(S)-1-[4-[[2-(2-Aminopyrimidin-5-yl)-7-methyl-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one

Apitolisib (GDC-0980) is a selective, potent, orally bioavailable Class I PI3 kinase and mTOR kinase (TORC1/2) inhibitor with IC50s of 5 nM/27 nM/7 nM/14 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ, and with a Ki of 17 nM for mTOR.

Apitolisib has been used in trials studying the treatment of Solid Cancers, Breast Cancer, Prostate Cancer, Renal Cell Carcinoma, and Endometrial Carcinoma, among others.|Apitolisib is an orally available agent targeting phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinase in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Apitolisib inhibits both PI3K kinase and mTOR kinase, which may result in tumor cell apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated in a PI3K-independent fashion.

The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3, 2-d]pyrimidine (590 mg) was reacted with lactic acid via General Procedure B-2 to give (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3, 2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.The Suzuki-type coupling reaction is useful to attach a monocyclic heteroaryl at the 2-position of the pyrimidine ring (see Scheme 4). Generally, substituted 2-chloro-4-morpholinothieno[3, 2-d]pyrimidine 5 or substituted 2-chloro-4-morpholinothieno[2, 3-d]pyrimidine 6 may be combined with 1.5 equivalents of 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-amine 7a, and dissolved in 3 equivalents of sodium or potassium carbonate as a 1 molar solution in water and an equal volume of acetonitrile. A catalytic amount, or more, of a low valent palladium reagent, such as bis(triphenylphosphine)palladium(II) dichloride, is added. A variety of boronic acids or boronic esters can be used in place of the pinacol boronic ester indicated. Also alternatively, the nitrogen of the pyrimidin-2-amine may be protected, for example with a tetrahydropyranyl group. In some cases potassium acetate was used in place of sodium carbonate to adjust the pH of the aqueous layer. The reaction was then heated, for example to about 100-150° C. under pressure in a Biotage Optimizer microwave reactor (Biotage, Inc.) for 10 to 30 minutes. The contents are extracted with ethyl acetate, or another organic solvent. After evaporation of the organic layer the product, 8a or 9a, may be purified on silica or by reverse phase HPLC. (S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3, 2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A-2 to give 10 mg of Formula Ib (WO 2008/070740, incorporated by reference).The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3, 2-d]pyrimidine (590 mg) was reacted with lactic acid via General Procedure B-2 to give (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3, 2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.The Suzuki-type coupling reaction is useful to attach a monocyclic heteroaryl at the 2-position of the pyrimidine ring (see Scheme 4). Generally, substituted 2-chloro-4-morpholinothieno[3, 2-d]pyrimidine 5 or substituted 2-chloro-4-morpholinothieno[2, 3-d]pyrimidine 6 may be combined with 1.5 equivalents of 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-amine 7a, and dissolved in 3 equivalents of sodium or potassium carbonate as a 1 molar solution in water and an equal volume of acetonitrile. A catalytic amount, or more, of a low valent palladium reagent, such as bis(triphenylphosphine)palladium(II) dichloride, is added. A variety of boronic acids or boronic esters can be used in place of the pinacol boronic ester indicated. Also alternatively, the nitrogen of the pyrimidin-2-amine may be protected, for example with a tetrahydropyranyl group. In some cases potassium acetate was used in place of sodium carbonate to adjust the pH of the aqueous layer. The reaction was then heated, for example to about 100-150° C. under pressure in a Biotage Optimizer microwave reactor (Biotage, Inc.) for 10 to 30 minutes. The contents are extracted with ethyl acetate, or another organic solvent. After evaporation of the organic layer the product, 8a or 9a, may be purified on silica or by reverse phase HPLC. (S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3, 2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A-2 to give 10 mg of Formula Ib (WO 2008/070740, incorporated by reference).

Molecular Weight:498.6
XLogP3:0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:5
Exact Mass:498.21615802
Monoisotopic Mass:498.21615802
Topological Polar Surface Area:162
Heavy Atom Count:35
Complexity:715
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes