1224944-77-7

Usage

Uses

Used in Pharmaceutical Industry:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate is used as a key intermediate in the synthesis of antitumor pyrazolopyrimidine compounds. Its unique chemical structure allows for the development of molecules with potential antiproliferative and cytotoxic properties, making it a valuable component in the creation of new cancer therapies.
In the synthesis of these antitumor agents, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate can be further modified through various chemical reactions to introduce functional groups and structural motifs that enhance the biological activity and selectivity of the resulting compounds. This allows researchers to explore a wide range of potential therapeutic agents with improved efficacy and reduced side effects compared to existing treatments.
Furthermore, the use of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as a starting material in the synthesis of pyrazolopyrimidine-based drugs enables the exploration of structure-activity relationships and the optimization of drug candidates. This can lead to the discovery of novel compounds with superior pharmacological properties, ultimately contributing to the advancement of cancer treatment options.

Upstream product

• 1260243-04-6 ethyl 5-amino-1H-pyrazole-4-carboxylate 
• 42466-67-1 ethyl (ethoxymethylene)cyanoacetate 
• 94-05-3 ethyl (ethoxymethylene)cyanoacetate 
• 144918-37-6 (E)-ethyl 2-cyano-3-ethoxyacrylate 
• 926663-00-5 5-hydroxypyrazole[1,5-a]pyrimidine-3-carboxylic acid ethyl ester 
• 6994-25-8 3-amino-4-pyrazolecarboxylic acid ethyl ester 

Downstream Products

• 1260845-57-5 ethyl (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 
• 1260840-74-1 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((S)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260846-60-3 (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 
• 1260842-01-0 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((S)-2,3-dihydroxypropoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260846-92-1 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260845-56-4 (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 
• 1260845-64-4 (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 
• 1260843-28-4 5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260840-05-8 (R)-N-tert-butyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260840-10-5 (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(3-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 
• 1260846-57-8 (R)-ethyl 5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 
• 1260845-87-1 (R)-ethyl 5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 
• 1431654-51-1 5-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 
• 1431645-12-3 N-(pyridin-4-yl)-5-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 

Relevant academic research and scientific papers

Discovery of a novel series of pyrazolo[1,5-a]pyrimidine-based phosphodiesterase 2A inhibitors structurally different from N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the treatment of cognitive disorders

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

Discovery and structure ? activity relationship exploration of pyrazolo[1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors

Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance- conferring mutations, FLT3D835Y, both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.

A class of FLT3 kinase inhibitors, preparation and application thereof

The invention relates to a class of FLT3 kinase inhibitors, preparation and application thereof, wherein specifically the compound has a structure represented by a formula (I), and all groups and substituents are defined in the specification. The invention also discloses a preparation method of the compound, and application of the compound in inhibition of FLT3.

Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma

Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure?activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell–like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.

DEGRADERS THAT TARGET ALK AND THERAPEUTIC USES THEREOF

Disclosed are bispecific compounds (degraders) that target ALK for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat diseases and disorders characterized or mediated by aberrant ALK activity

Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors

‘precision medicine’ is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.

FORMULATIONS OF A MACROCYCLIC TRK KINASE INHIBITOR

The present application in some embodiments provides a pharmaceutical composition comprising Compound (1), and a compounding agent. Further provided herein are methods of making and methods of using the pharmaceutical compositions, for example, in the treatment of cancer.

Compound used as protein-kinase regulator and application thereof

The invention discloses a compound shown in formula I, wherein all symbols are defined as Claims. The compound shown in Formula I has good inhibitory activity to ALK, ROS1 and/or TRK kinase, can be used for preparing a drug inhibiting the ALK, ROS1 and/or

PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF

In some embodiments, provided herein are processes for preparing a compound of Formula C or a salt thereof, as disclosed herein. In some embodiments, provided herein is a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, provided herein is a solid form of the compound, such as a crystalline form of the compound crystalline Form I.

CHIRAL DIARYL MACROCYCLES AS MODULATORS OF PROTEIN KINASES

The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.