612501-81-2

Upstream product

• 612501-52-7 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 
• 141699-59-4 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate 
• 26791-93-5 methyl 4,5-dimethoxy-2-nitrobenzoate 
• 100905-33-7 ethyl 2-nitro-4,5-dimethoxybenzoate 
• 26759-46-6 methyl 2-amino-4,5-dimethoxybenzoate 
• 5382-16-1 4-HYDROXYPIPERIDINE 
• 24424-99-5 di-tert-butyl dicarbonate 
• 20323-74-4 2-carboethoxy-4,5-dimethoxyaniline 
• 109384-19-2 t-butyl 4-hydroxy piperidine-1-carboxylate 
• 13794-72-4 3H-6,7-dimethoxyquinazolin-4-one 
• 179688-52-9 6-hydroxy-7-methoxyquinazolin-4(3H)-one 
• 179688-53-0 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one 
• 118811-07-7 tert-butyl 4-(tosyloxy)piperidin-1-carboxylate 
• 612501-80-1 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate monohydrochloride 

Downstream Products

• 612500-78-4 N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine 
• 1441145-46-5 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylethyl)piperidin-4-yl]oxy}quinazoline 
• 848942-61-0 Sapitinib 
• 1441146-12-8 tert-butyl [4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]propionate 
• 1441145-10-3 4-(3-chloro-2-fluoroanilino)-6-{[1-(N-isopropylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline 
• 848942-78-9 4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline 

Relevant academic research and scientific papers

Design of a "two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites

Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.

The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling

The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [11C]CO2and decay corrected to end of bombardment (EOB) with 370-1110 GBq/μmol specific activity at EOB.

Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

NOVEL SALT-554

4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate, pharmaceutical compositions containing the difumarate, the use of the difumarate in the treatment of hyperproliferative disorders such as canc

Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics

The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.

PIPERIDYL-QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS

The invention concerns quinazoline derivatives of formula (I) wherein R1and R2 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB, particularly EGF, receptor tyrosine kinases.

QUINAZOLINE DERIVATIVES

The invention concerns quinazoline derivatives of Formula (I): wherein each of R1, R2, X1, R5 and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

QUINAZOLINE DERIVATIVES

The invention concerns quinazoline derivatives of Formula (I): wherein each of R1, X1, R2, R3, R5, n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

4-ANILINO QUINAZOLINE DERIVATIVES AS ANTIPROLIFERATIVE AGENTS

The invention concerns quinazoline derivatives of Formula (I) wherein each of Q1, Z, R1 and Q2 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases.