623155-19-1

Upstream product

• 303133-89-3 N-cyclopropyl-4-methyl-3-nitrobenzamide 
• 10397-30-5 4-methyl-3-nitrobenzoyl chloride 
• 96-98-0 4-methyl-3-nitrobenzoic acid 
• 2458-12-0 3-amino-p-toluic acid 
• 765-30-0 Cyclopropylamine 
• 2592-95-2 benzotriazol-1-ol 

Downstream Products

• 851847-38-6 3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide 
• 851848-01-6 N-cyclopropyl-4-methyl-3-[(2-nitrobenzoyl)amino]benzamide 
• 851847-23-9 N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-methoxy-2-nitrobenzamide 
• 851847-21-7 N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-fluoro-2-nitrobenzamide 
• 1148050-78-5 N-cyclopropyl-3-(1-(3-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-ylamino)-4-methylbenzamide 
• 1195760-08-7 N-cyclopropyl-3-(3,4-difluorobenzamido)-4-methylbenzamide 
• 851847-97-7 N-cyclopropyl-3-(6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide 
• 1222076-94-9 C₂₂H₁₉FN₆O 
• 1222076-97-2 C₂₂H₁₈F₂N₆O 
• 1222077-03-3 C₂₂H₁₈F₂N₆O 
• 1222077-13-5 C₂₃H₂₁FN₆O 
• 1222077-16-8 C₂₃H₂₀F₂N₆O 
• 858359-57-6 3-(5-amino-6-chloro-pyrimidin-4-ylamino)-N-cyclopropyl-4-methyl-benzamide 
• 857355-35-2 N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylthio)pyrimidine-5-carboxamide 

Relevant academic research and scientific papers

Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine

We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.

The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4- oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin- 3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.

Bicyclic Derivatives as P38 Inhibitors

New bicyclic derivatives of formula (I); wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

CYCLOPROPYL BENZAMIDE DERIVATIVES AS INTERMEDIATES FOR CYTOKINE INHIBITORS

A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein Qa is as defined in the specification, the compounds being useful in the preparation of therapeutic agents, in particular cytokine inhibitors. Novel compounds of formula (I) are also provided.

ISOQUINOLINE DERIVATIVES AND THEIR USE AS INHIBITORS OF CYTOKINE MEDIATED DISEASES

The invention concerns a compound of formula (I) or pharmaceutically-acceptable salts thereof wherein R1, R2, R3, R4, R5 and m are as defined in the specification, processes for their preparation, pha

AMIDE DERIVATIVES

The invention concerns a compound of the Formula I (A chemical formula should be inserted here - please see paper copy enclosed herewith) wherein m is 0-2 and each R1 is a group such as hydroxy, halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R2 is halogeno, trifluoromethyl or (1-6C)alkyl; R3 is hydrogen, halogeno or (1-6C)alkyl; and R4 is (3-6C)cycloalkyl;or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by cytokines.

Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein

Processes are provided for selectively preparing novel stable crystalline salt forms, selectively and consistently, namely, preparing Form N-1 of the methanesulfonic acid salt, and Form N-1 and Form N-4 of the hydrochloric acid salt of the p38 kinase inhibitor 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide. The processes preferably employ solvent systems including formic acid/acetone and formic acid/methylethyl ketone which produce crystals having suitable flow properties and desired particle size, and solvents such as N,N-dimethylformamide and N,N-dimethylacetamide may be employed as well. Novel Form N-1 crystals of the Form N-1 and Form N-4 crystals of the hydrochloride salt and Form N-1 crystals of the methanesulfonic acid salt of the above free base, pharmaceutical compositions containing such novel forms and a method of treating p38 kinase associated conditions, including rheumatoid arthritis are also provided.

AMIDE DERIVATIVES

The invention concerns a compound of the Formula (I) wherein m is 0-2 and each R1 is a group such as hydroxy, halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R2 is halogeno, trifluoromethyl or (1-6C)alkyl; R3 is hydrogen, halogeno or (1-6C)alkyl; and R4 is (3-6C)cycloalkyl;or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by cytokines.

AMIDE DERIVATIVES BEARING A CYCLOPROPYLAMINOACARBONYL SUBSTITUENT USEFUL AS CYTO KINE INHIBITORS

The invention concerns a compound of the Formula (I), wherein Qa is heteroaryl and is substituted with halogeno; R1 and R2 are each hydrogen; and Qb is phenyl or heteroaryl, and Qb may optionally bear 1 or 2 substituents selected from hydroxy, halogeno and (1-6C)alkyl, or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by cytokines.