937273-29-5

Upstream product

• 859517-90-1 [3-(2-chloropyrimidine-4-yl) phenyl]methanol 
• 106-95-6 allyl bromide 
• 87199-15-3 [3-(hydroxymethyl)phenyl]boronic acid 

Downstream Products

• 1312603-52-3 (3-allyloxymethyl-4-methoxyphenyl)-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine 
• 1312603-53-4 (3-allyloxymethyl-4-morpholin-4-yl-phenyl)-[4-(3-allyloxymethylphenyl)-pyrimidin-2-yl]-amine 
• 1312603-54-5 4-{2-allyloxymethyl-4-[4-(3-allyloxymethylphenyl)-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester 
• 1312603-55-6 [3-allyloxymethyl-4-(4-methylpiperazin-1-yl)phenyl]-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine 
• 1312603-56-7 2-allyloxymethyl-N'-[4-(3-allyloxymethyl-phenyl)-pyrimidin-2-yl]-N'-(2-dimethylamino-ethyl)-N'-methyl-benzene-1,4-diamine 
• 1312603-57-8 N-(4-(2-chloroethoxy)-3-((allyloxy)methyl)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine 
• 1312603-58-9 [3-allyloxymethyl-5-(2-chloroethoxy)phenyl]-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine 
• 1312603-60-3 [3-allyloxymethyl-5-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine 
• 1354567-51-3 {3-[(allylmethylamino)methyl]phenyl}-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine 

Relevant academic research and scientific papers

Large circular kinase inhibitor compound, preparation method and use thereof as a medicament

The invention relates to a compound shown in a formula (I), wherein L, R1, Z, A, B and C are defined in the application specification. The invention also relates to the application of the compound shown the formula (I) as kinase inhibitors.

Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines

Blockage of more than one oncoprotein or pathway is now a standard approach in modern cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vorinostat, to create bispecific single molecules with both JAK and HDAC targeted inhibition. A preferred ether hydroxamate, 51, inhibits JAK2 and HDAC6 with low nanomolar potency, is 50-fold selective for JAK2 in a panel of 97 kinases. Broad cellular antiproliferative potency is supported by demonstration of JAK-STAT and HDAC pathway blockade in several hematological cell lines, inhibition of colony formation in HEL cells, and analysis of apoptosis. This study provides new tool compounds for further exploration of dual JAK-HDAC pathway inhibiton achieved with a single molecule.

Macrocyclic compounds as anti-cancer agents: Design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2

A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2V617F mutation.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5, 7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27) ,9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26h as a preferred compound with target IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7, 26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27) ,16,21,23-decaene (SB1518), a potent Janus Kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2 WT and JAK2V617F, respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

PYRIMIDINE DERIVATIVES

The present invention relates to pyrimidine compounds that are useful as agents for the treatment of kinase related disorders such as proliferative disorders. More particularly, the present invention relates to substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of kinase related disorders such as proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with kinases.

OXYGEN LINKED PYRIMIDINE DERIVATIVES

The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with kinases.