84478-89-7

Upstream product

• 84478-88-6 2-chloro-4-fluoro-methoxycarbonyloxybenzene 
• 1996-41-4 2-chloro-4-fluorophenol 

Downstream Products

• 84478-75-1 2-chloro-4-fluoro-5-nitrophenol 
• 1005788-02-2 3-amino-4-fluorophenyl methyl carbonate hydrochloride 
• 1092391-56-4 N-[5-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo-[1,5-a]pyridin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide 
• 1092394-11-0 ethyl {[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-fluorophenoxy)pyridine-2-yl]carbamothioyl}carbamate 
• 1514914-63-6 C₁₇H₁₄BrFN₄O₂ 
• 1514914-97-6 C₁₇H₁₄ClFN₄O₂ 
• 1514914-92-1 C₁₁H₈BrFN₂O 
• 1514914-94-3 C₁₁H₈ClFN₂O 
• 62257-16-3 5-hydroxy-2-fluoroaniline 
• 84478-72-8 4-chloro-2-fluoro-5-hydroxyaniline 
• 1020173-38-9 2-fluoro-5-(6-nitropyridin-3-yloxy)benzenamine 
• 1005788-04-4 N-(2-fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide 
• 1092394-02-9 N-{2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide 
• 1092394-01-8 N-{5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide 

Relevant academic research and scientific papers

Development of a scalable synthesis of a vascular endothelial growth factor receptor-2 kinase inhibitor: Efficient construction of a 6-etherified [1,2,4]triazolo[1,5-a]pyridine-2-amine Core

A practical and scalable synthesis of the vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitor 1 has been developed. The key features of the process development include facile preparation of the key raw material 3-amino-4- fluorophenol, chemoselective nucleophilic aromatic substitution of 5-chloro-2-nitropyridine with phenol, a safe one-pot synthesis of a substituted urea using an isothiocyanate generated in situ from inexpensive materials, and improvement of the yield of acylation in the end game. The optimized six-step synthesis afforded 1·H2O in 54% overall yield, twice as much as the yield of the original synthesis, without chromatographic purification. In addition, a robust recrystallization procedure to afford the desired crystal form of 1 was also developed.

METHODS AND COMPOSITIONS FOR THE TREATMENT OF MYELOPROLIFERATIVE DISEASES AND OTHER PROLIFERATIVE DISEASES

Compounds of the present invention find utility in the treatment of hyperproliferative diseases, mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites secondary sites, myeloproliferative diseases, chronic myelogenous leukemia, acute lymphocytic leukemia, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, thyroid cancer, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, i.e. diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resorptive diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof, a disease caused by c-ABL kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, c-KIT kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, VEGFR kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, PDGFR kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, FLT-3 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, TIE-2 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, TRK kinases, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, c-MET kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a HER kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

CYCLOPROPANE AMIDES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including, but not limited to, malignant melanomas, solid tumors, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocytosis, mast cell leukemia, and diseases caused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase, c-MET kinase, and oncogenic forms, aberrant fusion proteins and polymorphs of any of the foregoing kinases.

Compounds and Methods of Treatment

A derivative, which is useful as a ret kinase inhibitor is described herein. The described invention also includes methods of using the same in the treatment of diseases mediated by inappropriate ret kinase activity.

KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFERATIVE DISEASES AND OTHER PROLIFERATIVE DISEASES

The present invention is concerned with novel compounds useful in the treatment of hyperproliferative diseases and mammalian cancers, especially human cancers. The invention also pertains to methods of modulating kinase activities, pharmaceutical compositions, and methods of treating individuals, incorporating or using the compounds. The preferred compounds are active small molecules set forth in formulae Ia-Iww.

Substituted piperazines

Compounds are provided that act as potent antagonists of the CCR1 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC50 values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC50 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 μM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.