110234-68-9

Usage

Uses

Used in Pharmaceutical Industry:
4,4,4-Trifluoro-3-oxobutanenitrile is used as a reagent for the preparation of ((dimethoxyquinazolinyloxy)phenyl)urea derivatives, which are orally efficacious inhibitors of V-RAF murine sarcoma viral oncogene. These inhibitors have potential applications in the treatment of various cancers driven by the V-RAF oncogene.
4,4,4-Trifluoro-3-oxobutanenitrile is also used as a reagent in the preparation of orally active inhibitors of Brahma homolog (BRM)/SMARCA2 ATPase activity. These inhibitors are used for the treatment of Brahma related gene 1 (BRG1)/SMARCA4-mutant cancers, which are a subset of cancers with specific genetic mutations.
Furthermore, 4,4,4-Trifluoro-3-oxobutanenitrile is used as a reagent in the synthesis of 2-(trifluoromethyl)nicotinic acid derivatives from fluorinated precursors. These derivatives have potential applications in the development of new drugs targeting various diseases and conditions.

InChI:InChI=1/C4H2F3NO/c5-4(6,7)3(9)1-2-8/h1H2

Upstream product

• 383-63-1 ethyl trifluoroacetate, 
• 75-05-8 acetonitrile 
• 431-47-0 trifluoroacetic acid-methyl ester 

Downstream Products

• 149978-43-8 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 149978-42-7 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine 
• 110234-43-0 5-(trifluoromethyl)isoxazol-3-amine 
• 897373-39-6 ethyl 2-(3-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetate 
• 1006458-25-8 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 33561-24-9 3-amino-4,4,4-trifluoro-2-butenenitrile 
• 852443-61-9 5-amino-3-(trifluoromethyl)-1H-pyrazole 
• 182923-55-3 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 1226010-80-5 1-(5-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 1402585-38-9 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 1226417-61-3 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 1226291-40-2 1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine 
• 1260539-46-5 4-{5-Amino-3-(trifluoromethyl)-1H-pyrazolo-1-yl}-3-methylbenzonitrile 
• 1226309-46-1 1-[4-(methyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-amine 

Relevant academic research and scientific papers

Synthesis and Biological Activity of Novel Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with an EC50 value of 0.20 mg/L, close to that of commercial fungicide Fluxapyroxad (EC50 = 0.12 mg/L) and Boscalid (EC50 = 0.11 mg/L). For Valsa mali, compound 5IIc (EC50 = 3.68 mg/L) showed a significantly higher activity than Fluxapyroxad (EC50 = 12.67 mg/L) and Boscalid (EC50 = 14.83 mg/L). In addition, in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against S. sclerotiorum at 50 mg/L, while the positive control Fluxapyroxad showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound 5IIc interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-πinteraction, which could explain the probable mechanism of the action between compound 5IIc and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound 5IIc could be a promising fungicide candidate and provide a valuable reference for further investigation.

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

Substrate-controlled switchable asymmetric annulations to access polyheterocyclic skeletons

An unexpected domino process from Morita-Baylis-Hillman carbonates of isatins and acrylate and α-cyano-α,β-unsaturated ketones to deliver highly enantioenriched tetrahydrofuro[2′,3′:4,5]pyrano[2,3-b]indoles catalysed by cinchona-derived tertiary amines, involving α-regioselective cyclopropanation, ring-opening, and ring-closure cascade reactions, was disclosed. In contrast, spirooxindoles incorporating a cyclopentene motif were produced through [3+2] annulations by employing Morita-Baylis-Hillman carbonates from isatins and acrylonitrile under similar catalytic conditions. Density functional theory calculations were conducted to elucidate the novel domino process and the switchable annulation reactions.

Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAFV600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAFV600E inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.

ISOINDOLINONE COMPOUNDS

Disclosed herein is a compound or pharmaceutically acceptable salts or stereoisomers thereof of of formula I wherein X1 is linear or branched C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkyl C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 alkyl C6-10 aryl, C1-6 alkyl 5-10 membered heteroaryl, wherein X1 is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-C1- 6alkyl, -OC(O)-C1-6alkyl, -OC(O)-C1-4alkylamino, -C(O)O-C1-6alkyl, -COOH, - CHO, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-6 alkoxy or C1-6 alkylhydroxy; X2 is hydrogen, C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C1-4alkyl-4-8 membered heterocycloalkyl or C6 aryloxy, wherein X2 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, NH2, NMe2 or 5-6 membered heterocycloalkyl; n is 0, 1 or 2.

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.

UREA COMPOUNDS AND COMPOSITIONS AS SMARCA2/BRM ATPASE INHIBITORS

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a BRM-mediated and/or BRG1-mediated disease or disorder: Formula (I) wherein R1 through R6 are as defined herein.

Fluorine-containing pyrazole amide derivative, and preparation method and application thereof

The invention discloses a fluorine-containing pyrazole amide derivative, and a preparation method and application thereof. The structural formula of the fluorine-containing pyrazole amide derivative is as described in the invention. In the structural formula, R1 is a trifluoromethyl or difluoromethyl group; R2 is hydrogen, chlorine, fluorine, bromine or iodine; and R3 is polysubstituted benzene orpolysubstituted pyridine. The fluorine-containing pyrazole amide derivative has remarkable antifungal activity and can provide a basis for development of a novel bactericide with the fluorine-containing pyrazole amide compound derivative as an active ingredient.

Selective targeting of the αC and DFG-out pocket in p38 MAPK

The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.

SUBSTITUTED PYRAZOLOPYRIMIDINES AND SUBSTITUTED PURINES AND THEIR USE AS UBIQUITIN-SPECIFIC-PROCESSING PROTEASE 1 (USP1) INHIBITORS

The present disclosure provides compounds having Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein X1, X2, X11, X12, R1, R3, R5, R5', R6, and R7 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to inhibit a USP1 protein and/or to treat a disorder responsive to the inhibition of USP1 proteins and USP1 activity. Compounds of the present disclosure are especially useful for treating cancer.