955979-02-9

Usage

Uses

Used in Pharmaceutical Industry:
2-chloro-7-Methyl-4-Morpholinothieno[3,2-d]pyriMidine-6-carbaldehyde is used as a potential pharmaceutical agent for its possible biological activity. 2-chloro-7-Methyl-4-Morpholinothieno[3,2-d]pyriMidine-6-carbaldehyde's unique structure may contribute to its efficacy in treating various medical conditions, although specific applications have yet to be determined through further study.
Used in Organic Synthesis:
In the field of organic chemistry, 2-chloro-7-Methyl-4-Morpholinothieno[3,2-d]pyriMidine-6-carbaldehyde serves as a valuable building block for the synthesis of other complex organic molecules. Its diverse functional groups provide opportunities for chemical reactions that can lead to the creation of new compounds with specific properties and applications.

Upstream product

• 35265-88-4 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine 
• 85006-31-1 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester 
• 35265-81-7 7-methylthieno<3,2-d>pyrimidine-2,4-dione 
• 35265-83-9 2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine 
• 68-12-2 N,N-dimethyl-formamide 

Downstream Products

• 1032757-09-7 (R)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one 

Relevant academic research and scientific papers

PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof

The invention discloses a PARP-1/PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1/PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and/or PI3K.

DUAL KINASE-BROMODOMAIN INHIBITORS

Provided herein are compounds of Formula (I) that are dual inhibitors of kinases and bromo-domain proteins. The disclosure also relates to pharmaceutical compositions containing such compounds, methods for using such compounds in the treatment of cancers, particularly, the treatment of multiple myeloma cancers, and to related uses.

A practical, protecting-group-free synthesis of a PI3K/mTOR inhibitor

We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980. The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki-Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH3 was employed to replace Na(OAc)3BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with (S)-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC.

PROCESS FOR MAKING THIENOPYRIMIDINE COMPOUNDS

Process methods for making the dual mTOR/PI3K inhibitor GDC-0980, named as (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, having the structure: and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.

Discovery of a potent, selective, and orally available class i phosphatidylinositol 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer

The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a Ki of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.

Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.

PYRIMIDINE DERIVATIVES AS PI3K INHIBITORS

Thienopyrimidines of formula (Ia) or (Ib): wherein R1, R2, R3, are as defined in the claims.