WO2021133509A1 - Heterocyclic compounds as mtor inhibitors - Google Patents

Abstract

The present disclosure describes novel heterocyclic mTOR inhibitors and methods for preparing them. The pharmaceutical compositions comprising such mTOR inhibitors and methods of using them for treating cancer, infectious diseases, and other mTOR associated disorders are also described.

Description

HETEROCYCLIC COMPOUNDS AS mTOR INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/954,221, filed December 27, 2019; which is incorporated by reference by its entirety.

FIELD

The present disclosure relates to heterocyclic compounds, such as 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl-4((S)-3-methylmorpholino)quinazolin-7-yl)-N- methylbenzamine (1-7), as mTOR inhibitors, and pharmaceutical compositions comprising such compounds. The present disclosure also relates to the use of the compounds and compositions to treat cancer, infectious diseases, and other disorders.

BACKGROUND

The mammalian target of rapamycin (mTOR) is an important signaling node that integrates environmental cues to regulate cell survival, proliferation, and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORCI) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including cancer, diabetes, and neurodegeneration. mTORCI is a ubiquitously expressed protein complex that controls cell growth by inducing protein and nucleotide synthesis, ribosome biogenesis, and lipogenesis and by blocking autophagy. mTORCI is able to sense environmental signals including growth factors and nutrients and initiates cell growth in favorable environmental conditions. In contrast, unfavorable conditions such as acidity and hypoxia, which are frequently encountered in the tumor microenvironment, inhibit mTORCI activity. Among the different signaling pathways that transmit extracellular signals to mTORCI, oncogenic PI3K/AKT, and RAS/RAF/MEK/MAPK pathways have been well characterized. Activation of these pathways leads to the phosphorylation and inhibition of TSC2 which, in association with TSC1 , forms a protein complex that inhibits mTORCI . Of note, mutations in the TSC1 or TSC2 gene are responsible for the tuberous sclerosis complex (TSC), a disease characterized by a variety of benign tumors found in multiple organs including the brain, kidneys, liver, heart, and lungs. Following activation, mTORCI phosphorylates a variety of substrates such as S6K1 and 4E-BP1, leading overall to an anabolic cellular response and resulting in cell growth and proliferation.

Since mTORCI controls cell growth, it represents a potential target in cancer therapy. mTORCI hyperactivation is furthermore frequently observed in sporadic cancers, either through activating mutations of upstream effectors of mTORCI or through activating mutations of mTOR itself. Additionally, enhanced activation of mTORCI is observed in hamartoma syndromes including Peutz-Jeghers syndrome, Cowden disease, and TSC that are characterized by the development of benign tumors and mutations in tumor-suppressor genes that negatively regulate mTORCI activity.

While mTORCI signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes. AKT, a key substrate of mTORC2, is among the most commonly hyper-activated proteins in cancer. AKT integrates signals from PI3K/mTORC2 and from PI3K/PDK1 to promote cell growth and survival. Like mTORC2, AKT localization to the plasma membrane is regulated by PIP3. In PTEN null prostate cancer, loss of mTORC2 activity inhibits tumorigenesis, illustrating the importance of mTORC2 signaling downstream of PIP3. Interestingly, PTEN null glioma patients exhibit mTORC2-mediated chemotherapy resistance in an AKT independent manner, suggesting that inhibition of mTORC2 may be useful in treatment of patients with PTEN or PI3K mutations. mTORC2 also regulates cancer cells’ preferential use of glycolysis for energy production through the AKT-independent acetylation of Fox01/3, demonstrating a mTORC2-mediated role in cancer metabolism. In addition to its activation by mTORC2, AKT activates mTORCI signaling (13,21), adding another layer of complexity to this signaling pathway, genomic alterations, suggesting a distinct role for mTORC2 in cancer as well.

Accordingly, the identification and development of small molecules that inhibit the activity of mTOR and related kinases (AKT and PI3K) will serve as an effective therapeutic approach for the treatment of a variety of disorders, such as cancers.

SUMMARY

This disclosure relates to heterocyclic compounds comprising pyrido[2,3-d]pyrimidine derivatives, such as a compound of Formula 1, certain optionally substituted 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aS)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2- ((4aS,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)pyrido[2,3-d]pyrimidin-7-yl)benzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2-((4aS,8aS)-octahydro-4H- benzo[b][1,4]oxazin-4-yl)pyrido[2,3-d]pyrimidin-7-yl)benzamide, optionally substituted 3-(2- ((4aS,7aS)-hexahydro-4H-furo[3,4-b][1,4]oxazin-4-yl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aR)-hexahydro-4H- furo[3,4-b][1,4]oxazin-4-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N- methylbenzamide, optionally substituted (S)-3-(2-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(3- methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted 2- fluoro-5-(2-((4aS,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3- methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted (4aS,7aR)-4-(7-(3-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-2-yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7-(3- (5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-2-yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(4-((S)- 3-methylmorpholino)-7-(3-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(4-((S)-3- methylmorpholino)-7-((methylsulfonyl)methyl)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7- ((cyclopropylsulfonyl)methyl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7-(1- (cyclopropylsulfonyl)cyclopropyl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, or a pharmaceutically acceptable salt thereof, or a combination thereof (referred to collectively herein as a “subject compound”).

Some embodiments include a compound represented by Formula 1:

or a pharmaceutically acceptable salt thereof; wherein any ring carbon in Formula 1 is optionally substituted; wherein the dashed line represents the presence or absence of a double bond; wherein R¹ is C_1-6 alkyl; R² is an optionally substituted phenyl, or an optionally substituted sulfone methyl group; and Ring A is an optionally substituted 4- to 6-membered ring. In some embodiments, Ring A is an optionally substituted C₆ aromatic ring, an optionally substituted saturated C_4-6 cyclic hydrocarbon ring, or an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom.

Some embodiments include a method of treating cancer, infectious diseases, and other mTOR-related diseases or disorders comprising administering a subject compound to a patient in need thereof.

Some embodiments include use of a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other mTOR -related diseases or disorders.

Some embodiments include a product kit containing a dosage form that comprises an effective amount of a subject compound for treating cancer, infectious diseases, and other mTOR- related diseases or disorders. The kit may also include written instructions indicating that the dosage form should be used as described herein.

Some embodiments include a method of treating a patient in need thereof, having a disease, a disorder, or a condition associated with the inhibition of mTOR kinase, comprising administering a therapeutically effective amount of a subject compound to the patient. In some embodiments, the disease is cancer. In some embodiment, the disease is an infectious disease. Some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of a subject compound in combination with at least one pharmaceutically acceptable carrier.

Some embodiments include a process for synthesizing a subject compound.

Some embodiments include a process for making a pharmaceutical composition comprising combining a subject compound and at least one pharmaceutically acceptable carrier.

Some embodiments include a kit containing a subject compound and a label with instructions to use the subject compound, or a composition or dosage form containing the subject compound, for the treatment of cancer, infectious diseases, and other mTOR related disorders.

DETAILED DESCRIPTION

Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts, etc.; or hydrochloride salt, hydrobromide salt, acetic acid salt, and maleic acid salt, etc.; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

If stereochemistry is not indicated, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.

In some embodiments, a compound of Formula 1 is a single enantiomer.

Unless otherwise indicated, when a compound or chemical structural feature such as aryl is referred to as being “optionally substituted”, it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is “substituted”, meaning that the feature has one or more substituents. The term “substituent” is broad; and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 g/mol to 60 g/mol, 15 g/mol to 70 g/mol, 15 g/mol to 80 g/mol, 15 g/mol to 90 g/mol, 50 g/mol to 60 g/mol, 60 g/mol to 70 g/mol, 70 g/mol to 80 g/mol, 80 g/mol to 90 g/mol, 90 g/mol to 100 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol _to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some embodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0- 10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom and N, S and P can be optionally oxidized. Examples of substituents include, but are not limited to, deuterium, tritium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, phosphonic acid, etc.

In some embodiments, some substituents include C_{1 -12} alkyl, C_2-12 alkenyl, C_2-12 alkynyl, - NR^AR^B, -OR^A, -S-R^A, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, aryloxy, -C(O)-R^A, R^A-C(O)O- alkylcarboxylate, -SH, -CN, F, Cl, Br, I, -C(=S)-R^A, -OC(O)-NR^AR^B, R^A-OC(O)-N(R^A)-, -OC(=S)- NR^AR^B, R^A-OC(=S)-N(R^A)-, -C(O)NR^AR^B, R^A-C(O)N(R^A)-, (R^AR^B)N-S(O)₂-, -N(R^A)-S(O)₂-R^A, -NO₂, R^A-S(=O)-, -S(O)₂-R^a, haloalkyl, haloalkoxyl, -S(O)₂C(X’)₃ wherein X’ is halogen, - N(R^A)S(O)₂C(X’)₃ wherein X’ is halogen, amino, -N(R^A)C(O)-heteroaryi, -N(R^A)C(O)-heterocyclyi, -C(O)N(R^A)-heteroaryl,. -C(O)N(R^A)-heterocyclyi, or a combination thereof.

For convenience, the term “molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.

The structures associated with some of the chemical names referred to herein are depicted below. These structures may be unsubstituted, as shown below, or substituted with a substituent that may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by

, attachment may occur at any position normally occupied by a hydrogen atom.

pyrido[2,3-d]pyrimidine-2,4,7-tri-yl cyclopentane- 1 ,2-diyl

cis-cyclopentane-1 ,2-diyl trans-cyclopentane-diyl

trans- tetrahydrofuran-3,4-diyl cyclohexane- 1 ,2-diyl

cis- cyclohexane- 1 ,2-diyl trans- cyclohexane- 1 ,2-diyl

With respect to the structural representation of Formula 1, the dashed line represents the presence or absence of a double bond;

With respect to the structural representation of Formula 1, any ring carbon is optionally substituted. In some embodiments, any or each of the substituents of Ring carbon may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol. Potential substituents of Ring carbon may include halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C₂ alkyl, C₂ alkenyl, C₂ alkynyl, C₃ alkyl, C₃ cycloalkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C4 cycloalkyl, C₄ alkenyl, C₄ alkynyl, C₅ alkyl, C₅ cycloalkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆ cycloalkyl, C₆ alkenyl, C₆ alkynyl, phenyl, etc.; CN_0-1 O_0-2F_0-3H_0-4; C₂N_0-1 O_0-3F_0-5H_0-6; C₃N_0-1 O_0-3F_0-7H_0-8; C₄N_0-1 O_0-3F_0-9H_0-10; C₅N_0-1 O_{0- 3}F_{0-1 1} H_0-12; C₆N_0-1 O_0-3F_0-13H_0-14; etc. In some embodiments, Formula 1 is further represented by Formula 2:

With Respect to Formula 2, R^2a or R^2b is independently H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, -CO₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R^1j, of R^{1 k} is independently H or any substituent, such as such as R^A, F, Cl, CN, -OR^A, CF₃, -NR^AR^B, -COR^A, -CO₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. Some of the structures with attachment points are shown below. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R^1J, or R^{1 k} may independently be H; F; Cl; CN; CF₃; OH; NH₂; C_1-6 alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl, cyclopropyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), any one of the pentyl isomers, any one of the cyclopentyl isomers, any one of the hexyl isomers, and any one of the cyclohexyl isomers, etc.; or C_1-6 alkoxy, such as -O-methyl, -O-ethyl, any one of the isomers of -O-propyl, -O-cyclopropyl, any one of the isomers of -O-butyl, any one of the isomers of -O-cyclobutyl, any one of the isomers of -O-pentyl, any one of the isomers of -O-cyclopentyl, any one of the isomers of -O-hexyl, any one of the isomers of -O-cyclohexyl, etc. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R^1j, or R^{1 k} may independently be H, F, Cl, or CH₃. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R^1j, or R^{1 k} may independently be H. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R¹’, or R^{1 k} is F. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^{1 c}, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R^1j, or R^{1 k} may independently be CH₃. In some embodiments, R^2a, R^2b, R^1a, R^{1 b}, R^1c, R^1d, R^1e, R^1f, R¹⁹, R^{1 h}, R^{1 i}, R¹’, and R^{1 k} may be all H.

With respect to any relevant structural representation, each R^A may independently be H, or C_{1 -12} hydrocarbyl, such as C_{1 -12} alkyl, C_{1 -12} alkenyl, C_{1 -12} alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C_aH_2a+1, or cycloalkyl having a formula C_aH_2a-1, wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁ C,₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁ , etc., or cycloalkyl with a formula: C₃H₅, C₄H₇, C₅H₉, C₆Hn, C₇H ₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^A may be H or C1-6 alkyl. In some embodiments, R^A may be H or C_{1 -3} alkyl. In some embodiments, R^A may be H or CH₃. In some embodiments, R^A may be H.

With respect to any relevant structural representation, each R^B may independently be H, or C_{1 -12} hydrocarbyl, such as C_{1 -12} alkyl, C_{1 -12} alkenyl, C_{1 -12} alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C_aH_2a+1, or cycloalkyl having a formula C_aH_2a-1, wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H_{1 1} , C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁ , etc., or cycloalkyl with a formula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H ₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^B may be H or C1-3 alkyl. In some embodiments, R^B may be H or CH₃. In some embodiments, R^B may be H.

With respect to any relevant structural representation, such as Formula 1 or Formula 2, Ring A is an optionally substituted 4- to 6-membered ring; and wherein Ring A is an optionally substituted C₆ aromatic ring, an optionally substituted saturated C_4-6 cyclic hydrocarbon ring, or an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom. In some embodiments, any or each of the substituents of Ring A may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol. Potential substituents of Ring A may include halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C₂ alkyl, C₂ alkenyl, C₂ alkynyl, C₃ alkyl, C₃ cycloalkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C₄ cycloalkyl, C₄ alkenyl, C₄ alkynyl, C₅ alkyl, C₅ cycloalkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆ cycloalkyl, C₆ alkenyl, C₆ alkynyl, phenyl, etc.; CN_0-1O_0-2F_0-3H0-4; C2N_0-1O_0-3F_0-5H_0-6; C₃N_0-1O_0-3F_0-7H_0-8; C₄N_0-1O_0-3F_0-9H_{0- 10}; C₅N_0-1O_0-3F_{0-1 1}H_0-12; C₆N_0-1O_0-3F_0-13H_0-14; etc. In some embodiments, Ring A is an optionally substituted C₆ aromatic ring having 0, 1, 2, 3, or 4 substituents, such as a benzene ring substituted with F, Cl, Br, C_1-6 alkyl, -CO₂H, , -CN, -CO- C_1-6 alkyl , -C(O)O-C_1-6 alkyl , - C_1-6 alkyl-OH, OH, NH₂, etc. In some embodiments, Ring A is unsubstituted benzene ring. In some embodiments, Ring A is an optionally substituted saturated C_4-6 cyclic hydrocarbon ring. In some embodiments, Ring A is an optionally substituted saturated C₄ cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, or 6 substituents. In some embodiments, Ring A is an optionally substituted saturated C₅ cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents. In some embodiments, Ring A is an optionally substituted saturated C₆ cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents. In some embodiments, Ring A is an optionally substituted cis-cyclopentane-1,2- diyl. In some embodiments, Ring A is an optionally substituted trans-cyclopentane-diyl. In some embodiments, Ring A is an optionally substituted cis-cyclohexane-1,2-diyl. In some embodiments, Ring A is an optionally substituted trans-cyclohexane- 1, 2-diyl. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen atom. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring nitrogen atom. In some embodiments, Ring A is an optionally substituted cis-tetrahydrofuran-3,4-diyl. In some embodiments, Ring A is an optionally substituted trans-tetrahydrofuran-3,4-diyl. In some embodiments, Ring A is unsubstituted.

In some embodiments, the two bonds of Ring A directly attaching to the morpholine ring are in c/s-conformation. In some embodiments, the two bonds of Ring A directly attaching to the morpholine ring are in trans-conformation.

With respect to Formula 1 or Formula 2, in some embodiments, Ring A is represented by Formula A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, orA14:

With respect to any relevant structural representation, such as Formula A1, R³, R⁴, R⁵, or R⁶is independently H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, -CO₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R³, R⁴, R⁵, or R⁶ may independently be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R³, R⁴, R⁵, or R⁶ may independently be H, F, or Cl. In some embodiments, R³, R⁴, R⁵, or R⁶ may independently be H. In some embodiments, R³, R⁴, R⁵, or R⁶ may be F. In some embodiments, R³, R⁴, R⁵, and R⁶ are all H.

With respect to any relevant structural representation, such as Formula A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, or A14, R^A1, R^A2, R^A3, R^A4, R^A5, R^A6, R^A7, R^A8, R^A9, or R^A1° is independently H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NR^AR^B, -COR^A, -CO₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R^A1, R^A2, R^A3, R^A4, R^A5, R^A6, R^A7, R^A8, R^A9, or R^A10 may independently be H, F, Cl, CN, CF₃, OH, NH₂, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R^A1, R^A2, R^A3, R^A4, R^A5, R^A6, R^A7, R^A8, R^A9, or R^A1° may independently be H. In some embodiments, R^A1, R^A2, R^A3, R^A4, R^A5, R^A6, R^A7, R^A8, R^A9, or R^A1° may independently be F. In some embodiments, R^A1, R^A2, R^A3, R^A4, R^A5, R^A6, R^A7, R^A8, R^A9, or R^A10are all H.

In some embodiments, Ring A may be optionally substituted benzene-1, 2-diyl, optionally substituted cyclopentane-1, 2-diyl, optionally substituted cis-cyclopentane-1, 2-diyl, optionally substituted trans-cyclopentane-diyl, optionally substituted tetrahydrofuran-3,4-diyl, optionally substituted cis-tetrahydrofuran-3,4-diyl, optionally substituted trans-tetrahydrofuran-3,4-diyl, optionally substituted cyclohexane- 1, 2-diyl, optionally substituted cis-cyclohexane-1,2-diyl, optionally substituted trans-cyclohexane-1, 2-diyl, optionally substituted cyclobutane-1, 2-diyl, optionally substituted pyrrolidine-3, 4-di-yl, optionally substituted tetrahydropyran-3,4-di-yl, or optionally substituted piperidine-4, 5-diyl.

In some embodiments, Ring A may be one of the following groups:

With respect to any relevant structural representation, such as Formula 1 or 2, R¹ is Ci-e alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl, cyclopropyl and isopropyl), any one of the butyl isomers (e.g. cyclobutyl and methylcyclopropyl), any one of the pentyl isomers, any one of the cyclopentyl isomers, any one of the hexyl isomers, and any one of the cyclohexyl isomers, etc. In some embodiments, R¹ is methyl. In some embodiments, the ring carbon atom of Formula 1 or 2, directly attaching to R¹, has (S)-configuration. In some embodiments, the ring carbon atom directly attaching to R¹ has (R)-configuration.

With respect to any relevant structural representation, such as Formula 1 or 2, R² is an optionally substituted phenyl, or an optionally substituted sulfone methyl group, as represented in Formula 3 and Formula 4 respectfully shown below. In some embodiments, R² is an optionally substituted phenyl. In some embodiments, R² is an optionally substituted sulfone methyl group. In some embodiments, R²is an optionally substituted phenyl having 0, 1, 2, 3, 4, or 5 substituents. In some embodiments, R²is an optionally substituted sulfone methyl group having 0, 1, 2, 3, or 4 substituents. In some embodiments, any or each of the substituents of phenyl or sulfone methyl group as R² may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol. Potential substituents of R² may include halo, such as F, Cl, Br, or I; hydrocarbyl, such as methyl, C₂ alkyl, C₂ alkenyl, C₂ alkynyl, C₃ alkyl, C₃ cycloalkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C₄ cycloalkyl, C₄ alkenyl, C₄ alkynyl, C₅ alkyl, C₅ cycloalkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆ cycloalkyl, Ce alkenyl, Ce alkynyl, or phenyl, etc.; CN_0-1O_0-2F_0-3H_0-4; C₂N_0-1O_0-3F_0-5H_0-6; C₃N_0-1O_{0- 3}F_0-7H_0-8; C₄N_0-1O_0-3F_0-9H_0-10; C₅N_0-1O_0-3F_{0-1 1}H_0-12; or C₆N_0-1O_0-3F_0-13H_0-14; etc. In some embodiments, R² is a substituted phenyl and has a -CONHR^A substituent, wherein R^A is H, C_1-3 alkyl, or cyclopropyl. In some embodiments, R² a substituted phenyl which has a -SO₂R^A substituent, wherein R^A is H, C_1-3 alkyl, or cyclopropyl. In some embodiments, R² is a substituted phenyl which has an optionally substituted 4,5-dihydro-1H-imidazol-2-yl substituent. In some embodiments, R² is a substituted phenyl which has a 4,5-dihydro-1H-imidazol-2-yl substituent. In some embodiments, R² is a substituted phenyl which has a 4, 4-dimethyl-4, 5-dihydro-1H-imidazol- 2-yl substituent. In some embodiments, R² is a substituted phenyl which has a F substituent. In some embodiments, R² is a substituted phenyl which has a -CONHR^A substituent and a F substituent. In some embodiments, R² is a sulfone methyl group which has one or two cyclopropyl substituents. In some embodiments, R² is methylsulfonylmethyl. In some embodiments, R² is (cyclopropylsulfonyl) cyclopropyl.

In some embodiments, R² is represented by Formula 3 or 4:

With respect to any relevant structural representation, such as Formulas 3, R³, R⁴, R⁵, R⁶, or R⁷ is independently H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF3, -NO2, -NR^AR^B, - COR^A, -CO₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R³, R⁴, R⁵, R⁶, or R⁷ may be independently H, F -CO(NH)CH₃, -SO2CH₃, 4,5-dihydro-1H-imidazol-2-yl, 4- dimethyl-5-dihydro-1H-imidazol-2-yl, or a combination thereof. In some embodiments, R⁴ may be -CO(NH)CH_3. In some embodiments, R⁴ may be -SO2CH₃. In some embodiments, R⁴ may be 4,5-dihydro-1H-imidazol-2-yl. In some embodiments, R⁴ may be 4,4-dimethyl-4,5-dihydro-1H- imidazol-2-yl. In some embodiments, R⁵ is F. In some embodiments, R⁴ is -CO(NH)CH₃, and R⁵ is F.

With respect to any relevant structural representation, such as Formulas 4, R⁸, R⁹, R¹⁰, R¹¹, or R¹² may be independently H or any substituent, such as R^A, F, Cl, -OH, CF₃, -NR^AR^B, etc. In some embodiments, R⁸ and R⁹ together with the carbon atom they attached to form a cyclopropyl ring. In some embodiments, R¹¹ and R¹² together with the carbon atom they attached to form a cyclopropyl ring. In some embodiments, R⁸ and R⁹ together with the carbon atom they attached to form a cyclopropyl ring, and R¹¹ and R¹² together with the carbon atom they attached to form a cyclopropyl ring. In some embodiments, R⁸ and R⁹ together with the carbon atom they attached to form a cyclopropyl ring, R¹¹ and R¹² together with the carbon atom they attached to form a cyclopropyl ring, and R¹⁰ is H. In some embodiments, R⁸, R⁹, R¹⁰, R¹¹, or R¹² may be H. In some embodiments, R⁸, R⁹, R¹⁰, R¹¹, or R¹² may be CH₃. In some embodiments, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are all H.

Some embodiments include optionally substituted 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aS)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2- ((4aS,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)pyrido[2,3-d]pyrimidin-7-yl)benzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2-((4aS,8aS)-octahydro-4H- benzo[b][1,4]oxazin-4-yl)pyrido[2,3-d]pyrimidin-7-yl)benzamide, optionally substituted 3-(2- ((4aS,7aS)-hexahydro-4H-furo[3,4-b][1,4]oxazin-4-yl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aR)-hexahydro-4H- furo[3,4-b][1,4]oxazin-4-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N- methylbenzamide, optionally substituted (S)-3-(2-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(3- methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted 2- fluoro-5-(2-((4aS,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3- methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide, optionally substituted (4aS,7aR)-4-(7-(3-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-2-yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7-(3- (5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-4-((S)-3-methylmorpholino)pyrido[2,3- d]pyrimidin-2-yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(4-((S)- 3-methylmorpholino)-7-(3-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(4-((S)-3- methylmorpholino)-7-((methylsulfonyl)methyl)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7- ((cyclopropylsulfonyl)methyl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, optionally substituted (4aS,7aR)-4-(7-(1- (cyclopropylsulfonyl)cyclopropyl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-2- yl)octahydrocyclopenta[b][1,4]oxazine, or a pharmaceutically acceptable salt thereof, or a combination thereof (referred to collectively herein as a “subject compound”).

Some embodiments include one of the compounds listed in Table 1 below, wherein each structure can be optionally substituted:

Table 1. Compound structures and their ID numbers

A pharmaceutical composition comprising a subject compound may be adapted for oral, or parental, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. The dosage of a subject compound may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated. A pharmaceutical composition provided herein may optionally comprise two or more subject compounds without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e. , a therapeutic agent other than a compound provided herein). For example, the compounds of the disclosure can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti-inflammatory agents, antiviral agents, and anticancer agents that are known in the art. The pharmaceutical composition may be used for the treatment of cancer, and other mTOR-related diseases or disorders in patients. The term "patient" herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.

The pharmaceutical composition described herein can be prepared by combining a compound of Formula 1 with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

Some embodiments include a method of treating a disease or disorder associated with mTOR comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutical composition comprising a compound of Formula 1 to a patient in need thereof. The term a "therapeutically effective amount" herein refers to an amount of a compound or a pharmaceutical composition of the present disclosure provided herein sufficient to be effective in inhibiting mTOR enzyme and thus providing a benefit in the treatment of cancer, infectious diseases and other mTOR associated disorders, to delay or minimize symptoms associated with cancer, infectious diseases and other mTOR associated disorders, or to ameliorate a disease or infection or cause thereof. In some embodiments, about 0.01-1000 mg of a subject compound may be a therapeutically effective amount. The term "treatment" refers to causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying causes of symptoms, postponing, preventing the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.

Some embodiments include a kit containing an effective therapeutic amount of a subject compound and a label with instructions to use the subject compound, or a composition or dosage form containing an effective therapeutic amount of the subject compound, for the treatment of cancer, infectious diseases, and/or other mTOR related disorders.

Experimental Section

Preparation of Compounds

The compounds of the disclosure can be made using procedures known in the art. The following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable for using to prepare these compounds. For examples in Formula 1, wherein R¹ or R² is not hydrogen, those skilled in the art will recognize that changes to the requisite reagents can be made at the appropriate steps in the synthetic methods outlined below. Reactions may involve monitoring for consumption of starting materials, and there are many methods for the monitoring, including but not limited to thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS). Those skilled in the art will recognize that any synthetic method specified in the examples shown below can be substituted by other non- limiting methods when suitable.

Some of the techniques, solvents and reagents can be referred to by their abbreviations as follows.

Acetonitrile: MeCN or ACN Aqueous: aq.

Benzyl: Bn

N,O-Bis(trimethylsilyl)acetamide: BSA

[1 , 1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium (II): Pd(dppf)Cl₂ Dichloromethane: DCM

Diisopropylethylamine: DIPEA, DIEA or iPr₂Net Dimethylacetamide: DMA Dimethylformamide: DMF Dimethylsulfoxide: DMSO Equivalents: equiv.

Ether or diethyl ether: Et₂O

Ethyl acetate: AcOEt or EtOAc or EA

Example: Ex. or ex.

Formic acid: FA Grams: g

High performance liquid chromatography: HPLC Inhibition: Inh.

Liquid chromatography mass spectrometry: LCMS or LC-MS

Lithium aluminum hydride: LAH

Methansulfonyl chloride: MeSO₂CI

Methyl iodide: Mel

Methanol: MeOH

Microliter: μL Micrometer: μm Milligram: mg Milliliter: mL

Millimole: mmol

Nuclear magnetic resonance spectroscopy: NMR Petroleum ether: PE Phosphoryl chloride: POCI₃ Retentional time: t_R

Room temperature (ambient, ~25 °C): rt or RT Potassium tert-butoxide: t-BuOK Preparative HPLC: Prep-HPLC Preparative TLC: Prep-TLC Supercritical Fluid Chromatography: SFC Temperature: temp.

Tetrahydrofuran: THF Thin layer chromatography: TLC p-Toluenesulfonic acid: TsOH Triethylamine: Et₃N or TEA Trifluoroacetic acid: TFA

In the synthetic schemes described below, unless otherwise indicated all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents and solvents were purchased from commercial suppliers such as Aldrich Chemical Company and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N,N- dimethylformamide (DMF) were purchased from commercial sources in Sure Seal bottles and used as received.

The reactions set forth below were done generally under a positive pressure of argon or nitrogen at an ambient temperature (unless otherwise stated) in anhydrous solvents. Glassware was oven dried and/or heat dried. The reactions were assayed by TLC and/or analyzed by LC- MS and terminated as judged by the consumption of starting material. Analytical thin layer chromatography (TLC) was performed on glass plates pre-coated with silica gel 60 F254 0.25 mm plates (EM Science), and visualized with UV light (254 nm) and/ or heating with commercial ethanolic phosphomolybdic acid, preparative thin layer chromatography (TLC) was performed on glass-plates pre-coated with silica gel 60 F254 0.5 mm plates (20 x 20 cm, from commercial sources) and visualized with UV light (254 nm).

Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated. Product solutions were dried over anhydrous Na₂SO₄ and/or Mg₂SO₄ prior to filtration and evaporation of the solvents under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Column chromatography was completed under positive pressure using 230-400 mesh silica gel.

¹H-NMR spectra and ¹³C-NMR were recorded on a Varian Mercury-VX400 instrument operating at 400 MHZ. NMR spectra were obtained as CDCI₃ solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm for the proton and 77.00 ppm for carbon), CD₃OD (3.4 and 4.8 ppm for the protons and 49.3 ppm for carbon), DMSO-d₆ (2.49 ppm for proton), or internally tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed.

Some of the typical synthetic methods are described in the examples shown below.

Method 1 :

Example 1 : Synthesis of 3-(2-((4aS,7aR)-hexahvdrocvclopenta[b] [1,4]oxazin-4(4aH)-yl-4((S)-3- methylmorpholino)quinazolin-7-yl)-N-methylbenzamine (compound 1-7)

Scheme 1

Into a 2 L pressure tank reactor were added 100 g (521 mmol) of 2,6-dichloropyridine-3- carboxylic acid and 1 L of NH₃.H₂O at RT. The mixture was stirred at 130 °C overnight and cooled to RT. The mixture was diluted with 4 L of water and acidified to pH 3 with aqueous HCI. The mixture was filtered; the filter cake was washed with water (3 x 1 L) to give compound 1 1 LC- MS: m/e = 173 [M+H]⁺.

Step 2: To a stirred solution of 73.0 g (412 mmol) of compound 1-1 in 400 mL of THF was added 155 g (1240 mmol) of SOCI₂ dropwise at 0 °C. The mixture was stirred at 60 °C for 2 h and concentrated under vacuum to give a residue. It was dissolved with 400 mL of THF and added dropwise into a 3 L 3-necked round-bottom flask containing 650 mL of NH₃ (7M in MeOH). The solution was stirred at RT for additional 2 h, the solids were filtered out and the filtrate was concentrated. The residue was diluted with water and extracted with two 300 mL portions of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give a residue , which was purified by slurry with EA/PE (600 mL, 1 : 6) to afford compound 1 2 LC-MS: m/e = 172 [M+H]⁺.

Step 3:

To a stirred solution of 60.0 g (350 mmol) of compound 1-2 in 700 mL of toluene was added 53.7 g (423 mmol) of oxalic dichloride dropwise at 0 °C under argon atmosphere. The mixture was stirred at 115 °C for 4 h and cooled to RT. It was concentrated under vacuum till 1/2 volume remained; the precipitate was collected by filtration and washed with EA (2 x 200 mL) to give compound 1 3 LC-MS: m/e = 196 [M+H]⁺.

Step 4:

To a stirred solution of 25.0 g (127 mmol) of compound 1-3 in 300 mL of toluene was added 16.4 g (127 mmol) of DIEA in portions at RT under argon atmosphere. The mixture was stirred at 70 °C for 30 min and cooled to RT. To the above mixture was added 58.2 g (380 mmol) of POCI₃ dropwise at RT. The mixture was stirred at 100 °C for 3 h and cooled to RT. It was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE/EtOAc (9:1) to afford compound 1 4 LC-MS: m/e = 234 [M+H]⁺.

Step 5:

To a stirred solution of 6.00 g (25.6 mmol) of compound 1-4 in 40 mL of DCM were added 2.59 g (25.6 mmol) of (3S)-3-methylmorpholine and 6.62 g (51.3 mmol) of DIEA at RT. The mixture was stirred at RT for 1h and diluted with 80 mL of H₂O. It was extracted with two 50 mL portions of DCM; the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE/EA (2:1) to afford compound 1 5 LC-MS: m/e = 299 [M+H]⁺.

Step 6: To a stirred solution of 7.00 g (23.4 mmol) of compound 1-5 in 100 mL of dioxane and 10 mL of H₂O were added 6.72 g (25.7 mmol) of intermediate 14, 4.96 g (46.8 mmol) of Na₂CO₃ and 1.71 g (2.3 mmol) of Pd(dppf)Cl₂ in portions at RT under nitrogen atmosphere. The mixture was stirred at 90 °C for 3 h and cooled to RT. The reaction was quenched with water and extracted with two 50 mL portions of EA. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with DCM/MeOH (97:3) to afford compound 1-6. LC-MS: m/e = 398 [M+H]⁺.

Step 1:

To a stirred solution of 2.00 g (5.0 mmol) of compound 1-6 and 4.11 g (25.2 mmol) of (4aS,7aR)-octahydrocyclopenta[b][1,4]oxazine hydrochloride (3 HCI salt) in 50 mL of DMA was added 6.65 ml (40.2 mmol) of DIEA in portions at RT under nitrogen atmosphere. The mixture was stirred at 100 °C for 40 h and cooled to RT. It was diluted with 50 mL of water and extracted with two 50 mL portions of EA. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with DCM/MeOH (4:1) to afford Example 1- 7. LC-MS: m/e = 489 [M+H]⁺.

Using the procedure outlined in Method 1, step 7, the following analogs in Table 2 were prepared from compound 1-6 by employing the requisite bicyclic amines. Other compounds of Formula 1 may be prepared in a similar way.

Table 2. Synthesis of heterocyclic analogs

Method 2:

Example 2: Synthesis of 2-fluoro-5-(2-((4aS.7aR)-hexahvdrocvcloenta[b] [1,4] oxazin-4(4aH)-yl- 4((S)-3-methylmorpholino)quinazolin-7-y)-N-methylbenzamine (compound 2-2)

Scheme 2

Compound 2-1 was prepared from intermediate 1-5 by a similar procedure described in Scheme 1 , step 6 using boronic ester 11. LC-MS: m/e = 416 [M+H]⁺.

Compound 2-2 was prepared from intermediate 2-1 by a similar procedure described in Scheme 1, step 7. LC-MS: m/e = 507 [M+H]⁺.

Method 3:

Example 3: Synthesis of (4aS,7aR)-4-(7-(3-(4,5-dihvdro-1H-imidazol-2-yl)phenyl)-4-((S)-3- methymorpholino)quinazolin-2-yl)octahydrocyclopenta[b] [1,4]oxazine (compound 3-3) and compounds 3-4 and 3-5

Step 1:

Compound 3-1 was prepared from intermediate 1-5 by a similar procedure described in Scheme 1 , step 6 using 3-cyanophenylboronic acid instead. LC-MS: m/e = 366 [M+H]⁺.

Step 2:

Compound 3-2 was prepared from intermediate 3-1 by a similar procedure describe in Scheme 1 , step 7. LC-MS: m/e = 457 [M+H]⁺.

Step 3:

A mixture of 50 mg ( 0.11 mmol) of compound 3-2 and 1.8 mg ( 0.06 mmol) of sulfur powder in 1 mL of ethane-1, 2-diamine was stirred at 110 °C for 3 h under nitrogen atmosphere. It was cooled to RT and quenched by 5 mL of water. The mixture was extracted with three 5 mL portions of EA; the combined organic layers were washed with three 5 mL portions of brine and dried over anhydrous Na₂SO₄. After filtration, it was concentrated to give a residue, which was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm 5 mhi; Mobile Phase A:Water(10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 43% B in 8 min; 254 nm) to afford compound 3-3. LC-MS: m/e = 500 [M+H]⁺.

Step 4:

A mixture of 50 mg (0.11 mmol) of intermediate 3-2 and 8.5 mg (0.04 mmol) of P2S5 in 1 mL of 2-methylpropane-1 , 2-diamine was irradiated with microwave radiation at 100 °C for 1 h. It was quenched with 5 mL of water and extracted with three 5 mL portions of CH₂CI₂. The combined organic layers were washed with three 5 mL portions of brine and dried over anhydrous Na₂SO₄. After filtration, it was concentrated to give a residue, which was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm 5 mhi; Mobile Phase A:Water(10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min; 254 nm) to afford compound 3-4. LC-MS: m/e = 528 [M+H]⁺.

Method 4:

Example _ 4\ _ Synthesis _ of _ (4aS,7aR)-4-(4-((S)-3-methylmorpholino)-7-(3-

(methylsulfonyl)phenyl)quinazolin-2-yl)octahydrocyclopenta[b] [1,4]oxazine (compound 4-2)

Scheme 4

Stepl:

To a stirred solution of 500 mg (1.67 mmol) of compound 1-5 and 212 mg (1.67 mmol) of intermediate 3 in 10 mL of DMA was added 216 mg (1.67 mol) of DIEA dropwise at RT. The mixture was stirred at 80 °C overnight under argon atmosphere. The mixture was diluted with water and extracted with three 30 mL portions of EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (4:1) to afford compound 4-1 plus its isomer. LC-MS: m/e = 390 [M+H]⁺.

Step 2:

Compound 4-2 was prepared from intermediate 4-1 by a similar procedure described in Scheme 1, step 6 using boronic ester 15. LC-MS: m/e = 510 [M+H]⁺.

Method 5:

Example _ 5; _ Synthesis _ of _ (4aS,7aR)-4-(4-((S)-3-methylmorpholino)-7-

((methylsulfonyl)methyl)quinazolin-2-yl)octahvdrocyclopenta[b] [1,4]oxazine (compound 5-4), (4aS,7aR)-4-(7-((cvclopropylsulfonyl)methyl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 2-yl)octahvdrocyclopenta[b] [1,4]oxazine (compound 5-5) and (4aS,7aR)-4-(7-(1- (cyclopropylsulphonyl)cyclopropyl)-4-((S)-3-methylmorpholino)pyridor2,3-dlpyrimidin-2- yl)octahvdrocvclopenta[b] [1,4]oxazine (compound 5-6)

Step 1:

To a 50 mL pressure tank reactor were added 1.00 g (2.57 mmol) of compound 4-1 , 38 mg (0.051 mmol) of Pd(dppf)Cl2, 519 mg (5.130mmol) of Et₃N and 5 mL of MeOH at RT. The mixture was stirred for overnight at 60 °C under CO atmosphere (10-20 atm) and cooled to RT. It was concentrated and extracted with three 10 mL portions of CH₂CI₂. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The residue was purified by silica gel column chromatography eluting with ( CH₂CI₂/EtOAc 9 : 1) to afford compound 5-1. LC- MS: m/e = 414 [M+H]⁺.

Step 2: To a stirred solution of 500 mg(1.21 mmol) of compound 5-1 in 5 mL of THF was added 0.61 mL(2 M in THF, 1.21 mmol) of UBH₄ dropwise at 0 °C under argon atmosphere. The mixture was stirred 0 °C for 30 min and quenched with water. It was extracted with three 30 mL portions of EtOAc; the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The residue was purified by silica gel column chromatography eluting with CH₂CI₂/MeOH (20:1) to afford compound 5-2. LC-MS: m/e = 386 [M+H]⁺.

Step 3:

To a stirred solution of 100 mg (0.26 mmol) of compound 5-2, 88 mg (2.08 mmol) of LiCI and 105 mg (1.04 mmol) of Et₃N was added 59 mg (0.52 mmol) of MsCI dropwise at 0 °C. The mixture was stirred for additional at 60 °C for 1 h and quenched with water. It was extracted with three 20 mL portions of CH2Cb_; the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The residue was purified by Prep-TLC (CH₂CI₂/EtOAc 8:1) to afford compound 5-3. LC-MS: m/e = 404 [M+H]⁺.

Step 4:

To a stirred mixture of 82 mg (0.20 mmol) of compound 5-3 and 104 mg (1.02 mmol) of sodium methanesulfinate in 3 mL of ethanol was added 61 mg (0.41 mmol) of sodium iodide at RT under argon atmosphere. The mixture was stirred at 60 °C for 3 h and concentrated under reduced pressure. The residue was diluted with 10 mL of water and extracted with three 20 mL portions of CH₂CI₂. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, it was concentrated to give a residue, which was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm ; Mobile Phase A:Water(10 mM NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:30 B to 50 B in 8 min; 254 nm) to afford compound 5-4. LC-MS: m/e = 448 [M+H]⁺.

Step 5:

To a stirred mixture of 120 mg (0.30 mmol) of compound 5-4 and 191 mg (1.49 mmol) of sodium cyclopropanesulfinate in 5 mL of ethanol was added 89 mg (0.60 mmol) of sodium iodide at RT under argon atmosphere. The resulting mixture was stirred for 3 h at 60 °C under argon atmosphere. The mixture was concentrated under reduced pressure; the residue was diluted with 10 mL of water. It was extracted with three 30 mL portions of CH₂CI₂. The combined organic extracts were concentrated to give a residue, which was purified by Prep-TLC (DCM/EA 80:1) to afford compound 5-5. LC-MS: m/e = 474 [M+H]⁺. Step 6:

To a stirred mixture of 98 mg (0.21 mmol) of compound 5-5 and 13 mg (0.041 mmol) of tetrabutylammonium bromide in 3 mL of toluene were added 83 mg (2.1 mmol) of sodium hydroxide solution (40% wt.) and 78 mg (0.41 mmol) of 1 ,2-dibromoethane at RT under argon atmosphere. The mixture was stirred at 60 °C for 3 h under argon atmosphere and concentrated under reduced pressure. It was diluted with 10 mL of water and extracted with three 15 mL portions of CH₂CI₂. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, it was concentrated to give a residue, which was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm 5 Dm; Mobile Phase A:Water(10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B:ACN; Flow rate: 60 mL/min; Gradient:30 B to 60 B in 8 min; 254 nm) to afford compound 5-6. LC-MS: m/e = 500 [M+H]⁺.

Synthesis of Intermediates 1. Synthesis of intermediate 3:

Step 1:

To a stirred solution of 24.0 g (237 mmol) of (1R,2S)-2-aminocyclopentan-1-ol in 240 mL of THF were added a solution of 98.4 g (712 mmol) of K2CO3 in 240 mL of H₂O followed by 53.6 g ( 475 mmol) of chloroacetyl chloride dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for additional 1 h at 0 °C and then concentrated under reduced pressure. The aqueous solution was extracted with three 250 mL portions of CH₂CI₂; the combined organic extracts were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to afford compound 1 , which was used in the next step directly without further purification. LC- MS: m/e = 178 [M+H]⁺.

Step 2:

To a stirred solution of 27.0 g (152 mmol) of compound 1 in 270 mL of DCM were added 270 mL of i-PrOH and 68.2 g (608 mmol) of potassium tert-butoxide dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 1 h and concentrated under reduced pressure. The residue was neutralized to pH 7 with 1N HCI solution and extracted with three 200 mL portions of CH₂CI₂. The combined organic extracts were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to afford compound 2, which was used in the next step directly without further purification. LC-MS: m/e = 142 [M+H]⁺.

Step 3:

Into a 1000 mL 3-necked round-bottom flask were added 340 mL (1 M in THF) of LAH at 0 °C under argon atmosphere. To the above solution was added 24.0 g (170 mmol) of compound 2 in 240 mL of THF dropwise at 0 °C. The mixture was stirred at RT overnight and then quenched with Na₂SO_4*10H₂O at 0 °C. The mixture was filtered; the filter cake was washed with three 200 mL portions of EtOAc. The filtrate was concentrated under to afford compound 3, which was used in the next step directly without further purification. LC-MS: m/e = 128 [M+H]⁺.

The following intermediates listed in Table 3 were prepared from the corresponding amino alcohols similarly:

Table 3. Synthesis of bicyclic amine intermediates

2. Synthesis of intermediate 11

Scheme 7

Step 1:

To a 50 L three-neck round bottom flask were added 1.00 g (4.61 mmol) of 5-bromo-2- fluorobenzoic acid and 10 mL of thionyl chloride at RT. The mixture was stirred at 70 °C for 4 h under argon atmosphere and concentrated under reduced pressure to afford compound 9, which was used in the next step directly without further purification. LC-MS: m/e = 459 [M+H]⁺. Step 2:

To a stirred solution of 600 mg (2.53 mmol) of compound 9 in 10 mL of DCM was added 523 mg (5.1 mmol) of CH₃NH₂ in EtOH solution (30% wt) dropwise at RT under argon atmosphere. The resulting mixture was stirred at RT overnight and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EA(10:1) to afford compound 10. LC-MS: m/e = 432 [M+H]⁺.

Step 3:

To a stirred solution of 500 mg (2.2 mmol) of compound 10 and 821 mg (3.2 mmol) of 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in 10 mL of dioxane was added 634 mg (6.46 mmol) of potassium acetate and 158 mg (0.215 mmol) of Pd(dppf)Cl₂ in portions at RT. The mixture was stirred at 90 °C for 5 h and cooled to RT. The mixture was diluted with water and extracted with three 30 mL portions of EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE/EA (2:1) to afford compound 11. LC-MS: m/e = 280 [M+H]⁺.

3. Synthesis of intermediate 14

Step 1-3: Compound 14 was prepared from 3-bromobenzoic acid following the 3-step reaction sequences described in Scheme 7. LC-MS: m/e = 262 [M+H]⁺.

4. Synthesis of intermediate 15:

Step 1:

Intermediate 15 was prepared from 1-bromo-3-methanesulfonylbenzene following the procedure described in Scheme 7, step 3. LC-MS: m/e = 283 [M+H]⁺.

LC-MS conditions used in the experimental procedures described above:

Conditions A: Shimadzu LC20AD/LCMS2020; Column: Shim-pack XR-ODS (50*3.0 mm) 2.2 μm; Mobile phase: A: 0.05%Trifluoroacetic acid in Water, B: 0.05%Trifluoroacetic acid in Acetonitrile; Gradient: 95:5 to 0:100(A:B) over 1.1 min, 0:100(A:B) for 0.55 min, Flow Rate: 1.2ml/min; UV detection: 190-400 nm.

Conditions B: Shimadzu LC₃0AD/LCMS2020, Column: HALO C18(3.0*30 mm) 2 μm; Mobile phase: A: 0.1% Formic acid in Water, B: 0.1% Formic acid in Acetonitrile; Gradient: 95:5 to 0:100(A:B) over 0.7 min, 0:100(A:B) for 0.40 min, Flow Rate: 1.5ml/min. UV detection: 190-400 nm.

Conditions C: Shimadzu LC₃0AD/LCMS2020, Column: HALO C18(3.0*30 mm) 2 μm; Mobile phase: A: 0.05%Trifluoroacetic acid in Water, B: 0.05%Trifluoroacetic acid in Acetonitrile; Gradient: 95:5 to 0:100(A:B) over 0.7 min, 0:100(A:B) for 0.40 min, Flow Rate: 1.5ml/min. UV detection: 190-400 nm.

Conditions D: Shimadzu LC20ADXR/LCMS2020, Column: Poroshell HPH-C18 (50*3.0 mm) 2.7 μm; Mobile phase: A: 5 Mm Ammonium Bicarbonate in Water, B: Acetonitrile; Gradient: 90:10 to 5:95(A:B) over 1.2 min, 5:95(A:B) for 0.50 min, Flow Rate: 1.2ml/min. UV detection: 190-400 nm. Conditions E: Shimadzu LC20ADXR/LCMS2020, Column: Titank C18 (30*2.1mm) 1.7 μm; Mobile phase: A: 0.04%NH40H in Water, B: Acetonitrile; Gradient: 90:10 to 5:95(A:B) over 0.9 min, 5:95(A:B) for 0.40 min, Flow Rate: 0.8ml/min. UV detection: 190-400 nm.

Conditions F: Shimadzu LCMS2020, Column: Kinetex C18 100A (30*2.1 mm) 1.7 mhi; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.0 mL/min; Gradient:5%B to 100%B in 0.7min, hold 0.4 min; 254 nm

ASSAYS

Protocols that may be used to determine the recited potency for the compounds of the disclosure are describe below.

Meso Scale Discovery (MSP) Immunoassay:

4000/well of HepG2 cells was seeded onto a 96-well cell culture plate overnight. Next day, the cells were treated with test and reference compounds at two doses (0.5 mM and 0.05 mM for phospho-Akt Ser473 samples, 0.2 μM and 0.02 μM for phospho-p70S6K Thr389, and 1 μM and 0.1 μM for phospho-4E-BP1 Thr37/46 samples) in duplicate for 1 hour. The culture medium was removed, and the cells were washed by 1X PBS. 50 mL of ice-cold MSD lysis buffer (containing proteinase/phosphatase inhibitor cocktail) was added to each well. The cells in the wells were lysed with the MSD lysis buffer on a 4 °C shaker for 30 min. 150 pL of Blocking Buffer was added to each well of MSD plate. The plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature. Following blocking, MSD plate was washed 3 time with 150 μL/well 1X Tris wash buffer. 25 μL/well of cell lysate was transferred from cell culture plate to the MSD plate. The plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature. MSD plate was washed 3 time with 150 μL/well 1X Tris wash buffer. 25 μl/well Detection Antibody Solution was added to the wells of MSD plate. The plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature. MSD plate was washed 3 time with 150 μL/well 1X Tris wash buffer. 150 μL/well of 1X Read Buffer T was added to each well of the MSD plate. Electrochemiluminescence was recorded by MSD QuickPlex SQ 120. Phospho-Akt(Ser473), phospho-p70S6K (Thr389), and Phospho-4E-BP1 (Thr37/46) expression graphs were plotted with GraphPad Prism 4 program . The testing results for selected compounds are summarized in Table 4. The inhibitory effects of each compound on mTORCI and mTORC2 kinase activities were monitored using 4E-BP1 and p70S6K as specific mTORCI substrates, and AKT as specific mTORC2 substrate. Table 4. mTOR Inhibitory Activity of Representative Examples

*AZD2014 is a reference compound, which has CAS# [1009298-59-2]

**NA means that the data is not yet available.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and etc. used in herein are to be understood as being modified in all instances by the term “about.” Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters may be modified according to the desired properties sought to be achieved, and should, therefore, be considered as part of the disclosure. At the very least, the examples shown herein are for illustration only, not as an attempt to limit the scope of the disclosure.

The terms “a,” “an,” “the” and similar referents used in the context of describing embodiments of the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illustrate embodiments of the present disclosure and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non- claimed element essential to the practice of the embodiments of the present disclosure.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the embodiments of the present disclosure to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

What is claimed is:

1. A compound represented by a formula:

or a pharmaceutically acceptable salt thereof; wherein any ring carbon in the formula is optionally substituted; wherein the dashed line represents the presence or absence of a double bond; wherein R¹ is C_{1 -6} alkyl;

R² is an optionally substituted phenyl, or an optionally substituted sulfone methyl group; and Ring A is an optionally substituted 4- to 6-membered ring.

2. The compound of claim 1 , wherein Ring A is an optionally substituted C₆ aromatic ring, an optionally substituted saturated C cyclic hydrocarbon ring, or an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom.

3. The compound of claim 1 or 2, wherein Ring A is an optionally substituted saturated C₅ cyclic hydrocarbon ring.

4. The compound of claim 1 or 2, wherein Ring A is an optionally substituted saturated C₆ cyclic hydrocarbon ring.

5. The compound of claim 1 or 2, wherein Ring A is an optionally substituted C₆ aromatic ring.

6. The compound of claim 1 or 2, wherein Ring A is an optionally substituted tetrahydrofuran.

7. The compound of claim 1, 2, 3, 4, 5, or 6, wherein R¹ is CH₃.

8. The compound of claim 1, 2, 3, 4, 5, 6, or 7, wherein R² is an optionally substituted phenyl.

9. The compound of claim 1, 2, 3, 4, 5, 6, or 7, wherein R² is an optionally substituted sulfone methyl group.

10. The compound of claim 9, wherein R² has one or two cyclopropyl substituent.

11. The compound of claim 1 , 2, 3, 4, 5, 6, 7, or 8, wherein R² has a -CONHR^A substituent, wherein R^A is H, C_1-3 alkyl, or cyclopropyl.

12. The compound of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein R² has a -SO₂R^A substituent, wherein R^A is H, C_1-3 alkyl, or cyclopropyl.

13. The compound of claim 1 , 2, 3, 4, 5, 6, 7, or 8, wherein R² has an optionally substituted 4,5-dihydro-1H-imidazol-2-yl substituent.

14. The compound of claim 1 , 2, 3, 4, 5, 6, 7, or 8, wherein R² has a F substituent.

15. The compound of claim 1 , 2, 3, 4, 5, 6, 7, or 8, wherein R² has a -CONHR^A substituent and a F substituent.

16. The compound of claim 1 or 2, wherein, if present, each substituent on a ring carbon is F,

Cl, Br, I, C_1-6O_0-2N_0-2H_0-15, C_0-6O_1-2N_0-2H_0-15, or C_0-6O_0-2N_1-2H_0-15·

17. The compound of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or 16, wherein the ring carbon atom directly attaching to R¹ has (S)-configuration.

18. The compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 , wherein the two bonds of Ring A directly attaching to the morpholine ring are in c/s-conformation.

19. The compound of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, or 17, wherein the two bonds of Ring A directly attaching to the morpholine ring are in frans-conformation.

20. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and at least one pharmaceutically acceptable carrier.

22. A method of treating a patient having a disease, a disorder, or a condition associated with the inhibition of mTOR and related kinases (AKT and PI3K), comprising administering a therapeutically effective amount of a compound of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 to the patient.

23. The method of claim 22, wherein the disease is cancer or an infectious disease.

24. Use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 in the manufacture of a medicament for the treatment of cancer, infectious diseases, or other mTOR -related diseases or disorders.