1032903-48-2

Upstream product

• 1780-31-0 2,6-dichloro-5-methylpyrimidine 
• 76697-50-2 1-amino-2-(isopropylsulphonyl)benzene 

Downstream Products

• 1032903-61-9 N₂-(5-bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N₄-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine 
• 1445895-27-1 N₂-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenyl)-N₄-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine 
• 1445895-25-9 2-(4-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-2-methylphenyl)piperidin-1-yl)ethanol 
• 1445894-96-1 N₂-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N₄-(2-(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine 

Relevant academic research and scientific papers

Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) na?ve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.

Small molecule inhibitors of leucine-rich repetitive kinase 2 and their applications

The present invention provides a small molecule inhibitor of leucine-rich repetitive kinase 2 and applications thereof; compounds as small molecule inhibitors such as compounds shown in formula I of the present invention or isotopic forms thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs. The compound has a high LRRK2 inhibitory activity and has high application value in the preparation of drugs for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases.

DIPHENYLAMINOPYRIMIDINE AND TRIAZINE COMPOUND, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF

The invention relates to a diphenylaminopyrimidine and triazine compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof: wherein A is C or N; X and Y are independently selected from hydrogen, halo, cyano, trifluoromethyl, alkoxy, alkyl, aryl, alkenyl, alkynyl and nitro; or X and Y, together with the atoms to which they are attached, form a phenyl or an heteroaromatic ring; R1 is R2 is CD3 or CD2CD3; R3 is R4 is hydrogen, methyl, trifluoromethyl, cyano or halo; R5 is hydrogen, alkyl, substituted and unsubstituted phenyl, allyl or propargyl; R6 and R7 are independently selected from hydrogen, alkyl, substituted and unsubstituted phenyl, allyl and propargyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl group. The compound herein has excellent pharmacodynamic and pharmacokinetic properties and ALK kinase inhibitory activity.

Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC

Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC.

PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS

The invention features compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- N 2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)- N 4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS

The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-1R), or a combination thereof.