COMBINATION OF KINASE INHIBITORS AND USES THEREOF

- Intellikine LLC

The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject.

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Description
CROSS-REFERENCE

This application is a continuation-in-part of PCT/US2012/026399 filed Feb. 23, 2012, published as WO 2012/148540, which claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 61/446,016, filed on Feb. 23, 2011, each incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Kinase signaling pathways play a central role in numerous biological processes. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al., Current Medicinal Chemistry (2007) 14:2214-2234). In recent years, kinases that are associated with oncogenic signaling pathways have emerged as important drug targets in the treatment of various diseases including many types of cancers.

The mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin, is a serine/threonine protein kinase that regulates cell growth, translational control, angiogenesis and/or cell survival. mTOR is encoded by the FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) gene. mTOR is the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 is composed of mTOR, regulatory associated protein of mTOR (Raptor), mammalian LST8/G-protein β-subunit like protein (mLST8/GβL), PRAS40, and DEPTOR. mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).

Apart from their subunits, mTORC1 and mTORC2 are distinguished by their differential sensitivities to rapamycin and its analogs (also known as rapalogs). Rapamycin binds to and allosterically inhibits mTORC1, but mTORC2 is generally rapamycin-insensitive. As a result of this rapamycin-insensitive mTOR signaling mediated by mTORC2, cancer cells treated with rapamycin analogs usually display only partial inhibition of mTOR signaling, which can lead to enhanced survival and resistance to rapamycin treatment.

Another group of kinases involved in cellular functions that are commonly deregulated in diseases is the Phosphatidylinositol-3-kinases (PI 3-kinases or PI3Ks) family of enzymes. These lipid kinases phosphorylate the 3-position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns), activating signaling cascades associated with such processes as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Disruption of these processes involving PI3K leads to many diseases including cancer, allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.

The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. The class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which engages downstream effectors such as those in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rho family GTPases.

The alpha (α) isoform of type I PI3K has been implicated in a variety of human cancers. Angiogenesis has been shown to selectively require the α isoform of PI3K in the control of endothelial cell migration. (Graupera et al., Nature 2008; 453; 662-6). Mutations in the gene coding for PI3K α or mutations which lead to upregulation of PI3K α are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain and skin cancers. Often, mutations in the gene coding for PI3K α are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. While other PI3K isoforms such as PI3K δ or PI3K γ are expressed primarily in hematopoietic cells, PI3K α, along with PI3K β, is expressed constitutively.

The delta (δ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes. PI3K δ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. PI3K δ is integrally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, PI3K δ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes PI3K γ, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.

PI3K β has been implicated primarily in various types of cancer including PTEN-negative cancer (Edgar et al. Cancer Research (2010) 70(3): 1164-1172), and HER2-overexpressing cancer such as breast cancer and ovarian cancer.

SUMMARY OF THE INVENTION

Due to the diverse essential functions of mTOR and PI3Ks, drugs that bind to and inhibit a broad range of kinase isoforms and complexes with low specificity can lead to deleterious side effects. For example, excessive inhibition of PI3K β may lead to undesirable effects on metabolic pathways and disruption of insulin signaling. Alternatively, excessive inhibition of PI3K δ and/or PI3K γ may disrupt or reduce immune function. The present disclosure provides an alternative approach that effectively targets disease-related pathways, while limiting undesirable side effects.

Accordingly, the invention provides a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a therapeutically effective amount of a combination of a PI3-kinase α inhibitor and an mTOR inhibitor, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In one aspect, the combination comprises a therapeutic effective amount of a PI3-kinase α inhibitor and a therapeutic effective amount of an mTOR inhibitor. In another aspect, the combination comprises a synergistically effective therapeutic amount of PI3-kinase α inhibitor and an mTOR inhibitor, wherein the PI3-kinase α inhibitor and/or the mTOR inhibitor is present in a sub-therapeutic amount.

The invention also provides a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor according to a first dosing regimen and (b) a therapeutically effective amount of an mTOR inhibitor according to a second dosing regimen, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ, wherein each dosing regimen independently comprising repeating cycles of a treatment period followed by a rest period, wherein at least one dosing regimen has one rest period of more than 0 day. In some methods, the first dosing regimen and the second dosing regimen are the same and are administered simultaneously. In some methods, the first dosing regimen and the second dosing regimen are different. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of at least 1 day followed by a rest period of at least 1 day. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 1 day. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of 2, 3, 4, 5, 6 or 7 consecutive days followed by a rest period of at least 3, 4, or 5 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one cycle of a treatment period of at least 1 day followed by a rest period of 6 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 3 consecutive days followed by a rest period of 4 consecutive days, optionally the first dosing regimen and the second dosing regimen are the same and are administered simultaneously. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle of a treatment period of 1 consecutive days followed by a rest period of 6 consecutive days. In some methods, the first and/or the second dosing regimen independently comprises at least one 7-day cycle comprising at least 3 treatment periods on alternate days within the 7 days.

In some methods, the second dosing regimen has a rest period of 0 day. In some methods, the first dosing regimen has a rest period of 0 day. In some methods, the first dosing regimen has a rest period of 0 day, and the second dosing regimen comprises at least one 7-day cycle of a treatment period of 5 consecutive days followed by a rest period of 2 consecutive days. In some methods, the first dosing regimen has a rest period of 0 day, the second dosing regimen comprises at least one 7-day cycle of a treatment period of 1 consecutive days followed by a rest period of 6 consecutive days.

The invention also provides a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to said subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ, wherein the clinical and therapeutic effects of the treatment of the disease condition continue for a durability of effect period of at least as long as the administration period. In some methods, the combination comprises a synergistically effective therapeutic amount of PI3-kinase α inhibitor and an mTOR inhibitor, wherein the PI3-kinase α inhibitor and/or the mTOR inhibitor is present in a sub-therapeutic amount. In some methods, the clinical and therapeutic effects are selected from the group consisting of sustained tumor regression, inhibited tumor re-growth, reduction of proliferation, increased apoptosis, or downregulation of activity of a target protein. In some methods, the clinical and therapeutic effects are sustained tumor regression and inhibited tumor re-growth. In some methods, the durability of effect period is at least 30 days. In some methods, the durability of effect period is at least 5 days. In some methods, the PI3-kinase α inhibitor is administered according to a first intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period. In some methods, the mTOR inhibitor is administered according to a second intermittent dosing regimen comprising repeating cycles of a treatment period followed by a rest period.

The invention also provides a method of treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to the subject simultaneously or sequentially a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor according to an intermittent regimen effective to achieve (a) higher therapeutic efficacy, (b) similar or better tolerability of the PI3-kinase α inhibitor and/or mTOR inhibitor, and (c) similar or smaller area under the curve, as compared to administering an equivalent dose of the PI3-kinase α inhibitor and/or mTOR inhibitor once daily; wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the disease condition associated with PI3-kinase α and/or mTOR can include but are not limited to a neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease and kidney disease. For example, the neoplastic condition can be NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers, renal cell carcinoma, prostate cancer, neuroendocrine cancer, endometrial cancers, and other forms of cancer.

The invention further provides a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell, comprising contacting a cell with an effective amount of a PI3-kinase α inhibitor and an mTOR inhibitor that selectively inhibits both mTORC1 and mTORC2 activity relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α relative to all other type I phosphatidylinositol-3-kinases (PI3-kinase) consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

For instance, the PI3-kinase α inhibitor utilized in the subject methods inhibits PI3-kinase α with an IC50 value of about 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 10 nM or less, 1 nM or less as ascertained in an in vitro kinase assay. In another instance, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is at least 2, 5, 10, 50, 100, 1000 times less than its IC50 value against one, two, three or all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 200 nM, and said IC50 value is at least 2, 5 or 10 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α and/or PI3-kinase β with an IC50 value that is at least 5 times less than its IC50 value against PI3-kinase γ or PI3-kinase δ. In yet other embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α and/or PI3-kinase β with an IC50 value that is at least 50 times less than its IC50 value against PI3-kinase γ or PI3-kinase δ. In still other embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is at least 50 times less than its IC50 value against PI3-kinase γ or PI3-kinase δ.

In some embodiments of the methods of the invention, the mTOR inhibitor binds to and directly inhibits both mTORC1 and mTORC2. For example, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, or 1 nM or less, as ascertained in an in vitro kinase assay. In another embodiment, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTOR inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. Alternatively, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and the IC50 value is at least 2, 5 or 10 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the mTor inhibitor inhibits mTORC1 selectively. For example, the mTor inhibitor inhibits mTORC1 with an IC50 value of about 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, as ascertained in an in vitro kinase. In some embodiments, the mTor inhibitor is rapamycin or an analogue of rapamycin. In other embodiments, the mTor inhibitor is sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), zotarolimus (ABT-578), or biolimus A9 (umirolimus).

In some embodiments, the mTOR inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is N or C-E1, X2 is N or C, X3 is N or C, X4 is C—R9 or N, X5 is N or C-E1, X6 is C or N, and X7 is C or N; and wherein no more than two nitrogen ring atoms are adjacent;

R1 is H, L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, C1-10alkylhetaryl, -L-C1-10alkylheterocylyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

E1 and E2 are independently —(W1)j—R4;

M1 is a 5, 6, 7, 8, 9, or -10 membered ring system, wherein the ring system is monocyclic or bicyclic, substituted with R5 and additionally optionally substituted with one or more —(W2)k—R2;

each k is 0 or 1;

j in E1 or j in E2, is independently 0 or 1;

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), hetaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylhetaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylhetaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylhetaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocylyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heteroalkyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, hetaryl-C3-8cycloalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, hetaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylhetaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylhetaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylhetaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocylyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, hetaryl-C3-8cycloalkyl, heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

each of R31, R32, and R33 is independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, hetaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R7 and R8 is independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6;

R6 is halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35; and

R9 is H, halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35. In other embodiments, the mTOR inhibitor is a compound of formula:

In other embodiments, the PI3-kinase α inhibitor is a compound of formula:

or its pharmaceutically acceptable salts thereof, wherein:

    • W1′ is N, NR3′, or CR3′; W2′ is N, NR4′, CR4′, or C═O; W3′ is N, NR5′ or CR5′; W4′ is N, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N;
    • W6 is N or CR8′;
    • Wa′ and Wb′ are independently N or CR9′;
    • one of WC′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety;
    • R5′, R6′, R7″ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In still other embodiments, the PI3-kinase α inhibitor is a compound of formula:

or its pharmaceutically acceptable salts thereof, where:

    • X is O or S or N;
    • W1′ is S, N, NR3′ or CR3′, W2′ is N or CR4′, W3′ is S, N or CR5′, W4′ is N or C, and W7′ is N or C, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N or CR7′;
    • W6′ is N or CR8′;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety; and

R5′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

For any of the methods of the invention, the PI3-kinase α inhibitor and/or the mTOR inhibitor can be administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally. In some embodiments, the PI3-kinase α inhibitor and/or the mTOR inhibitor are co-administered to the subject in the same formulation. In other embodiments, the PI3-kinase α inhibitor and/or the mTOR inhibitor are co-administered to the subject in different formulations.

The invention also provides a pharmaceutical composition comprising a combination of an amount of PI3-kinase α inhibitor and an amount of mTOR inhibitor, wherein said combination provides a synergistic therapeutic effect in a subject in need thereof. For example, the pharmaceutical composition is formulated in an oral dosage. In some embodiments, at least one of the amounts is administered as a sub-therapeutic amount. In other embodiments, the pharmaceutical composition is formulated a tablet or a capsule. For example, the PI3-kinase α inhibitor and the mTOR inhibitor are packaged as separate tablets. In other embodiments, the PI3-kinase α inhibitor and the mTOR inhibitor are formulated as a single oral dosage form.

The invention also provides a pharmaceutical kit comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise (a) a therapeutically effective amount of a PI3-kinase α inhibitor and/or (b) a therapeutically effective amount of an mTOR inhibitor; wherein the daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor are effective for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, and (ii) a number of daily dosage units containing no active agent placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units containing no active agent is at least 1. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units containing no active agent is at least 3, 4, or 5 or multiple of 3, 4, or 5. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is at least 1, and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is 3, or multiple of 3, and wherein the number of daily dosage units containing no active agent is 4 or multiple of 4. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is 5, or multiple of 5, and wherein the number of daily dosage units containing no active agent is 2 or multiple of 2. In some kits, the number of daily dosage units comprising the PI3-kinase α inhibitor and/or mTOR inhibitor is 1, or multiple of 1, and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6.

The invention further provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor; and (ii) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a therapeutically effective amount of a PI3-kinase α inhibitor. In some kits, the number of daily dosage units comprising the combination is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units comprising PI3-kinase α inhibitor only is at least 1. In some kits, the number of daily dosage units comprising the combination is 2, 3, 4, 5, 6 or 7, or multiple of 2, 3, 4, 5, 6 or 7, and wherein the number of daily dosage units comprising PI3-kinase α inhibitor only is at least 3, 4, or 5 or multiple of 3, 4, or 5. In some kits, the number of daily dosage units comprising the combination is at least 1, and wherein the number of daily dosage units comprising PI3-kinase α inhibitor only is 6 or multiple of 6. In some kits, the number of daily dosage units comprising the combination is 3, or multiple of 3, and wherein the number of daily dosage units comprising PI3-kinase α inhibitor only is 4 or multiple of 4. In some kits, the number of daily dosage units comprising the combination is 5, or multiple of 5, and wherein the number of daily dosage units containing no active agent is 2 or multiple of 2. In some kits, the number of daily dosage units comprising the combination is 1, or multiple of 1, and wherein the number of daily dosage units containing no active agent is 6 or multiple of 6.

The invention further provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject comprising (i) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a combination of (a) a therapeutically effective amount of a PI3-kinase α inhibitor and (b) a therapeutically effective amount of an mTOR inhibitor; and (ii) a number of daily dosage units placed in a packaging unit and intended for administration for a period or a multiple of a period of at least 1 day, wherein the daily dosage units each comprise a therapeutically effective amount of an mTOR inhibitor.

The invention also provides a method comprising: (a) determining the presence in a subject of a mutation in PI3-kinase α that is associated with a disease condition mediated by PI3-kinase α; and (b) administering to said subject a pharmaceutical composition of the invention. For example, the mutation is in the nucleotide sequence coding for PI3-kinase α. Exemplary mutations can include without limitation, deletion, insertion, translation, which can result in point mutations, frame shifts, and/or translation of the nucleic acid sequence coding for PI3-kinase α. In another example, the mutation is in the amino acid sequence of PI3-kinase α.

In some embodiments of any of the methods of the invention, the subject or cell comprises a mutation in PI3-kinase α which is associated with a disease condition mediated by PI3-kinase α.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 is a schematic illustration of multiple and distinct signaling pathways that are activated in human cancer.

FIG. 2 is a graph showing the synergistic effect of combined treatment with a PI3-kinase α inhibitor (Compound A) and an mTor inhibitor (Compound B) on tumor weight in a preclinical breast cancer model.

FIG. 3 is a western blot depicting the synergistic effect of combined treatment with Compound A and Compound B in terms of downregulating Akt and S6 phosphorylation.

FIG. 4 is a graph showing the synergistic effect of combined treatment with Compound A and rapamycin in terms of reducing tumor volume of a preclinical breast cancer model.

FIG. 5 shows A) an illustration of the distinct signaling pathways mediated by mTORC1 and mTORC2 and B) a western blot depicting sensitivity of mTORC1-dependent NRDG1 phosphorylation to Compound B, but not rapamycin.

FIG. 6 shows A) a graph depicting the selectivity of Compound B over Compound A in a PTEN-mutant negative control tumor model, B) a western blot depicting selective inhibition of Akt, S6, and 4EBP phosphorylation by Compound B and not Compound A in PTEN mutant cells, and C) a chart depicting the specificity of Compound A in inhibiting PI3K α over mTOR and other PI3K isoforms, and the specificity of Compound B in inhibiting mTOR over PI3K isoforms.

FIG. 7 is a western blot depicting differential inhibition of Akt phosphorylation at serine 473 over threonine 308 by Compound B (top panel). Also shown is the comparison of Akt phosphorylation inhibition for Pan-PI3K inhibitor versus Compound B.

FIG. 8 is a graph showing that Pan-PI3K inhibitor, but not Compound A, blocks B cell function in vivo. Mice were immunized with TNP-Ficoll and treated with 1) vehicle; 2) 70 mg/kg GDC0941; 3) 30 mg/kg Compound A; 4) 60 mg/kg Compound A; or 5) 120 mg/kg Compound A for 7 days. Antibody production was measured as a percentage of control group that were treated with vehicle.

FIG. 9 shows, left panel, a graph showing reduction in tumor weight of a breast cancer model using 70 mg/kg Pan-PI3K inhibitor and 60 mg/kg compound A and, right panel, reduced presence of MZB cells in mouse spleen for 70 mg/kg Pan-PI3K inhibitor compared to 60 mg/kg Compound A.

FIG. 10 illustrates the frequency of PI3K α mutation in various human cancers.

FIG. 11 is a western blot depicting inhibition of the PI3K pathway by Compound A in cell lines with elevated PI3K α activity. The left column shows data from MDA-MB-361 breast cancer cells harboring PIK3CA mutation. The middle column shows data from MDA-MB-453 breast cancer cells harboring PIK3CA mutation. The right column shows data from SKBr3breast cancer cells harboring HER2 mutation.

FIG. 12 shows A) a western blot showing inhibition of Akt phosphorylation at serine 473 by Compound A; and B) reduced inhibition of Akt phosphorylation at serine 473 by Compound A in a PTEN-mutant cell line.

FIG. 13 is a chart showing that Compound A preferentially inhibits proliferation of tumor cells harboring PI3K α mutations.

FIG. 14 is an isobologram depicting the additive or synergistic anticancer activity achieved by a combination of Compound A and Compound B. The in vitro combination analysis demonstrated the additive or synergistic effects of the combination across tumor types or genetic types.

FIG. 15 is a western blot depicting induction of cell apoptosis by Compound A, Compound B, or combination thereof in breast cell cancer cells. Cleaved PARP is a biomarker for apoptosis. The result show that a greater degree of apoptosis and pathway regulation (TORC1 and 2 substrates) can be induced by a combination of compound A and compound B as compared to single agents. The left column shows data from MDA-MB-361 breast cancer cells harboring PIK3CA and HER2 mutations. The right column shows data from HCC-1419 breast cancer cells harboring HER2 mutation.

FIG. 16 shows that an intermittent dosing regimen of the combination of Compound A and Compound B leads to tumor growth inhibition similar to that observed on the QD schedule in vivo.

FIG. 17 shows that the combination of Compound A and Compound B leads to increased durability of tumor control in vivo, and sustained tumor regression whereas the single agent control arms demonstrate re-growth.

FIG. 18 shows that the combination of Compound A and Compound B leads to increased tumor growth inhibition in a PTEN null model, suggesting utility of this combination in diverse genotypes.

FIG. 19 shows that the combination of Compound A and Compound B demonstrates activity in a KRAS/PIK3CA colon model, whereas either single agent is not effective.

DETAILED DESCRIPTION OF THE INVENTION

Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”.

The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

“Treatment”, “treating”, “palliating” and “ameliorating”, as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

As used herein, the term “neoplastic condition” refers to the presence of cells possessing abnormal growth characteristics, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, perturbed oncogenic signaling, and certain characteristic morphological features. This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.

The term “effective amount” or “therapeutically effective amount” refers to that amount of an inhibitor described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

A “sub-therapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.

A “synergistically effective therapeutic amount” of an agent or therapy is an amount which, when combined with an effective or sub-therapeutic amount of another agent or therapy, produces a greater effect than when either of the two agents are therapies are used alone. In some embodiments, a synergistically effective therapeutic amount of an agent or therapy produces a greater effect when used in combination than the additive effects of each of the two agents or therapies when used alone.

As used herein, “agent” or “biologically active agent” refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present invention.

The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.

The phrase “mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases” when used: herein refers to an mTOR inhibitor that interacts with and reduces the kinase activity of both mTORC1 and mTORC2 complexes.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

The terms “co-administration,” “administered in combination with,” and their grammatical equivalents, encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. Co-administered agents may be in the same formulation. Co-administered agents may also be in different formulations.

A “therapeutic effect,” as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

“Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

“Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics, pre-clinical, and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

The term “in vivo” refers to an event that takes place in a subject's body.

The term “in vitro” refers to an event that takes places outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject assay. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that “consist of” or “consist essentially of” the described features.

The following abbreviations and terms have the indicated meanings throughout: PI3K=Phosphoinositide-3-kinase; PI=phosphatidylinositol.

Unless otherwise stated, the connections of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any linking moieties, and ends with the linking moiety. For example, heteroarylthio C1-4 alkyl has a heteroaryl group connected through a thio sulfur to a C1-4 alkyl radical that connects to the chemical species bearing the substituent. This condition does not apply where a formula such as, for example “-L-C1-10 alkyl C3-8cycloalkyl” is represented. In such case, the terminal group is a C3-8cycloalkyl group attached to a linking C1-10 alkyl moiety which is attached to an element L, which is itself connected to the chemical species bearing the substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, it is a C1-C4 alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8-chlorononyl, and the like.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and (heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl functionality. In some embodiments, it is a C1-C10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e. three other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e., C2-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C3-C8 cycloalkyl radical. In some embodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “C1-10alkyl C3-8cycloalkyl” is used to describe an alkyl group, branched or straight chain and containing 1 to 10 carbon atoms, attached to a linking cycloalkyl group which contains 3 to 8 carbons, such as for example, 2-methyl cyclopropyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “bicycloalkyl” refers to a structure consisting of two cycloalkyl moieties, unsubstituted or substituted, that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be “fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be “bridged”. Examples include, but are not limited to, bicyclo[2.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

As used herein, the term “heteroatom” or “ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given, e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. For example, a CH2OCH2CH3 radical is referred to as a “C4” heteroalkyl, which includes the heteroatom center in the atom chain length description. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “heteroalkylaryl” refers to a heteroalkyl group as defined above which is attached to an aryl group, and may be attached at a terminal point or through a branched portion of the heteroalkyl, for example, an benzyloxymethyl moiety. Either portion of the moiety is unsubstituted or substituted.

The term “heteroalkylheteroaryl” refers likewise to a heteroalkyl group which is attached to a heteroaryl moiety, for example, an ethoxymethylpyridyl group. Either portion of the moiety is unsubstituted or substituted.

The term “heteroalkyl-heterocyclyl” refers to a heteroalkyl group as defined above, which is attached to a heterocyclic group, for example, 4(3-aminopropyl)-N-piperazinyl. Either portion of the moiety is unsubstituted or substituted.

The term “heteroalkyl-C3-8cycloalkyl” refers to a heteroalkyl group as defined above, which is attached to a cyclic alkyl containing 3 to 8 carbons, for example, 1-aminobutyl-4-cyclohexyl. Either portion of the moiety is unsubstituted or substituted.

The term “heterobicycloalkyl” refers to a bicycloalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.

The term “heterospiroalkyl” refers to a spiroalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.

An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C2-C5 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “C2-10 alkenyl-heteroalkyl” refers to a group having an alkenyl moiety, containing 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroalkyl group, such as, for example, allyloxy, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10 alkynyl-heteroalkyl” refers to a group having an alkynyl moiety, which is unsubstituted or substituted, containing 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroalkyl group, such as, for example, 4-but-1-ynoxy, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “haloalkenyl” refers to an alkenyl group substituted with one or more halo groups.

Unless otherwise specified, the term “cycloalkenyl” refers to a cyclic aliphatic 3 to 8 membered ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, and the like.

“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., C2-C10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (e.g., C2-C5 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term C2-10 alkynyl-C3-8 cycloalkyl refers to a group containing an alkynyl group, containing 2 to 10 carbons and branched or straight chain, which is attached to a linking cycloalkyl group containing 3 to 8 carbons, such as, for example 3-prop-3-ynyl-cyclopent-1yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “haloalkenyl” refers to an alkynyl group substituted with one or more independent halo groups.

“Amino” or “amine” refers to a —N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(Ra)2 group has two Ra other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —N(Ra)2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, —N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of these moieties may be optionally substituted as defined herein.

“Amide” or “amido” refers to a chemical moiety with formula C(O)N(R)2 or NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. In some embodiments it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. The R2 of —N(R)2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

“Aromatic” or “aryl” refers to an aromatic radical with six to ten ring atoms (e.g., C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The terms “aryl-alkyl”, “arylalkyl” and “aralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a linking portion with the terminal aryl, as defined above, of the aryl-alkyl moiety. Examples of aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4-(trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl, 4-phenylbutyl, 4-(4-chlorophenyl)butyl, 4-(2-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl, 4-(2-methoxphenyl)butyl, and 10-phenyldecyl. Either portion of the moiety is unsubstituted or substituted.

The term “C1-10alkylaryl” as used herein refers to an alkyl group, as defined above, containing 1 to 10 carbon atoms, branched or unbranched, wherein the aryl group replaces one hydrogen on the alkyl group, for example, 3-phenylpropyl. Either portion of the moiety is unsubstituted or substituted.

The term C2-10 alkyl monocycloaryl” refers to a group containing a terminal alkyl group, branched or straight chain and containing 2 to 10 atoms attached to a linking aryl group which has only one ring, such as for example, 2-phenyl ethyl. Either portion of the moiety is unsubstituted or substituted.

The term “C1-10 alkyl bicycloaryl” refers to a group containing a terminal alkyl group, branched or straight chain and containing 2 to 10 atoms attached to a linking aryl group which is bicyclic, such as for example, 2-(1-naphthyl)-ethyl. Either portion of the moiety is unsubstituted or substituted.

The terms “aryl-cycloalkyl” and “arylcycloalkyl” are used to describe a group wherein the terminal aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “heteroaryl-C3-8cycloalkyl” and “heteroaryl-C3-8cycloalkyl” are used to describe a group wherein the terminal heteroaryl group is attached to a cycloalkyl group, which contains 3 to 8 carbons, for example pyrid-2-yl-cyclopentyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heteroaryl-heteroalkyl” refers to a group wherein the terminal heteroaryl group is attached to a linking heteroalkyl group, such as for example, pyrid-2-yl methylenoxy, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “aryl-alkenyl”, “arylalkenyl” and “aralkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a linking portion of the aralkenyl moiety with the terminal aryl portion, as defined above, for example styryl (2-phenylvinyl), phenpropenyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “aryl-C2-10alkenyl” means an arylalkenyl as described above wherein the alkenyl moiety contains 2 to 10 carbon atoms such as for example, styryl (2-phenylvinyl), and the like. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkenyl-aryl” is used to describe a group wherein the terminal alkenyl group, which contains 2 to 10 carbon atoms and can be branched or straight chain, is attached to the aryl moiety which forms the linking portion of the alkenyl-aryl moiety, such as for example, 3-propenyl-naphth-1-yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “aryl-alkynyl”, “arylalkynyl” and “aralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the aryl-alkynyl moiety with the terminal aryl portion, as defined above, for example 3-phenyl-1-propynyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “aryl-C2-10alkynyl” means an arylalkynyl as described above wherein the alkynyl moiety contains two to ten carbons, such as, for example 3-phenyl-1-propynyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkynyl-aryl” means a group containing an alkynyl moiety attached to an aryl linking group, both as defined above, wherein the alkynyl moiety contains two to ten carbons, such as, for example 3-propynyl-naphth-1-yl. Either portion of the moiety is unsubstituted or substituted.

The terms “aryl-oxy”, “aryloxy” and “aroxy” are used to describe a terminal aryl group attached to a linking oxygen atom. Typical aryl-oxy groups include phenoxy, 3,4-dichlorophenoxy, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “aryl-oxyalkyl”, “aryloxyalkyl” and “aroxyalkyl” are used to describe a group wherein an alkyl group is substituted with a terminal aryl-oxy group, for example pentafluorophenoxymethyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term“C1-10alkoxy-C1-10alkyl” refers to a group wherein an alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example methoxypropyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term“C1-10alkoxy-C2-10alkenyl” refers to a group wherein an alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkenyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example 3-methoxybut-2-en-1-yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term“C1-10alkoxy-C2-10alkynyl” refers to a group wherein alkoxy group, containing 1 to 10 carbon atoms and an oxygen atom within the branching or straight chain, is attached to a linking alkynyl group, branched or straight chain which contains 1 to 10 carbon atoms, such as, for example 3-methoxybut-2-in-1-yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heterocycloalkenyl” refers to a cycloalkenyl structure, which is unsubstituted or substituted in which at least one carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.

The terms “heteroaryl-oxy”, “heteroaryl-oxy”, “heteroaryloxy”, “heteroaryloxy”, “hetaroxy” and “heteroaroxy” are used to describe a terminal heteroaryl group, which is unsubstituted or substituted, attached to a linking oxygen atom. Typical heteroaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.

The terms “heteroarylalkyl”, “heteroarylalkyl”, “heteroaryl-alkyl”, “heteroaryl-alkyl”, “hetaralkyl” and “heteroaralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a linking portion of the heteroaralkyl moiety with the terminal heteroaryl portion, as defined above, for example 3-furylmethyl, thenyl, furfuryl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heteroaryl-C1-10alkyl” is used to describe a heteroaryl alkyl group as described above where the alkyl group contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.

The term “C1-10alkyl-heteroaryl” is used to describe a alkyl attached to a hetaryl group as described above where the alkyl group contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.

The terms “heteroarylalkenyl”, “heteroarylalkenyl”, “heteroaryl-alkenyl”, “heteroaryl-alkenyl”, “hetaralkenyl” and “heteroaralkenyl” are used to describe a heteroarylalkenyl group wherein the alkenyl chain can be branched or straight chain forming a linking portion of the heteroaralkenyl moiety with the terminal heteroaryl portion, as defined above, for example 3-(4-pyridyl)-1-propenyl. Either portion of the moiety is unsubstituted or substituted.

The term “heteroaryl-C2-10alkenyl” group is used to describe a group as described above wherein the alkenyl group contains 2 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkenyl-heteroaryl” is used to describe a group containing an alkenyl group, which is branched or straight chain and contains 2 to 10 carbon atoms, and is attached to a linking heteroaryl group, such as, for example 2-styryl-4-pyridyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “heteroarylalkynyl”, “heteroarylalkynyl”, “heteroaryl-alkynyl”, “heteroaryl-alkynyl”, “hetaralkynyl” and “heteroaralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the heteroaralkynyl moiety with the heteroaryl portion, as defined above, for example 4-(2-thienyl)-1-butynyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heteroaryl-C2-10alkynyl” is used to describe a heteroarylalkynyl group as described above wherein the alkynyl group contains 2 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkynyl-heteroaryl” is used to describe a group containing an alkynyl group which contains 2 to 10 carbon atoms and is branched or straight chain, which is attached to a linking heteroaryl group such as, for example, 4(but-1-ynyl) thien-2-yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl” refers to a four-, five-, six-, or seven-membered ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. The four-membered ring has zero double bonds, the five-membered ring has zero to two double bonds, and the six- and seven-membered rings have zero to three double bonds. The term “heterocyclyl” also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclyl group, or a four- to seven-membered aromatic or nonaromatic carbocyclic ring. The heterocyclyl group can be attached to the parent molecular moiety through any carbon atom or nitrogen atom in the group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocycloalkyl. In some embodiments, it is a C4-C10 heterocycloalkyl. In some embodiments, it is a C3-C10 heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 hetero atoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

The terms “heterocyclylalkyl”, “heterocyclyl-alkyl”, “hetcyclylalkyl”, and “hetcyclyl-alkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a linking portion of the heterocyclylalkyl moiety with the terminal heterocyclyl portion, as defined above, for example 3-piperidinylmethyl and the like. The term “heterocycloalkylene” refers to the divalent derivative of heterocycloalkyl.

The term “C1-10alkyl-heterocycyl” refers to a group as defined above where the alkyl moiety contains 1 to 10 carbon atoms. Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C1-10alkyl” refers to a group containing a terminal heterocyclic group attached to a linking alkyl group which contains 1 to 10 carbons and is branched or straight chain, such as, for example, 4-morpholinyl ethyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “heterocyclylalkenyl”, “heterocyclyl-alkenyl”, “hetcyclylalkenyl” and “hetcyclylalkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a linking portion of the heterocyclylalkenyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-morpholinyl-1-propenyl and the like. The term “heterocycloalkenylene” refers to the divalent derivative of heterocyclylalkenyl. Either portion of the moiety is unsubstituted or substituted.

The term “heterocycyl-C2-10 alkenyl” refers to a group as defined above where the alkenyl group contains 2 to 10 carbon atoms and is branched or straight chain, such as, for example, 4-(N-piperazinyl)-but-2-en-1-yl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “heterocyclylalkynyl”, “heterocyclyl-alkynyl”, “hetcyclylalkynyl” and “hetcyclylalkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a linking portion of the heterocyclylalkynyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-pyrrolidinyl-1-butynyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heterocycyl-C2-10 alkynyl” refers to a group as defined above where the alkynyl group contains 2 to 10 carbon atoms and is branched or straight chain, such as, for example, 4-(N-piperazinyl)-but-2-yn-1-yl, and the like.

The term “aryl-heterocycyl” refers to a group containing a terminal aryl group attached to a linking heterocyclic group, such as for example, N4-(4-phenyl)-piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heteroaryl-heterocycyl” refers to a group containing a terminal heteroaryl group attached to a linking heterocyclic group, such as for example, N4-(4-pyridyl)-piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “carboxylalkyl” refers to a terminal carboxyl (—COOH) group attached to branched or straight chain alkyl groups as defined above.

The term “carboxylalkenyl” refers to a terminal carboxyl (—COOH) group attached to branched or straight chain alkenyl groups as defined above.

The term “carboxylalkynyl” refers to a terminal carboxyl (—COOH) group attached to branched or straight chain alkynyl groups as defined above.

The term “carboxylcycloalkyl” refers to a terminal carboxyl (—COOH) group attached to a cyclic aliphatic ring structure as defined above.

The term “carboxylcycloalkenyl” refers to a terminal carboxyl (—COOH) group attached to a cyclic aliphatic ring structure having ethylenic bonds as defined above.

The terms “cycloalkylalkyl” and “cycloalkyl-alkyl” refer to a terminal cycloalkyl group as defined above attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “cycloalkylalkenyl” and “cycloalkyl-alkenyl” refer to a terminal cycloalkyl group as defined above attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “cycloalkylalkynyl” and “cycloalkyl-alkynyl” refer to a terminal cycloalkyl group as defined above attached to an alkynyl group, for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “cycloalkenylalkyl” and “cycloalkenyl-alkyl” refer to a terminal cycloalkenyl group as defined above attached to an alkyl group, for example 2-(cyclopenten-1-yl)ethyl and the like. Either portion of the moiety is unsubstituted or substituted.

The terms “cycloalkenylalkenyl” and “cycloalkenyl-alkenyl” refer to terminal a cycloalkenyl group as defined above attached to an alkenyl group, for example 1-(cyclohexen-3-yl)allyl and the like.

The terms “cycloalkenylalkynyl” and “cycloalkenyl-alkynyl” refer to terminal a cycloalkenyl group as defined above attached to an alkynyl group, for example 1-(cyclohexen-3-yl)propargyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers to alkoxy groups containing one to six carbons. In some embodiments, C1-C4 alkyl, is an alkyl group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.

The term “haloalkoxy” refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the like.

The term “alkoxyalkoxyalkyl” refers to an alkyl group substituted with an alkoxy moiety which is in turn is substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, and the like. This moiety is substituted with further substituents or not substituted with other substituents.

The term “alkylthio” includes both branched and straight chain alkyl groups attached to a linking sulfur atom, for example methylthio and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “alkoxyalkenyl” refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “alkoxyalkynyl” refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkenylC3-8cycloalkyl” refers to an alkenyl group as defined above substituted with a three to eight membered cycloalkyl group, for example, 4-(cyclopropyl)-2-butenyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “C2-10alkynylC3-8cycloalkyl” refers to an alkynyl group as defined above substituted with a three to eight membered cycloalkyl group, for example, 4-(cyclopropyl)-2-butynyl and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C1-10alkyl” refers to a heterocyclic group as defined above substituted with an alkyl group as defined above having 1 to 10 carbons, for example, 4-(N-methyl)-piperazinyl, and the like. Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C2-10alkenyl” refers to a heterocyclic group as defined above, substituted with an alkenyl group as defined above, having 2 to 10 carbons, for example, 4-(N-allyl)piperazinyl, and the like. Moieties wherein the heterocyclic group is substituted on a carbon atom with an alkenyl group are also included. Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C2-10alkynyl” refers to a heterocyclic group as defined above, substituted with an alkynyl group as defined above, having 2 to 10 carbons, for example, 4-(N-propargyl)piperazinyl, and the like. Moieties wherein the heterocyclic group is substituted on a carbon atom with an alkenyl group are also included. Either portion of the moiety is unsubstituted or substituted.

The term “oxo” refers to an oxygen that is double bonded to a carbon atom. One in the art understands that an “oxo” requires a second bond from the atom to which the oxo is attached. Accordingly, it is understood that oxo cannot be substituted onto an aryl or heteroaryl ring, unless it forms part of the aromatic system as a tautomer.

The term “oligomer” refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.

“Sulfonamidyl” or “sulfonamido” refers to a S(═O)2—NR′R′ radical, where each R′ is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R′ groups in NR′R′ of the S(═O)2—NR′R′ radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively.

Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Compounds may be shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of the disclosed compounds and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

The present invention includes all manner of rotamers and conformationally restricted states of an inhibitor of the invention.

Substituents for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivative radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN and NO2 in a number ranging from zero to (2 m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″ and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When an inhibitor of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present.

When R′ and R″ or R″ and R′″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl, 4 piperazinyl, and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF3 and CH2CF3) and acyl (e.g., —C(O)CH3, —C(O)CF3, —C(O)CH2OCH3, and the like).

Similar to the substituents described for alkyl radicals above, exemplary substituents for aryl and heteroaryl groups (as well as their divalent derivatives) are varied and are selected from, for example: halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′—CN and NO2, —R′, —N3, —CH(Ph)2, fluoro(C1-C4)alkoxo, and fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on aromatic ring system; and where R′, R″, R′″ and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When an inhibitor of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present.

As used herein, 0-2 in the context of —S(O)(0-2)— are integers of 0, 1, and 2.

Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)q—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)2—, —S(O)2NR′— or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)s—X′—(C″R′″)d—, where s and d are independently integers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)2—, or —S(O)2NR′—. The substituents R, R′, R″ and R′″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

The term “treatment period” as used herein is defined as the time period in which a subject is administered the daily doses of the pharmaceutical composition according to a dosing regimen. The term “resting period” refers to a period of time during which a subject is not administered a pharmaceutical composition according to a dosing regimen. For example, if the pharmaceutical composition has been given on a daily basis, there would be rest period if the daily administration is discontinued, e.g., for some number of days or weeks. If a dose is administered on a different schedule a rest period would occur where that dosing is discontinued for some time. In some dosing regimens, a rest period occurs where the concentration of the pharmaceutical composition is maintained at a sub-therapeutic level. Preferably, during the rest period, the plasma concentration of the pharmaceutical composition is maintained at sub-therapeutic level. A combination therapy can have different dosing regimens for different compounds, e.g., one dosing regimen for a first compound and another dosing regimen for a second compound. Under such a combination therapy, a subject can undergo a rest period with respect to the first compound, at the same time undergoes a treatment period with respect to the second compound. In some combination therapy, a rest period refers to a period of time during which a subject is not administered any pharmaceutical composition.

The term “intermittent dosing regimen” refers to a dosing regimen that comprises administering a pharmaceutical composition, followed by a rest period.

The term “durability of effect” refers to the continuation of at least one of the clinical and/or therapeutic effects of the PI3-kinase α inhibitor and/or mTOR inhibitor after discontinuing the administration thereof. Such continuation of the clinical and therapeutic effects can last for a period of time at least as long as the administration period of the PI3-kinase α inhibitor and/or mTOR inhibitor. The term “durability of effect period” refers to the period beginning immediately following the administration period. This period occurring after the administration period relates is characterized by no PI3-kinase α inhibitor or mTOR inhibitor being administered, but where the therapeutic and clinical effects of the inhibitor administration still continue. Depending on the dosage as well as the length of the administration, the durability of effect period lasts at least as long as the administration period, but can last up to about 5 or more times the length of the administration period. In some regimens, the durability of effect period is at least 5, 10, 20, 30 days. In some regimens, the durability of effect period is at least a month, three months, six months, or a year.

The present invention provides methods for treating a disease condition associated with PI3-kinase α and/or mTOR, in particular neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease and kidney disease, which provide for durability of effect periods which are at least as long as the administration period of PI3-kinase α inhibitor or mTOR inhibitor. The clinical and therapeutic effects which are extended from the administration period into the durability of effect period can include sustained tumor regression, inhibited tumor re-growth, reduction of proliferation, increased apoptosis, or downregulation of activity of a target protein, or combinations thereof. An administration period refers to the period of time in which a dosing regimen (e.g., an intermittent dosing regimen) is administered to a subject. The administration period can be from about 1 to about 52 weeks, or from about 4 to about 24 weeks, or from about 6 to about 12 weeks, or about 8 weeks, or about 4 weeks. The administration period can include one or more treatment periods and one or more rest periods. With each administration period there is a corresponding durability of effect period which lasts at least as long as the administration period.

Methods

In one aspect, the present invention provides a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. The method typically comprises administering to a subject simultaneously or sequentially a therapeutically effective amount of a combination of a PI3-kinase α inhibitor and an mTOR inhibitor.

As used herein, a therapeutically effective amount of a combination of a PI3-kinase α inhibitor and an mTOR inhibitor refers to a combination of a PI3-kinase α inhibitor and an mTOR inhibitor, wherein the combination is sufficient to effect the intended application including but not limited to disease treatment, as defined herein. Encompassed in this subject method is the use of therapeutically effective amount of a PI3-kinase α inhibitor and/or an mTOR inhibitor in combination to effect such treatment. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a PI3-kinase α inhibitor and/or an mTOR inhibitor in the combination for treating an intended disease condition. The individual inhibitors, though present in sub-therapeutic amounts, synergistically yield an efficacious effect and/or reduced a side effect in an intended application.

Accordingly, in a separate but related aspect, the present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject, comprising administering to the subject simultaneously or sequentially a synergistically effective therapeutic amount of a combination of a PI3-kinase α inhibitor and an mTOR inhibitor.

The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

The PI3-kinase α inhibitor utilized in the subject methods typically exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) including, e.g., PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

Selective inhibition of PI3-kinase α can be ascertained by an in vitro or an in vivo method. Any assay known in the art may be used, including without limitation, immunoassays, immunoprecipitation, fluorescence or cell-based assays. In some embodiments, an in vitro assay is used to determine selective inhibition of PI3-kinase α by an assay which measures the activity of the PI3Kα protein relative to the activity of another PI3-kinase such as PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. For example, a time resolved FRET assay that indirectly measures PIP3 product formed by the activity of a PI3-K may be used to determine an IC50 value for a test compound for PI3-kinase α and/or any of the other PI3-kinases.

As used herein, the term “IC50” refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required for obtaining 50% of a maximum effect in vivo.

Determination of IC50 can be made by determining and constructing a dose-response curve and examining the effect of different concentrations of an inhibitor on reversing agonist activity. In vitro assays that are useful in making these determinations are referred to as “in vitro kinase assays.”

In some embodiments, an in vitro kinase assay includes the use of labeled ATP as a phosphate donor, and following the kinase reaction the substrate peptide is captured on an appropriate filter. Unreacted labeled ATP and metabolites are resolved from the radioactive peptide substrate by various techniques, involving trichloroacetic acid precipitation and extensive washing. Addition of several positively charged residues allows capture on phosphocellulose paper followed by washing. Radioactivity incorporated into the substrate peptide is detected by scintillation counting. This assay is relatively simple, reasonably sensitive, and the peptide substrate can be adjusted both in terms of sequence and concentration to meet the assay requirements.

Other exemplary kinase assays are detailed in U.S. Pat. No. 5,759,787 and U.S. application Ser. No. 12/728,926, both of which are incorporated herein by reference.

In other embodiments, a cell-based assay is used to ascertain selective inhibition of PI3-kinase α. For example, an inhibitor can be shown to be selective for PI3-kinase α if it selectively downregulates PI3-kinase signal transduction in cells that express PI3-kinase α, preferably in cells that exhibit abnormally high level or activity of PI3-kinase α. A variety of cells having PI3-kinase α mutations and hence exhibiting such PI3-kinase α abnormalities are known in the art. Non-limiting examples of cell lines harboring such mutations include those that carry point mutations, deletions, substitutions, or translation of nucleic acid sequence of the PI3-kinase α gene. Examples of such cell lines include but are not limited to BT20 (H1047R mutation), MCF-7 (E545K mutation), MDA-MB-361 (E545K mutation), MDA-MB-453 (H1047R mutation), T47D (H1047R mutation), Hec-1A (G1049R mutation) and HCT-116 (H1047R mutation). Other cell lines having mutations in the PI3Kα protein may be used, such as cells harboring mutations in the p85, C2, helical or kinase domains.

In addition, inhibition of PI3-kinase α activity can be determined by a reduction in signal transduction of the PI3-kinase α pathway. A wide variety of readouts can be utilized to establish a reduction of the output of such signaling pathway. Some non-limiting exemplary readouts include (1) a decrease in phosphorylation of Akt at residues, including but not limited to S473 and T308; (2) a decrease in activation of Akt as evidenced by a reduction of phosphorylation of Akt substrates including but not limited to FoxO1/O3a T24/32, GSK3α/β S21/9, and TSC2 T1462; (3) a decrease in phosphorylation of signaling molecules downstream of PI3-kinase α, including but not limited to ribosomal S6 S240/244, 70S6K T389, and 4EBP1 T37/46; (4) inhibition of proliferation of cells including but not limited to normal or neoplastic cells, mouse embryonic fibroblasts, leukemic blast cells, cancer stem cells, and cells that mediate autoimmune reactions; (5) induction of apoptosis of cells or cell cycle arrest; (6) reduction of cell chemotaxis; and (7) an increase in binding of 4EBP1 to eIF4E. The term “eIF4E” refers to a 24-1d) eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs, having human gene locus 4q21-q25.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α relative to one, two or three other type I phosphatidylinositol-3-kinases (PI3-kinases) consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In other embodiments, some of the subject inhibitors selectively inhibit PI3-kinase α and PI3-kinase γ as compared to the rest of the type I PI3-kinases. In yet other embodiments, some of the subject inhibitors selectively inhibit PI3-kinase α and PI3-kinase β as compared to the rest of the type I PI3-kinases. In still yet other embodiments, some of the subject inhibitors selectively inhibit PI3-kinase α and PI3-kinase δ as compared to the rest of the type I PI3-kinases.

In some embodiments, the subject methods utilizes a PI3-kinase α inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro kinase assay. In some embodiments, the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM, or less.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less than its IC50 value against one, two, or three other type I PI3-kinase(s) selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM, and said IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less than its IC50 value against one, two or three other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay.

In some instances, the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 200 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 100 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some instances, the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 50 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 20 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 20 nM, and said IC50 value is at 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some instances, the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 20 nM or less as ascertained in an in vitro kinase assay and the IC50 value is at least 100 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

Alternatively, the PI3-kinase α inhibitor inhibits PI3-kinase α with an EC50 value of about 10 μM or less, 5 μM or less, 2.5 μM or less, 1 μM or less, 500 nM or less, 100 nM or less, 75 nM or less, 50 nM or less, 25 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 500 μM or less, or 100 μM or less as ascertained in an in vitro kinase assay.

In some embodiments, the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an EC50 value that is at least 5, 10, 15, 20, 25, 50, 100, or 1000 times less than its EC50 value against one, two or three other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the PI3-kinase α inhibitor inhibits PI3-kinase α with an EC50 value of about 10 μM or less, 5 μM or less, 2.5 μM or less, 1 μM or less, 500 nM or less, 100 nM or less, 75 nM or less, 50 nM or less, 25 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 500 μM or less, or 100 μM or less as ascertained in an in vitro kinase assay, and such EC50 value is at least 5, 10, 15, 20, 25, 50, or 100, 1000 times less than its EC50 value against one, two or three other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The mTOR inhibitor utilized in the subject methods is typically highly selective for the target molecule. In one aspect, the mTOR inhibitor binds to and directly inhibits both mTORC1 and mTORC2. Such ability can be ascertained using any method known in the art or described herein. For example, inhibition of mTorC1 and/or mTorC2 activity can be determined by a reduction in signal transduction of the PI3K/Akt/mTor pathway. A wide variety of readouts can be utilized to establish a reduction of the output of such signaling pathway. Some non-limiting exemplary readouts include (1) a decrease in phosphorylation of Akt at residues, including but not limited to S473 and T308; (2) a decrease in activation of Akt as evidenced by a reduction of phosphorylation of Akt substrates including but not limited to FoxO1/O3a T24/32, GSK3α/β S21/9, and TSC2 T1462; (3) a decrease in phosphorylation of signaling molecules downstream of mTor, including but not limited to ribosomal S6 S240/244, 70S6K T389, and 4EBP1 T37/46; (4) inhibition of proliferation of cells including but not limited to normal or neoplastic cells, mouse embryonic fibroblasts, leukemic blast cells, cancer stem cells, and cells that mediate autoimmune reactions; (5) induction of apoptosis of cells or cell cycle arrest; (6) reduction of cell chemotaxis; and (7) an increase in binding of 4EBP1 to eIF4E.

mTor exists in two types of complexes, mTorC1 containing the raptor subunit and mTorC2 containing rictor. As known in the art, “rictor” refers to a cell growth regulatory protein having human gene locus 5p13.1. These complexes are regulated differently and have a different spectrum of substrates. For instance, mTorC1 phosphorylates S6 kinase (S6K) and 4EBP1, promoting increased translation and ribosome biogenesis to facilitate cell growth and cell cycle progression. S6K also acts in a feedback pathway to attenuate PI3K/Akt activation. Thus, inhibition of mTorC1 (e.g. by a biologically active agent as discussed herein) results in activation of 4EBP1, resulting in inhibition of (e.g. a decrease in) RNA translation.

mTorC2 is generally insensitive to rapamycin and selective inhibitors and is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt. In many cellular contexts, mTorC2 is required for phosphorylation of the S473 site of Akt. Thus, mTorC1 activity is partly controlled by Akt whereas Akt itself is partly controlled by mTorC2.

Growth factor stimulation of PI3K causes activation of Akt by phosphorylation at the two key sites, S473 and T308. It has been reported that full activation of Akt requires phosphorylation of both S473 and T308Active. Akt promotes cell survival and proliferation in many ways including suppressing apoptosis, promoting glucose uptake, and modifying cellular metabolism. Of the two phosphorylation sites on Akt, activation loop phosphorylation at T308, mediated by PDK1, is believed to be indispensable for kinase activity, while hydrophobic motif phosphorylation at S473 enhances Akt kinase activity.

Selective mTor inhibition may also be determined by expression levels of the mTor genes, its downstream signaling genes (for example by RT-PCR), or expression levels of the proteins (for example by immunocytochemistry, immunohistochemistry, Western blots) as compared to other PI3-kinases or protein kinases.

Cell-based assays for establishing selective inhibition of mTorC1 and/or mTorC2 can take a variety of formats. This generally will depend on the biological activity and/or the signal transduction readout that is under investigation. For example, the ability of the agent to inhibit mTorC1 and/or mTorC2 to phosphorylate the downstream substrate(s) can be determined by various types of kinase assays known in the art. Representative assays include but are not limited to immunoblotting and immunoprecipitation with antibodies such as anti-phosphotyrosine, anti-phosphoserine or anti-phosphothreonine antibodies that recognize phosphorylated proteins. Alternatively, antibodies that specifically recognize a particular phosphorylated form of a kinase substrate (e.g. anti-phospho AKT S473 or anti-phospho AKT T308) can be used. In addition, kinase activity can be detected by high throughput chemiluminescent assays such as AlphaScreen™ (available from Perkin Elmer) and eTag™ assay (Chan-Hui, et al. (2003) Clinical Immunology 111: 162-174). In another aspect, single cell assays such as flow cytometry as described in the Phosflow experiment can be used to measure phosphorylation of multiple downstream mTOR substrates in mixed cell populations.

One advantage of the immunoblotting and Phosflow methods is that the phosphorylation of multiple kinase substrates can be measured simultaneously. This provides the advantage that efficacy and selectivity can be measured at the same time. For example, cells may be contacted with an mTOR inhibitor at various concentrations and the phosphorylation levels of substrates of both mTOR and other kinases can be measured. In one aspect, a large number of kinase substrates are assayed in what is termed a “comprehensive kinase survey.” Selective mTOR inhibitors are expected to inhibit phosphorylation of mTOR substrates without inhibiting phosphorylation of the substrates of other kinases. Alternatively, selective mTOR inhibitors may inhibit phosphorylation of substrates of other kinases through anticipated or unanticipated mechanisms such as feedback loops or redundancy.

Effect of inhibition of mTorC1 and/or mTorC2, or PI3-kinase α can be established by cell colony formation assay or other forms of cell proliferation assay. A wide range of cell proliferation assays are available in the art, and many of which are available as kits. Non-limiting examples of cell proliferation assays include testing for tritiated thymidine uptake assays, BrdU (5′-bromo-2′-deoxyuridine) uptake (kit marketed by Calbiochem), MTS uptake (kit marketed by Promega), MTT uptake (kit marketed by Cayman Chemical), CyQUANT® dye uptake (marketed by Invitrogen).

Apoptosis and cell cycle arrest analysis can be performed with any methods exemplified herein as well other methods known in the art. Many different methods have been devised to detect apoptosis. Exemplary assays include but are not limited to the TUNEL (TdT-mediated dUTP Nick-End Labeling) analysis, ISEL (in situ end labeling), and DNA laddering analysis for the detection of fragmentation of DNA in populations of cells or in individual cells, Annexin-V analysis that measures alterations in plasma membranes, detection of apoptosis related proteins such p53 and Fas.

A cell-based assay typically proceeds with exposing the target cells (e.g., in a culture medium) to a test compound which is a potential mTorC1 and/or mTorC2 selective inhibitor, or a PI3-kinase α inhibitor and then assaying for readout under investigation. Depending on the nature of the candidate mTor inhibitors or PI3-kinase α inhibitors, they can directly be added to the cells or in conjunction with carriers. For instance, when the agent is nucleic acid, it can be added to the cell culture by methods well known in the art, which include without limitation calcium phosphate precipitation, microinjection or electroporation. Alternatively, the nucleic acid can be incorporated into an expression or insertion vector for incorporation into the cells. Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operatively linked are well known in the art. Such vectors are capable of transcribing RNA in vitro or in vitro, and are commercially available from sources such as Stratagene (La Jolla, Calif.) and Promega Biotech (Madison, Wis.). In order to optimize expression and/or in vitro transcription, it may be necessary to remove, add or alter 5′ and/or 3′ untranslated portions of the clones to eliminate extra, potential inappropriate alternative translation initiation codons or other sequences that may interfere with or reduce expression, either at the level of transcription or translation. Alternatively, consensus ribosome binding sites can be inserted immediately 5′ of the start codon to enhance expression. Examples of vectors are viruses, such as baculovirus and retrovirus, bacteriophage, adenovirus, adeno-associated virus, cosmid, plasmid, fungal vectors and other recombination vehicles typically used in the art which have been described for expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple protein expression. Among these are several non-viral vectors, including DNA/liposome complexes, and targeted viral protein DNA complexes. To enhance delivery to a cell, the nucleic acid or proteins of this invention can be conjugated to antibodies or binding fragments thereof which bind cell surface antigens. Liposomes that also comprise a targeting antibody or fragment thereof can be used in the methods of this invention. Other biologically acceptable carriers can be utilized, including those described in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 19th Ed. (2000), in conjunction with the subject compounds.

The subject agents can also be utilized to inhibit phosphorylation of both Akt (S473) and Akt (T308) in a cell. Accordingly, the present invention provides a method comprises the step of contacting a cell with an effective amount of such biologically active agent such that Akt phosphorylation at residues S473 and T308 is simultaneously inhibited. In one aspect, the biologically active agent inhibits phosphorylation of S473 of Akt more effectively than phosphorylation of T308 of Akt when tested at a comparable molar concentration, preferably at an identical molar concentration.

Inhibition of Akt phosphorylation can be determined using any methods known in the art or described herein. Representative assays include but are not limited to immunoblotting and immunoprecipitation with antibodies such as anti-phosphotyrosine antibodies that recognize the specific phosphorylated proteins. Cell-based ELISA kit quantifies the amount of activated (phosphorylated at S473) Akt relative to total Akt protein is also available (SuperArray Biosciences).

In practicing the subject methods, any cells that express PI3-kinase α, mTorC1, mTorC2 and/or Akt can be utilized. Non-limiting examples of specific cell types whose proliferation can be inhibited include fibroblast, cells of skeletal tissue (bone and cartilage), cells of epithelial tissues (e.g. liver, lung, breast, skin, bladder and kidney), cardiac and smooth muscle cells, neural cells (glia and neurones), endocrine cells (adrenal, pituitary, pancreatic islet cells), melanocytes, and many different types of haemopoietic cells (e.g., cells of B-cell or T-cell lineage, and their corresponding stem cells, lymphoblasts). Also of interest are cells exhibiting a neoplastic propensity or phenotype. Of particular interest is the type of cells that differentially expresses (over-expresses or under-expresses) a disease-causing gene. The types of diseases involving abnormal functioning of genes include but are not limited to autoimmune diseases, cancer, obesity, hypertension, diabetes, neuronal and/or muscular degenerative diseases, cardiac diseases, endocrine disorders, and any combinations thereof.

In some embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. For example, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 200, 100, 75, 50, 25, 10, 5, 1 or 0.5 nM or less as ascertained in an in vitro kinase assay. In one instance, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay. Alternatively, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay.

In some embodiments, the present invention provides the use of an mTOR inhibitor, wherein the mTOR inhibitor directly binds to and inhibits both mTORC1 and mTORC2 with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro kinase assay. In some embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM or less, 60 μM or less, 70 μM or less, 80 μM or less, 90 μM or less, 100 μM or less, 200 μM or less, 300 μM or less, 400 μM or less, or 500 μM or less.

In some embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM or less, 60 μM or less, 70 μM or less, 80 μM or less, 90 μM or less, 100 μM or less, 200 μM or less, 300 μM or less, 400 μM or less, or 500 μM or less, and the mTOR inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTOR inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

As used herein, the terms “substantially inactive” refers to an inhibitor that inhibits the activity of its target by less than approximately 1%, 5%, 10%, 15% or 20% of its maximal activity in the absence of the inhibitor, as determined by an in vitro enzymatic assay (e.g. in vitro kinase assay).

In other embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 2, 5, 10, 15, 20, 50, 100 or 100 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. For example, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 5 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the mTOR inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and said IC50 value is at least 5 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

In some embodiments, the mTOR inhibitor utilized in the subject methods inhibits one of mTORC1 and mTORC2 selectively with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase. For example, the mTOR inhibitor utilized in the subject methods inhibits mTORC1 selectively with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in vitro kinase. For example, rapamycin and rapamycin derivatives or analogues have been shown to primarily inhibit mTORC1 and not mTORC2. Suitable mTORC1 inhibitors compounds include, for example, sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), zotarolimus (ABT-578), and biolimus A9 (umirolimus).

PI3-kinase α inhibitors or mTOR inhibitors suitable for use in the subject methods can be selected from a variety types of molecules. For example, an inhibitor can be biological or chemical compound such as a simple or complex organic or inorganic molecule, peptide, peptide mimetic, protein (e.g. antibody), liposome, or a polynucleotide (e.g. small interfering RNA, microRNA, anti-sense, aptamer, ribozyme, or triple helix). Some exemplary classes of chemical compounds suitable for use in the subject methods are detailed in the sections below.

The advantages of selective inhibition of a cellular target as a way of treating a disease condition mediated by such target are manifold. Because healthy cells depend on the signaling pathways that are activated in cancers for survival, inhibition of these pathways during cancer treatment can cause harmful side effects. In order for a method of treating cancer to be successful without causing excessive damage to healthy cells, a very high degree of specificity in targeting the aberrant signaling component or components is desirable. Moreover, cancer cells may depend on overactive signaling for their survival (known as the oncogene addiction hypothesis). In this way, cancer cells are frequently observed to adapt to drug inhibition of an aberrant signaling component by selecting for mutations in the same pathway that overcome the effect of the drug. Therefore, cancer therapies may be more successful in overcoming the problem of drug resistance if they target a signaling pathway as a whole, or target more than one component within a signaling pathway.

Without being bound by theory, selective inhibition of PI3-kinase α provides a more targeted treatment to a disease condition mediated by PI3-kinase without disrupting one or more pathways that are implicated by one or more other type I phosphatidylinositol-3-kinases, namely PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

Some signaling pathways that contain PI3K and mTOR are illustrated in FIG. 1. One major downstream effector of PI3K and mTOR signaling is the Akt serine/threonine kinase. Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, which binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either PIP3 (phosphatidylinositol (3,4,5)-trisphosphate, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate, PtdIns(3,4)P2). PI3K phosphorylates PIP2 in response to signals from chemical messengers, such as ligand binding to G protein-coupled receptors or receptor tyrosine kinases. Phosphorylation by PI3K converts PIP2 to PIP3, recruiting Akt to the cell membrane where it is phosphorylated at serine 473 (S473) by mTORC2. Phosphorylation of Akt at another site, threonine 308 (T308), is not directly dependent on mTORC2, but requires PI3K activity. Therefore, PI3K activity towards Akt can be isolated from mTOR activity by examining Akt threonine 308 phosphorylation status in cells lacking mTORC2 activity.

The subject methods are useful for treating a disease condition associated with PI3-kinase α and/or mTOR. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PI3-kinase α and/or mTOR can be an intended disease condition.

A vast diversity of disease conditions associated with PI3-kinase α and/or mTOR have been reported. PI3-kinase α has been implicated, for example, in a variety of human cancers. Angiogenesis has been shown to selectively require the α isoform of PI3K in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene coding for PI3K α or mutations which lead to upregulation of PI3K α are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain and skin cancers. Often, mutations in the gene coding for PI3K α are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of PI3K α mutations, targeting of this pathway provides valuable therapeutic opportunities. While other PI3K isoforms such as PI3K δ or PI3K γ are expressed primarily in hematopoietic cells, PI3K α, along with PI3K β, is expressed constitutively.

Disease conditions associated with PI3-kinase α and/or mTOR can also be characterized by abnormally high level of activity and/or expression of downstream messengers of PI3-kinase α. For example, proteins or messengers such as PIP2, PIP3, PDK, Akt, PTEN, PRAS40, GSK-3β, p21, p27 may be present in abnormal amounts which can be identified by any assays known in the art.

Deregulation of the mTOR pathway is emerging as a common theme in diverse human diseases and as a consequence drugs that target mTOR have therapeutic value. The diseases associated with deregulation of mTORC1 include, but are not limited to, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), both of which are caused by mutations in TSC1 or TSC2 tumor suppressors. Patients with TSC develop benign tumors that when present in brain, however, can cause seizures, mental retardation and death. LAM is a serious lung disease Inhibition of mTORC1 may help patients with Peutz-Jeghers cancer-prone syndrome caused by the LKB 1 mutation. mTORC1 may also have role in the genesis of sporadic cancers. Inactivation of several tumor suppressors, in particular PTEN, p53, VHL and NF1, has been linked to mTORC1 activation. Rapamycin and its analogues (e.g. CCI-779, RAD001 and AP23573) inhibit TORC1 and have shown moderate anti-cancer activity in phase II clinical trials. However, due to the negative signal from S6K1 to the insulin/PI3K/Akt pathway, it is important to note that inhibitors of mTORC1, like rapalogs, can activate PKB/Akt. If this effect persists with chronic rapamycin treatment, it may provide cancer cells with an increased survival signal that may be clinically undesirable. The PI3K/Akt pathway is activated in many cancers. Activated Akt regulates cell survival, cell proliferation and metabolism by phosphorylating proteins such as BAD, FOXO, NF-KB, p21Cip1, p27Kip1, GSK3β and others. Akt might also promote cell growth by phosphorylating TSC2. Akt activation probably promotes cellular transformation and resistance to apoptosis by collectively promoting growth, proliferation and survival, while inhibiting apoptotic pathways. The combination of an inhibitor of mTORC1 and mTORC2 and a PI3-kinase α inhibitor is beneficial for treatment of tumors with elevated Akt phosphorylation, and should down-regulate cell growth, cell survival and cell proliferation.

Where desired, the subject to be treated is tested prior to treatment using a diagnostic assay to determine the sensitivity of tumor cells to a PI3Kα kinase inhibitor. Any method known in the art that can determine the sensitivity of the tumor cells of a subject to a PI3Kα kinase inhibitor can be employed. Where the subject is tested prior to treatment using a diagnostic assay to determine the sensitivity of tumor cells to an PI3Kα kinase inhibitor, in one embodiment, when the subject is identified as one whose tumor cells are predicted to have low sensitivity to an PI3Kα kinase inhibitor as a single agent, are likely to display enhanced sensitivity in the presence of an mTOR inhibitor, or vice versa, when the subject is administered, simultaneously or sequentially, a therapeutically effective amount of a combination of an PI3Kα kinase inhibitor and an mTOR inhibitor. In another embodiment, when the subject is identified as one whose tumor cells are predicted to have high sensitivity to an PI3Kα kinase inhibitor as a single agent, but may also display enhanced sensitivity in the presence of an mTOR inhibitor based on the results described herein, the subject is administered, simultaneously or sequentially, a therapeutically effective amount of a combination of an PI3Kα kinase inhibitor and an mTOR inhibitor. In these methods one or more additional anti-cancer agents or treatments can be co-administered simultaneously or sequentially with the PI3Kα kinase inhibitor and mTOR inhibitor, as judged to be appropriate by the administering physician given the prediction of the likely responsiveness of the subject to the combination of PI3Kα kinase inhibitor and mTOR inhibitor, in combination with any additional circumstances pertaining to the individual subject.

Accordingly, in some embodiments, the present invention provides for a method comprising: (a) determining the presence in a subject of a mutation in PI3-kinase α that is associated with a disease condition mediated by PI3-kinase α; and (b) administering to said subject a pharmaceutical composition of the invention.

In yet another embodiment, the present invention provides for a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell, comprising contacting a cell with an effective amount of a PI3-kinase α inhibitor and an mTOR inhibitor, biologically active agent that selectively inhibits both mTORC1 and mTORC2 activity relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol-3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The data presented in the Examples herein below demonstrate that the anti-tumor effects of a combination of an mTOR inhibitor and PI3K α inhibitor are superior to the anti-tumor effects of either inhibitor by itself, and co-administration of an mTOR inhibitor with a PI3K α inhibitor can be effective for treatment of a neoplastic condition associated with PI3-kinase α and/or mTOR. Non-limiting examples of such conditions include but are not limited to Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple myeloma, Mycosis Fungoides, Myelodysplastic Disease, Myelodysplastic Syndromes, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget's disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

In other embodiments, the methods of using a PI3Kα inhibitor and an mTOR inhibitor described herein are applied to the treatment of heart conditions including atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstriction. The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a PI3Kα inhibitor and an mTOR inhibitor of the present invention, or any pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.

In some embodiments, the invention provides for the use of a PI3Kα inhibitor and an mTOR inhibitor for treating a disease condition associated with PI3-kinase α and/or mTOR, including, but not limited to, conditions related to an undesirable, over-active, harmful or deleterious immune response in a mammal, collectively termed “autoimmune disease.” Autoimmune disorders include, but are not limited to, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, juvenile arthritis and ankylosing spondilitis, Other non-limiting examples of autoimmune disorders include autoimmune diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), rheumatoid spondylitis, gouty arthritis, allergy, autoimmune uveitis, nephrotic syndrome, multisystem autoimmune diseases, autoimmune hearing loss, adult respiratory distress syndrome, shock lung, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis, silicosis, idiopathic interstitial lung disease, chronic obstructive pulmonary disease, asthma, restenosis, spondyloarthropathies, Reiter's syndrome, autoimmune hepatitis, inflammatory skin disorders, vasculitis oflarge vessels, medium vessels or small vessels, endometriosis, prostatitis and Sjogren's syndrome. Undesirable immune response can also be associated with or result in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis, auto-immune diseases, rheumatoid arthritis, graft versus host disease, transplantation rejection, lung injuries, and lupus erythematosus. The pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing. The compositions of the invention can be further used to treat multiorgan failure.

The invention also provides methods of using a PI3Kα inhibitor and an mTOR inhibitor for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced renal disease) or pain in a mammal.

The invention also provides a method of using a PI3Kα inhibitor and an mTOR inhibitor for the treatment of sperm motility. The invention further provides a method of using a PI3Kα inhibitor and an mTOR inhibitor for the treatment of neurological or neurodegenerative diseases including, but not limited to, Alzheimer's disease, Huntington's disease, CNS trauma, and stroke.

The invention further provides a method of using a PI3Kα inhibitor and an mTOR inhibitor for the prevention of blastocyte implantation in a mammal.

The invention also relates to a method of using a PI3Kα inhibitor and an mTOR inhibitor for treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.

The invention further provides a method of using a PI3Kα inhibitor and an mTOR inhibitor for the treatment of disorders involving platelet aggregation or platelet adhesion, including but not limited to Bernard-Soulier syndrome, Glanzmann's thrombasthenia, Scott's syndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, and Gray platelet syndrome.

In some embodiments, methods of using a PI3Kα inhibitor and an mTOR inhibitor are provided for treating a disease which is skeletal muscle atrophy, skeletal muscle hypertrophy, leukocyte recruitment in cancer tissue, invasion metastasis, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, glomerulo sclerosis, glomerulo, nephritis, or progressive renal fibrosis.

Certain embodiments contemplate a human subject such as a subject that has been diagnosed as having or being at risk for developing or acquiring a disease condition associated with PI3-kinase α and/or mTOR. Certain other embodiments contemplate a non-human subject, for example a non-human primate such as a macaque, chimpanzee, gorilla, vervet, orangutan, baboon or other non-human primate, including such non-human subjects that can be known to the art as preclinical models, including preclinical models for inflammatory disorders. Certain other embodiments contemplate a non-human subject that is a mammal, for example, a mouse, rat, rabbit, pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or other mammal. There are also contemplated other embodiments in which the subject or biological source can be a non-mammalian vertebrate, for example, another higher vertebrate, or an avian, amphibian or reptilian species, or another subject or biological source. In certain embodiments of the present invention, a transgenic animal is utilized. A transgenic animal is a non-human animal in which one or more of the cells of the animal includes a nucleic acid that is non-endogenous (i.e., heterologous) and is present as an extrachromosomal element in a portion of its cell or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells).

Exemplary mTor Inhibitor Compounds

In one aspect, the invention provides a compound which is an inhibitor of mTor of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is N or C-E1, X2 is N or C, X3 is N or C, X4 is C—R9 or N, X5 is N or C-E1, X6 is C or N, and X7 is C or N; and wherein no more than two nitrogen ring atoms are adjacent;

R1 is H, -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, -L-C1-10alkylhetaryl, -L-C1-10alkylheterocylyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

E1 and E2 are independently —(W1)j—R4;

M1 is a 5, 6, 7, 8, 9, or -10 membered ring system, wherein the ring system is monocyclic or bicyclic, substituted with R5 and additionally optionally substituted with one or more —(W2)k—R2;

each k is 0 or 1;

j in E1 or j in E2, is independently 0 or 1;

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), hetaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylhetaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylhetaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylhetaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocylyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heteroalkyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, hetaryl-C3-8cycloalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, hetaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylhetaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylhetaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylhetaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocylyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, hetaryl-C3-8cycloalkyl, heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

each of R31, R32, and R33 is independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, hetaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R7 and R8 is independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6;

R6 is halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35; and

R9 is H, halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C1-10alkyl, hetaryl-C2-10alkenyl, hetaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35.

M1 is a 5, 6, 7, 8, 9, or -10 membered ring system, wherein the ring system is monocyclic or bicyclic. The monocyclic M1 ring is unsubstituted or substituted with one or more R5 substituents (including 0, 1, 2, 3, 4, or 5 R5 substituents). In some embodiments, the monocyclic M1 ring is aromatic (including phenyl) or heteroaromatic (including but not limited to pyridinyl, pyrrolyl, imidazolyl, thiazolyl, or pyrimidinyl). The monocyclic M1 ring may be a 5 or 6 membered ring (including but not limited to pyridinyl, pyrrolyl, imidazolyl, thiazolyl, or pyrimidinyl). In some embodiments, M2 is a five membered heteroaromatic group with one heteroatom, wherein the heteroatom is N, S, or O. In another embodiment, M2 is a five membered heteroaromatic group with two heteroatoms, wherein the heteroatoms are nitrogen and oxygen or nitrogen and sulfur.

The bicyclic M1 ring is unsubstituted or substituted with one or more R5 substituents (including 0, 1, 2, 3, 4, 5, 6 or 7 R5 substituents). Bicyclic M1 ring is a 7, 8, 9, or 10 membered aromatic or heteroaromatic. Examples of an aromatic bicyclic M1 ring include naphthyl. In other embodiments the bicyclic M1 ring is heteroaromatic and includes but is not limited to benzothiazolyl, quinolinyl, quinazolinyl, benzoxazolyl, and benzimidazolyl.

The invention also provides compounds wherein M1 is a moiety having a structure of Formula M1-A or Formula M1-B:

wherein W1, W2, and W7 are independently N or C—R5; W4 and W10 are independently N—R5, O, or S; W6 and W8 are independently N or C—R5; W5 and W9 are independently N or C—R2; and W3 is C or N, provided no more than two N and/or N—R5 are adjacent and no two O or S are adjacent.

In some embodiments of the invention, the M1 moiety of Formula M1-A is a moiety of Formula M1-A1, Formula M1-A2, Formula M1-A3, or Formula M1-A4:

wherein W4 is N—R5, O, or S; W6 is N or C—R5 and W5 is N or C—R2.

Some nonlimiting examples of the M1 moiety of Formula M1-A include:

wherein R5 is —(W1)k—R53 or R55; each k is independently 0 or 1, n is 0, 1, 2, or 3, and —(W1)k—R53 and R55 are as defined above.

In other embodiments of the invention, the M1 moiety of Formula M1-B is a moiety of Formula M1-B1, Formula M1-B2, Formula M1-B3, or Formula M1-B4:

wherein W10 is N—R5, O, or S, W8 is N or C—R5, and W5 is N or C—R2.

Some nonlimiting examples of the M1 moiety of Formula M1-B include:

wherein R′5 is —(W1)k—R53 or R55; k is 0 or 1, n is 0, 1, 2, or 3, and —(W1)k—R53 and R55 are as defined above.

The invention also provides compounds wherein M1 is a moiety having a structure of Formula M1-C or Formula M1-D:

wherein W12, W13, W14, and W15 are independently N or C—R5; W11 and W18 are independently N—R5, O, or S; W16 and W17 are independently N or C—R5; provided no more than two N are adjacent.

In other embodiments of the invention, the M1 moiety of Formula M1-C or Formula M1-D is a moiety of Formula M1-C1 or Formula M1-D1:

wherein W11 and W18 are N—R5, O, or S; and W16 and W17 are N or C—R5.

Some nonlimiting examples of the M1 moiety of Formula M1-C and Formula M1-D include:

wherein R′5 is —(W1)k—R53 or R55; k is 0 or 1, and —(W1)k—R53 and R55 are as defined above.

The invention also provides compounds wherein M1 is a moiety having a structure of Formula M1-E:

wherein X11, X12, X13, X14, X15, X16, and X17 are independently N, or C—R5; provided that no more than two N are adjacent.

In some embodiments of the invention, the M1 moiety having a structure of Formula M1-E, is a moiety having a structure of Formula M1-E1, M1-E2, M1-E3, M1-E4, M1-E5, M1-E6, M1-E7, or M1-E8:

In some embodiments of the invention, the M1 moiety having a structure of Formula M1-E, is a moiety having a structure:

Some nonlimiting examples of the M1 moiety of Formula M1-E include:

wherein R′5 is —(W1)k—R53 or R55; k is 0 or 1, n is 0, 1, 2, or 3, and —(W1)k—R53 or R55 are as defined above. In some embodiments, k is 0, and R5 is R53.

In some embodiments, R53 is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C8cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments, R53 is monocyclic or bicyclic aryl, wherein the R53 aryl is unsubstituted or substituted. Some examples of aryl include but are not limited to phenyl, naphthyl or fluorenyl. In some other embodiments, R53 is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R53 includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R53 includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, and purinyl. Additionally, R53 may be alkylcycloalkyl (including but not limited to cyclopropylethyl, cyclopentylethyl, and cyclobutylpropyl), -alkylaryl (including but not limited to benzyl, phenylethyl, and phenylnaphthyl), -alkylhetaryl (including but not limited to pyridinylmethyl, pyrrolylethyl, and imidazolylpropyl), or -alkylheterocyclyl (non-limiting examples are morpholinylmethyl, 1-piperazinylmethyl, and azetidinylpropyl). For each of alkylcycloalkyl, alkylaryl, alkylhetaryl, or alkylheterocyclyl, the moiety is connected to M1 through the alkyl portion of the moiety In other embodiments, R53 is unsubstituted or substituted C2-C10alkenyl (including but not limited to alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C10alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl).

Further embodiments provide R53 wherein R53 is alkenylaryl, alkenylheteroaryl, alkenylheteroalkyl, or alkenylheterocyclyl, wherein each of alkenyl, aryl, heteroaryl, heteroalkyl, and heterocyclyl is as described herein and wherein the alkenylaryl, alkenylhetaryl, alkenylheteroalkyl, or alkenylheterocycicyl moiety is attached to M1 through the alkenyl. Some nonlimiting examples in include styryl, 3-pyridinylallyl, 2-methoxyethoxyvinyl, and 3-morpholinlylallyl In other embodiments, R53 is -alkynylaryl, -alkynylhetaryl, -alkynylheteroalkyl, -alkynylheterocylyl, -alkynylcycloalkyl, or -alkynylC3-8cycloalkenyl, wherein each of alkynyl, aryl, heteroaryl, heteroalkyl, and heterocyclyl is as described herein and wherein the alkynylaryl, alkynylhetaryl, alkynylheteroalkyl, or alkynylheterocyclyl moiety is attached to M1 through the alkynyl. Alternatively, R53 is -alkoxyalkyl, -alkoxyalkenyl, or -alkoxyalkynyl, wherein each of alkoxy, alkyl, alkenyl, and alkynyl is as described herein and wherein the -alkoxyalkyl, -alkoxyalkenyl, or -alkoxyalkynyl moiety is attached to M1 through the alkoxy. In yet other embodiments, R53 is -heterocyclylalkyl, -heterocyclylalkenyl, or -heterocyclylalkynyl, wherein the heterocyclyl, alkyl, alkenyl, or alkynyl is as described herein and wherein the -heterocyclylalkyl, -heterocyclylalkenyl, or -heterocyclylalkynyl is attached to M1 through the heterocyclyl portion of the moiety. Further, R53 may be aryl-alkenyl, aryl-alkynyl, or aryl-heterocyclyl, wherein the aryl, alkenyl, alkynyl, or heterocyclyl is as described herein and wherein the aryl-alkenyl, aryl-alkynyl, or aryl-heterocyclyl moiety is attached to M1 through the aryl portion of the moiety. In some other embodiments, R53 is heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, and heterocyclyl is as described herein and wherein the heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl moiety is attached to M1 through the heteroaryl portion of the moiety.

For each of the aryl or heteroaryl moieties forming part or all of R53, the aryl or heteroaryl is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NNR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32 substituents. Additionally, each of the alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moieties forming part of all of R53 is unsubstituted or substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NNR34R35, or —C(═O)NR31R32 substituents.

In other embodiments, R5 is —W1—R53. In some embodiments, R5 is —OR53, including but not limited to —O-alkyl (including but not limited to methoxy or ethoxy), —O-aryl (including but not limited to phenoxy), —O-heteroaryl (including but not limited to pyridinoxy) and —O-heterocycloxy(including but not limited to 4-N-piperidinoxy). In some embodiments R5 is —NR6R53 including but not limited to anilinyl, diethylamino, and 4-N-piperidinylamino. In yet other embodiments R5 is —S(O)0-2R53, including but not limited to phenylsulfonyl and pyridinylsulfonyl. The invention also provides compounds wherein R5 is —C(O) (including but not limited to acetyl, benzoyl, and pyridinoyl) or —C(O)O R53 (including but not limited to carboxyethyl, and carboxybenzyl). In other embodiments, R5 is —C(O)N(R6)R53 (including but not limited to C(O)NH(cyclopropyl) and C(O)N(Me)(phenyl)) or —CH(R6)N(R7)R53 (including but not limited to —CH2—NH-pyrrolidinyl, CH2—NHcyclopropyl, and CH2-anilinyl). Alternatively, R5 is —N(R6)C(O)R53 (including but not limited to —NHC(O)phenyl, —NHC(O)cyclopentyl, and to —NHC(O)piperidinyl) or —N(R6)S(O)2 R53 (including but not limited to —NHS(O)2phenyl, —NHS(O)2piperazinyl, and —NHS(O)2-methyl. Additionally, R5 is —N(R6)S(O)R53, —CH(R6)N(C(O)OR7) R53, —CH(R7)N(C(O)R7) R53, —CH(R6)N(SO2R7) R53, —CH(R6)N(R7) R53, —CH(R6)C(O)N(R7) R53, —CH(R6)N(R7)C(O)R53, —CH(R6)N(R7)S(O)R53, or —CH(R6)N(R7)S(O)2 R53.

Alternatively, R5 is R55. R55 is halo, —OH, —NO2, —CF3, —OCF3, or —CN. In some other embodiments, R55 is —R31, —OR31 (including but not limited to methoxy, ethoxy, and butoxy) —C(O)R31 (non-limiting examples include acetyl, propionyl, and pentanoyl), or —CO2R31 (including but not limited to carboxymethyl, carboxyethyl and carboxypropyl). In further embodiments, R55 is —NR31R32, —C(═O)NR31R32, —SO2NR31R32, or —S(O)0-2R31. In other embodiments, R55 is —NR34R35 or —SO2 NR34R35, wherein R34R35 are taken together with the nitrogen to which R34R35 are attached to form a cyclic moiety. The cyclic moiety so formed may be unsubstituted or substituted, wherein the substituents are selected from the group consisting of alkyl, —C(O)alkyl, —S(O)2alkyl, and —S(O)2aryl. Examples include but are not limited to morpholinyl, piperazinyl, or —SO2-(4-N-methyl-piperazin-1-yl. Additionally, R55 is —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —C(═O)NNR34R35, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32. In yet another embodiment, R55 is —O-aryl, including but not limited to phenoxy, and naphthyloxy.

The invention further provides a compound which is an mTor inhibitor, wherein the compound has the Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is N or C-E1, X2 is N, X3 is C, and X4 is C—R9 or N; or X1 is N or C-E1, X2 is C, X3 is N, and X4 is C—R9 or N;

R1 is —H, -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, -L-C1-10alkylheteroaryl, -L-C1-10alkylheterocyclyl, -L-C2-10alkenyl, -L-C2-10alkyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

M1 is a moiety having the structure of Formula M1-F1 or M1-F2:

k is 0 or 1;

E1 and E2 are independently —(W1)j—R4;

j, in each instance (i.e., in E1 or j in E2), is independently 0 or 1

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heteroalkyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, heteroaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

R7 and R8 are each independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6;

R6 is halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35; and

R9 is H, halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35.

In some embodiments, X4 is C—R9.

The invention also provides an inhibitor as defined above, wherein the compound is of Formula I:

or a pharmaceutically acceptable salt thereof, and wherein the substituents are as defined above.

In various embodiments the compound of Formula I-B or its pharmaceutically acceptable salt thereof, is a compound having the structure of Formula I-B1 or Formula I-B2:

or a pharmaceutically acceptable salt thereof.

In various embodiments of Formula I-B1, X1 is N and X2 is N. In other embodiments, X1 is C-E1 and X2 is N. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In various embodiments of Formula I-B2, X1 is N and X2 is C. In further embodiments, X1 is C-E1 and X2 is C.

In various embodiments, X1 is C—(W1)j—R4, where j is 0.

In another embodiment, X1 is CH. In yet another embodiment, X1 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X1, it is C—(W1)j—R4. In various embodiments of X1, j is 1, and W1 is —O—. In various embodiments of X1, j is 1, and W1 is —NR7—. In various embodiments of X1, j is 1, and W1 is —NH—. In various embodiments of X1, j is 1, and W1 is —S(O)0-2—. In various embodiments of X1, j is 1, and W1 is —C(O)—. In various embodiments of X1, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of X1, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of X1, j is 1, and W1 is —C(O)O—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)OR8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In another embodiment, X1 is CH2. In yet another embodiment, X1 is CH-halogen, where halogen is Cl, F, Br, or I.

In another embodiment, X1 is N.

In various embodiments, X2 is N. In other embodiments, X2 is C.

In various embodiments, E2 is —(W1)j—R4, where j is 0.

In another embodiment, E2 is CH. In yet another embodiment, E2 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E2, it is —(W1)j—R4. In various embodiments of E2, j is 1, and W1 is —O—. In various embodiments of E2, j is 1, and W1 is —NR7—. In various embodiments of E2, j is 1, and W1 is —NH—. In various embodiments of E2, j is 1, and W1 is —S(O)0-2—. In various embodiments of E2, j is 1, and W1 is —C(O)—. In various embodiments of E2, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of E2, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of E2, j is 1, and W1 is —C(O)O—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)OR8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In various embodiments when M1 is a moiety of Formula M1-F1, M1 is benzoxazolyl substituted with —(W2)k—R2. In some embodiments, M1 is a benzoxazolyl substituted at the 2-position with —(W2)j—R2. In some embodiments, M1 is either a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally substituted at the 2-position with (W2)j—R2. Exemplary Formula M1-F1 M1 moieties include but are not limited to the following:

In various embodiments when M1 is a moiety of Formula M1-F2, Formula M1-F2 is an aza-substituted benzoxazolyl moiety having a structure of one of the following formulae:

Exemplary Formula M1-F2 M1 moieties include but are not limited to the following:

In various embodiments of M1, k is 0. In other embodiments of M1, k is 1, and W2 is selected from one of the following: —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, or —N(R7)C(O)N(R8)—. In yet another embodiment of M1, k is 1, and W2 is —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, or —CH(R7)N(SO2R8)—. In a further embodiment of M1, k is 1, and W2 is —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, or —CH(R7)N(R8)S(O)—. In yet another embodiment of M1, k is 1, and W2 is —CH(R7)N(R8)S(O)2—.

The invention provides an inhibitor of mTor which is a compound of Formula I-C or Formula I-D:

or a pharmaceutically acceptable salt thereof, wherein X1 is N or C-E1, X2 is N, and X3 is C; or X1 is N or C-E1, X2 is C, and X3 is N;

R1 is —H, -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, -L-C1-10alkylheteroaryl, -L-C1-10alkylheterocyclyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

E1 and E2 are independently —(W1)j—R4;

j in E1 or j in E2, is independently 0 or 1;

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

k is 0 or 1;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocyclcyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32 s, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom; and

R7 and R8 are each independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6; and R6 is halo, —OR31, —SH, NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl; or R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, each of which is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35.

In various embodiments of the compound of Formula I-C, the compound has a structure of Formula I-C1 or Formula I-C2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I-C1, X1 is N and X2 is N. In other embodiments, X1 is C-E1 and X2 is N. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In several embodiments of Formula I-C2, X1 is N and X2 is C. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In various embodiments of the compound of Formula I-D, the compound has a structure of Formula I-D1 or Formula I-D2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I-D1, X1 is N and X2 is N. In other embodiments, X1 is C-E1 and X2 is N. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In several embodiments of Formula I-D2, X1 is N and X2 is C. In further embodiments, X1 is C-E1 and X2 is C.

In various embodiments, X1 is C—(W1)j—R4, where j is 0.

In another embodiment, X1 is CH. In yet another embodiment, X1 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X1, it is C—(W1)j—R4. In various embodiments of X1, j is 1, and W1 is —O—. In various embodiments of X1, j is 1, and W1 is —NR7—. In various embodiments of X1, j is 1, and W1 is —NH—. In various embodiments of X1, j is 1, and W1 is —S(O)0-2—. In various embodiments of X1, j is 1, and W1 is —C(O)—. In various embodiments of X1, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of X1, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of X1, j is 1, and W1 is —C(O)O—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)OR8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In various embodiments, X1 is CH—(W1)j—R4, where j is 0.

In another embodiment, X1 is CH2. In yet another embodiment, X1 is CH-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X1, it is CH—(W1)j—R4. In various embodiments of X1, j is 1, and W1 is —O—. In various embodiments of X1, j is 1, and W1 is —NR7—. In various embodiments of X1, j is 1, and W1 is —NH—. In various embodiments of X1, j is 1, and W1 is —S(O)0-2—. In various embodiments of X1, j is 1, and W1 is —C(O)—. In various embodiments of X1, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of X1, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of X1, j is 1, and W1 is —C(O)O—. In various embodiments of X1, j is 1, and W1 is CH(R7)N(C(O)OR8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In another embodiment, X1 is N.

In various embodiments, X2 is N. In other embodiments, X2 is C.

In various embodiments, E2 is —(W1)j—R4, where j is 0.

In another embodiment, E2 is CH. In yet another embodiment, E2 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E2, it is —(W1)j—R4. In various embodiments of E2, j is 1, and W1 is —O—. In various embodiments of E2, j is 1, and W1 is —NR7—. In various embodiments of E2, j is 1, and W1 is —NH—. In various embodiments of E2, j is 1, and W1 is —S(O)0-2—. In various embodiments of E2, j is 1, and W1 is —C(O)—. In various embodiments of E2, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of E2, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of E2, j is 1, and W1 is —C(O)O—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)OR8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In various embodiments, k is 0. In other embodiments, k is 1 and W2 is —O—. In another embodiment, k is 1 and W2 is —NR7—. In yet another embodiment of, k is 1, and W2 is —S(O)0-2—. In another embodiment of, k is 1 and W2 is —C(O)—. In a further embodiment, k is 1 and W2 is —C(O)N(R7)—. In another embodiment, k is 1, and W2 is —N(R7)C(O)—. In another embodiment, k is 1 and W2 is —N(R7)C(O)N(R8)—. In yet another embodiment, k is 1 and W2 is —N(R7)S(O)—. In still yet another embodiment, k is 1 and W2 is —N(R7)S(O)2—. In a further embodiment, k is 1 and W2 is —C(O)O—. In another embodiment, k is 1 and W2 is —CH(R7)N(C(O)OR8)—. In another embodiment, k is 1 and W2 is —CH(R7)N(C(O)R8)—. In another embodiment, k is 1 and W2 is —CH(R7)N(SO2R8)—. In a further embodiment, k is 1 and W2 is —CH(R7)N(R8)—. In another embodiment, k is 1 and W2 is —CH(R7)C(O)N(R8)—. In yet another embodiment, k is 1 and W2 is —CH(R7)N(R8)C(O)—. In another embodiment, k is 1 and W2 is —CH(R7)N(R8)S(O)—. In yet another embodiment, k is 1 and W2 is —CH(R7)N(R8)S(O)2—.

The invention also provides a compound which is an mTor inhibitor of Formula I-E:

or a pharmaceutically acceptable salt thereof, wherein: X1 is N or C-E1, X2 is N, and X3 is C; or X1 is N or C-E1, X2 is C, and X3 is N;

R1 is —H, -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, -L-C1-10alkylheteroaryl, -L-C1-10alkylheterocyclyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

M1 is a moiety having the structure of Formula M1-F1 or Formula M1-F2:

k is 0 or 1;

E1 and E2 are independently —(W1)j—R4;

j in E1 or j in E2, is independently 0 or 1;

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, heteroaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32—NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

R7 and R8 are each independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6;

R6 is halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkenyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35; and

R9 is H, halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35.

In various embodiments of the compound of Formula I-E, the compound has a structure of Formula I-E1 or Formula I-E2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I-E1, X1 is N and X2 is N. In other embodiments, X1 is C-E1 and X2 is N. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In several embodiments of Formula I-E2, X1 is N and X2 is C. In further embodiments, X1 is C-E1 and X2 is C.

In various embodiments, X1 is C—(W1)j—R4, where j is 0.

In another embodiment, X1 is CH. In yet another embodiment, X1 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X1, it is C—(W1)j—R4. In various embodiments of X1, j is 1, and W1 is —O—. In various embodiments of X1, j is 1, and W1 is —NR7—. In various embodiments of X1, j is 1, and W1 is —NH—. In various embodiments of X1, j is 1, and W1 is —S(O)0-2—. In various embodiments of X1, j is 1, and W1 is —C(O)—. In various embodiments of X1, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of X1, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of X1, j is 1, and W1 is —C(O)O—. In various embodiments of X1, j is 1, and W1 is CH(R7)N(C(O)OR8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In another embodiment, X1 is N.

In various embodiments, X2 is N. In other embodiments, X2 is C.

In various embodiments, E2 is —(W1)j—R4, where j is 0.

In another embodiment, E2 is CH. In yet another embodiment, E2 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E2, it is —(W1)j—R4. In various embodiments of E2, j is 1, and W1 is —O—. In various embodiments of E2, j is 1, and W1 is —NR7—. In various embodiments of E2, j is 1, and W1 is —NH—. In various embodiments of E2, j is 1, and W1 is —S(O)0-2—. In various embodiments of E2, j is 1, and W1 is —C(O)—. In various embodiments of E2, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of E2, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of E2, j is 1, and W1 is —C(O)O—. In various embodiments of E2, j is 1, and W1 is CH(R7)N(C(O)OR8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In various embodiments when M1 is a moiety of Formula I-E1, M1 is benzoxazolyl substituted with —(W2)k—R2. In some embodiments, M1 is a benzoxazolyl moiety, substituted at the 2-position with —(W2)k—R2. In some embodiments, M1 is either a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally substituted with (W2)k—R2. Exemplary Formula I-E1 M1 moieties include but are not limited to the following:

In various embodiments when M1 is a moiety of Formula I-E2, Formula I-E2 is an aza-substituted benzoxazolyl moiety having a structure of one of the following formulae:

Exemplary Formula I-E2 M1 moieties include but are not limited to the following:

In various embodiments of M1, k is 0. In other embodiments of M1, k is 1 and W2 is —O—. In another embodiment of M1, k is 1 and W2 is —NR7—. In yet another embodiment of M1, k is 1 and W2 is —S(O)0-2—. In another embodiment of M1, k is 1 and W2 is —C(O)—. In a further embodiment of M1, k is 1 and W2 is —C(O)N(R7)—. In another embodiment of M1, k is 1 and W2 is —N(R7)C(O)—. In another embodiment, k is 1 and W2 is —N(R7)C(O)N(R8)—. In yet another embodiment of M1, k is 1 and W2 is —N(R7)S(O)—. In still yet another embodiment of M1, k is 1 and W2 is —N(R7)S(O)2—. In a further embodiment of M1, k is 1 and W2 is —C(O)O—. In another embodiment of M1, k is 1 and W2 is —CH(R7)N(C(O)OR8)—. In another embodiment of M1, k is 1 and W2 is —CH(R7)N(C(O)R8)—. In another embodiment of M1, k is 1 and W2 is —CH(R7)N(SO2R8)—. In a further embodiment of M1, k is 1 and W2 is —CH(R7)N(R8)—. In another embodiment of M1, k is 1 and W2 is —CH(R7)C(O)N(R8)—. In yet another embodiment of M1, k is 1 and W2 is —CH(R7)N(R8)C(O)—. In another embodiment of M1, k is 1 and W2 is —CH(R7)N(R8)S(O)—. In yet another embodiment of M1, k is 1 and W2 is —CH(R7)N(R8)S(O)2—.

Additional embodiments of compounds of Formula I, including I-A, I-B, I-C, I-D, I-E and others are described below.

In various embodiments of compounds of Formula I, L is absent. In another embodiment, L is —(C═O)—. In another embodiment, L is —C(═O)O—. In a further embodiment, L is —C(═O)NR31—. In yet another embodiment, L is —S—. In one embodiment, L is —S(O)—. In another embodiment, L is —S(O)2—. In yet another embodiment, L is —S(O)2NR31—. In another embodiment, L is —NR31—.

In various embodiments of compounds of Formula I, R1 is L-C1-10alkyl, which is unsubstituted. In another embodiment, R1 is L-C1-10alkyl, which is substituted by one or more independent R3.

In yet another embodiment, R1 is L-unsubstituted C1-10alkyl, where L is absent. In another embodiment, R1 is L-C1-10alkyl, which is substituted by one or more independent R3, and L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is L-C3-8cycloalkyl, which is substituted by one or more independent R3. In yet another embodiment, R1 is -L-C3-8cycloalkyl, which is unsubstituted, and L is absent. In a further embodiment, R1 is -L-C3-8cycloalkyl which is substituted by one or more independent R3, and L is absent.

In various embodiments of compounds of Formula I, R1 is H.

In various embodiments of compounds of Formula I, R1 is -L-aryl, which is unsubstituted. In another embodiment, R1 is -L-aryl, which is substituted by one or more independent R3. In another embodiment, R1 is -L-aryl which is unsubstituted, and L is absent. In yet another embodiment, R1 is -L-aryl, which is substituted by one or more independent R3, and L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroaryl, which is unsubstituted. In another embodiment, R1 is -L-heteroaryl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroaryl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroaryl, which is substituted by one or more independent R3, and L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C1-10alkyl-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is -L-C1-10alkyl-C3-8cycloalkyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C1-10alkyl-C3-8cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C1-10alkyl-C3-8cycloalkyl, which is substituted by one or more independent R3, and L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C1-10alkylaryl, which is unsubstituted. In another embodiment, R1 is -L-C1-10alkylaryl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C1-10alkylaryl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C1-10 alkylaryl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C1-10alkylheteroaryl, which is unsubstituted. In another embodiment, R1 is -L-C1-10alkylheteroaryl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C1-10alkylheteroaryl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C1-10alkylheteroaryl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C1-10alkylheterocyclyl, which is unsubstituted. In another embodiment, R1 is -L-C1-10alkylheterocyclyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C1-10alkylheterocyclyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C1-10alkylheterocyclyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C2-10alkenyl, which is unsubstituted. In another embodiment, R1 is -L-C2-10alkenyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C2-10alkenyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C2-10alkenyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C2-10alkynyl, which is unsubstituted. In another embodiment, R1 is -L-C2-10alkynyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C2-10alkynyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C2-10alkynyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C2-10alkenyl-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is -L-C2-10alkenyl-C3-8cycloalkyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C2-10alkenyl-C3-8cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C2-10alkenyl-C3-8cycloalkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C2-10alkynyl-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is -L-C2-10alkynyl-C3-8cycloalkyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C2-10alkynyl-C3-8 cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C2-10alkynyl-C3-8cycloalkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-C2-10alkynyl-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is -L-C2-10alkynyl-C3-8cycloalkyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-C2-10alkynyl-C3-8 cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-C2-10alkynyl-C3-8cycloalkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroalkyl, which is unsubstituted. In another embodiment, R1 is -L-heteroalkyl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroalkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroalkylaryl, which is unsubstituted. In another embodiment, R1 is -L-heteroalkylaryl which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroalkylaryl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroalkylaryl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroalkylheteroaryl, which is unsubstituted. In another embodiment, R1 is -L-heteroalkylheteroaryl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroalkylheteroaryl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroalkylheteroaryl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula, R1 is -L-heteroalkyl-heterocyclyl, which is unsubstituted. In another embodiment, R1 is -L-heteroalkyl-heterocyclyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroalkyl-heterocyclyl which is unsubstituted, and L is absent. In yet another embodiment, R1 is -L-heteroalkyl-heterocyclyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroalkyl-C3-8cycloalkyl, which is unsubstituted. In another embodiment, R1 is -L-heteroalkyl-C3-8cycloalkyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroalkyl-C3-8cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroalkyl-C3-8cycloalkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-aralkyl, which is unsubstituted. In another embodiment, R1 is -L-aralkyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-aralkyl which is unsubstituted. In yet another embodiment, R1 is -L-aralkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heteroaralkyl, which is unsubstituted. In another embodiment, R1 is -L-heteroaralkyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heteroaralkyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heteroaralkyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is -L-heterocyclyl, which is unsubstituted. In another embodiment, R1 is -L-heterocyclyl, which is substituted by one or more independent R3. In a further embodiment, R1 is -L-heterocyclyl which is unsubstituted and L is absent. In yet another embodiment, R1 is -L-heterocyclyl, which is substituted by one or more independent R3, where L is absent.

In various embodiments of compounds of Formula I, R1 is a substituent as shown below:

In various embodiments of compounds of Formula I, R2 is hydrogen. In another embodiment, R2 is halogen. In another embodiment, R2 is —OH. In another embodiment, R2 is —R31. In another embodiment, R2 is —CF3. In another embodiment, R2 is —OCF3. In another embodiment, R2 is —OR31. In another embodiment, R2 is —NR31R32. In another embodiment, R2 is —NR34R35. In another embodiment, R2 is —C(O)R31. In another embodiment, R2 is —CO2R31. In another embodiment, R2 is —C(═O)NR31R32. In another embodiment, R2 is —C(═O)NR34R35. In another embodiment, R2 is —NO2. In another embodiment, R2 is —CN. In another embodiment, R2 is —S(O)0-2R3. In another embodiment, R2 is —SO2NR31R32. In another embodiment, R2 is —SO2NR34R35. In another embodiment, R2 is —NR31C(═O)R32. In another embodiment, R2 is —NR31C(═O)OR32. In another embodiment, R2 is —NR31C(═O)NR32R33. In another embodiment, R2 is —NR31S(O)0-2R32. In another embodiment, R2 is —C(═S)OR31. In another embodiment, R2 is —C(═O)SR31. In another embodiment, R2 is —NR31C(═NR32)NR33R32. In another embodiment, R2 is —NR31C(═NR32)OR33. In another embodiment, R2 is —NR31C(═NR32)SR33. In another embodiment, R2 is —OC(═O)OR33. In another embodiment, R2 is —OC(═O)NR31R32. In another embodiment, R2 is —OC(═O)SR31. In another embodiment, R2 is —SC(═O)OR31. In another embodiment, R2 is —P(O)OR31OR32. In another embodiment, R2 is —SC(═O)NR31R32. In another embodiment, R2 is monocyclic aryl. In another embodiment, R2 is bicyclic aryl. In another embodiment, R2 is substituted monocyclic aryl. In another embodiment, R2 is heteroaryl. In another embodiment, R2 is C1-4alkyl. In another embodiment, R2 is C1-10alkyl. In another embodiment, R2 is C3-8cycloalkyl. In another embodiment, R2 is C3-8cycloalkyl-C1-10alkyl. In another embodiment, R2 is C1-10alkyl-C3-8cycloalkyl. In another embodiment, R2 is C1-10alkyl-monocyclic aryl. In another embodiment, R2 is C2-10alkyl-monocyclic aryl. In another embodiment, R2 is monocyclic aryl-C2-10alkyl. In another embodiment, R2 is C1-10alkyl-bicyclic aryl. In another embodiment, R2 is bicyclic aryl-C1-10alkyl. In another embodiment, R2 is —C1-10alkylheteroaryl. In another embodiment, R2 is —C1-10alkylheterocyclyl. In another embodiment, R2 is —C2-10alkenyl. In another embodiment, R2 is —C2-10alkynyl. In another embodiment, R2 is C2-10alkenylaryl. In another embodiment, R2 is C2-10alkenylheteroaryl. In another embodiment, R2 is C2-10alkenylheteroalkyl. In another embodiment, R2 is C2-10alkenylheterocycicyl. In another embodiment, R2 is —C2-10alkynylaryl. In another embodiment, R2 is —C2-10alkynylheteroaryl. In another embodiment, R2 is —C2-10alkynylheteroalkyl. In another embodiment, R2 is —C2-10alkynylheterocyclyl. In another embodiment, R2 is —C2-10alkynylC3-8cycloalkyl. In another embodiment, R2 is —C2-10alkynylC3-8cycloalkenyl. In another embodiment, R2 is —C1-10alkoxy C1-10alkyl. In another embodiment, R2 is —C1-10alkoxy-C2-10alkenyl. In another embodiment, R2 is —C1-10alkoxy-C2-10alkynyl. In another embodiment, R2 is -heterocyclyl C1-10alkyl. In another embodiment, R2 is heterocyclylC2-10alkenyl. In another embodiment, R2 is heterocyclylC2-10alkynyl. In another embodiment, R2 is aryl-C2-10alkyl. In another embodiment, R2 is aryl-C1-10alkyl. In another embodiment, R2 is aryl-C2-10alkenyl. In another embodiment, R2 is aryl-C2-10alkynyl. In another embodiment, R2 is aryl-heterocyclyl. In another embodiment, R2 is heteroaryl-C1-10alkyl. In another embodiment, R2 is heteroaryl-C2-10alkenyl. In another embodiment, R2 is heteroaryl-C2-10alkynyl. In another embodiment, R2 is heteroaryl-C3-8cycloalkyl. In another embodiment, R2 is heteroaryl-heteroalkyl. In another embodiment, R2 is heteroaryl-heterocyclyl.

In various embodiments of compounds of Formula I, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is unsubstituted. In various embodiments, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent halo. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OH. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —R31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —CF3. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OCF. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OR31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR34R35. In another embodiment, when R4 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(O)R31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —CO2R31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)NR31R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)NR34R35. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclylC1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NO2. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —CN. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —S(O)0-2R31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SO2NR31R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SO2NR34R35. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent NR31C(═O)R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)OR32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)NR32R33. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31S(O)0-2R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═S)OR31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)SR31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═NR32)NR33R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent, —NR31C(═NR32)OR33. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═NR32)SR33. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)OR33. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)NR31R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)SR31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)OR31. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —P(O)OR31OR32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)NR31R32. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent alkyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent heteroalkyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent alkenyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent alkynyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent cycloalkyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent heterocycloalkyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent aryl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent arylalkyl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent heteroaryl. In another embodiment, when R2 is bicyclic aryl, monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, monocyclic aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent heteroarylalkyl.

In various embodiments of compounds of Formula I, R3 is hydrogen. In another embodiment, R3 is halogen. In another embodiment, R3 is —OH. In another embodiment, R3 is —R31. In another embodiment, R3 is —CF3. In another embodiment, R3 is —OCF3. In another embodiment, R3 is —OR31. In another embodiment, R3 is —NR31R32. In another embodiment, R3 is —NR34R35. In another embodiment, R3 is —C(O)R31. In another embodiment, R3 is —CO2R31. In another embodiment, R3 is —C(═O)NR31R32. In another embodiment, R3 is —C(═O)NR34R35. In another embodiment, R3 is —NO2. In another embodiment, R3 is —CN. In another embodiment, R3 is —S(O)0-2R3. In another embodiment, R3 is —SO2NR31R32. In another embodiment, R3 is —SO2NR34R35. In another embodiment, R3 is —NR31C(═O)R32. In another embodiment, R3 is —NR31C(═O)OR32. In another embodiment, R3 is —NR31C(═O)NR32R33. In another embodiment, R3 is —NR31S(O)0-2R32. In another embodiment, R3 is —C(═S)OR31. In another embodiment, R3 is —C(═O)SR31. In another embodiment, R3 is —NR31C(═NR32)NR33R32. In another embodiment, R3 is —NR31C(═NR32)OR33. In another embodiment, R3 is —NR31C(═NR32)SR33. In another embodiment, R3 is —OC(═O)OR33. In another embodiment, R3 is —OC(═O)NR31R32. In another embodiment, R3 is —OC(═O)SR31. In another embodiment, R3 is —SC(═O)OR31. In another embodiment, R3 is —P(O)OR31OR32. In another embodiment, R3 is —SC(═O)NR31R32. In another embodiment, R3 is aryl. In another embodiment, R2 is heteroaryl. In another embodiment, R3 is C1-4alkyl. In another embodiment, R3 is C1-10alkyl. In another embodiment, R3 is C3-8cycloalkyl. In another embodiment, R3 is C3-8cycloalkyl-C1-10alkyl. In another embodiment, R3 is —C1-10alkyl-C3-8cycloalkyl. In another embodiment, R3 is C2-10alkyl-monocyclic aryl. In another embodiment, R3 is monocyclic aryl-C2-10alkyl. In another embodiment, R3 is C1-10alkyl-bicyclicaryl. In another embodiment, R3 is bicyclic aryl-C1-10alkyl. In another embodiment, R3 is C1-10alkylheteroaryl. In another embodiment, R3 is C1-10alkylheterocyclyl. In another embodiment, R3 is C2-10alkenyl. In another embodiment, R3 is C2-10alkynyl. In another embodiment, R3 is C2-10alkenylaryl. In another embodiment, R3 is C2-10alkenylheteroaryl. In another embodiment, R3 is C2-10alkenylheteroalkyl. In another embodiment, R3 is C2-10alkenylheterocycicyl. In another embodiment, R3 is —C2-10alkynylaryl. In another embodiment, R3 is —C2-10alkynylheteroaryl. In another embodiment, R3 is —C2-10alkynylheteroalkyl. In another embodiment, R3 is C2-10alkynylheterocyclyl. In another embodiment, R3 is —C2-10alkynylC3-8cycloalkyl. In another embodiment, R3 is C2-10alkynylC3-8cycloalkenyl. In another embodiment, R3 is —C1-10alkoxy-C1-10alkyl. In another embodiment, R3 is C1-10alkoxy-C2-10alkenyl. In another embodiment, R3 is —C1-10alkoxy-C2-10alkynyl. In another embodiment, R3 is heterocyclyl-C1-10alkyl. In another embodiment, R3 is -heterocyclylC2-10alkenyl. In another embodiment, R3 is heterocyclyl-C2-10alkynyl. In another embodiment, R3 is aryl-C1-10alkyl. In another embodiment, R3 is aryl-C2-10alkenyl. In another embodiment, R3 is aryl-C2-10alkynyl. In another embodiment, R3 is aryl-heterocyclyl. In another embodiment, R3 is heteroaryl-C1-10alkyl. In another embodiment, R3 is heteroaryl-C2-10alkenyl. In another embodiment, R3 is heteroaryl-C2-10alkynyl. In another embodiment, R3 is heteroaryl-C3-8cycloalkyl. In another embodiment, R3 is heteroaryl-heteroalkyl. In another embodiment, R3 is heteroaryl-heterocyclyl.

In various embodiments of compounds of Formula I, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is unsubstituted. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent halo. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OH. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —R31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CF3. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OCF. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OR31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR31R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR34R35. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —C(O)R31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CO2R31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —C(═O)NR31R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)NR34R35. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NO2. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CN. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —S(O)0-2R31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —SO2NR31R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —SO2NR34R35. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent NR31C(═O)R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)OR32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)NR32R33. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31S(O)0-2R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═S)OR31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)SR31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR31C(═NR32)NR33R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═NR32)OR33. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═NR32)SR33. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)OR33. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)NR31R32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)SR31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)OR31. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —P(O)OR31OR32. In another embodiment, when R3 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)NR31R32.

In various embodiments of compounds of Formula I, R4 is hydrogen. In another embodiment, R4 is halogen. In another embodiment, R4 is —OH. In another embodiment, R4 is —R31. In another embodiment, R4 is —CF3. In another embodiment, R4 is —OCF3. In another embodiment, R4 is —OR31. In another embodiment, R4 is —NR31R32. In another embodiment, R4 is —NR34R35. In another embodiment, R4 is —C(O)R31. In another embodiment, R4 is —CO2R31. In another embodiment, R4 is —C(═O)NR31R32. In another embodiment, R4 is —C(═O)NR34R35. In another embodiment, R4 is —NO2. In another embodiment, R4 is —CN. In another embodiment, R4 is —S(O)0-2R3. In another embodiment, R4 is —SO2NR31R32. In another embodiment, R4 is —SO2NR34R35. In another embodiment, R4 is —NR31C(═O)R32. In another embodiment, R4 is —NR31C(═O)OR32. In another embodiment, R4 is —NR31C(═O)NR32R33. In another embodiment, R4 is —NR31S(O)0-2R32. In another embodiment, R4 is —C(═S)OR31. In another embodiment, R4 is —C(═O)SR31. In another embodiment, R4 is —NR31C(═NR32)NR33R32. In another embodiment, R4 is —NR31C(═NR32)OR33. In another embodiment, R4 is —NR31C(═NR32)SR33. In another embodiment, R4 is —OC(═O)OR33. In another embodiment, R4 is —OC(═O)NR31R32. In another embodiment, R4 is —OC(═O)SR31. In another embodiment, R4 is —SC(═O)OR31. In another embodiment, R4 is —P(O)OR31OR32. In another embodiment, R4 is —SC(═O)NR31R32. In another embodiment, R4 is aryl. In another embodiment, R4 is heteroaryl. In another embodiment, R4 is C1-4alkyl. In another embodiment, R4 is C1-10alkyl. In another embodiment, R4 is C3-8cycloalkyl. In another embodiment, R4 is C1-10alkyl-C3-8cycloalkyl. In another embodiment, R4 is C1-10alkylaryl. In another embodiment, R4 is C1-10alkylheteroaryl. In another embodiment, R4 is C1-10alkylheterocyclyl. In another embodiment, R4 is C2-10alkenyl. In another embodiment, R4 is C2-10alkynyl. In another embodiment, R4 is C2-10alkynyl-C3-8cycloalkyl. R4 is C2-10alkenyl-C3-8cycloalkyl. In another embodiment, R4 is C2-10alkenylaryl. In another embodiment, R4 is C2-10alkenyl-heteroaryl. In another embodiment, R4 is C2-10alkenylheteroalkyl. In another embodiment, R4 is C2-10alkenylheterocycicyl. In another embodiment, R4 is —C2-10alkynylaryl. In another embodiment, R4 is C2-10alkynylheteroaryl. In another embodiment, R4 is C2-10alkynylheteroalkyl. In another embodiment, R4 is C2-10alkynylheterocyclyl. In another embodiment, R4 is C2-10alkynylC3-8cycloalkyl. In another embodiment, R4 is heterocyclyl C1-10alkyl. In another embodiment, R4 is heterocyclylC2-10alkenyl. In another embodiment, R4 is heterocyclyl-C2-10alkynyl. In another embodiment, R4 is aryl-C1-10alkyl. In another embodiment, R4 is aryl-C2-10alkenyl. In another embodiment, R4 is aryl-C2-10alkynyl. In another embodiment, R4 is aryl-heterocyclyl. In another embodiment, R4 is heteroaryl-C1-10alkyl. In another embodiment, R4 is heteroaryl-C2-10alkenyl. In another embodiment, R4 is heteroaryl-C2-10alkynyl. In another embodiment, R4 is C3-8cycloalkyl-C1-10alkyl. In another embodiment, R4 is C3-8cycloalkyl-C2-10alkenyl. In another embodiment, R4 is C3-8cycloalkyl-C2-10alkynyl.

In various embodiments of compounds of Formula I, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is unsubstituted. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent halo. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OH. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —R31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CF3. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OCF. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —OR31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR31R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR34R35. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —C(O)R31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CO2R31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —C(═O)NR31R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)NR34R35. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NO2. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —CN. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —S(O)0-2R31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —SO2NR31R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8 cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —SO2NR34R35. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)OR32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═O)NR32R33. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31S(O)0-2R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═S)OR31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —C(═O)SR31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —NR31C(═NR32)NR33R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent, —NR31C(═NR32)OR33. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —NR31C(═NR32)SR33. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)OR33. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)NR31R32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —OC(═O)SR31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)OR31. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, heterocyclyl, heterocyclyl C1-10alkyl, or heteroalkyl, it is substituted with one or more independent —P(O)OR31OR32. In another embodiment, when R4 is aryl, heteroaryl, C1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C2-10alkenyl, C2-10alkynyl, aryl-C2-10alkyl, heterocyclyl C1-10alkyl, or C3-8cycloalkyl-C1-10alkyl, it is substituted with one or more independent —SC(═O)NR31R32.

In various embodiments of compounds of Formula I, R5 is hydrogen. In another embodiment, R5 is halogen. In another embodiment, R5 is —OH. In another embodiment, R5 is —R31. In another embodiment, R5 is —CF3. In another embodiment, R5 is —OCF3. In another embodiment, R5 is —OR31. In another embodiment, R5 is —NR31R32. In another embodiment, R5 is —NR34R35. In another embodiment, R5 is —C(O)R31. In another embodiment, R5 is —CO2R31. In another embodiment, R5 is —C(═O)NR31R32. In another embodiment, R5 is —C(═O)NR34R35. In another embodiment, R5 is —NO2. In another embodiment, R5 is —CN. In another embodiment, R5 is —S(O)0-2R31. In another embodiment, R5 is —SO2NR31R32. In another embodiment, R5 is —SO2NR34R35. In another embodiment, R5 is —NR31C(═O)R32. In another embodiment, R5 is —NR31C(═O)OR32. In another embodiment, R5 is —NR31C(═O)NR32R33. In another embodiment, R5 is —NR31S(O)0-2R32. In another embodiment, R5 is —C(═S)OR31. In another embodiment, R5 is —C(═O)SR31. In another embodiment, R5 is —NR31C(═NR32)NR33R32. In another embodiment, R5 is —NR31C(═NR32)OR33. In another embodiment, R5 is —NR31C(═NR32)SR33. In another embodiment, R5 is —OC(═O)OR33. In another embodiment, R5 is —OC(═O)NR31R32. In another embodiment, R5 is —OC(═O)SR31. In another embodiment, R5 is —SC(═O)OR31. In another embodiment, R5 is —P(O)OR31OR32. In another embodiment, R5 is or —SC(═O)NR31R32.

In various embodiments of compounds of Formula I, R7 is hydrogen. In another embodiment, R7 is unsubstituted C1-10alkyl. In another embodiment, R7 is unsubstituted C2-10alkenyl. In another embodiment, R7 is unsubstituted aryl. In another embodiment, R7 is unsubstituted heteroaryl. In another embodiment, R7 is unsubstituted heterocyclyl. In another embodiment, R7 is unsubstituted C3-10cycloalkyl. In another embodiment, R7 is C1-10alkyl substituted by one or more independent R6. In another embodiment, R7 is C2-10alkenyl substituted by one or more independent R6. In another embodiment, R7 is aryl substituted by one or more independent R6. In another embodiment, R7 is heteroaryl substituted by one or more independent R6. In another embodiment, R7 is heterocyclyl substituted by one or more independent R6. In another embodiment, R7 is C3-10cycloalkyl substituted by one or more independent R6.

In various embodiments of compounds of Formula I, R8 is hydrogen. In another embodiment, R8 is unsubstituted C1-10alkyl. In another embodiment, R8 is unsubstituted C2-10alkenyl. In another embodiment, R8 is unsubstituted aryl. In another embodiment, R8 is unsubstituted heteroaryl. In another embodiment, R8 is unsubstituted heterocyclyl. In another embodiment, R8 is unsubstituted C3-10cycloalkyl. In another embodiment, R8 is C1-10alkyl substituted by one or more independent R6. In another embodiment, R8 is C2-10alkenyl substituted by one or more independent R6. In another embodiment, R8 is aryl substituted by one or more independent R6. In another embodiment, R8 is heteroaryl substituted by one or more independent R6. In another embodiment, R8 is heterocyclyl substituted by one or more independent R6. In another embodiment, leis C3-10cycloalkyl substituted by one or more independent R6.

In various embodiments of compounds of Formula I, R6 is halo, in another embodiment, R6 is OR31. In another embodiment, R6 is —SH. In another embodiment, R6 is NH2. In another embodiment, R6 is —NR34R35. In another embodiment, R6 is —NR31R32. In another embodiment, R6 is —CO2R31. In another embodiment, R6 is —CO2aryl. In another embodiment, R6 is —C(═O)NR31R32. In another embodiment, R6 is —C(═O)NR34R35. In another embodiment, R6 is —NO2. In another embodiment, R6 is —CN. In another embodiment, R6 is —S(O)0-2 C1-10alkyl. In another embodiment, R6 is —S(O)0-2aryl. In another embodiment, R6 is —SO2NR34R35. In another embodiment, R6 is —SO2NR31R32. In another embodiment, R6 is C1-10alkyl. In another embodiment, R6 is C2-10alkenyl. In another embodiment, R6 is C2-C3alkynyl. In another embodiment, R6 is unsubstituted aryl-C1-10alkyl. In another embodiment, R6 is unsubstituted aryl-C2-10alkenyl. In another embodiment, R6 is unsubstituted aryl-C2-10alkynyl. In another embodiment, R6 is unsubstituted heteroaryl-C1-10alkyl. In another embodiment, R6 is unsubstituted heteroaryl-C2-10alkenyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent halo. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent cyano. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent nitro. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —OC1-10alkyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C1-10alkyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C2-10alkenyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C2-10alkynyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C1-10alkyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C2-10alkenyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C2-10alkynyl. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —COOH. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C(═O)NR31R32. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C(═O)NR34R35. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —SO2NR34R35. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —SO2 NR31R32. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —NR31R32. In another embodiment, R6 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —NR34R35.

In various embodiments of compounds of Formula I, R9 is H. In another embodiment, R9 is halo. In another embodiment, R9 is —OR31. In another embodiment, R9 is —SH. In another embodiment, R9 is NH2. In another embodiment, R9 is —NR34R35. In another embodiment, R9 is —NR34R35. In another embodiment, R9 is —CO2R31. In another embodiment, R9 is —CO2aryl. In another embodiment, R9 is —C(═O)NR31R32. In another embodiment, R9 is C(═O) NR34R35. In another embodiment, R9 is —NO2. In another embodiment, R9 is —CN. In another embodiment, R9 is —S(O)0-2 C1-10alkyl. In another embodiment, R9 is —S(O)0-2aryl. In another embodiment, R9 is —SO2NR34R35. In another embodiment, R9 is —SO2NR31R32. In another embodiment, R9 is C1-10alkyl. In another embodiment, R9 is C2-10alkenyl. In another embodiment, R9 is C2-10alkynyl. In another embodiment, R9 is unsubstituted aryl-C1-10alkyl. In another embodiment, R9 is unsubstituted aryl-C2-10alkenyl. In another embodiment, R9 is unsubstituted aryl-C2-10alkynyl. In another embodiment, R9 is unsubstituted heteroaryl-C1-10alkyl. In another embodiment, R9 is unsubstituted heteroaryl-C2-10alkenyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent halo. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent cyano. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent nitro. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —OC1-10alkyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C1-10alkyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C2-10alkenyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C2-10alkynyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C1-10alkyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C2-10alkenyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent -(halo)C2-10alkynyl. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —COOH. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C(═O)NR31R32. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —C(═O)NR34R35. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —SO2NR34R35. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —SO2 NR31R32. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —NR31R32. In another embodiment, R9 is aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, or heteroaryl-C2-10alkenyl substituted by one or more independent —NR34R35.

In various embodiments of compounds of Formula I, R31 is H. In some embodiments, R31 is unsubstituted C1-10alkyl. In some embodiments, R31 is substituted C1-10alkyl. In some embodiments, R31 is C1-10alkyl substituted with one or more aryl. In some embodiments, R31 is C1-10alkyl substituted with one or more heteroalkyl. In some embodiments, R31 is C1-10alkyl substituted with one or more heterocyclyl. In some embodiments, R31 is C1-10alkyl substituted with one or more heteroaryl. In some embodiments, when R31 is C1-10alkyl substituted with one or more aryl, each of said aryl substituents is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl, —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R31 is C1-10alkyl substituted with one or more heteroalkyl, each of said heteroalkyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35 substituents. In some embodiments, when R31 is C1-10alkyl substituted with one or more heterocyclyl, each of said heterocyclyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R31 is C1-10alkyl substituted with one or more heteroaryl, each of said heteroaryl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R31 is substituted C1-10alkyl, it is substituted by a combination of aryl, heteroalkyl, heterocyclyl, or heteroaryl groups.

In various embodiments of compounds of Formula I, R32 is H. In some embodiments, R32 is unsubstituted C1-10alkyl. In some embodiments, R32 is substituted C1-10alkyl. In some embodiments, R32 is C1-10alkyl substituted with one or more aryl. In some embodiments, R32 is C1-10alkyl substituted with one or more heteroalkyl. In some embodiments, R32 is C1-10alkyl substituted with one or more heterocyclyl. In some embodiments, R32 is C1-10alkyl substituted with one or more heteroaryl. In some embodiments, when R32 is C1-10alkyl substituted with one or more aryl, each of said aryl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R32 is C1-10alkyl substituted with one or more heteroalkyl, each of said heteroalkyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R32 is C1-10alkyl substituted with one or more heterocyclyl, each of said heterocyclyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R32 is C1-10alkyl substituted with one or more heteroaryl, each of said heteroaryl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R32 is substituted C1-10alkyl, it is substituted by a combination of aryl, heteroalkyl, heterocyclyl, or heteroaryl groups.

In various embodiments of compounds of Formula I, R33 is unsubstituted C1-10alkyl. In some embodiments, R33 is substituted C1-10alkyl. In some embodiments, R33 is C1-10alkyl substituted with one or more aryl. In some embodiments, R33 is C1-10alkyl substituted with one or more heteroalkyl. In some embodiments, R33 is C1-10alkyl substituted with one or more heterocyclyl. In some embodiments, R33 is C1-10alkyl substituted with one or more heteroaryl. In some embodiments, when R33 is C1-10alkyl substituted with one or more aryl, each of said aryl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R33 is C1-10alkyl substituted with one or more heteroalkyl, each of said heteroalkyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R33 is C1-10alkyl substituted with one or more heterocyclyl, each of said heterocyclyl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R33 is C1-10alkyl substituted with one or more heteroaryl, each of said heteroaryl group is unsubstituted or substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35. In some embodiments, when R33 is substituted C1-10alkyl, it is substituted by a combination of aryl, heteroalkyl, heterocyclyl, or heteroaryl groups.

In various embodiments of compounds of Formula I, R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen.

In some embodiments, the R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form:

In another embodiment, X1 is C—NH2.

In various embodiments, X1 is C—NH—R4, where —NH—R4 is:

In one embodiment, the invention provides an inhibitor of Formula I-C1 where R5 is H. In another embodiment, the invention provides an inhibitor of Formula I-C2 where R5 is H.

In some embodiments, the invention provides an inhibitor of Formula I-C1a:

or a pharmaceutically acceptable salt thereof wherein:

E2 is —H;

X1 and X2 are N;

R1 is -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

R3 is hydrogen, —OH, —OR31, —NR31R32, —C(O)R31, —C(═O)NR31R32, —C(═O)NR34R35, aryl, heteroaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, or heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

—(W2)k— is —NH—, —N(H)C(O)— or —N(H)S(O)2—;

R2 is hydrogen, halogen, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, bicyclic aryl, substituted monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C2-10alkyl-monocyclic aryl, monocyclic aryl-C2-10alkyl, C1-10alkylbicycloaryl, bicycloaryl-C1-10alkyl, substituted C1-10alkylaryl, substituted aryl-C1-10alkyl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxyC2-10alkenyl, C1-10alkoxyC2-10alkynyl, heterocyclyl, heterocyclyl C1-10alkyl, heterocyclylC2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted; and

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen.

In another aspect, an inhibitor of Formula I-C1 is a compound of Formula I-C1a:

or a pharmaceutically acceptable salt thereof, wherein: E2 is —H; X1 is CH and X2 is N;

R1 is -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

R3 is hydrogen, —OH, —OR31, —NR31R32, —C(O)R31, —C(═O)NR31R32, —C(═O)NR34R35, aryl, heteroaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, or heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

—(W2)k— is —NH—, —N(H)C(O)— or —N(H)S(O)2—;

R2 is hydrogen, halogen, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, bicyclic aryl, substituted monocyclic aryl, heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C2-10alkyl-monocyclic aryl, monocyclic aryl-C2-10alkyl, C1-10alkylbicycloaryl, bicycloaryl-C1-10alkyl, substituted C1-10alkylaryl, substituted aryl-C1-10alkyl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10 alkenyl, C2-10alkynyl, heterocyclyl, heterocyclyl C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted; and

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen.

The invention further provides a compound which is an mTor inhibitor, wherein the compound has the Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

X1 is N or C-E1, X2 is N, X3 is C, and X4 is C—R9 or N; or X1 is N or C-E1, X2 is C, X3 is N, and X4 is C—R9 or N;

R1 is —H, -L-C1-10alkyl, -L-C3-8cycloalkyl, -L-C1-10alkyl-C3-8cycloalkyl, -L-aryl, -L-heteroaryl, -L-C1-10alkylaryl, -L-C1-10alkylheteroaryl, -L-C1-10alkylheterocyclyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C2-10alkenyl-C3-8cycloalkyl, -L-C2-10alkynyl-C3-8cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C3-8cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R3;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R31)—, —S—, —S(O)—, —S(O)2—, —S(O)2N(R31)—, or —N(R31)—;

M1 is benzothiazolyl substituted with —(W2)k—R2;

k is 0 or 1;

E1 and E2 are independently —(W1)j—R4;

j, in each instance (i.e., in E1 or j in E2), is independently 0 or 1

W1 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

W2 is —O—, —NR7—, —S(O)0-2—, —C(O)—, —C(O)N(R7)—, —N(R7)C(O)—, —N(R7)C(O)N(R8)—, —N(R7)S(O)—, —N(R7)S(O)2—, —C(O)O—, —CH(R7)N(C(O)OR8)—, —CH(R7)N(C(O)R8)—, —CH(R7)N(SO2R8)—, —CH(R7)N(R8)—, —CH(R7)C(O)N(R8)—, —CH(R7)N(R8)C(O)—, —CH(R7)N(R8)S(O)—, or —CH(R7)N(R8)S(O)2—;

R2 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl (e.g. C2-10alkyl-monocyclic aryl, C1-10alkyl-substituted monocyclic aryl, or C1-10alkylbicycloaryl), C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heteroalkyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl (e.g. monocyclic aryl-C2-10alkyl, substituted monocyclic aryl-C1-10alkyl, or bicycloaryl-C1-10alkyl), aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R3 and R4 are independently hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, —SC(═O)NR31R32, aryl, heteroaryl, C1-4alkyl, C1-10alkyl, C3-8cycloalkyl, C1-10alkyl-C3-8cycloalkyl, C3-8cycloalkyl-C1-10alkyl, C3-8cycloalkyl-C2-10alkenyl, C3-8cycloalkyl-C2-10alkynyl, C1-10alkyl-C2-10alkenyl, C1-10alkyl-C2-10alkynyl, C1-10alkylaryl, C1-10alkylheteroaryl, C1-10alkylheterocyclyl, C2-10alkenyl, C2-10alkynyl, C2-10alkenyl-C1-10alkyl, C2-10alkynyl-C1-10alkyl, C2-10alkenylaryl, C2-10alkenylheteroaryl, C2-10alkenylheteroalkyl, C2-10alkenylheterocycicyl, C2-10alkenyl-C3-8cycloalkyl, C2-10alkynyl-C3-8cycloalkyl, C2-10alkynylaryl, C2-10alkynylheteroaryl, C2-10alkynylheteroalkyl, C2-10alkynylheterocyclyl, C2-10alkynyl-C3-8cycloalkenyl, C1-10alkoxy C1-10alkyl, C1-10alkoxy-C2-10alkenyl, C1-10alkoxy-C2-10alkynyl, heterocyclyl, heterocyclyl-C1-10alkyl, heterocyclyl-C2-10alkenyl, heterocyclyl-C2-10alkynyl, aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, aryl-heterocyclyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, heteroaryl-C3-8cycloalkyl, heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32, and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R31, —CF3, —OCF3, —OR31, —O-aryl, —NR31R32—NR34R35, —C(O)R31, —CO2R31, —C(═O)NR34R35, or —C(═O)NR31R32;

R5 is hydrogen, halogen, —OH, —R31, —CF3, —OCF3, —OR31, —NR31R32, —NR34R35, —C(O)R31, —CO2R31, —C(═O)NR31R32, —C(═O)NR34R35, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —SO2NR34R35, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R32, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —P(O)OR31OR32, or —SC(═O)NR31R32;

R31, R32, and R33, in each instance, are independently H or C1-10alkyl, wherein the C1-10alkyl is unsubstituted or is substituted with one or more aryl, heteroalkyl, heterocyclyl, or heteroaryl group, wherein each of said aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more halo, —OH, —C1-10alkyl, —CF3, —O-aryl, —OCF3, —OC1-10alkyl, —NH2, —N(C1-10alkyl)(C1-10alkyl), —NH(C1-10alkyl), —NH(aryl), —NR34R35, —C(O)(C1-10alkyl), —C(O)(C1-10alkyl-aryl), —C(O)(aryl), —CO2—C1-10alkyl, —CO2—C1-10alkylaryl, —CO2-aryl, —C(═O)N(C1-10alkyl)(C1-10alkyl), —C(═O)NH(C1-10alkyl), —C(═O)NR34R35, —C(═O)NH2, —OCF3, —O(C1-10alkyl), —O-aryl, —N(aryl)(C1-10alkyl), —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2 C1-10alkylaryl, —S(O)0-2 aryl, —SO2N(aryl), —SO2 N(C1-10alkyl)(C1-10alkyl), —SO2 NH(C1-10alkyl) or —SO2NR34R35;

R34 and R35 in —NR34R35, —C(═O)NR34R35, or —SO2NR34R35, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR31R32, hydroxyl, halogen, oxo, aryl, heteroaryl, C1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

R7 and R8 are each independently hydrogen, C1-10alkyl, C2-10alkenyl, aryl, heteroaryl, heterocyclyl or C3-10cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R6;

R6 is halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35; and

R9 is H, halo, —OR31, —SH, —NH2, —NR34R35, —NR31R32, —CO2R31, —CO2aryl, —C(═O)NR31R32, C(═O)NR34R35, —NO2, —CN, —S(O)0-2 C1-10alkyl, —S(O)0-2aryl, —SO2NR34R35, —SO2NR31R32, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; aryl-C1-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, heteroaryl-C1-10alkyl, heteroaryl-C2-10alkenyl, heteroaryl-C2-10alkynyl, wherein each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or is substituted with one or more independent halo, cyano, nitro, —OC1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloC2-10alkynyl, —COOH, —C(═O)NR31R32, —C(═O)NR34R35, —SO2NR34R35, —SO2 NR31R32, —NR31R32, or —NR34R35.

In some embodiments, X4 is C—R9.

The invention also provides an inhibitor as defined above, wherein the compound is of Formula I-B:

or a pharmaceutically acceptable salt thereof, and wherein the substituents are as defined above.

In various embodiments the compound of Formula I-B or its pharmaceutically acceptable salt thereof, is an inhibitor having the structure of Formula I-B1 or Formula I-B2:

or a pharmaceutically acceptable salt thereof.

In various embodiments of Formula I-B1, X1 is N and X2 is N. In other embodiments, X1 is C-E1 and X2 is N. In yet other embodiments, X1 is NH and X2 is C. In further embodiments, X1 is CH-E1 and X2 is C.

In various embodiments of Formula I-B2, X1 is N and X2 is C. In further embodiments, X1 is C-E1 and X2 is C.

In various embodiments, X1 is C—(W1)j—R4, where j is 0.

In another embodiment, X1 is CH. In yet another embodiment, X1 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X1, it is C—(W1)j—R4. In various embodiments of X1, j is 1, and W1 is —O—. In various embodiments of X1, j is 1, and W1 is —NR7—. In various embodiments of X1, j is 1, and W1 is —NH—. In various embodiments of X1, j is 1, and W1 is —S(O)0-2—. In various embodiments of X1, j is 1, and W1 is —C(O)—. In various embodiments of X1, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of X1, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of X1, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of X1, j is 1, and W1 is —C(O)O—. In various embodiments of X1, j is 1, and W1 is CH(R7)N(C(O)OR8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of X1, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In another embodiment, X1 is CH2. In yet another embodiment, X1 is CH-halogen, where halogen is Cl, F, Br, or I.

In another embodiment, X1 is N.

In various embodiments, X2 is N. In other embodiments, X2 is C.

In various embodiments, E2 is —(W1)j—R4, where j is 0.

In another embodiment, E2 is CH. In yet another embodiment, E2 is C-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E2, it is —(W1)j—R4. In various embodiments of E2, j is 1, and W1 is —O—. In various embodiments of E2, j is 1, and W1 is —NR7—. In various embodiments of E2, j is 1, and W1 is —NH—. In various embodiments of E2, j is 1, and W1 is —S(O)0-2—. In various embodiments of E2, j is 1, and W1 is —C(O)—. In various embodiments of E2, j is 1, and W1 is —C(O)N(R7)—. In various embodiments of E2, j is 1, and W1 is —N(R7)C(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)—. In various embodiments of E2, j is 1, and W1 is —N(R7)S(O)2—. In various embodiments of E2, j is 1, and W1 is —C(O)O—. In various embodiments of E2, j is 1, and W1 is CH(R7)N(C(O)OR8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(C(O)R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(SO2R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)C(O)N(R8)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)C(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)—. In various embodiments of E2, j is 1, and W1 is —CH(R7)N(R8)S(O)2—.

In various embodiments of Formula I-A, I-B, I-B1 and I-B2, M1 is:

In some embodiments of the invention, M1 is benzothiazolyl substituted with —(W2)k—R2. W2 can be —O—, —S(O)0-2— (including but not limited to —S—, —S(O)—, and —S(O)2—), —C(O)—, or —C(O)O—.

In other embodiments, W1 is —NR6— or —CH(R6)N(R7)—, wherein R6 and R7 are each independently hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), unsubstituted or substituted C2-C10alkenyl (including but not limited to alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl). Additionally when W2 is —NR6— or —CH(R6)N(R7)—, R6 and R7 are each independently unsubstituted or substituted aryl (including phenyl and naphthyl). In yet other embodiments, when W2 is —NR6— or —CH(R6)N(R7)—, R6 and R7 are each independently heteroaryl, wherein the heteroaryl is unsubstituted or substituted. R6 and R7 heteroaryl is monocyclic heteroaryl, and includes but is not limited to imidazolyl, pyrrolyl, oxazolyl, thiazolyl, and pyridinyl. In some other embodiments, when W2 is —NR6— or —CH(R6)N(R7)—, R6 and R7 are each independently unsubstituted or substituted heterocyclyl (which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl) or unsubstituted or substituted C3-8cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl). Non limiting exemplary W2 include —NH—, —N(cyclopropyl), and —N(4-N-piperidinyl).

For example, exemplary mTor inhibitors of the invention have the Formulas:

Reaction Schemes—mTor Inhibitor Compounds

The mTor inhibitor compounds disclosed herein may be prepared by the routes described below. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed or by any particular substituents employed for illustrative purposes. Numbering does not necessarily correspond to that of claims or other tables.

In one embodiment, compounds are synthesized by condensing a functionalized heterocycle A-1 with formamide, to provide a pyrazolopyrimidine A-2. The pyrazolopyrimidine is treated with N-iodosuccinimide, which introduces an iodo substituent in the pyrazole ring as in A-3. The R1 substituent is introduced by reacting the pyrazolopyrimidine A3 with a compound of Formula R1-Lg in the presence of a base such as potassium carbonate to produce a compound of Formula A-4. Other bases that are suitable for use in this step include but are not limited to sodium hydride and potassium t-butoxide. The compound of Formula R1-Lg has a moiety R1 as defined for R1 of a compound of Formula I-A, and wherein Lg is an appropriate leaving group such as halide (including bromo, iodo, and chloro), tosylate, or other suitable leaving group,

The substituents corresponding to M1 are thereafter introduced by reacting aryl or heteroaryl boronic acids with the compound of Formula A-4 to obtain compound A-5.

Alternatively, Mitsunobu chemistry can be used to obtain alkylated pyrazolopyrimidine A-4, as shown in Scheme A-1. Iodopyrazolopyrimidine A-3 is reacted with a suitable alcohol, in the presence of triphenylphosphine and diisopropylazodicarboxylate (DIAD) to produce pyrazolopyrimidine A-4.

The compounds of the invention may be synthesized via a reaction scheme represented generally in Scheme B. The synthesis proceeds via coupling a compound of Formula A with a compound of Formula B to yield a compound of Formula C. The coupling step is typically catalyzed by using, e.g., a palladium catalyst, including but not limited to palladium tetrakis (triphenylphosphine). The coupling is generally performed in the presence of a suitable base, a nonlimiting example being sodium carbonate. One example of a suitable solvent for the reaction is aqueous dioxane.

A compound of Formula A for use in Scheme B has a structure of Formula A, wherein T1 is inflate or halo (including bromo, chloro, and iodo), and wherein R1, X1, X2, X3, R31 and R32 are defined as for a compound of Formula I-A. For boronic acids and acid derivatives as depicted in Formula B, M is either M1 or M2. M1 is defined as for a compound of Formula I-A. For example, M1 can be a 5-benzoxazolyl or a 6-benzoxazolyl moiety, including but not limited to those M1 moieties disclosed herein. M2 is a moiety which is synthetically transformed to form M1, after the M2 moiety has been coupled to the bicyclic core of the compound of Formula A.

For a compound of Formula B, G is hydrogen or RG1, wherein RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 is taken together to form a 5- or 6-membered cyclic moiety. In some embodiments, the compound of Formula B is a compound having a structure of Formula E:

wherein G is H or RG1; RG1 is alkyl, alkenyl, or aryl. Alternatively,

forms a 5- or 6-membered cyclic moiety; and R2 is a RG2 moiety, wherein the RG2 moiety is H, acyl, or an amino protecting group including but not limited to tert-butyl carbamate (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and the like.

In some embodiments, a compound of Formula B is a compound of Formula B′, wherein G is RG1. or a compound of Formula B″, wherein G is hydrogen. Scheme C depicts an exemplary scheme for synthesizing a compound of Formula B′ or, optionally, Formula B″ for use in Reaction Scheme C. This reaction proceeds via reacting a compound of Formula D with a trialkyl borate or a boronic acid derivative to produce a compound of Formula B′. The reaction is typically run a solvent such as dioxane or tetrahydrofuran. The trialkyl borate includes but is not limited to triisopropyl borate and the boronic acid derivative includes but is not limited to bis(pinacolato)diboron.

When the reaction is performed with trialkyl borate, a base such as n-butyl lithium is first added to the compound of Formula D to generate an anion, prior to the addition of the borate. When the reaction is performed with a boronic acid derivative such as bis(pinacolato)diboron, a palladium catalyst and a base is used. Typical palladium catalysts include but are not limited to palladium chloride (diphenylphosphino)ferrocene. A suitable base includes but is not limited to potassium acetate.

A compound of Formula D for use in Scheme C is a compound wherein T2 is halo or another leaving group, and M is as defined above in Scheme B. The compound of Formula B′ may further be converted to a compound of Formula B″ by treatment with an acid such as hydrochloric acid.

In one embodiment of a compound of Formula B, B′, B″, or E, the G groups are hydrogen. In another of a compound of Formula B, B′, B″, or E, the G groups are RG1.

In some embodiments, no further synthetic transformation of M1 moiety is performed after the coupling reaction when, e.g. M1 is 2-N-acetyl-benzoxazol-5-yl.

Some exemplary compounds of Formula B that can be synthesized via Scheme C include but are not limited to compounds of the following formulae:

In other embodiments of the invention, a compound of Formula E is synthesized from a compound of Formula F, as shown in Scheme C-1:

Scheme C-1 depicts an exemplary scheme for synthesizing a compound of Formula E. This reaction proceeds via reacting a compound of Formula F with a trialkyl borate or a boronic acid derivative to produce a compound of Formula E. The conditions of the reaction are as described above in Scheme C.

A compound of Formula F for use in Scheme C-1 is a compound wherein T2 is halo (including Br, Cl, and I) or another leaving group (including but not limited to triflate, tosylate, and mesylate), and the Gp moiety is H, acyl, or an amino protecting group including but not limited to tert-butyl carbamate (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and the like.

The compound of Formula E, wherein G is alkyl, may further be converted to a compound of Formula E, wherein G is hydrogen, by treatment with an acid such as hydrochloric acid

Where desired, deprotection of a substituent (e.g., removal of Boc protection from an amino substituent) on the benzoxazolyl moiety (i.e. M1 of Formula C) is performed after coupling the compound of Formula B to the compound of Formula A.

Some exemplary compounds with such protecting groups, include but are not limited to compounds of the following formulae:

An exemplary transformation of M2 to M1 can be carried out via Scheme D as shown below.

In Step 1, a compound of Formula 3-1 is reacted with boronic acid 3-2, in the presence of palladium tetrakis (triphenylphosphine) and a suitable base, such as sodium carbonate in an aqueous/organic solvent mixture to produce a compound of Formula 3-3. In Step 2, the compound of Formula 3-3 is reacted with about 2 equivalents of nitric acid in acetic acid as solvent to produce a compound of Formula 3-4. Two alternative transformations may be used to effect the next transformation of Step 3. In the first method, the compound of Formula 3-4 is treated with sodium dithionite and sodium hydroxide in water to produce a compound of Formula 3-5. Alternatively, the compound of Formula 3-4 is reduced using palladium on carbon in a suitable solvent under a hydrogen atmosphere to yield a compound of Formula 3-5.

In Step 4, compound 3-5 is reacted with about 1.2 equivalents of cyanogen bromide in a solvent such as methanol/tetrahydrofuran mixture to produce a compound of Formula 3-6. The compound of Formula 3-6 may be further transformed by other substitution or derivatization.

A compound of Formula 3-1 useful in the method of Scheme D is a compound having a structure of Formula 3-1, wherein T1 is triflate or halo (including bromo, chloro, and iodo), and wherein R1, X1, X2, X3, R31 and R32 are defined as for a compound of Formula I-A.

Exemplary compounds having a pyrazolopyrimidine core can be synthesized via Scheme E.

In Step 1 of Scheme E, compound A-2 in dimethylformamide (DMF), is reacted with an N-halosuccinimide (NT1S) at about 80° C., to provide compound 4-1, where T1 is iodo or bromo. In Step 2, compound 4-1 in DMF is reacted with a compound R1Tx, in the presence of potassium carbonate, to provide compound 4-2. In Step 4, compound 4-2 is coupled with a compound of Formula B using palladium catalysis such as palladium tetrakis (triphenylphosphine), and in the presence of sodium carbonate, to yield a pyrazolopyrimidine compound as shown.

A compound of Formula R1Tx suitable for use in Reaction Scheme E is the compound wherein R1 is cycloalkyl or alkyl and Tx is halo (including bromo, iodo, or chloro) or a leaving group, including but not limited to mesylate or tosylate.

Reaction Schemes F-M illustrate methods of synthesis of borane reagents useful in preparing intermediates of use in synthesis of the compounds of the invention as described in Reaction Schemes A, B, and E above, to introduce M1 substituents.

In an alternative method of synthesis, a compound of Formula N-1 and a compound of N-2 are coupled to produce a compound of Formula C. The coupling step is typically catalyzed by using, e.g., a palladium catalyst, including but not limited to palladium tetrakis (triphenylphosphine). The coupling is generally performed in the presence of a suitable base, a nonlimiting example being sodium carbonate. One example of a suitable solvent for the reaction is aqueous dioxane.

A compound of Formula N-1 for use in Scheme N has a structure of Formula N-1, wherein G is hydrogen or RG1, wherein RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 of the compound of Formula N-1 is taken together to form a 5- or 6-membered cyclic moiety. R1, X1, X2, X3, R31 and R32 of the compound of Formula N-1 are defined as for a compound of Formula I-A.

A compound of Formula N-2 for use in Scheme N has a structure of Formula N-2 wherein T1 is triflate or halo (including bromo, chloro, and iodo). M of the compound of Formula N-2 is either M1 or M2. M1 is defined as for a compound of Formula I. For example, M1 can be a 5-benzoxazolyl or a 6-benzoxazolyl moiety, including but not limited to those M1 moieties disclosed herein. M2 is a moiety which is synthetically transformed to form M1, after the M2 moiety has been coupled to the bicyclic core of the compound of Formula N-1.

A compound of Formula N-1 may be synthesized as shown in Scheme N-1. A compound of Formula N-1 is reacted with a trialkyl borate or a boronic acid derivative to produce a compound of Formula N-1. The reaction is typically run a solvent such as dioxane or tetrahydrofuran. The trialkyl borate includes but is not limited to triisopropyl borate and the boronic acid derivative includes but is not limited to bis(pinacolato)diboron.

When the reaction is performed with trialkyl borate, a base such as n-butyl lithium is first added to the compound of Formula N-3 to generate an anion, prior to the addition of the borate. When the reaction is performed with a boronic acid derivative such as bis(pinacolato)diboron, a palladium catalyst and a base is used. Typical palladium catalysts include but is not limited to palladium chloride (diphenylphosphino)ferrocene). A suitable base includes but is not limited to potassium acetate.

A compound of Formula N-3 suitable for use in Scheme N-1 is a compound wherein T2 is halo or another leaving group such as mesylate, tosylate, or triflate. X1, X2, X3, R1, R31, and R32 of the compound of Formula N-3 is as defined for a compound of Formula I-A.

In some embodiments of the invention, a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ is provided as its salt, including but not limited to hydrochloride, acetate, formate, nitrate, sulfate, and boronate.

In some embodiments of the invention, a palladium compound, including but not limited to palladium chloride (diphenylphosphino)ferrocene) and palladium tetrakis (triphenylphosphine), is used in the synthesis of a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″. When a palladium compound is present in the synthesis of a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″, it is present in an amount ranging from about 0.005 molar equivalents to about 0.5 molar equivalents, from about 0.05 molar equivalents to about 0.20 molar equivalents, from about 0.05 molar equivalents to about 0.25 molar equivalents, from about 0.07 molar equivalents to about 0.15 molar equivalents, or about 0.8 molar equivalents to about 0.1 molar equivalents of the compound of Formula A, B, B′, B″, C, D, E, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1, or N-3. In some embodiments, a palladium compound, including but not limited to palladium chloride (diphenylphosphino)ferrocene) and palladium tetrakis (triphenylphosphine) is present in the synthesis of a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ in about 0.07, about 0.08, about 0.09, about 0.10, about 0.11, about 0.12, about 0.13, about 0.14, or about 0.15 molar equivalents of a starting material of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ that is used to synthesize a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″.

In some embodiments of the above reaction schemes B, D, E, N or N-1, another embodiment of the compounds of Formula A, C, 3-1, 3-3, 3-4, 3-5, 3-6, A-2, 4-1, 4-2, N-1 and N-3 is as shown in Schemes B′. D′. E′, N′ or N-1′ below. In these alternative syntheses, producing a compound of Formula C, 3-1, 3-3, 3-4, 3-5, 3-6, A-2, 4-1, 4-2, N-1 or N-3, use compounds that comprise an amino moiety having a RG2 moiety present during one or more of the synthetic steps, wherein RG2 is an amino protecting group including but not limited to tert-butyl carbamate (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and the like. These compounds include a compound of Formula A″, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, A-2″, 4-1″, 4-2″, N-1″ or N-3″.

The RG2 moiety is removed, using suitable methods, at any point desired, whereupon the compound of Formula C, 3-1, 3-3, 3-4, 3-5, 3-6, A-2, 4-1, 4-2, N-1 or N-3 has a R31 hydrogen replacing the RG2 moiety on the amino moiety. This transformation is specifically illustrated for the conversion of a compound of Formula C″ to a compound of C (i.e., as in Step 4 of Scheme E′) and for the conversion of a compound of Formula 3-6″ to a compound of Formula 3-6 (i.e., as in Step 5 of Scheme D′). This illustration is in no way limiting as to the choice of steps wherein a compound comprising a NR31RG2 moiety may be converted to a compound comprising a NR31R32 moiety wherein the R32 moiety is hydrogen.

Additionally, the invention encompasses methods of synthesis of the compounds of A, B, B′, B″, C, E, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 or N-3, wherein one or more of M, M1, or R1 has a protecting group present during one or more steps of the synthesis. Protecting groups suitable for use for a M, M1, or R1 moiety are well known in the art, as well as the methods of incorporation and removal, and the reagents suitable for such transformations.

Compounds of the invention where X4 is C—R9 may be prepared by methods analogous to the ones described in the Schemes illustrated above.

Reaction Schemes O, P and Q illustrate methods of synthesis of borane reagents useful in preparing intermediates of use in synthesis of the compounds of the invention as described in Reaction Schemes 1 and 2 above, to introduce benzothiazolyl substituents.

A compound of Formula O-1 is treated with, for example, nitric acid to produce a compound of Formula O-2. The compound of Formula O-2 is treated with a reducing agent such as stannous chloride to produce a compound of Formula O-3. The compound of O-3 is treated with sodium nitrate in acid and cupric bromide to produce a compound of Formula O-4. The compound of O-4 is treated a base such as butyl lithium and boron tris-isopropoxide to produce a compound of Formula O-5.

A compound of Formula P-1 is treated with, for example, potassium thiocyanate and bromine in acetic acid to produce a compound of Formula P-2. The compound of Formula P-2 is treated with an acetylating reagent such as acetyl chloride to produce a compound of Formula P-3. The compound of P-3 is reacted with, for example, bis(pinacolato)diboron (compound P-4) in the presence of a catalyst such as palladium chloride to produce a compound of Formula P-5.

The compound of Formula P-2 is reacted with, for example, methyl carbamic acid chloride to produce a compound of Formula Q-1. The compound of Formula Q-1 is reacted with bis(pinacolato)diboron (compound P-4) in the presence of a catalyst such as Pd2(dba)3, 2-chlorohexylphosphino-2,4,6-triisopropylbiphenyl, a base such as potassium acetate, to produce the compound of Formula Q-2.

Some illustrative compounds of the invention which are mTor inhibitors are described below. The compounds of the invention are not limited in any way to the compounds illustrated herein.

Illustrative compounds of the invention include those of subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b, where the substituents R1, X1, and V are as described below.

In some embodiments, when R1 is H and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is H and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is CH3 and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is CH3 and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is Et and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is Et and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is iPr and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is iPr and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In one embodiment, R1 is iPr, X1 is N, and V is NH2. In another embodiment, R1 is iPr, X1 is N, and V is NHCOMe. In other embodiments, when R1 is cyclobutyl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is cyclobutyl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is cyclopentyl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is cyclopentyl and X1 is N V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is phenyl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is phenyl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is pyridin-2-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is pyridin-2-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylaminocyclohex-4-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylaminocyclohex-4-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylpiperidin-4-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylpiperidin-4-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylaminocyclobut-3-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is N-methylaminocyclobut-3-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is tert-butyl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is tert-butyl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 1-cyano-but-4-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 1-cyano-but-4-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 1-cyano-prop-3-yl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 1-cyano-prop-3-yl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 3-azetidinyl and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is 3-azetidinyl and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me.

In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me.

In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me.

In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me. In other embodiments, when R1 is

and X1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO2Me.

In the noted embodiments, pyridin-2-yl is

N-methylaminocyclohex-4-yl is

N-methylpiperidin-4-yl is

and N-methylaminocyclobut-3-yl is

Illustrative compounds of the invention include those of subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b, where the substituents R1, X1, and V are as described below. In some embodiments, when R1 is H and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is H and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is CH3 and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is CH3 and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is Et and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is Et and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is iPr and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is iPr and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is cyclobutyl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is cyclobutyl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is cyclopentyl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is cyclopentyl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is phenyl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is phenyl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is pyridin-2-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is pyridin-2-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is N-methylaminocyclohex-4-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is N-methylaminocyclohex-4-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is N-methylpiperidin-4-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is N-methylpiperidin-4-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some embodiments, when R1 is N-methylaminocyclobut-3-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is N-methylaminocyclobut-3-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is tert-butyl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is tert-butyl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 1-cyano-but-4-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 1-cyano-but-4-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 1-cyano-prop-3-yl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 1-cyano-prop-3-yl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 3-azetidinyl and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is 3-azetidinyl and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino.

In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino.

In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is CH, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other embodiments, when R1 is

and X1 is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino.

In the noted embodiments, cyclopropanecarboxamido is

cyclopropylamino is

2-morpholinoethylamino is

hydroxyethylamino is

and N-morpholino is

TABLE 1 Biological activity of several illustrative mTor inhibitor compounds of the invention. mTOR PI3K α PI3K β PI3K γ PI3K δ PC3 Structure IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) EC50 (nM)  1 ++++ +++ ++ ++++ +++ ++++  2 ++++ ++ + +++ +++ +++  3 ++ + ++ ++ ++  4 +++ ++ ++ +++ +++ ++  5 ++++ +++ ++ ++++ +++ ++++  6 ++++ ++ + ++ +++ +++  7 ++++ +++ ++ ++ +++ ++  8 ++++ +++ + +++ +++ ++++  9 ++++ ++ + +++ +++ ++++ 10 ++ + 11 +++ + 12 +++ + 13 ++ ++ +++ +++ 14 ++ ++ +++ ++ 15 + + + + 16 + + ++ + 17 + + + + 18 + + + + 19 ++ + + + 20 ++ ++ + ++ 21 +++ + + + + 22 ++++ ++++ ++ +++ +++ ++ 23 ++++ ++ + ++ ++ 24 + + + + 25 +++ ++ ++++ +++ 26 ++++ +++ ++++ +++ 27 ++ + + +++

Table 1 shows the biological activity in mTOR and PI3K kinase assays of several compounds of the invention. The scale utilized in Table 1 is as follows: ++++ less than 100 nM; +++ less than 1.0 μM; ++ less than 10 μM; and + greater than 10 μM.

In other embodiments, the present invention provides the following compounds:

Any of the compounds shown above may show a biological activity in an mTOR or PI3K inhibition assay of between about 0.5 nM and 25 μM (IC50).

Additional compounds which are mTor inhibitors of the invention are shown in Table 2.

TABLE 2 In vitro IC50 values for Illustrative mTor Inhibitor Compounds of the Invention. mTORC PI3K α PI3K β PI3K γ PI3K δ PC3 pro- IC50 IC50 IC50 IC50 IC50 liferation # Structure (nM) (nM) (nM) (nM) (nM) (nM)  1 ++++ + + ++ ++ +++  2 +  3 ++ +  4 + +  5 + + +  6 + + +  7 +++ + +  8 + + +  9 ++++ + + 10 +++++ + + + + + 11 +++++++ + + ++ ++ ++++ 12 ++++++ + + ++ + ++++ 13 + + + 14 + + 15 +++++++ + + ++++ ++++ ++++ 16 +++++++ + + ++ +++ ++ 17 + + + 18 + * * 19 + + 20 + + 21 ++++ ++ + ++ ++ + 22 +++++++ + + + ++ 23 + + 24 + + + 25 ++ + + 26 ++++++ + + ++ +++ ++ 27 +++++ ++ 28 ++ + + + + 29 + 30 +++++ + + + + 31 +++++ + + ++ + 32 ++ + + + + 33 ++ + + + + 34 + + + + 35 + + + + 36 ++++++ + +++ ++ +++ 37 + ++ ++ ++ 38 ++ + + + + 39 ++++++ + + + + 40 +++ + + + + 41 ++++++ + + ++++ + + 42 +++++++ + + +++ + 43 + + + + 44 +++ + + + 45 + 46 47 48 ++++ + + + + 49 ++++++ + + ++ ++ 50 ++++ + + ++ ++ 51 ++++ + + ++ ++ 52 ++ + + + ++ 53 +++ + + + 54 +++++ + + + 55 ++ + + + 56 + + + + 57 +++++ + + + 58 + + + + 59 + + + + 60 +++ + + +++ 61 +++++ + + + + 62 +++++++ + + + +++ 63 +++++++ ++ + +++++ +++++ 64 +++++ + + ++ ++ 65 ++++++ ++++ + +++++ +++++ 66 + + + + + 67 + + + + + 68 +++++++ ++ + ++++ +++++ 69 +++++++ + + + ++ 70 +++++++ ++ + +++ +++++ 71 +++ + + + +

In Table 2 above, a +++++++ indicates an IC50 of 5 nM or less; a ++++++ indicates an IC50 of 10 nM or less; a +++++ indicates an IC50 of 25 nM or less; an ++++ indicates an IC50 of 50 nm or less, a +++ indicates an IC50 of 100 nM or less, a ++ indicates an IC50 of 500 nM or less, and a + indicates an IC50 of more than 500 nM.

Exemplary PI3Kα Inhibitor Compounds

In one aspect, the present invention provides a PI3Kα inhibitor which is a compound of Formula I:

or its pharmaceutically acceptable salts thereof, wherein:

    • W1′ is N, NR3′, or CR3′; W2′ is N, NR4′, CR4′, or C═O; W3′ is N, NR5′ or CR5′; W4′ is N, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N;
    • W6′ is N or CR8′;
    • Wa′ and Wb′ are independently N or CR9′;
    • one of Wc′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety;
    • R5′, R6′, R7′ and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

For example, the present invention provides a PI3Kα inhibitor which is a compound of Formula I:

or its pharmaceutically acceptable salts thereof, wherein:

    • X is O or S or N;
    • W1′ is N, NR3′, CR3′, or C═O, W2′ is N, NR4′, CR4′, or C═O, W3′ is N, NR5′ or CR5′, W4′ is N, C═O or CR6′, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N or CR7′;
    • W6′ is N or CR8′;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety; and
    • R5′, R6′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, the compound of Formula II exists as a tautomer, and such tautomers are contemplated by the present invention.

In some embodiments, the compound of Formula II has the formula:

For example, a compound of Formula II is:

In some embodiments of the compound of Formula II, W1′ is CR3′, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′; W1′ is N, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′; or W1′ is CR3′, W2′ is N, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′. Formulas for such embodiments are shown below:

In some embodiments, X is O. In other embodiments, X is S.

In some embodiments, R1′ is hydrogen. In other embodiments, R1′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, R2′ is hydrogen. In other embodiments, R2′ is, for example, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R2′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R2′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R2′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R2′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R2′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-1][1,2,4]triazinyl. The present invention also provides compounds wherein R2′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R2′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R2′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R2′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R2′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R2′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R2′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R2′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R2′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R2′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

In some embodiments of the compound of Formula II, W1′ is CR3. R3′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R3′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R3′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R3′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R3′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R3′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R3′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

R3′ of the compounds of Formula II can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

The invention also provides compounds of Formula II, wherein when R3′ is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR′R″ (wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety), then R3′ is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, heterocycloalkyloxy, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. Each of the above substituents may be further substituted with one or more substituents chosen from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.

For example, the invention provides compounds wherein when R3′ is alkyl, the alkyl is substituted with NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety. The cyclic moiety so formed can be unsubstituted or substituted. Non-limiting exemplary cyclic moieties includes but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In other examples of the compounds of Formula II, when R3′ is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloaklyl substituents can be unsubstituted or substituted.

In yet other examples of the compounds of Formula II, when R3′ is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. The monocyclic heteroaryl includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. The bicyclic heteroaryl includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In other embodiments of the compound of Formula II, R3′ is —NHR3″, —N(CH3)R3″, —N(CH2CH3)R3″, —N(CH(CH3)2)R3″, or —OR3″, wherein R3″ is unsubstituted or substituted heterocycloalkyl (nonlimiting examples thereof include 4-NH piperidin-1-yl, 4-methyl piperidin-1-yl, 4-ethyl piperidin-1-yl, 4-isopropyl-piperidin-1-yl, and pyrrolidin-3-yl), unsubstituted or substituted monocyclic aryl, or unsubstituted or substituted monocyclic heteroaryl (including but not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl). In one example, R3′ is —O-aryl, i.e. phenoxy. In another example, R3′ is —O-(4-methyl)piperidin-1-yl or —O-(4-isopropyl)piperidin-1-yl.

In some embodiments of the compound of Formula II, R3′ is one of the following moieties:

In some embodiments of the compound of Formula II, W1′ is NR3′, wherein R3′ is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula II, R3′ is unsubstituted or substituted heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R3′ is unsubstituted or substituted monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In still other embodiments, W1′ is C═O.

In some embodiments of the compound of Formula II, W2′ is CR4′. R4′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

The present invention also provides compounds of Formula II wherein R4′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R4′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R4′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R4′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R4′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In some embodiments, R4′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R4′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, or carbonate. Also contemplated are R4′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

R4′ of the compounds of Formula II, can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

The invention also provides compounds of Formula II, wherein when R4′ is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR′R″ (wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety), then R4′ is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. Each of the above substituents may be further substituted with one or more substituents chosen from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.

For example, the invention provides compounds wherein when R4′ is alkyl, the alkyl is substituted with NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety. The cyclic moiety so formed can be unsubstituted or substituted. Non-limiting exemplary cyclic moieties includes but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. In other examples of the compounds of Formula II, when R4′ is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloaklyl substituents can be unsubstituted or substituted.

In yet other examples of the compounds of Formula II, when R4′ is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. The monocyclic heteroaryl includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. The bicyclic heteroaryl includes but is not limited benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula II, W2′ is NR4′, wherein R4′ is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula II, R4′ is unsubstituted or substituted heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R4′ is unsubstituted or substituted monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In some embodiments R3′ and R4′ taken together form a cyclic moiety. Such a moiety may have, for example, from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted. In some embodiments, the substituent is C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl); monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl. The cyclic moiety may have one or more substituents, which may be the same or different.

In some embodiments, the cyclic moiety formed by R3′ and R4′ is substituted with at least one of the following substituents:

In some embodiments of the compound of Formula II, W3′ is CR5′. R5′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R5′ is H. In other embodiments, R5′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R5′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R5′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R5′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R5′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula II, W3′ is N or NR5′, wherein R5′ is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula II, R5′ is unsubstituted or substituted heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R5′ is unsubstituted or substituted monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In some embodiments of the compound of Formula II, W4′ is CR6′. R6′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R6′ is H. In other embodiments, R6′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R6′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R6′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R6′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R6′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula II, W4′ is N or NR6′, wherein R6′ is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula II, R6′ is unsubstituted or substituted heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R6′ is unsubstituted or substituted monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In other embodiments, W4′ is C═O.

In some embodiments of the compound of Formula II, W5′ is N. In other embodiments of the compound of Formula II, W5′ is CR7′. R7′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R7′ is H. In other embodiments, R7′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R7′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R7′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R7′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R7′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula II, W6′ is N. In other embodiments of the compound of Formula II, W6′ is CR8′. R8′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R8′ is H. In other embodiments, R8′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R8′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R8′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R8′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R8′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments, the compound of Formula II has the formula:

In other embodiments, the compound of Formula II is:

For example, the compound of Formula II is:

In some embodiments, the compound of Formula II is:

In another aspect, the invention provides compounds of Subformula IIa.

In one embodiment, R1′, R3′, R4′, R5′, and R8′ are hydrogen. In another embodiment, R1′, R3′, R5′, and R8′ are hydrogen and R4′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R4′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In another aspect, the invention provides compounds of Subformula IIa′ and IIb′, where W1′ is CR3′, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In one embodiment, R1′, R3′, R4′, R5′, R7′ and R8′ are hydrogen. In another embodiment, R1′, R4′, R5′, R7′ and R8′ are hydrogen and R3′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R3′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R3′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R3′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R3′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R3′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R3′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R3′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3. In some embodiments R3′ can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

In another aspect, the invention provides compounds of Subformula IIb:

In one embodiment, R1′, R4′, R5′ and R8′ are hydrogen. In another embodiment, R1′, R5′, and R8′ are hydrogen and R4′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R4′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In another aspect, the invention provides compounds of Subformula IIc and IId, where W1′ is N, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′:

In one embodiment, R1′, R4′, R5′, R7′ and R8′ are hydrogen. In another embodiment, R1′, R5′, R7′ and R8′ are hydrogen and R4′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R4′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R4′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R4′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R4′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R4′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R4′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R4′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R4′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3. In some embodiments R4′ can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

In another aspect, the invention provides compounds of Subformula IIe and IIf, where W1′ is CR3′, W2′ is N, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′:

In one embodiment, R1′, R3′, R5, R7′ and R8′ are hydrogen. In another embodiment, R1′, R5′, R7′ and R8′ are hydrogen and R3′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R3′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R3′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R3′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R3′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R3′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R3′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R3′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3. In some embodiments R3′ can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

In some embodiments, the substituents R3′, R4′, R5′, R6′ or R8′ may be any of the sub substituents shown in Table 1:

TABLE 1 R3′, R4′, R5′, R6′, R8′ moieties of the compounds of Formula II, each independently includes but is not limited to the following: Sub- class # R R-1  R-2  R-3  R-4  R-5  R-6  R-7  R-8  R-9  —CH(CH3)2 R-10 R-11 R-12 R-13 R-14 R-15 R-16 R-17 R-18 R-19 R-20 R-21 R-22 R-23 R-24 R-25 R-26 R-27 R-28 R-29 R-30 R-31 R-32 R-33 R-34 R-35 R-36 R-37 R-38 R-39 R-40 H R-41 R-42 R-43 R-44 R-45 R-46 R-47 R-48 R-49 R-50 R-51 R-52 R-53 R-54 R-55 R-56 R-57 R-58 R-59 R-60 R-61 R-62 R-63 R-64 R-65 R-66 R-67 R-68 R-69 R-70 R-71 R-72 R-73 R-74 R-75 R-76 R-77 R-78 R-79 R-80 R-81

In another aspect, the invention provides a PI3Kα inhibitor which is a compound of Formula III:

or its pharmaceutically acceptable salts thereof, where:

    • X is O or S or N;
    • W1′ is S, N, NR3′ or CR3′, W2′ is N or CR4′, W3′ is S, N or CR5′, W4′ is N or C, and W7′ is N or C, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N or CR7′;
    • W6′ is N or CR8′;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety; and
    • R5′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, the compound of Formula III exists as a tautomer, and such tautomers are contemplated by the present invention.

In some embodiments, the PI3Kα inhibitor is a compound of Formula III which has the Formula:

In yet other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is N, and W6′ is CR8′. In still other embodiments, W1′ is NR3′, W2′ is CR4′, W3′ is N, W4′ is C, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is S, W2′ is CR4′, W3′ is N, W4′ is C, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is S, W4′ is C, W5′ is N, and W6′ is N.

In other embodiments, an inhibitor of Formula III is a compound according to one of the formulas:

wherein for each of the above formulas, each respective R variable includes a ‘prime’ (′).

In some embodiments, X is O. In other embodiments, X is S.

In some embodiments, R1′ is hydrogen. In other embodiments, R1′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments, R2′ is hydrogen. In other embodiments, R2′ is, for example, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R2′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R2′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R2′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R2′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R2′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds wherein R2′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R2′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R2′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula III, R2′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R2′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R2′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R2′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R2′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R2′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R2′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

In some embodiments of the compound of Formula III, W1′ is CR3. R3′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula III wherein R3′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R3′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula III, R3′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R3′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R3′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R3′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

R3′ of the compounds of Formula III, can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more hetero atoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

The invention also provides compounds of Formula III, wherein when R3′ is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR′R″ (wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety), then R3′ is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, heterocycloalkyloxy, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. Each of the above substituents may be further substituted with one or more substituents chosen from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.

For example, the invention provides compounds wherein when R3′ is alkyl, the alkyl is substituted with NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety. The cyclic moiety so formed can be unsubstituted or substituted. Non-limiting exemplary cyclic moieties includes but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In other examples of the compounds of Formula III, when R3′ is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloaklyl substituents can be unsubstituted or substituted.

In yet other examples of the compounds of Formula III, when R3′ is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. The monocyclic heteroaryl includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. The bicyclic heteroaryl includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In other embodiments of the compound of Formula III, R3′ is —NHR3″, —N(CH3)R3″, —N(CH2CH3)R3″, —N(CH(CH3)2)R3″, or —OR3″, wherein R3″ is unsubstituted or substituted heterocycloalkyl (nonlimiting examples thereof include 4-NH piperidin-1-yl, 4-methyl piperidin-1-yl, 4-ethyl piperidin-1-yl, 4-isopropyl-piperidin-1-yl, and pyrrolidin-3-yl), unsubstituted or substituted monocyclic aryl, or unsubstituted or substituted monocyclic heteroaryl (including but not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl). In one example, R3′ is —O-aryl, i.e. phenoxy. In another example, R3′ is —O-(4-methyl)piperidin-1-yl or —O-(4-isopropyl)piperidin-1-yl.

In some embodiments of the compound of Formula III, R3′ is one of the following moieties:

In some embodiments of the compound of Formula III, W1′ is NR3′, wherein R3′ is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula III, R3′ is unsubstituted or substituted heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R3′ is unsubstituted or substituted monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.

In other embodiments, W1′ is N. In still other embodiments, W1′ is S.

In some embodiments of the compound of Formula III, W2 is CR4′. R4′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

The present invention also provides compounds of Formula III wherein R4′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R4′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula III, R4′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R4′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R4′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In some embodiments, R4′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R4′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, or carbonate. Also contemplated are R4′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3.

R4′ of the compounds of Formula III, can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more hetero atoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

The invention also provides compounds of Formula III, wherein when R4′ is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR′R″ (wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety), then R4′ is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. Each of the above substituents may be further substituted with one or more substituents chosen from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.

For example, the invention provides compounds wherein when R4′ is alkyl, the alkyl is substituted with NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety. The cyclic moiety so formed can be unsubstituted or substituted. Non-limiting exemplary cyclic moieties includes but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1, 2, dioxide, and thiomorpholinyl. In other examples of the compounds of Formula III, when R4′ is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloaklyl substituents can be unsubstituted or substituted.

In yet other examples of the compounds of Formula III, when R4′ is alkyl, the alkyl is substituted with a 5, 6, 7, 8, 9, or 10 membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. The monocyclic heteroaryl includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. The bicyclic heteroaryl includes but is not limited benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. In some embodiments of the compound of Formula III, W2′ is N.

In some embodiments R3′ and R4′ taken together form a cyclic moiety. Such a moiety may have, for example, from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted. In some embodiments, the substituent is C1-C10alkyl (which includes but is not limited to —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or C3-C7cycloalkyl (which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloalkyl (which includes but is not limited to oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), C2-C10heteroalkyl (which includes but is not limited to methoxyethoxy, methoxymethyl, and diethylaminoethyl); monocyclic heteroaryl (which includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl. The cyclic moiety may have one or more substituents, which may be the same or different.

In some embodiments, the cyclic moiety formed by R3′ and R4′ is substituted with at least one of the following substituents:

In some embodiments of the compound of Formula III, W3′ is CR5′. R5′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R5′ is H. In other embodiments, R5′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R5′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R5′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R5′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R5′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. In some embodiments of the compound of Formula III, W3′ is N. In other embodiments, W3′ is S.

In some embodiments of the compound of Formula III, W4′ is C. In other embodiments, W4′ is N.

In some embodiments of the compound of Formula III, W5′ is N. In other embodiments of the compound of Formula III, W5′ is CR7′. R7′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R7′ is H. In other embodiments, R7′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R7′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R7′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R7′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R7′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula III, W6′ is N. In other embodiments of the compound of Formula III, W6′ is CR8′. R8′ can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R8′ is H. In other embodiments, R8′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2—O5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R8′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R8′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R8′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R8′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In some embodiments of the compound of Formula III, W7′ is C. In other embodiments, W7′ is N.

The invention also provides compounds of Formula III which are defined as defined by the following subclasses:

wherein for each of the above formulas, each respective R variable includes a ‘prime’ (′).

In some embodiments of compounds of Subclasses IIIa-IIIj, R1′ is hydrogen. In other embodiments of compounds of Subclasses IIIa-IIIl, R2′ is NH2 of NHCO(alkyl). In other embodiments of compounds of Subclasses IIIa-IIIl, R4′ is hydrogen. In other embodiments of compounds of Subclasses IIIc-IIIf and IIIi-IIIl, R7′ is hydrogen. In other embodiments of compounds of Subclasses IIIa-IIIh and IIIk-IIIl, R8′ is hydrogen.

In some embodiments of compounds of Subclasses IIIa through IIIl, R3′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety. R3′ can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3′ is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3′ is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3′ is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3′ includes but is not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3′ includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolopyrimidinyl, indazolyl, pyrazolylpyridinyl, imidazo[1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R3′ is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic heteroaryl as described above, that are linked to alkyl, which in turn includes but is not limited to CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3′ is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some further embodiments, R3′ is unsubstituted or substituted heterocycloalkyl which includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R3′ is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3′ can also be unsubstituted or substituted heterocycloalkyloxy, including but not limited to 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl-piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3′ is unsubstituted or substituted amino, wherein the substituted amino includes but is not limited to dimethylamino, diethylamino, di-isopropyl amino, N-methyl N-ethyl amino, and dibutylamino. In some embodiments, R3′ is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3′ is halo, which is —I, —F, —Cl, or —Br. In some embodiments, R3′ is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R3′ being —CH3, —CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, —OCH3, —OCH2CH3, or —CF3. In some embodiments R3′ can also be NR′R″ wherein R′ and R″ are taken together with the nitrogen to form a cyclic moiety having from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. Further non-limiting exemplary cyclic moieties are the following:

The invention further provides a PI3Kα inhibitor which is a compound of Formula IV:

or its pharmaceutically acceptable salts thereof, wherein

    • W1′ is CR3′, W2′ is C-benzoxazolyl substituted with R2′ and W3′ is S;
    • W1′ is CR3′, W2′ is C-benzoxazolyl substituted with R2′ and W3′ is CR5′;
    • W1′ is N or NR3′, W2′ is CR4′, and W3′ is C-benzoxazolyl substituted with R2;
    • W1′ is CR3′, W2′ is CR4′, and W3′ is C-benzoxazolyl substituted with R2; or
    • W1′ is N or NR3′, W3′ is NR4′, and W3′ is C-benzoxazolyl substituted with R2;
    • X is N;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R5′, R6′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula IV, the compound is:

and wherein W1′ is CR3′ or NR3′ and W3′ is CR4′.

In another aspect, the invention provides a PI3Kα inhibitor which is a compound of Formula V:

or its pharmaceutically acceptable salts thereof, wherein:

    • W1′ is N, NR3′, CR3′, or C═O; W2′ is N, NR4′, CR4′, or C═O; W3′ is N, NR5′ or CR5′; W4′ is N, C═O or CR6′, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N or CR7′;
    • W6′ is N or CR8′;
    • Wa′ and Wb′ are independently N or CR9′;
    • one of Wc′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety;
    • R5′, R6′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula IV, W1′ is CR3′, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′; W1′ is N, W2′ is CR4′, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′; or W1′ is CR3′, W2′ is N, W3′ is CR5′, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In some embodiments of the compound of Formula IV, Wb′ is N. In other embodiments, Wa′ is CR9′ and R9′ is alkyl.

The invention also provides a PI3Kα inhibitor which is a compound of Formula VI:

or its pharmaceutically acceptable salts thereof, wherein

    • W1′ is S, N, NR3′ or CR3′, W2′ is N or CR4′, W3′ is S, N or CR5′, W4′ is N or C, and W7′ is N or C, wherein no more than two N atoms and no more than two C═O groups are adjacent;
    • W5′ is N or CR7′;
    • W6′ is N or CR8′;
    • Wa′ and Wb′ are independently N or CR9′;
    • one of Wc′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety;
    • R5′, R7′ and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula VI, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is N, W4′ is N, W5′ is N, and W6′ is CR8′. In still other embodiments, W1′ is NR3′, W2′ is CR4′, W3′ is N, W4′ is C, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is S, W2′ is CR4′, W3′ is N, W4′ is C, W5′ is CR7′, and W6′ is CR8′. In other embodiments, W1′ is CR3′, W2′ is CR4′, W3′ is S, W4′ is C, W5′ is N, and W6′ is N.

In some embodiments of the compound of Formula VI, Wb′ is N. In other embodiments, Wa′ is CR9′ and R9′ is alkyl.

The invention further provides PI3Kα inhibitors which are compounds of Formula VI-A and VI-B:

or its pharmaceutically acceptable salts thereof, wherein

    • W1′ is CR3;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • and R3′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

Also provided herein are PI3Kα inhibitors which are compounds of Formula VI-C and VI-D:

or its pharmaceutically acceptable salts thereof, wherein

    • W1′ is CR3′;
    • W5′ is N or CR7′;
    • Wa′ and Wb′ are independently N or CR9′;
    • one of Wc′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R7′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula V-C or V-D, Wb′ is N. In other embodiments, Wa′ is CR9′ and R9′ is alkyl.

Also provided herein is a PI3Kα inhibitor which is a compound of Formula VII:

or its pharmaceutically acceptable salts thereof, wherein

    • W1′ is CR3′; W2′ is CR4′;
    • Wa′ is CH or N;
    • R1′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R4′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety; and
    • R10′ and R11′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

The invention further provides a PI3Kα inhibitor which is a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein

    • X1 is CR3′, NR3′, or S;
    • X2 is CR4′, NR4′,

    • X3 and X4 are independently C or N;
    • X5 is CR6′, NR6′, or S;
    • X4 is CR7′, NR7′,

    • Wa′ and Wb′ are independently N or CR9′;
    • one of Wc′ and Wd′ is N, and the other is O, NR10′, or S;
    • R1′ and R2′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R3′ and R4′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • or R3′ and R4′ taken together form a cyclic moiety;
    • R5′, R6′, R7′, and R8′ are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
    • R9′ is alkyl or halo; and
    • R10′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In some embodiments of the compound of Formula VIII, Wb′ is N. In other embodiments, Wa′ is CR9′ and R9′ is alkyl.

In some embodiments, the mTor inhibitor is a compound as described in U.S. Pat. Nos. 7,651,687 or 7,585,868; or as described International Patent Applications WO 2007/079164, WO 2007/061737, WO 2007/106503, WO 2007/134828 or WO2011/025889 which are hereby incorporated by reference in their entirety.

In other embodiments, the mTor inhibitor is NVP-BEZ235 (Novartis), BGT226 (Novartis), XL765 (Sanofi-Aventis, Exelixis), GDC0980 (Genentech), SF1126 (Semafore), PKI587 (Wyeth), PF04691502 (Pfizer), or GSK2126458 (GlaxoSmithKline). In still other embodiments, the mTor inhibitor is CC223 (Celgene), OSI027 (OSI Pharmaceuticals), AZD8055 (Astra Zeneca), AZD2014 (Astra Zeneca), or Palomid 529 (Paloma Pharmaceuticals).

Structures of exemplary mTor inhibitors are shown below:

mTor inhibitor Structure NVP-BEZ235 XL765 GDC0980 SF1126 PKI587 PF04691502 GSK2126458 OSI027 AZD8055 P529

Reaction Schemes—PI3Kα Inhibitor Compounds

In general, compounds of the invention may be prepared by the following reaction scheme:

For example, compounds of the invention may be prepared by the following reaction schemes:

The compounds of the invention may be synthesized via a reaction scheme represented generally in Schemes A′, A″ and B′. The synthesis proceeds via coupling a compound of Formula A with a compound of Formula B to yield a compound of Formula C. The coupling step is typically catalyzed by using a palladium catalyst, including but not limited to palladium tetrakis (triphenylphosphine). The coupling is generally performed in the presence of a suitable base, a nonlimiting example being sodium carbonate. One example of a suitable solvent for the reaction is aqueous dioxane.

A compound of Formula A for use in Scheme A′ or A″ has a structure of Formula A, wherein T1 is halo including bromo, chloro, fluoro, and iodo, and wherein the remaining substituents are defined for Formulas I and II of compounds of the invention. For boronic acids and acid derivatives as depicted in Formula B, X is either O or S, and the benzoxazole or benzothiazole moiety can be attached at the 4-, 5-, 6- or 7-position.

For a compound of Formula B, G is hydrogen or RG1, wherein RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 is taken together to form a 5- or 6-membered cyclic moiety. In some embodiments, the compound of Formula B is a compound having a structure of Formula E:

wherein G is H or RG1; RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 is taken together to form a 5- or 6-membered cyclic moiety; and RG2 is H, tert-butyl carbamate, or acyl.

Scheme C′ depicts an exemplary scheme for synthesizing a compound of Formula B′ or, optionally, Formula B″ for use in Reaction Scheme C′. M is a heterocyclic moiety such as a benzoxazolyl or benzothiazolyl moiety as described by Formula B. This reaction proceeds via reacting a compound of Formula D with a trialkyl borate or a boronic acid derivative to produce a compound of Formula B′. The trialkyl borate includes but is not limited to triisopropyl borate and the boronic acid derivative includes but is not limited to bis(pinacolato)diboron. The reaction typically is run in the presence of a base, a nonlimiting example being potassium acetate. The reaction may be run in a solvent such as dioxane or tetrahydrofuran.

A compound of Formula D for use in Scheme C′ is a compound wherein T2 is halo or another leaving group, and M is as defined above. The compound of Formula B′ may further be converted to a compound of Formula B″ by treatment with an acid such as hydrochloric acid.

Some exemplary compounds of Formula B that can be synthesized via Scheme C′ include but are not limited to compounds of the following formulae:

Where desired, deprotection of a substituent (e.g., removal of Boc protection from an amino substituent) on the benzoxazolyl moiety (i.e. M1 of Formula C) is performed after coupling the compound of Formula B to the compound of Formula A.

Some exemplary compounds with such protecting groups, include but are not limited to compounds of the following formulae:

The following Reaction Schemes illustrate the preparation of several compounds of the invention.

Table 3 shows exemplary PI3Kα inhibitors of the invention.

TABLE 3 In Vitro IC50 data for selected compounds of the invention. The following symbols are used: + (greater than 10 microMolar), ++ (less than 10 microMolar), +++ (less than 1 microMolar), and ++++ (less than 100 nM). PC3 T47D Mass mTORC PI3K α PI3K β PI3K δ PI3K γ prolif- prolif- Charac- IC50 IC50 IC50 IC50 IC50 eration eration teriza- Structure (nM) (nM) (nM) (nM) (nM) (nM)* (nM) tion  1 +++ ++++ +++ ++++ ++++ +++ +++ Calcd: 388.1 Found: 389.0 [M + H]+  2 + +++ + + +++ ++ Calcd: 396.10 Found: 397.0 [M + H]+  3 +++ ++++ + +++ +++ Calcd: 354.09 Found: 355.0 [M + H]+  4 +++ ++++ ++++ ++++ ++++ ++++ Calcd: 338.12 Found: 339.0 [M + H]+  5 +++ +++ + ++ +++ Calcd: 348.14 Found: 349.0 [M + H]+  6 ++ ++++ ++ +++ ++++ ++ +++ Calcd: 327.11 Found: 328.0 [M + H]+  7 ++++ ++++ ++++ ++++ ++++ ++++ Calcd: 474.18 Found: 475.0 M + H]+  8 + ++ + +++ Calcd: 349.13 Found: 350.0 [M + H]+  9 + +++ ++ +++ Calcd: 349.13 Found: 350.0 [M + H]+  10 +++ ++++ +++ ++++ +++ +++ Calcd: 328.11 Found: 329.0 [M + H]+  11 + ++++ ++ +++ + Calcd: 326.12 Found: 327.0 [M + H]+  12 + + + + Calcd: 354.09 Found: 355.0 [M + H]+  13 ++++ +++ +++ +++ Calcd: 354.09 Found: 355.0 [M + H]+  14 ++ + + ++ Calcd: 344.09 Found: 345.0 [M + H]+  15 ++++ ++++ ++++ +++ +++ Calcd: 338.12 Found: 339.0 [M + H]+  16 ++++ ++ ++ +++ +++ Calcd: 338.12 Found: 339.0 [M + H]+  17 ++++ +++ +++ ++++ Calcd: 354.09 Found: 355.0 [M + H]+  18 ++ + + ++ Calcd: 338.12 Found: 339.0 [M + H]+  19 + + + + Calcd: 379.14 Found: 380.0 [M + H]+  20 ++++ ++++ ++++ Calcd: 327.11 Found: 328.0 [M + H]+  21 +++ ++ ++ ++ Calcd: 359.17 Found: 360.0 [M + H]+  22 +++ ++++ ++++ ++++ ++++ Calcd: 347.14 Found: 348.0 [M + H]+  23 ++++ +++ ++ ++++ Calcd: 360.17 Found: 361.0 [M + H]+  24 ++++ +++ ++++ ++++ Calcd: 361.15 Found: 362.0 [M + H]+  25 ++ + + ++  26 +++ ++++ ++++ ++++ Calcd: 341.13 Found: 342.2 [M + H]+  27 +++ ++ ++++ Calcd: 374.17 Found: 375.2 [M + H]+  28 ++++ +++ ++++ Calcd: 346.14 Found: 347.2 [M + H]+  29 ++++ ++++ ++++ Calcd: 361.15 Found: 362.0 [M + H]+  30 ++++ ++++ ++++ Calcd: 436.20 Found: 437.2 [M + H]+  31 ++++ ++++ ++++ Calcd: 338.12 Found: 339.2 [M + H]+  32 ++ + ++ Calcd: 360.16 Found: 361.2 [M + H]+  33 ++++ +++ +++ Calcd: 389.19 Found: 390.2 [M + H]+  34 ++++ +++ +++ Calcd: 375.7 Found: 376.0 [M + H]+  35 ++ ++++ ++++ ++++ ++ Calcd: 374.19 Found: 375.0 [M + H]+  36 ++ ++++ ++ + ++ Calcd: 375.17 Found: 376.0 [M + H]+  37 ++++ ++++ ++++ Calcd: 327.11 Found: 328.0 [M + H]+  38 ++++ ++++ ++++ Calcd: 316.11 Found: 317.0 [M + H]+  39 ++++ ++++ ++++ Calcd: 314.12 Found: 315.0 [M + H]+  40 ++ ++ + ++ Calcd: 250.09 Found: 251.0 [M + H]+  41 ++ ++++ +++ +++ ++ Calcd: 330.12 Found: 331.0 [M + H]+  42 + ++++ +++ +++ ++ Calcd: 425.20 Found: 426.0 [M + H]+  43 ++++ ++++ ++++  44 ++ ++++ ++ ++ Calcd: 376.16 Found: 377.0 [M + H]+  45 ++++ ++++ ++++ Calcd: 406.18 Found: 407.0 [M + H]+  46 ++++ ++++ ++++ ++++ Calcd: 363.11 Found: 364.0 [M + H]+  47 ++++ ++++ +++ +++ +++ +++ Calcd: 362.14 Found: 363.0 [M + H]+  48 ++ + + + Calcd: 334.14 Found: 335.0 [M + H]+  49 ++ ++++ ++ +++ ++ Calcd: 362.14 Found: 363.0 [M + H]+  50 + ++++ ++ ++++ ++ Calcd: 382.12 Found: 383.0 [M + H]+  51 ++++ +++ +++ +++ Calcd: 412.16 Found: 413.0 [M + H]+  52 ++ ++++ ++++ ++++ Calcd: 412.16 Found: 413.0 [M + H]+  53 ++ + + + Calcd: 335.14 Found: 336.0 [M + H]+  54 ++ ++++ ++ ++ ++ ++ Calcd: 363.13 Found: 364.2 [M + H]+  55 + +++ + + Calcd: 342.12 Found: 363.0 [M + H]+  56 +++ ++++ +++ + ++++ ++ Calcd: 342.12 Found: 343.0 [M + H]+  57 +++ +++ + ++ Calcd: 336.13 Found: 337.0 [M + H]+  58 ++++ ++++ ++++ ++++ Calcd: 328.11 Found: 329.0 [M + H]+  59 ++++ ++++ +++ ++++ Calcd: 317.10 Found: 318.0 [M + H]+  60 +++ ++++ ++ +++ ++++ Calcd: 402.18 Found: 403.0 [M + H]+  61 + + + + Calcd: 328.11 Found: 329.0 [M + H]+  62 ++++ ++++ ++++ ++++ ++++ Calcd: 328.11 Found: 329.0 [M + H]+  63 ++ + + + Calcd: 362.14 Found: 363.2 [M + H]+  64 ++ ++++ +++ + ++++ ++ Calcd: 347.14 Found: 348.0 [M + H]+  65 + ++++ ++++ ++ +++ ++ Calcd: 360.17 Found: 361.2 [M + H]+  66 ++ + + Calcd: 403.16 Found: 404.2 [M + H]+  67 +++ + + Calcd: 439.13 Found: 440.0 [M + H]+  68 ++++ ++ ++ +++ Calcd: 328.11 Found: 329.0 [M + H]+  69 +++ ++ ++ +++ Calcd: 317.10 Found: 318.0 [M + H]+  70 ++++ ++++ ++++ ++++ Calcd: 354.09 Found: 355.0 [M + H]+  71 ++++ ++ +++ ++++ Calcd: 339.11 Found: 340.0 [M + H]+  72 +++ ++++ +++ + ++++ Calcd: 278.08 Found: 279.0 [M + H]+  73 +++ ++ + + Calcd: 389.19 Found: 390.2 [M + H]+  74 ++ ++++ ++ + ++ ++ Calcd: 403.20 Found: 404.2 [M + H]+  75 ++++ ++ + ++ Calcd: 361.15 Found: 362.0 [M + H]+  76 ++ ++++ + + +++ ++ Calcd: 339.11 Found: 340.0 [M + H]+  77 +++ Calcd: 320.05 Found: 321.0 [M + H]+  78 ++++ +++ +++ ++++ Calcd: 328.11 Found: 329.0 [M + H]+  79 ++ + + + Calcd: 390.18 Found: 391.2 [M + H]+  80 +++ + + + Calcd: 377.15 Found: 378.0 [M + H]+  81 ++++ +++ ++++ +++ Calcd: 374.19 Found: 375.2 [M + H]+  82 ++++ ++ ++++ ++++ Calcd: 402.18 Found: 403.2 [M + H]+  83 ++++ ++ ++++ ++++ Calcd: 377.15 Found: 378.0 [M + H]+  84 ++++ ++++ +++ ++++ ++ Calcd: 388.20 Found: 389.2 [M + H]+  85 ++++ ++++ ++++ ++++ Calcd: 388.16 Found: 389.0 [M + H]+  86 ++++ +++ +++ ++++ Calcd: 424.13 Found: 425.0 [M + H]+  87 ++++ +++ ++++ ++++ Calcd: 438.15 Found: 439.0 [M + H]+  88 ++++ ++++ ++ +++ ++ Calcd: 346.15 Found: 347.2 [M + H]+  89 ++++ ++ ++++ ++++ Calcd: 428.20 Found: 429.2 [M + H]+  90 ++++ +++ ++ +++ +++ Calcd: 452.16 Found: 453.0 [M + H]+  91 + + + + Calcd: 390.18 Found: 391.0 [M + H]+  92 + + + + Calcd: 377.15 Found: 378.0 [M + H]+  93 ++ +++ + + +++ Calcd: 286.09 Found: 287.0 [M + H]+  94 ++++ +++ ++ ++++ Calcd: 342.12 Found: 343.0 [M + H]+  95 ++++ ++ ++++ ++++ Calcd: 438.15 Found: 439.0 [M + H]+  96 ++++ ++ +++ ++++ +++ Calcd: 361.15 Found: 362.0 [M + H]+  97 ++ + + + Calcd: 374.14 Found: 375.0 [M + H]+  98 ++++ + + ++++ Calcd: 395.11 Found: 396.0 [M + H]+  99 ++++ ++ +++ +++ ++ Calcd: 361.15 Found: 362.2 [M + H]+ 100 ++++ ++++ ++ +++ +++ Calcd: 390.18 Found: 391.0 [M + H]+ 101 ++++ ++ +++ ++ ++ Calcd: 402.22 Found: 403.0 [M + H]+ 102 ++++ +++ +++ ++++ Calcd: 420.17 Found: 421.0 [M + H]+ 103 ++++ +++ +++ +++ ++ Calcd: 445.22 Found: 446.0 [M + H]+ 104 ++ + + ++ Calcd: 377.16 Found: 378.0 [M + H]+ 105 +++ ++ + +++ Calcd: 364.13 Found: 365.0 [M + H]+ 106 ++ + + ++ Calcd: 391.16 Found: 392.0 [M + H]+ 107 +++ + + ++ Calcd: 411.10 Found: 412.0 [M + H]+ 108 ++++ ++ + ++++ +++ Calcd: 372.13 Found: 373.2 [M + H]+ 109 + + + + Calcd: 399.10 Found: 400.0 [M + H]+ 110 + + + + Calcd: 412.13 Found: 413.0 [M + H]+ 111 ++++ ++ + + Calcd: 362.15 Found: 363.0 [M + H]+ 112 ++++ + ++ +++ +++ Calcd: 440.13 Found: 441.0 [M + H]+ 113 ++++ + + +++ ++ Calcd: 404.16 Found: 405.2 [M + H]+ 114 ++++ + + +++ Calcd: 363.12 Found: 364.0 [M + H]+ 115 ++++ ++++ + ++ ++ Calcd: 376.15 Found: 377.0 [M + H]+ 116 ++++ +++ + +++ +++ Calcd: 363.12 Found: 364.0 [M + H]+ 117 ++++ +++ + +++ ++ Calcd: 347.14 Found: 348.2 [M + H]+ 118 +++ ++++ + ++ Calcd: 360.17 Found: 361.0 [M + H]+ 119 ++ ++++ ++ ++ ++ ++ Calcd: 418.18 Found: 419.0 [M + H]+ 120 ++++ +++ ++ + +++ Calcd: 417.19 Found: 418.0 [M + H]+ 121 + ++++ ++++ ++++ ++++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 122 + + + + Calcd: 364.13 Found: 365.0 [M + H]+ 123 ++ + + + Calcd: 377.16 Found: 378.2 [M + H]+ 124 +++ +++ + +++ Calcd: 363.13 Found: 364.0 [M + H]+ 125 +++ + ++ +++ Calcd: 379.11 Found: 380.0 [M + H]+ 126 +++ ++ + +++ Calcd: 379.11 Found: 380.0 [M + H]+ 127 +++ ++++ + ++ Calcd: 376.15 Found: 377.2 [M + H]+ 128 ++++ ++ ++++ ++++ Calcd: 375.17 Found: 376.2 [M + H]+ 129 +++ ++++ +++ +++ ++++ +++ Calcd: 529.16 Found: 530.0 [M + H]+ 130 + + + + Calcd: 587.14 Found: 588.0 [M + H]+ 131 +++ +++ +++ +++ Calcd: 374.19 Found: 375.2 [M + H]+ 132 +++ + + ++ Calcd: 375.17 Found: 376.2 [M + H]+ 133 + ++++ +++ +++ +++ ++ Calcd: 390.18 Found: 390.2 [M + H]+ 134 ++++ +++ +++ ++ +++ Calcd: 417.19 Found: 418.0 [M + H]+ 135 + ++++ +++ + +++ +++ Calcd: 360.13 Found: 361.0 [M + H]+ 136 +++ +++ + ++ Calcd: 374.19 Found: 375.2 [M + H]+ 137 + ++++ +++ +++ +++ +++ Calcd: 416.20 Found: 417.2 [M + H]+ 138 ++++ +++ ++++ +++ + Calcd: 457.22 Found: 458.2 [M + H]+ 139 + ++++ +++ +++ +++ +++ Calcd: 431.21 Found: 432.2 [M + H]+ 140 +++ ++ + + Calcd: 390.18 Found: 391.2 [M + H]+ 141 +++ + + ++ Calcd: 390.18 Found: 391.2 [M + H]+ 142 ++ + + + Calcd: 390.18 Found: 391.2 [M + H]+ 143 + ++++ ++ ++++ ++++ +++ Calcd: 391.16 Found: 392.2 [M + H]+ 144 +++ ++ + + Calcd: 392.14 Found: 393.0 [M + H]+ 145 +++ ++ + ++ Calcd: 376.16 Found: 377.2 [M + H]+ 146 ++ ++ + + Calcd: 392.14 Found: 393.0 [M + H]+ 147 +++ ++ ++ ++ Calcd: 418.18 Found: 419.2 [M + H]+ 148 ++++ + + ++ ++ Calcd: 406.18 Found: 407.2 [M + H]+ 149 ++++ ++++ ++ +++ + Calcd: 360.17 Found: 361.0 [M + H]+ 150 +++ + + + Calcd: 424.16 Found: 425.0 [M + H]+ 151 ++++ ++ +++ ++ ++ Calcd: 388.20 Found: 389.0 [M + H]+ 152 ++++ ++++ ++ +++ ++ Calcd: 374.19 Found: 375.0 [M + H]+ 153 ++++ ++++ +++ +++ +++ Calcd: 400.20 Found: 401.0 [M + H]+ 154 ++++ +++ ++ ++++ +++ Calcd: 403.18 Found: 404.0 [M + H]+ 155 ++++ ++++ +++ ++++ Calcd: 388.20 Found: 389.0 [M + H]+ 156 + ++++ +++ +++ +++ +++ Calcd: 443.21 Found: 444.0 [M + H]+ 157 ++ + + + Calcd: 388.16 Found: 389.0 [M + H]+ 158 ++ + + + Calcd: 375.13 Found: 376.0 [M + H]+ 159 ++++ +++ ++++ +++ ++ Calcd: 390.18 Found: 391.0 [M + H]+ 160 ++++ ++ + + ++ Calcd: 404.20 Found: 405.0 [M + H]+ 161 +++ ++ ++ ++ Calcd: 416.20 Found: 417.0 [M + H]+ 162 +++ + + ++ Calcd: 377.15 Found: 378.0 [M + H]+ 163 +++ ++ ++ ++ Calcd: 446.21 Found: 447.0 [M + H]+ 164 +++ +++ + + Calcd: 377.15 Found: 378.0 [M + H]+ 165 +++ ++ ++ + +++ Calcd: 404.20 Found: 405.0 [M + H]+ 166 +++ ++ + ++ Calcd: 404.20 Found: 405.2 [M + H]+ 167 ++ + + + Calcd: 424.16 Found: 425.0 [M + H]+ 168 ++++ +++ ++ + ++ Calcd: 360.17 Found: 361.0 [M + H]+ 169 ++ ++++ +++ +++ +++ +++ Calcd: 430.18 Found: 431.0 [M + H]+ 170 ++ ++++ +++ +++ ++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 171 + ++++ +++ +++ +++ +++ Calcd: 430.21 Found: 431.0 [M + H]+ 172 ++++ ++++ ++++ +++ Calcd: 388.20 Found: 389.0 [M + H]+ 173 ++++ +++ ++ ++++ ++ Calcd: 361.15 Found: 362.0 [M + H]+ 174 ++++ +++ ++ ++++ ++ Calcd: 342.12 Found: 343.0 [M + H]+ 175 ++++ + + ++ + Calcd: 345.16 Found: 346.0 [M + H]+ 176 ++++ +++ +++ ++++ +++ Calcd: 331.14 Found: 332.0 [M + H]+ 177 ++++ + + +++ + Calcd: 343.12 Found: 343.0 [M]+ 178 ++++ ++++ +++ +++ Calcd: 360.17 Found: 361.0 [M + H]+ 179 ++++ +++ ++ ++ ++ Calcd: 360.17 Found: 361.0 [M + H]+ 180 +++ + + + Calcd: 338.12 Found: 339.0 [M + H]+ 181 ++++ ++ +++ ++++ ++ Calcd: 466.18 Found: 467.0 [M + H]+ 182 ++++ +++ +++ +++ ++ Calcd: 402.22 Found: 403.2 [M + H]+ 183 ++++ ++ ++ ++++ ++ Calcd: 306.11 Found: 307.0 [M + H]+ 184 ++++ ++ + +++ ++ Calcd: 322.11 Found: 323.0 [M + H]+ 185 +++ + + + Calcd: 353.13 Found: 354.0 [M + H]+ 186 ++++ ++ +++ ++++ ++ Calcd: 347.14 Found: 348.0 [M + H]+ 187 ++++ ++ +++ ++++ +++ Calcd: 333.12 Found: 334.0 [M + H]+ 188 ++++ +++ +++ ++++ +++ Calcd: 321.12 Found: 322.0 [M + H]+ 189 ++++ +++ +++ +++ +++ Calcd: 337.12 Found: 338.0 [M + H]+ 190 ++++ + +++ ++++ + Calcd: 370.12 Found: 371.0 [M + H]+ 191 ++++ ++ ++ ++ Calcd: 418.21 Found: 419.0 [M + H]+ 192 ++++ +++ +++ +++ Calcd: 403.18 Found: 404.0 [M + H]+ 193 ++++ +++ ++ ++++ Calcd: 404.16 Found: 405.0 [M + H]+ 194 ++++ + + ++++ Calcd: 353.13 Found: 354.0 [M + H]+ 195 +++ ++ + ++++ Calcd: 339.11 Found: 340.0 [M + H]+ 196 +++ ++ + ++ Calcd: 361.15 Found: 362.0 [M + H]+ 197 ++++ ++ ++ ++++ Calcd: 333.12 Found: 334.0 [M + H]+ 198 ++++ ++ ++ +++ Calcd: 468.16 Found: 469.0 [M + H]+ 199 ++++ ++ ++++ ++++ Calcd: 482.17 Found: 483.0 [M + H]+ 200 ++++ ++ ++ ++++ ++ Calcd: 349.12 Found: 350.0 [M + H]+ 201 ++++ ++ + ++ ++ Calcd: 377.15 Found: 378.0 [M + H]+ 202 ++++ ++ ++ +++ +++ Calcd: 363.13 Found: 364.0 [M + H]+ 203 ++++ ++++ +++ ++++ Calcd: 391.18 Found: 392.0 [M + H]+ 204 ++++ +++ + + Calcd: 376.16 Found: 377.0 [M + H]+ 205 ++++ + + + Calcd: 332.13 Found: 333.0 [M + H]+ 206 ++++ + + +++ Calcd: 320.13 Found: 321.0 [M + H]+ 207 ++++ ++++ +++ ++++ +++ Calcd: 417.19 Found: 418.0 [M + H]+ 208 ++++ +++ +++ ++ ++ Calcd: 417.19 Found: 418.0 [M + H]+ 209 ++++ +++ ++ ++++ ++ Calcd: 347.14 Found: 348.0 [M + H]+ 210 +++ + + + Calcd: 355.12 Found: 356.0 [M + H]+ 211 ++++ ++++ ++++ ++++ +++ Calcd: 403.18 Found: 404.0 [M + H]+ 212 ++++ +++ +++ +++ +++ Calcd: 375.18 Found: 376.0 [M + H]+ 213 ++++ +++ +++ + +++ Calcd: 431.21 Found: 432.0 [M + H]+ 214 ++++ ++++ ++ +++ Calcd: 374.15 Found: 375.0 [M + H]+ 215 ++++ +++ ++ +++ Calcd: 400.16 Found: 401.0 [M + H]+ 216 ++++ +++ ++ ++++ Calcd: 333.12 Found: 334.0 [M + H]+ 217 ++++ +++ +++ +++ Calcd: 431.21 Found: 432.0 [M + H]+ 218 +++ +++ +++ ++ Calcd: 376.20 Found: 377.2 [M + H]+ 219 +++ +++ +++ +++ Calcd: 374.19 Found: 375.0 [M + H]+ 220 ++++ +++ ++++ +++ Calcd: 390.22 Found: 391.2 [M + H]+ 221 ++++ +++ ++++ ++++ Calcd: 388.20 Found: 389.0 [M + H]+ 222 ++++ +++ ++++ +++ Calcd: 404.20 Found: 405.0 [M + H]+ 223 ++++ + + +++ Calcd: 425.20 Found: 426.0 [M + H]+ 224 ++ + + + Calcd: 377.19 Found: 378.0 [M + H]+ 225 ++++ ++++ ++++ ++++ Calcd: 443.21 Found: 444.0 [M + H]+ 226 +++ + ++ ++ Calcd: 429.19 Found: 430.2 [M + H]+ 227 ++++ +++ ++++ ++ Calcd: 443.24 Found: 444.0 [M + H]+ 228 Calcd: 347.14 Found: 348.0 [M + H]+ 229 +++ +++ + ++ Calcd: 328.11 Found: 329.0 [M + H]+ 230 ++ +++ ++ +++ Calcd: 328.11 Found: 329.0 [M + H]+ 231 ++ ++++ +++ ++++ ++++ ++ +++ Calcd: 324.07 Found: 325.0 [M + H]+ 232 ++ +++ +++ ++ ++++ Calcd: 282.06 Found: 283.0 [M + H]+ 233 + + + + ++ Calcd: 227.08 Found: 228.0 [M + H]+ 234 +++ ++++ +++ ++++ ++++ ++++ +++ Calcd: 307.11 Found: 308.0 [M + H]+ 235 ++ ++ + ++ ++ Calcd: 274.05 Found: 275.0 [M + H]+ 236 + + + + Calcd: 265.10 Found: 266.0 [M + H]+ 237 +++ ++ ++ ++ Calcd: 285.12 Found: 286.0 [M + H]+ 238 +++ +++ ++ +++ Calcd: 257.09 Found: 258.0 [M + H]+ 239 ++ +++ ++ ++ Calcd: 339.09 Found: 340.0 [M + H]+ 240 ++ +++ ++ ++++ Calcd: 266.08 Found: 267.0 [M + H]+ 241 ++ +++ +++ ++++ Calcd: 266.08 Found: 267.0 [M + H]+ 242 ++++ ++++ + ++++ Calcd: 324.07 Found: 325.0 [M + H]+ 243 +++ ++++ + ++++ Calcd: 282.06 Found: 283.0 [M + H]+ 244 + + + + Calcd: 308.09 Found: 309.0 [M + H]+ 245 +++ ++ + +++ Calcd: 365.10 Found: 266.0 246 + + + + Calcd: 266.08 Found: 267.0 [M + H]+ 247 + ++ + ++ Calcd: 265.10 Found: 266.2 [M + H]+ 248 ++ +++ ++ +++ ++ Calcd: 282.06 Found: 283.0 [M + H]+ 249 ++++ ++++ +++ ++++ Calcd: 282.06 Found: 283.0 [M + H]+ 250 + + + ++++ Calcd: 324.07 Found: 325.0 [M + H]+ 251 ++++ ++++ ++++ ++++ Calcd: 324.07 Found: 325.0 [M + H]+ 252 + ++ ++ ++ 253 + ++ ++ ++ 254 +++ + + +++ Calcd: 318.11 Found: 319.0 [M + H]+ 255 ++ ++ ++ ++ Calcd: 375.17 Found: 376.0 [M + H]+ 256 ++ + + + Calcd: 346.14 Found: 347.0 [M + H]+ 257 ++++ + + + ++ Calcd: 374.15 Found: 375.0 [M + H]+ 258 ++++ ++++ + ++++ +++ Calcd: 390.14 Found: 391.0 [M + H]+ 259 +++ + + ++ Calcd: 390.14 Found: 391.0 [M + H]+ 260 +++ + + ++ Calcd: 390.14 Found: 391.0 [M + H]+ 261 ++++ +++ + +++ ++ Calcd: 386.19 Found: 387.0 [M + H]+ 262 ++ ++++ +++ + +++ ++ Calcd: 347.14 Found: 348.0 [M + H]+ 263 ++++ ++ ++ ++ ++ Calcd: 402.18 Found: 403.0 [M + H]+ 264 ++++ ++ ++ +++ +++ Calcd: 363.13 Found: 364.0 [M + H]+ 265 ++++ ++ ++ ++++ +++ Calcd: 363.13 Found: 364.0 [M + H]+ 266 ++++ ++ +++ +++ ++ Calcd: 418.18 Found: 419.2 [M + H]+ 267 ++ ++++ ++ +++ +++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 268 ++++ ++ ++ +++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 269 ++++ +++ +++ ++ ++ Calcd: 445.22 Found: 446.2 [M + H]+ 270 ++ ++++ +++ +++ +++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 271 +++ ++ ++ + Calcd: 389.19 Found: 390.2 [M + H]+ 272 +++ ++ + ++ Calcd: 336.12 Found: 337.0 [M + H]+ 273 +++ ++++ + + ++ +++ Calcd: 402.18 Found: 403.0 [M + H]+ 274 ++ ++++ ++ ++ ++ +++ Calcd: 415.21 Found: 416.2 [M + H]+ 275 ++++ +++ +++ +++ +++ Calcd: 403.21 Found: 404.0 [M + H]+ 276 ++ ++++ ++ +++ +++ +++ Calcd: 469.22 Found: 470.2 [M + H]+ 277 ++ ++++ +++ ++ +++ +++ Calcd: 374.15 Found: 375.0 [M + H]+ 278 ++++ +++ ++ +++ +++ Calcd: 457.22 Found: 458.2 [M + H]+ 279 ++++ ++ ++ ++ +++ Calcd: 459.24 Found: 460.2 [M + H]+ 280 ++ + + + Calcd: 404.20 Found: 405.2 [M + H]+ 281 +++ + ++ + Calcd: 391.20 Found: 392.2 [M + H]+ 282 + + + + + Calcd: 364.13 Found: 365.0 [M + H]+ 283 ++++ + + +++ ++ Calcd: 457.19 Found: 458.0 [M + H]+ 284 ++++ ++ ++ +++ ++ Calcd: 457.19 Found: 458.0 [M + H]+ 285 ++++ ++ +++ +++ +++ Calcd: 471.24 Found: 472.2 [M + H]+ 286 ++++ +++ +++ ++++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 287 ++++ ++ +++ +++ ++ Calcd: 483.24 Found: 484.2 [M + H]+ 288 +++ +++ +++ ++ ++ Calcd: 420.19 Found: 421.2 [M + H]+ 289 +++ ++ + +++ Calcd: 391.16 Found: 392.0 [M + H]+ 290 +++ + + + Calcd: 405.18 Found: 406.2 [M + H]+ 291 +++ + + + Calcd: 418.21 Found: 419.0 [M + H]+ 292 ++ + + + Calcd: 349.15 Found: 350.0 [M + H]+ 293 ++++ +++ ++++ +++ +++ Calcd: 404.20 Found: 405.0 [M + H]+ 294 ++++ + ++ ++++ ++ Calcd: 384.13 Found: 385.0 [M + H]+ 295 +++ +++ +++ +++ Calcd: 392.20 Found: 393.0 [M + H]+ 296 +++ ++ +++ + Calcd: 390.18 Found: 391.0 [M + H]+ 297 +++ + + ++ Calcd: 441.19 Found: 442.0 [M + H]+ 298 ++ ++++ +++ ++ ++ ++ Calcd: 433.19 Found: 434.0 [M + H]+ 299 ++++ +++ ++++ ++++ +++ Calcd: 433.19 Found: 434.0 [M + H]+ 300 ++ ++ + + Calcd: 328.11 Found: 329.0 [M + H]+ 301 ++ ++ + + Calcd: 328.11 Found: 329.0 [M + H]+ 302 +++ ++ ++++ ++ Calcd: 406.21 Found: 407.2 [M + H]+ 303 ++ ++++ + ++ + +++ Calcd: 431.21 Found: 432.2 [M + H]+ 304 +++ + + + Calcd: 404.20 Found: 405.2 [M + H]+ 305 ++ + + + Calcd: 348.13 Found: 349.0 [M + H]+ 306 ++++ +++ +++ +++ Calcd: 419.21 Found: 420.0 [M + H]+ 307 +++ +++ + + Calcd: 376.15 Found: 377.0 [M + H]+ 308 +++ +++ + ++ Calcd: 376.15 Found: 377.0 [M + H]+ 309 +++ +++ + ++ Calcd: 360.17 Found: 361.0 [M + H]+ 310 + + + + Calcd: 360.17 Found: 361.2 [M + H]+ 311 +++ + + + Calcd: 386.12 Found: 387.0 [M + H]+ 312 +++ ++ +++ ++++ Calcd: 288.07 Found: 289.0 [M + H]+ 313 ++ ++++ ++ ++ ++ Calcd: 441.23 Found: 442.2 [M + H]+ 314 +++ ++ ++ ++ Calcd: 386.19 Found: 387.2 [M + H]+ 315 +++ ++++ ++ ++ ++ Calcd: 402.18 Found: 403.2 [M + H]+ 316 +++ ++ + ++ Calcd: 381.14 Found: 382.0 [M + H]+ 317 + + + + Calcd: 363.13 Found: 364.0 [M + H]+ 318 +++ ++++ ++ + +++ Calcd: 383.15 Found: 384.2 [M + H]+ 319 ++++ +++ ++ +++ Calcd: 383.15 Found: 384.2 [M + H]+ 320 + ++++ ++ ++ ++ Calcd: 397.17 Found: 398.0 [M + H]+ 321 + + + + Calcd: 376.15 Found: 377.0 [M + H]+ 322 + ++++ +++ ++ +++ Calcd: 402.18 Found: 403.2 [M + H]+ 323 + ++++ ++ ++ +++ Calcd: 429.19 Found: 430.2 [M + H]+ 324 + ++++ ++ ++ +++ Calcd: 388.20 Found: 389.2 [M + H]+ 325 ++++ +++ ++ ++++ Calcd: 415.18 Found: 416.2 [M + H]+ 326 + ++++ +++ +++ +++ Calcd: 401.20 Found: 402.2 [M + H]+ 327 + ++++ ++ +++ +++ Calcd: 443.21 Found: 444.2 [M + H]+ 328 + ++++ ++ ++ ++ Calcd: 479.17 Found: 480.2 [M + H]+ 329 + ++++ +++ +++ ++ Calcd: 429.23 Found: 430.2 [M + H]+ 330 +++ +++ ++ + + Calcd: 478.21 Found: 479.2 [M + H]+ 331 + ++++ ++ ++ ++ Calcd: 443.24 Found: 444.2 [M + H]+ 332 +++ ++++ ++ +++ Calcd: 374.19 Found: 375.2 [M + H]+ 333 + ++++ ++ +++ ++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 334 ++++ ++ ++ ++ +++ Calcd: 450.15 Found: 451.0 [M + H]+ 335 + ++++ ++ ++ + +++ Calcd: 455.24 Found: 456.2 [M + H]+ 336 +++ +++ ++ + Calcd: 374.19 Found: 375.2 [M + H]+ 337 ++++ + + +++ Calcd: 411.18 Found: 412.2 [M + H]+ 338 ++++ ++ ++ ++ ++ Calcd: 425.20 Found: 426.2 [M + H]+ 339 ++++ +++ +++ +++ Calcd: 397.17 Found: 398.2 [M + H]+ 340 +++ + + +++ Calcd: 319.11 Found: 320.2 [M + H]+ 341 +++ + ++ ++ ++ Calcd: 416.20 Found: 417.2 [M + H]+ 342 + + + + Calcd: 360.17 Found: 361.2 [M + H]+ 343 + ++ + + Calcd: 360.17 Found: 361.2 [M + H]+ 344 ++++ ++ +++ ++ Calcd: 425.20 Found: 426.2 [M + H]+ 345 ++ ++++ +++ +++ +++ Calcd: 411.18 Found: 412.2 [M + H]+ 346 ++++ ++ + +++ Calcd: 347.14 Found: 348.2 [M + H]+ 347 +++ ++ + +++ Calcd: 363.13 Found: 364.2 [M + H]+ 348 +++ +++ ++++ ++ +++ Calcd: 420.20 Found: 421.2 [M + H]+ 349 + + + + Calcd: 377.15 Found: 378.2 [M + H]+ 350 + ++++ ++ ++ + Calcd: 415.21 Found: 416.2 [M + H]+ 351 ++ +++ + + Calcd: 374.19 Found: 375.0 [M + H]+ 352 + + + + Calcd: 377.15 Found: 378.2 [M + H]+ 353 + ++ + + + Calcd: 416.20 Found: 417.2 [M + H]+ 354 ++ ++++ ++ ++ ++ +++ Calcd: 397.17 Found: 398.0 [M + H]+ 355 ++++ ++ +++ ++ +++ Calcd: 415.21 Found: 416.2 [M + H]+ 356 ++++ ++++ ++++ ++++ +++ Calcd: 327.11 Found: 328.2 [M + H]+ 357 +++ ++ ++ +++ Calcd: 377.15 Found: 378.2 [M + H]+ 358 ++++ +++ +++ +++ Calcd: 436.14 Found: 437.0 [M + H]+ 359 ++++ +++ ++ ++++ Calcd: 397.09 Found: 398.0 [M + H]+ 360 ++++ +++ ++ ++++ Calcd: 381.12 Found: 382.0 [M + H]+ 361 ++++ +++ ++ +++ Calcd: 420.17 Found: 421.0 [M + H]+ 362 + + + + Calcd: 416.20 Found: 417.0 [M + H]+ 363 + + + + 364 +++ ++ + +++ Calcd: 377.15 Found: 378.0 [M + H]+ 365 ++ ++ ++ ++ Calcd: 416.20 Found: 417.0 [M + H]+ 366 ++++ ++ + ++ Calcd: 360.17 Found: 361.0 [M + H]+ 367 +++ +++ ++ +++ Calcd: 332.14 Found: 333.0 [M + H]+ 368 ++++ ++ +++ +++ Calcd: 361.15 Found: 362.0 [M + H]+ 369 + + + + Calcd: 377.15 Found: 378.0 [M + H]+ 370 ++ + + + Calcd: 397.09 Found: 398.0 [M + H]+ 371 +++ ++ + + Calcd: 436.14 Found: 437.0 [M + H]+ 372 +++ ++ ++ ++ Calcd: 381.12 Found: 382.2 [M + H]+ 373 + ++++ ++ ++ ++ Calcd: 420.17 Found: 421.2 [M + H]+ 374 +++ ++++ ++ + Calcd: 374.19 Found: 375.2 [M + H]+ 375 +++ ++ +++ +++ Calcd: 416.20 Found: 417.2 [M + H]+ 376 ++++ ++ ++ ++++ Calcd: 416.20 Found: 417.2 [M + H]+ 377 ++ ++++ ++ ++ +++ Calcd: 507.21 Found: 508.2 [M + H]+ 378 +++ ++++ ++++ ++ ++ Calcd: 374.19 Found: 375.2 [M + H]+ 379 ++ ++++ +++ ++ + Calcd: 429.23 Found: 430.2 [M + H]+ 380 +++ ++ + ++ Calcd: 376.16 Found: 377.0 [M + H]+ 381 ++++ +++ ++ ++ Calcd: 429.23 Found: 430.2 [M + H]+ 382 ++++ +++ ++ +++ Calcd: 374.19 Found: 375.20 [M + H]+ 383 +++ + + + Calcd: 416.20 Found: 417.2 [M + H]+ 384 +++ ++++ +++ ++ +++ Calcd: 414.14 Found: 415.2 [M + H]+ 385 ++++ ++ + + Calcd: 359.17 Found: 360.2 [M + H]+ 386 ++++ + + Calcd: 415.21 Found: 416.2 [M + H]+ 387 ++++ +++ + +++ Calcd: 404.20 Found: 405.2 [M + H]+ 388 ++++ ++++ +++ +++ +++ Calcd: 429.23 Found: 430.2 [M + H]+ 389 +++ + + ++ Calcd: 360.13 Found: 361.0 [M + H]+ 390 ++ + Calcd: 374.15 Found: 375.2 [M + H]+ 391 ++ + + + Calcd: 388.16 Found: 389.2 [M + H]+ 392 + + + + Calcd: 402.18 Found: 403.2 [M + H]+ 393 ++ + + + Calcd: 414.18 Found: 415.2 [M + H]+ 394 ++++ ++++ +++ ++++ Calcd: 383.15 Found: 384.2 [M + H]+ 395 ++++ + + ++++ Calcd: 428.16 Found: 429.2 [M + H]+ 396 ++++ ++++ + ++ Calcd: 359.17 Found: 360.2 [M + H]+ 397 ++++ +++ +++ ++++ Calcd: 341.13 Found: 342.2 [M + H]+ 398 +++ ++ ++ ++ Calcd: 446.21 Found: 447.2 [M + H]+ 399 + + + + Calcd: 365.13 Found: 366.2 [M + H]+ 400 ++++ ++ + ++ Calcd: 364.13 Found: 365.2 [M + H]+ 401 + + + ++ Calcd: 325.10 Found: 326.0 [M + H]+ 402 + + + + Calcd: 345.07 Found: 346.0 [M + H]+ 403 ++ + + + Calcd: 375.18 Found: 376.2 [M + H]+ 404 + + + + Calcd: 417.19 Found: 418.2 [M + H]+ 405 + + + + Calcd: 441.11 Found: 442.0 [M + H]+ 406 ++ ++ + + Calcd: 377.15 Found: 378.2 [M + H]+ 407 + ++ + + Calcd: 439.16 Found: 440.2 [M + H]+ 408 + + + + Calcd: 460.22 Found: 461.2 [M + H]+ 409 ++ + + + Calcd: 403.16 Found: 404.2 [M + H]+ 410 ++ + + + Calcd: 391.13 Found: 392.0 [M + H]+ 411 ++++ ++ ++ +++ Calcd: 436.15 Found: 437.2 [M + H]+ 412 ++ + + + Calcd: 364.13 Found: 365.0 [M + H]+ 413 ++++ +++ ++ +++ Calcd: 396.15 Found: 397.2 [M + H]+ 414 ++ + + + Calcd: 353.15 Found: 354.2 [M + H]+ 415 ++ + + + Calcd: 357.10 Found: 358.0 [M + H]+ 416 ++++ ++ ++ +++ Calcd: 431.13 Found: 432.0 [M + H]+ 417 +++ ++++ ++++ ++++ ++++ Calcd: 529.12 Found: 530.0 [M + H]+ 418 ++++ ++++ ++++ ++++ ++++ Calcd: 435.08 Found: 436.0 [M + H]+ 419 +++ ++++ ++++ ++++ ++++ Calcd: 533.07 Found: 534.0 [M + H]+ 420 ++++ + +++ +++ Calcd: 493.14 Found: 494.2 [M + H]+ 421 ++++ +++ ++++ ++++ Calcd: 511.13 Found: 512.0 [M + H]+ 422 ++++ ++ +++ ++++ Calcd: 511.13 Found: 512.0 [M + H]+ 423 ++++ +++ ++++ ++++ Calcd: 511.13 Found: 512.0 [M + H]+ 424 +++ + ++ +++ Calcd: 463.51 Found: 464.0 [M + H]+ 425 ++++ + +++ ++++ Calcd: 499.49 Found: 500.0 [M + H]+ 426 + + + + Calcd: 307.11 Found: 308.0 [M + H]+ 427 + + + + Calcd: 265.27 Found: 266.0 [M + H]+ 428 ++ ++ + +++ Calcd: 265.10 Found: 266.0 [M + H]+ 429 + + + + Calcd: 385.15 Found: 386.2 [M + H]+ 430 ++ ++ + ++ Calcd: 307.11 Found: 308.0 [M + H]+ 431 + + + + Calcd: 307.11 Found: 308.0 [M + H]+ 432 ++ +++ + ++++ Calcd: 284.07 Found: 285.0 [M + H]+ 433 +++ +++ ++ ++++ Calcd: 284.07 Found: 285.2 [M + H]+ 434 ++++ ++++ ++++ ++++ Calcd: 342.06 Found: 343.0 [M + H]+ 435 ++ ++ + ++++ Calcd: 342.06 Found: 343.0 [M + H]+ 436 ++++ ++++ +++ ++++ Calcd: 300.05 Found: 301.1 [M + H]+ 437 ++ +++ + +++ Calcd: 300.05 Found: 301.2 [M + H]+ 438 ++ + + + Calcd: 381.12 Found: 382.2 [M + H]+ 439 ++ + + + Calcd: 381.12 Found: 382.2 [M + H]+ 440 + + + + Calcd: 462.14 Found: 463.0 [M + H]+ 441 + + + + 442 + + + + Calcd: 400.12 Found: 401.0 [M + H]+ 443 + + + + Calcd: 400.12 Found: 401.2 [M + H]+ 444 ++ + + + Calcd: 492.15 Found: 493.0 [M + H]+ 445 + + + + Calcd: 430.13 Found: 431.0 [M + H]+ 446 +++ + + + Calcd: 376.16 Found: 377.2 [M + H]+ 447 ++ + + + Calcd: 463.13 Found: 464.0 [M + H]+ 448 +++ + + ++ Calcd: 377.40 Found: 378.2 [M + H]+ 449 +++ +++ + ++++ Calcd: 377.15 Found: 378.2 [M + H]+ 450 ++ + + + Calcd: 401.12 Found: 402.2 [M + H]+ 451 ++++ +++ ++++ ++++ +++ Calcd: 497.95 Found: 498.0 [M + H]+ 452 ++++ +++ ++++ ++++ ++ Calcd: 515.08 Found: 516.0 [M + H]+ 453 ++ + + ++ Calcd: 462.14 Found: 463.0 [M + H]+ 454 ++ + ++ ++ Calcd: 498.12 Found: 499.0 [M + H]+ 455 ++ + + ++ Calcd: 492.15 Found: 493.2 [M + H]+ 456 + + + + Calcd: 430.13 Found: 431.0 [M + H]+ 457 ++++ ++++ ++++ ++++ +++ Calcd: 515.08 Found: 516.0 [M + H]+ 458 ++++ ++++ ++++ ++++ +++ Calcd: 515.08 Found: 516.0 [M + H]+ 459 +++ + + +++ Calcd: 496.10 Found: 497.0 [M + H]+ 460 ++ + + + Calcd: 434.08 Found: 435.0 [M + H]+ 461 +++ ++ ++ +++ Calcd: 532.08 Found: 533.0 [M + H]+ 462 ++++ ++++ ++++ ++++ +++ Calcd: 494.14 Found: 495.0 [M + H]+ 463 ++++ ++ ++ +++ Calcd: 377.15 Found: 378.2 [M + H]+ 464 ++++ + + +++ ++ Calcd: 377.15 Found: 378.2 [M + H]+ 465 ++++ + + +++ Calcd: 432.19 Found: 433.2 [M + H]+ 466 +++ ++ ++ +++ Calcd: 432.19 Found: 433.2 [M + H]+ 467 ++++ ++ ++ ++++ +++ Calcd: 363.13 Found: 364.0 [M + H]+ 468 ++++ ++ + ++++ Calcd: 351.11 Found: 352.2 [M + H]+ 469 ++++ ++ ++ +++ ++ Calcd: 418.18 Found: 419.2 [M + H]+ 470 ++++ ++ ++ +++ ++ Calcd: 418.18 Found: 419.2 [M + H]+ 471 ++++ + + ++++ ++ Calcd: 383.12 Found: 384.2 [M + H]+ 472 ++++ ++ ++ +++ ++ Calcd: 391.16 Found: 392.2 [M + H]+ 473 ++++ + + ++++ +++ Calcd: 360.10 Found: 370.0 [M + H]+ 474 ++ + + + Calcd: 379.11 Found: 380.2 [M + H]+ 475 ++++ + ++ ++++ Calcd: 365.13 Found: 366.2 [M + H]+ 476 ++++ + + ++++ Calcd: 365.13 Found: 366.2 [M + H]+ 477 ++++ + ++ +++ Calcd: 413.16 Found: 414.2 [M + H]+ 478 ++++ ++ +++ +++ +++ Calcd: 413.16 Found: 414.2 [M + H]+ 479 ++++ + ++ +++ Calcd: 399.14 Found: 400.2 [M + H]+ 480 ++++ + ++ +++ +++ Calcd: 389.15 Found: 390.2 [M + H]+ 481 ++++ ++ ++ +++ Calcd: 361.15 Found: 362.0 [M + H]+ 482 ++++ + ++ +++ Calcd: 361.15 Found: 362.2 [M + H]+ 483 ++++ ++ + ++ ++ Calcd: 377.15 Found: 378.2 [M + H]+ 484 +++ + + + Calcd: 363.13 Found: 364.2 [M + H]+ 485 ++ + + + Calcd: 379.11 Found: 380.2 [M + H]+ 486 ++ + + ++ Calcd: 377.15 Found: 378.2 [M + H]+ 487 + + + + Calcd: 362.15 Found: 363.2 [M + H]+ 488 + + + + Calcd: 363.13 Found: 364.2 [M + H]+ 489 ++ + + + Calcd: 379.11 Found: 380.0 [M + H]+ 490 + + + + Calcd: 362.15 Found: 363.0 [M + H]+ 491 + + + + Calcd: 363.13 Found: 364.2 [M + H]+ 492 +++ ++ ++ ++ Calcd: 348.13 Found: 349.2 [M + H]+ 493 ++++ +++ + ++ Calcd: 399.14 Found: 400.0 [M + H]+ 494 ++++ ++ + +++ Calcd: 391.13 Found: 392.0 [M + H]+ 495 ++++ ++ + +++ Calcd: 377.15 Found: 378.2 [M + H]+ 496 +++ ++ + ++ Calcd: 363.13 Found: 364.2 [M + H]+ 497 + + + + Calcd: 393.13 Found: 394.0 [M + H]+ 498 +++ + + ++ Calcd: 438.16 Found: 439.0 [M + H]+ 499 +++ + + ++ Calcd: 405.14 Found: 406.0 [M + H]+ 500 +++ + ++ ++ Calcd: 452.18 Found: 452.2 [M + H]+ 501 +++ + + ++ Calcd: 397.14 Found: 398.0 [M + H]+ 502 ++++ + ++ +++ Calcd: 438.16 Found: 439.2 [M + H]+ 503 +++ + + ++++ Calcd: 379.14 Found: 380.2 [M + H]+ 504 +++ ++ + ++++ Calcd: 389.15 Found: 390.2 505 + + + + Calcd: 455.14 Found: 456.0 [M + H]+ 506 ++++ + + + Calcd: 348.13 Found: 349.2 [M + H]+ 507 + + + + Calcd: 377.15 Found: 378.2 [M + H]+ 508 ++++ ++ +++ ++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 509 + + + + Calcd: 439.16 Found: 440.0 [M + H]+ 510 ++++ ++ +++ ++ ++ Calcd: 431.21 Found: 432.2 [M + H]+ 511 ++++ ++ +++ ++ ++ Calcd: 431.21 Found: 432.2 [M + H]+ 512 ++++ ++ +++ ++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 513 +++ + + ++ Calcd: 391.16 Found: 392.2 [M + H]+ 514 +++ + + + Calcd: 391.16 Found: 392.2 [M + H]+ 515 ++++ ++ ++++ +++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 516 +++ + + + Calcd: 382.09 Found: 383.2 [M + H]+ 517 +++ + ++ ++ Calcd: 378.14 Found: 379.2 [M + H]+ 518 +++ + + + Calcd: 376.16 Found: 377.2 [M + H]+ 519 +++ ++ ++ +++ Calcd: 539.18 Found: 540.2 [M + H]+ 520 + + + + Calcd: 441.18 Found: 442.2 [M + H]+ 521 ++++ ++++ ++++ +++ Calcd: 537.16 Found: 538.0 [M + H]+ 522 ++++ ++++ ++++ ++++ +++ Calcd: 533.21 Found: 534.2 [M + H]+ 523 ++++ +++ ++++ ++++ ++ Calcd: 475.14 Found: 476.2 [M + H]+ 524 ++++ ++++ ++++ +++ +++ Calcd: 505.18 Found: 506.2 [M + H]+ 525 ++++ +++ ++++ ++ Calcd: 443.16 Found: 444.2 [M + H]+ 526 ++++ ++ +++ + ++ Calcd: 447.11 Found: 448.0 [M + H]+ 527 ++++ ++++ ++++ +++ Calcd: 509.13 Found: 510.2 [M + H]+ 528 +++ ++ + + Calcd: 347.14 Found: 348.2 [M + H]+ 529 +++ + + ++ Calcd: 371.18 Found: 372.2 [M + H]+ 530 ++++ + ++ + 531 ++++ ++ + ++++ 532 + ++ + + + 533 + ++++ +++ +++ +++ 534 ++ + + + 535 ++ + + + 536 ++ + + + 537 ++ + + ++ 538 + ++++ + ++ + 539 + + + + 540 + + + + Calcd: 389.15 Found: 390.2 [M + H]+ 541 + + + Calcd: 363.13 Found: 364.2 [M + H]+ 542 + + + + Calcd: 349.17 Found: 350.20 [M + H]+ 543 + ++ + + Calcd: 342.12 Found: 343.2 [M + H]+ 544 +++ + + + Calcd: 362.15 Found: 363.20 [M + H]+ 545 + + + + Calcd: 377.20 Found: 378.20 [M + H]+ 546 + + + + Calcd: 363.18 Found: 364.2 [M + H]+ 547 + + + + Calcd: 363.18 Found: 364.2 [M + H]+ 548 + + + + Calcd: 391.2 Found: 392.2 [M + H]+ 549 + + + + Calcd: 377.2 Found: 378.2 [M + H]+ 550 +++ ++ ++ +++ Calcd: 381.1 Found: 382.2 [M + H]+ 551 ++++ +++ ++ ++++ Calcd: 395.1 Found: 396.0 [M + H]+ *Starting with compound 438, proliferation data was obtained using an MDA-MB-361 cell line.

Table 4 shows additional exemplary PI3K α inhibitors of the invention.

TABLE 4 In Vitro IC50 data for selected compounds of the invention. The following symbols are used: + (greater than 10 microMolar), ++ (less than 10 microMolar), +++ (less than 1 microMolar), and ++++ (less than 100 nM). MDA- mTO MB-361 Mass RC PI3K α PI3K β PI3K δ PI3K γ prolifer- Charac- IC50 IC50 IC50 IC50 IC50 ation teriza- Structure (nM) (nM) (nM) (nM) (nM) (nM)* tion 552 +++ ++++ ++ ++ ++ Calcd: 361.17 Found: 362.2 [M + H]+ 553 ++++ +++ + ++++ +++ Calcd: 348.13 Found: 349.2 [M + H]+ 554 +++ ++ + +++ Calcd: 340.11 Found: 341.0 [M + H]+ 555 +++ +++ ++ ++ ++ Calcd: 361.17 Found: 362.2 [M + H]+ 556 ++ ++++ + ++ ++ ++ Calcd: 403.18 Found: 404.2 [M + H]+ 557 ++++ +++ +++ +++ +++ Calcd: 419.17 Found: 420.2 [M + H]+ 558 + + + + Calcd: 348.13 Found: 349.2 [M + H]+ 559 ++++ + ++ +++ ++ Calcd: 480.17 Found: 481.0 [M + H]+ 560 ++++ ++ ++ ++++ +++ Calcd: 416.16 Found: 417.2 [M + H]+ 561 ++ ++++ + ++ ++ ++ Calcd: 416.21 Found: 417.2 [M + H]+ 562 ++++ ++ + ++++ Calcd: 345.12 Found: 346.0 [M + H]+ 563 + ++++ + ++ + ++ Calcd: 416.21 Found: 417.0 [M + H]+ 564 ++++ + + ++++ ++ Calcd: 382.14 Found: 383.2 [M + H]+ 565 ++++ ++ ++ ++++ +++ Calcd: 362.15 Found: 363.2 [M + H]+ 566 ++++ ++ + ++++ +++ Calcd: 362.15 Found: 363.0 [M + H]+ 567 ++++ ++ ++ ++++ + Calcd: 339.11 Found: 340.0 [M + H]+ 568 +++ + + ++ Calcd: 431.21 Found: 432.2 [M + H]+ 569 +++ + + ++ Calcd: 417.19 Found: 418.0 [M + H]+ 570 + ++++ + + ++++ +++ Calcd: 374.15 Found: 375.0 [M + H]+ 571 +++ + + ++ Calcd: 429.19 Found: 430.2 [M + H]+ 572 ++++ + ++ + ++ Calcd: 430.22 Found: 431.0 [M + H]+ 573 ++++ +++ + ++++ ++ Calcd: 347.14 Found: 348.0 [M + H]+ 574 ++++ ++ + ++++ Calcd: 373.15 Found: 374.2 [M + H]+ 575 ++++ ++++ ++ +++ ++ Calcd: 360.17 Found: 361.2 [M + H]+ 576 ++++ + ++ ++ ++ Calcd: 430.22 Found: 431.2 [M + H]+ 577 +++ + ++ +++ Calcd: 334.15 Found: 335.2 [M + H]+ 578 ++++ ++++ ++ +++ ++ Calcd: 361.17 Found: 362.2 [M + H]+ 579 ++++ + + +++ +++ Calcd: 374.15 Found: 375.2 [M + H]+ 580 ++++ +++ ++ ++++ +++ Calcd: 361.13 Found: 362.0 [M + H]+ 581 ++++ ++++ ++++ ++++ Calcd: 418.19 Found: 419.2 [M + H]+ 582 ++++ ++ ++ +++ ++ Calcd: 418.19 Found: 419.2 [M + H]+ 583 ++++ +++ ++ +++ ++ Calcd: 389.45 Found: 390.2 [M + H]+ 584 ++++ ++ ++ ++ + Calcd: 404.43 Found: 405.2 [M + H]+ 585 +++ + + + + Calcd: 402.19 Found: 403.0 [M + H]+ 586 + ++++ ++ ++ ++ ++ Calcd: 456.2 Found: 457.2 [M + H]+ 587 ++++ ++ + ++++ +++ Calcd: 418.18 Found: 419.0 [M + H]+ 588 + ++++ +++ +++ +++ ++ Calcd: 403.18 Found: 404.2 [M + H]+ 589 ++++ +++ +++ +++ ++ Calcd: 417.19 Found: 418.0 [M + H]+ 590 ++++ ++++ +++ +++ ++ Calcd: 417.19 Found: 418.2 [M + H]+ 591 + ++++ ++ ++ ++ ++ Calcd: 432.20 Found: 433.2 [M + H]+ 592 ++ ++++ ++ ++ ++++ ++ Calcd: 430.19 Found: 431.0 [M + H]+ 593 ++++ +++ +++ ++++ +++ Calcd: 429.19 Found: 430.0 [M + H]+ 594 + ++++ ++ +++ +++ +++ Calcd: 431.21 Found: 432.2 [M + H]+ 595 + ++++ +++ +++ +++ ++ Calcd: 388.20 Found: 389.0 [M + H]+ 596 ++++ ++ + ++++ +++ Calcd: 362.15 Found: 363.0 [M + H]+ 597 + ++++ ++ ++ ++ ++ Calcd: 446.22 Found: 447.2 [M + H]+ 598 + ++++ ++++ ++ +++ ++ Calcd: 360.17 Found: 361.2 [M + H]+ 599 + ++++ +++ ++ ++ ++ Calcd: 360.17 Found: 361.2 [M + H]+ 600 ++ + + ++ Calcd: 417.19 Found: 418.2 [M + H]+ 601 + ++++ ++ ++ ++ ++ Calcd: 398.16 Found: 399.2 [M + H]+ 602 ++ + + + Calcd: 429.19 Found: 430.2 [M + H]+ 603 + ++++ ++ +++ ++ +++ Calcd: 430.22 Found: 431.2 [M + H]+ 604 + ++++ ++ ++ +++ ++ Calcd: 402.18 Found: 403.2 [M + H]+ 605 + ++++ ++ +++ ++ +++ Calcd: 415.21 Found: 416.2 [M + H]+ 606 + ++++ ++ +++ ++ +++ Calcd: 429.23 Found: 430.2 [M + H]+ 607 + ++++ ++ +++ +++ +++ Calcd: 415.21 Found: 416.2 [M + H]+ 608 + ++++ ++ +++ ++ +++ Calcd: 429.23 Found: 430.2 [M + H]+ 609 + ++++ ++ +++ +++ +++ Calcd: 429.23 Found: 430.3 [M + H]+ 610 ++++ + + ++++ +++ Calcd: 373.15 Found: 374.0 [M + H]+ 611 + ++++ ++ +++ ++ +++ Calcd: 455.24 Found: 456.2 [M + H]+ 612 + ++++ + ++ ++ + Calcd: 417.19 Found: 418.0 [M + H]+ 613 ++++ ++ ++ +++ ++ Calcd: 361.15 Found: 362.0 [M + H]+ 614 + ++++ ++ +++ ++++ ++ Calcd: 397.17 Found: 398.2 [M + H]+ 615 ++ ++++ ++ +++ ++++ +++ Calcd: 429.19; Found: 430.2 [M + H]+ 616 + ++++ ++ +++ +++ +++ Calcd: 445.22 Found: 446.2 [M + H]+ 617 ++++ ++ +++ ++++ ++ Calcd: 416.20 Found: 417.2 [M + H]+ 618 ++++ + ++ +++ ++ Calcd: 428.49 Found: 429.2 [M + H]+ 619 ++++ + + ++ ++ Calcd: 416.20 Found: 417.2 [M + H]+ 620 ++++ ++ ++ ++ ++ Calcd: 442.22 Found: 443.2 [M + H]+ 621 ++++ ++ ++ +++ ++ Calcd: 441.23 Found: 442.2 [M + H]+ 622 + ++++ ++ +++ + ++ Calcd: 416.21 Found: 417.2 [M + H]+ 623 + ++++ +++ +++ ++ +++ Calcd: 443.24 Found: 444.2 [M + H]+ 624 ++ + + ++ Calcd: 347.14 Found: 348.2 [M + H]+ 625 + ++++ +++ +++ +++ +++ Calcd: 415.21 Found: 416.2 [M + H]+ 626 + ++++ +++ +++ ++ +++ Calcd: 429.23 Found: 430.2 [M + H]+ 627 ++ ++++ ++ ++ ++ Calcd: 430.22 Found: 431.2 [M + H]+ 628 ++ + + + Calcd: 444.24 Found: 445.2 [M + H]+ 629 + ++++ +++ +++ ++ ++ Calcd: 387.18 Found: 388.2 [M + H]+ 630 + ++++ +++ +++ +++ ++ Calcd: 386.19 Found: 387.2 [M + H]+ 631 ++ ++ + + Calcd: 360.17 Found: 361.2 [M + H]+ 632 ++ + + ++ Calcd: 373.15 Found: 374.2 [M + H]+ 633 ++ + + ++ Calcd: 431.21 Found: 432.2 [M + H]+

In some embodiments, the invention provides a combination treatment comprising an mTor inhibitor, which can be a compound as provided herein and a PI3Kα inhibitor also as provided herein. In some embodiments, the mTor inhibitor is a compound of Formula I, Formula I-A, Formula I-B1, Formula I-C, Formula I-C1a, or a compound of Table 1 or Table 2, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3. For example, the mTor inhibitor is a compound of Formula I where M1 is a bicyclic heteroaryl system, including, for instance, benzothiazolyl, quinolinyl, quinazolinyl, benzoxazolyl, and benzimidazolyl, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3. In other embodiments, the mTor inhibitor is a compound of Formula I where M1 is of formula M1-A, M1-B, M1-C or M1-D, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3. In yet other embodiments, the mTor inhibitor is of Formula I-B1 and M1 is of formula M1-F1, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3. In still other embodiments, the mTor inhibitor is of Formula I-C, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3. In still other embodiments, the mTor inhibitor is of Formula I-C1a, and the PI3Kα inhibitor is a compound of Formula II, Subformula IIa, Subformula IIb, Formula III, Subclass IIIc, Subclass IIId, Formula VI-B, Formula VI-C, Formula VI-D, or Table 3.

In some embodiments, the mTor inhibitor is a compound of Formula I, Formula I-A, Formula I-B1, Formula I-C, Formula I-C1a, or a compound of Table 1 or Table 2, and the PI3Kα inhibitor is a compound of Formula II or Formula III. In other embodiments, the mTor inhibitor is a compound of Formula I, Formula I-A, Formula I-B1, Formula I-C, Formula I-C1a, or a compound of Table 1 or Table 2, and the PI3Kα inhibitor is a compound of Subformula IIa or Subformula IIb. In still other embodiments, the mTor inhibitor is a compound of Formula I, Formula I-A, Formula I-B1, Formula I-C, Formula I-C1a, or a compound of Table 1 or Table 2, and the PI3Kα inhibitor is a compound of Formula III, Subclass IIIc or Subclass IIId. In still other embodiments, the mTor inhibitor is a compound of Formula I, Formula I-A, Formula I-B1, Formula I-C, Formula I-C1a, or a compound of Table 1 or Table 2, and the PI3Kα inhibitor is a compound of Formula VI-B, VI-C, VI-D or of Table 3.

In some embodiments, the mTor inhibitor is a compound of Formula I where M1 is of formula M1-A, M1-B, M1-C or M1-D, and the PI3Kα inhibitor is a compound of Subclass IIIc or Subclass IIId. In other embodiments, the mTor inhibitor is a compound of Formula I-C and the PI3Kα inhibitor is a compound of Subclass IIIc or Subclass IIId.

In some embodiments, the mTor inhibitor is a compound of Table 1 or 2 and the PI3Kα inhibitor is a compound of Table 3.

Pharmaceutical Compositions and Administration

The invention provides, in one aspect, a combination treatment utilizing a PI3Kα inhibitor and an mTor inhibitor. The therapeutic agents (including compounds) that are provided for use in the combination therapies of the invention can be administered simultaneously or separately. This administration in combination includes, for example, simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, multiple therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively multiple therapeutic agents can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, an inhibitor of the present invention can be administered just followed by and any of the agents described above, or vice versa. In the separate administration protocol, an inhibitor of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart. The term “combination treatments” also embraces the administration of the therapeutic agents as described herein in further combination with other biologically active compounds or ingredients and non-drug therapies (e.g., surgery or radiation treatment).

Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. An effective amount of an inhibitor of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Sequential or substantially simultaneous administration of each inhibitor or therapeutic agent can be effected by any appropriate route as noted above and including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.

In some embodiments, administration of the inhibitors of the invention can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell or tissue being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

The amount of each inhibitor or compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.

In some embodiments, a combination treatment of the invention is administered in a single dose comprising at least a PI3Kα inhibitor and an mTor inhibitor. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a combination treatment of the invention may also be used for treatment of an acute condition.

In some embodiments, a combination treatment of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a PI3Kα inhibitor and an mTor inhibitor are administered together about once per day to about 6 times per day. In another embodiment the administration of a PI3Kα inhibitor and an mTor inhibitor continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

Administration of the combination treatments of the invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

When a combination treatment of the invention is administered as a composition that comprises one or more compounds, and one compound has a shorter half-life than another compound, the unit dose forms may be adjusted accordingly.

In some embodiments, combination treatments of the invention are tested to estimate pharmacokinetic properties and expected side effect profile. Various assays are known in the art for this purpose. For example, oral availability can be estimated during early stages of drug development by performing a Caco-2 permeability assay. Further, oral pharmacokinetics in humans can be approximated by extrapolating from the results of assays in mice, rats or monkey. In some embodiments, compounds of the invention show good oral availability across multiple species of organisms.

Other assays examine the effect of an inhibitor on liver function and metabolism. Cytochrome P450 (CYP) proteins are the main enzyme involved in metabolizing drugs administered to mammalian organisms. As such, undesired interaction of a drug candidate can be a significant source of adverse drug interactions. Generally, it is desirable for a drug to not interact with CYP isozymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. In some embodiments, an inhibitor of the invention exhibits an IC50 of greater than 10 μM for CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Additionally, liver microsome and hepatocyte metabolism assays using human preparations can be used to estimate the in-vitro half life of a drug candidate.

Cardiac toxicity is also an important consideration in evaluating compounds. For example, hERG is the gene coding for the Kv11.1 potassium ion channel, a protein is involved in mediating repolarizing current in the cardiac action potential in the heart Inhibition of the hERG gene product by a drug candidate can lead to an increase in the risk of sudden death and is therefore an undesirable property. In some embodiments, an inhibitor of the invention exhibits less than 10% hERG inhibition when administered at a suitable concentration.

Mutagenicity of compounds can be assayed via an Ames test or a modified Ames test using e.g., the liver S9 system. In some embodiments, compounds show negative activity in such a test.

Other undesired interactions of an inhibitor can also be ascertained via a receptor panel screen. In some embodiments, no significant interactions are detected for combination treatments of the invention. The subject pharmaceutical compositions can be formulated to provide a therapeutically effective amount of a combination of therapeutic agents of the present invention, or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered as a combination of a PI3Kα inhibitor and an mTor inhibitor, or in further combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject combinations and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

In some embodiments, the concentration of one or more of the compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. v/v.

In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more of the compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more of the compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more of the compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The combination treatments according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

A pharmaceutical composition of the present invention typically contains an active ingredient (e.g., an inhibitor of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.

Pharmaceutical Compositions for Oral Administration.

In some embodiments, the invention provides a pharmaceutical composition for oral administration containing at least one therapeutic agent, and a pharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) a compound which is a PI3Kα inhibitor; (ii) a second compound which is an mTor inhibitor; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) a third agent or even a fourth agent. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents is present in a sub-therapeutic amount, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition.

In some embodiments, the invention provides for a pharmaceutical composition comprising a combination of a PI3-kinase α inhibitor and an mTOR inhibitor. The PI3-kinase α inhibitor and the mTOR inhibitor can be packaged as a single oral dosage form. In other embodiments, the PI3-kinase α inhibitor and the mTOR inhibitor can be packaged as separate dosage forms, such as a tablet.

In one embodiment, the present invention provides an oral dosage form comprising 100 mg to 1.5 g of an inhibitor of the invention. The oral dosage form can be a tablet, formulated in form of liquid, in immediate or sustained release format.

In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, including liquid dosage forms (e.g., a suspension or slurry), and oral solid dosage forms (e.g., a tablet or bulk powder). As used herein the term “tablet” refers generally to tablets, caplets, capsules, including soft gelatin capsules, and lozenges. Oral dosage forms may be formulated as tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by an individual or a patient to be treated. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In one embodiment, the inhibitor of the invention is contained in capsules. Capsules suitable for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. Optionally, the inventive composition for oral use can be obtained by mixing the inhibitor with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

Lubricants can be also be used in conjunction with tissue barriers which include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.

When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

In some embodiments, the invention provides a pharmaceutical composition for injection containing at least one compound of the present invention and a pharmaceutical excipient suitable for injection. For example a pharmaceutical composition for injection is provided comprising at least one PI3Kα inhibitor and an mTor inhibitor. Also provided are pharmaceutical compositions comprising a PI3Kα inhibitor, and pharmaceutical compositions comprising an mTor inhibitor, where the PI3Kα inhibitor is administered separately or together with the mTor inhibitor. The PI3K α inhibitor and the mTor inhibitor may be formulated separately, and may further include a third therapeutic agent. Components and amounts of agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing at least one compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery. For example a pharmaceutical composition for topical delivery is provided comprising at least one PI3Kα inhibitor and an mTor inhibitor. Also provided are pharmaceutical compositions for topical delivery comprising a PI3Kα inhibitor, and pharmaceutical compositions for topical delivery comprising an mTor inhibitor, where the PI3Kα inhibitor is administered separately or together with the mTor inhibitor. The PI3K α inhibitor and the mTor inhibitor may be formulated separately, and may further include a third therapeutic agent.

Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of an inhibitor of the present invention in controlled amounts, either with or without another agent.

The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. For example a pharmaceutical composition for topical delivery is provided comprising at least one PI3Kα inhibitor and an mTor inhibitor. Also provided are pharmaceutical compositions for topical delivery comprising a PI3Kα inhibitor, and pharmaceutical compositions for topical delivery comprising an mTor inhibitor, where the PI3Kα inhibitor is administered separately or together with the mTor inhibitor. Compositions comprising a PI3K α inhibitor and an mTor inhibitor may be formulated separately, and may further include a third therapeutic agent.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

Administration of each compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

The amount of each compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.

In some embodiments, an inhibitor of the invention is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of an inhibitor of the invention may also be used for treatment of an acute condition.

In some embodiments, an inhibitor of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment an inhibitor of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of an inhibitor of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

An effective amount of an inhibitor of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. An inhibitor of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, an inhibitor of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053.

The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for an inhibitor of the invention may be found by routine experimentation in light of the instant disclosure.

The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and an inhibitor according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

The invention also provides kits. The kits include an inhibitor or compounds of the present invention as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

In some embodiments, the subject is a human in need of treatment for cancer, or a precancerous condition or lesion, wherein the cancer is preferably NSCL, breast, colon or pancreatic cancer. Subjects that can be treated with combination treatments of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivatives of the therapeutic agents, according to the methods of this invention include, for example, subjects that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer; central nervous system cancers (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Müllerian tumor; oral cavity and oropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and nonseminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as to thymomas, thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; and colon cancer.

The invention also relates to a method of treating diabetes in a mammal that comprises administering to said mammal a therapeutically effective amount of a combination treatment of the present invention.

In addition, the combination treatments described herein may be used to treat acne.

In addition, the combination treatments described herein may be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term describing any hardening of medium or large arteries. Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque.

Further the combination treatments described herein may be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria. There are many recognized types, divided in acute, subacute or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.

Additionally, the combination treatments described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barr syndrome (GBS), Hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Chagas'disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a combination treatment of the present invention. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion, carotid obstructive disease, or ischemic conditions.

In another aspect, the present invention provides methods of disrupting the function of a leukocyte or disrupting a function of an osteoclast. The method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a combination treatment of the invention.

In another aspect of the present invention, methods are provided for treating ophthalmic disease by applying one or more of the subject combination treatments to the eye of a subject. Methods are further provided for administering the combination treatments of the present invention via eye drop, intraocular injection, intravitreal injection, topically, or through the use of a drug eluting device, microcapsule, implant, or microfluidic device. In some cases, combination treatments are administered with a carrier or excipient that increases the intraocular penetrance of the compound such as an oil and water emulsion with colloid particles having an oily core surrounded by an interfacial film.

In some cases, the colloid particles include at least one cationic agent and at least one non-ionic surfactant such as a polyoxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxyl stearate. In some cases, the cationic agent is an alkylamine, a tertiary alkyl amine, a quaternary ammonium compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound or a mixture thereof. In some cases the cationic agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixture thereof. In some cases, the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristylalkonium halide, stearalkonium halide or a mixture of two or more thereof. In some cases, cationic agent is a benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

The invention further provides methods of modulating a PI3K and/or mTOR kinase activity by contacting the kinase with an effective amount of a composition comprising a PI3Kα inhibitor and an mTor inhibitor. Modulate can be inhibiting or activating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting the kinase with an effective amount of a composition comprising a PI3Kα inhibitor and an mTor inhibitor in solution. In some embodiments, the invention provides methods of inhibiting the kinase activity by contacting a cell, tissue, or organ that expresses the kinase of interest. In some embodiments, the invention provides methods of inhibiting kinase activity in subject including but not limited to rodents and mammal (e.g., human) by administering into the subject an effective amount of a composition comprising a PI3Kα inhibitor and an mTor inhibitor. In some embodiments, the percentage of inhibiting exceeds 50%, 60%, 70%, 80%, or 90%.

Further Combination Therapies

The present invention also provides methods for further combination therapies in which, in addition to a PI3Kα inhibitor and an mTor inhibitor, an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes is used or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of the composition comprising a PI3Kα inhibitor and an mTor inhibitor with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, where desired, a synergistic or additive therapeutic effect.

For treatment of autoimmune diseases, the subject compounds or pharmaceutical compositions can be used in combination with commonly pres