339016-21-6

Upstream product

• 110-91-8 morpholine 
• 6299-25-8 4,6-Dichloro-2-(methylthio)pyrimidine 

Downstream Products

• 1072084-49-1 [2-(3-chloro-phenyl)-ethyl]-[4-(6-fluoro-1H-indol-4-yl)-6-morpholin-4-yl-pyrimidin-2-yl]-amine 

Relevant academic research and scientific papers

INHIBITORS OF RAF KINASES

Provided herein are inhibitors of receptor tyrosine kinase effector, RAF, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

PIKFYVE KINASE INHIBITORS

The present invention relates to compounds useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as well as their use for treating diseases and disorders associated with PIKfyve.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS

The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.

PHARMACEUTICAL COMPOUNDS

The invention provides compounds which are pyrimidines of formula (I): wherein R2 is bonded at ring position 2 and -YR1 is bonded at ring position 5 or 6, or YR1 is bonded at ring position 2 and R2 is bonded at ring position 6; R is an indol-4-yl group which is substituted at the 5- or 6-position; either: (a) Y is selected from -O-(CH2)n-, -NH-(CH2)n-,. -NHC(O)-(CH2)n and -C(O)NH-(CH2)n- wherein n is 0 or an integer of 1 to 3, and R1 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted and a group -NR3R4 wherein R3 and R4, which are the same or different, are each independently selected from H, C1-C6 alkyl which is unsubstituted or substituted, C3 - C10 cycloalkyl which is unsubstituted or substituted, -C(O)R, -C(O)N(R)2 and -S(O)mR, or R3 and R4 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted; (b) Y is a direct bond and R1 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted, and a group -NR3R4 wherein R3 and R4, which are the same or different, are each independently selected from H, C1-C6 alkyl which is unsubstituted or substituted, C3-C10 cycloalkyl which is unsubstituted or substituted, -C(O)R, -C(O)N(R)2 and -S(O)mR; R is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, which group is unsubstituted or substituted; and m is 1 or 2; or a pharmaceutically acceptable salt thereof. These compounds are inhibitors of PO K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PB kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

PHARMACEUTICAL COMPOUNDS

The invention provides a compound which is a pyrimidine of formula (I): The compounds are inhibitors of PI3K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.