825618-95-9

Usage

Pyrazole derivative

A chemical compound derived from the pyrazole ring structure, which consists of a five-membered ring with one nitrogen atom and one carbon atom.

Carboxylic acid group

A functional group consisting of a carbonyl group (C=O) and a hydroxyl group (OH) attached to the same carbon atom, contributing to the acidic properties of the compound.

Difluorobenzoyl amino group

A functional group containing a benzene ring with two fluorine atoms and an amino group (NH2) attached to the carbonyl group, which may influence the compound's biological and pharmacological activities.

Biological and pharmacological activities

The potential for the compound to interact with biological systems and produce therapeutic effects, which could be explored in research and drug discovery.

Purity

The degree to which the compound is free from impurities or other substances, which can affect its properties and potential applications.

Concentration

The amount of the compound present in a given volume or mass, which can influence its effectiveness and potential uses.

Upstream product

• 55904-61-5 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester 
• 385-00-2 2,6-difluorobenzoic acid 
• 896467-54-2 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester 

Downstream Products

• 896467-54-2 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester 

Relevant academic research and scientific papers

AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.

Discovery of novel cyclin-dependent kinase (CDK) and histone deacetylase (HDAC) dual inhibitors with potent in vitro and in vivo anticancer activity

In the current study, we reported a series of novel 1-H-pyrazole-3-carboxamide-based inhibitors targeting histone deacetylase (HDAC) and cyclin-dependent kinase (CDK). The representative compounds N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (7c) and N-(4-(2-((2-aminophenyl)amino)-2-oxoethyl)phenyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (14a) with potent antiproliferative activities towards five solid cancer cell lines, showed excellent inhibitory activities against HDAC2 (IC50 = 0.25 and 0.24 nM respectively) and CDK2 (IC50 = 0.30 and 0.56 nM respectively). In addition, compounds 7c and 14a significantly inhibited the migration of A375 and H460 cells. Further studies revealed that compounds 7c and 14a could arrest cell cycle in G2/M phase and promote apoptosis in A375, HCT116, H460 and Hela cells, which was associated with increasing the intracellular reactive oxygen species (ROS) levels. More importantly, compound 7c possessed favorable pharmacokinetic properties with the intraperitoneal bioavailability of 63.6% in ICR mice, and potent in vivo antitumor efficacy in the HCT116 xenograft model. Our study demonstrated that compound 7c provides a promising strategy for the treatment of malignant tumors.

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

PHARMACEUTICAL COMPOUNDS

The invention provides a cyclin dependent kinase (e.g. cdk-4 kinase) inhibitor of the formula (I) or a salt, tautomer, solvate or N-oxide thereof; wherein R1 is an optionally substituted monocyclic or bicyclic aryl or heteroaryl group containing 0-2 heteroatoms selected from O, N and S wherein the optional substituents are selected from halogen, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl and cyano, and wherein the C1-4 alkyl and C1-4 alkoxy groups are each optionally further substituted by C1-2 alkoxy or one or more halogen atoms; and E is a group E1, E2, E3 or E4: formulae E1, E2, E3, E4 wherein n, q, A5 B, T, U, V, W, Z, R2, R5, R6 and R7 are as defined in the claims.

PYRAZOLE DERIVATIVES AS THAT MODULATE THE ACTIVITY OF CDK, GSK AND AURORA KINASES

The invention provides a compound of the formula (I): for use in medicine: or salts or tautomers or N-oxides or solvates thereof; wherein R1 is an optionally substituted heterocyclic group having from 3 to 12 ring members provided that the cyclic group joined to the pyrazole contains at least one heteroatom selected from N, O or S; A is a bond or -Y-(B)n-; B is C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; n is 0 or 1; Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from optionally substituted carbocyclic and heterocyclic groups having from 3 to 12 ring members or an optionally substituted C1-8 hydrocarbyl group; with the proviso that R1 is not formula (II): where X, R3’ and R4’ are defined in the claims.

3,4-DISUBSTITUTED PYRAZOLES AS CYCLIN DEPENDENT KINASES (CDK) OR AURORA KINASE OR GLYCOGEN SYNTHASE 3 (GSK-3) INHIBITORS

The invention provides compounds of the formula (I); or salts or solvates or N-oxides thereof; wherein: Rq is selected from groups (a), (b) and (c); the asterisk denoting the point of attachment to the pyrazole ring; X is N or CR5; X" is NR4', O, S or S(O); A is a bond or -(CH2)m-(B)n-; B is C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; m is 0, 1 or 2; n is 0 or 1; R0 is hydrogen or, together with NRg when present, forms a group -(CH2)p- wherein p is 2 to 4; and R1 to R6b are as defined in the description. Compounds of the formula (I) have activity as inhibitors of CDK, aurora and GSK-3 kinases are useful in treating or preventing diseases such as cancers that are mediated by the said kinases.

PYRAZOLE DERIVATIVES FOR THE INHIBITION OF CDK' S AND GSK' S

The invention provides compounds of the formula (I), or salts, tautomers, N-oxides or solvates thereof wherein: R1 is selected from: (a) 2,6-dichlorophenyl; (b) 2,6-difluorophenyl; (c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy; (d) a group R0; (e) a group R a; (f) a group Rlb; (g) a group Rlc; (h) a group Rld; and 0) 2,6-difluorophenylamino ; wherein R )0υ, r R> llaa, T Rj I1bD, T R) I1cC, r R> Iidα, r R?2zaa, r R>22bD and RJ are as defined in the claims. The compounds have activity as inhibitors of cdk kinase (such as cdkl or cdk2) and glycogen synthase kinase-3 activity.

PHARMACEUTICAL COMPOUNDS

The invention provides a combination of a cytotoxic compound or signalling inhibitor and a compound having the formula (0): or salts or tautomers or N-oxides or solvates thereof; wherein X is a group R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NRg(C=O) or 0(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

COMBINATIONS OF PYRAZOLE KINASE INHIBITORS AND FURTHER ANTITUMOR AGENTS

The invention provides a combination of a compound having the formula (0) and two or more further anti-cancer agents: or salts or tautomers or N-oxides or solvates thereof; wherein X is a group R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NR9(C=O) or 0(C=O) wherein R9 is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1 , 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

PHARMACEUTICAL COMPOUNDS

The invention provides a combination of an ancillary agent and a compound having the formula (0): or salts or tautomers or N-oxides or solvates thereof; wherein the ancillary agent is selected from: a monoclonal antibody, an alkylating agent, an anticancer agent, a further CDK inhibitor and a hormone, hormone agonist, hormone antagonist or hormone modulating agent; X is a group R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NR9(C=O) or 0(C=O) wherein R9 is hydrogen or C1-4hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1 , 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).