4-Triazol-5-yl]-1-methyl-1 H -Pyrazolo[4,3- c ]pyridine-6-carboxamide.

[0890] Scenario J:

[0891]

[0892] Step 1: Synthesis of 6-chloro-4-[3-(1-ethyl-3-methyl-1 H -pyrazol-5-yl)-1-methyl-1 H -1,2,4-Triazol-5-yl]-1-methyl-1 H -Pyrazolo[4,3- c ]pyridine (J-1)

[0893] to 3-(1-ethyl-3-methyl-1 H -pyrazol-5-yl)-1-methyl-1 H To a suspension of -1,2,4-triazole (Int-TG-04) (55.6 mg, 0.291 mmol) in toluene (1.5 mL) was added 4,6-dichloro-1-methyl-1 H -Pyrazolo[4,3- c ]pyridine (Int-HG-08) (88.7 mg, 0.439 mmol), Pd(OAc) 2 (6.5 mg, 0.029 mmol), P( n -Bu)Ad 2 (21.8 mg, 0.061 mmol), PivOH (8.9 mg, 0.087 mmol) and K 2 CO 3 (129.8 mg, 0.939 mmol). The solution was sparged with nitrogen for 2 minutes and then sealed. The reaction was heated at 120 °C for 16 h. LCMS analysis indicated that most of the starting triazole had been consumed and formatio...

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PUM

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Abstract

Compounds of general formula (I) or pharmaceutically acceptable salts thereof, processes for preparing these compounds, compositions containing these compounds, and uses of these compounds.

Description

[0001] Field of Invention [0002] The present invention relates to additional novel activators of STING (stimulator of interferon genes) useful in the treatment of diseases and disorders in mammals such as inflammatory diseases, allergic and autoimmune diseases, infectious diseases and abnormal cells Growth such as cancer, and used as a vaccine adjuvant. The present invention also relates to methods of using such compounds to treat abnormal cell growth in mammals, particularly humans, and to pharmaceutical compositions of such compounds. [0003] Background of the Invention [0004] The innate immune system is the first line of defense, triggered by pattern recognition receptors (PRRs) upon detection of ligands from pathogens as well as damage-related molecular patterns. An increasing number of these receptors have been identified, which include sensors of double-stranded DNA and unique nucleic acids called circular dinucleotides (CDNs). Activation of the PRR results in the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14C07D405/14C07D401/14C07D413/14C07D417/14C07D471/04C07D498/04C07D498/08C07D451/02C07D455/02C07D487/04C07D491/107A61P35/00A61K38/21C07D491/08A61K39/3955A61K31/4196A61K31/437A61K47/6803A61K31/5386A61K31/427A61K39/39558A61K31/454C07D487/06A61K31/5377A61K31/424
Inventor A·芬索姆E·L·费希尔K·S·加吉瓦拉许璨宇M·贾拉伊I·J·麦卡尔平R·帕特曼E·Y·芮T·P·陈M·J·怀瑟斯张磊周大卉
Owner PFIZER INC
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