COMBINATION OF CATALYTIC MTORCl/2 INHIBITORS AND SELECTIVE INHIBITORS OF AURORA A KINASE

PRIORITY CLAIM

[001] This application claims priority from U.S. Provisional Patent Application Serial Number 61/804,314 filed March 22, 2013 which is hereby incorporated by reference in its entirety.

BACKGROUND

[002] In 2008, there were an estimated 12.7 million cases of cancer diagnosed worldwide and about 7.6 million deaths. The global cancer burden is growing at an alarming pace; in 2030 alone, about 21.3 million new cancer cases and 13.1 million cancer deaths are expected to occur, simply due to the growth and aging of the population. Cancer is the second most common cause of death in the US, exceeded only by heart disease, accounting for nearly 1 of every 4 deaths. The National Cancer Institute estimates that approximately 13.7 million Americans with a history of cancer were alive on January 1, 2012. Some of these individuals were cancer free, while others still had evidence of cancer and may have been undergoing treatment. About 1,660,290 new cancer cases are expected to be diagnosed in the US in 2013. In 2013, about 580,350 Americans are expected to die of cancer, almost 1,600 people per day. Although medical advances have improved cancer survival rates, there is a continuing need for new and more effective treatment.

[003] 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 cancers.

[004] The cell division cycle, which regulates the transition from quiescence to cell proliferation, also involves various protein kinases that are frequently overexpressed in cancer cells. Because of their important role in the cell division cycle, such cell cycle kinases have also been explored as targets for cancer therapy.

[005] One kinase associated with an oncogenic signaling pathway is the mammalian / mechanistic target of rapamycin (mTOR), which 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 and is the catalytic subunit of two distinct protein complexes, mTOR complex 1 (mTORCl) and mTOR complex 2 (mTORC2).

[006] mTORCl function is involved in many growth-related processes such as protein translation, ribosome biogenesis, transcription, autophagy and hypoxic adaptation. mTORCl is best known as a key regulator of protein translation via its ability to phosphorylate the eukaryotic translation initiation factor 4EBP1, and S6 kinase (Hidalgo, M. J Clin One (2012) Vol 30, 1).

[007] To date mTORC2 has best been described to regulate two major cell functions, including regulation of Akt and cell cycle-dependent organization of the actin cytoskeleton. mTORC2 phosphorylates Akt on serine 473 (Ser473) in its C-terminal hydrophobic motif, which, in conjunction with PDK1 -mediated phosphorylation of threonine 308 (Thr308), confers full activation of Akt (Sarbassov D.D., et al. Science (2005) 307: 1098-1101). mTORC2 regulates the actin cytoskeleton through an unclear mechanism which is rapamycin insensitive (Jacinto E., et al. Nat Cell Biol. (2004) 6: 1122-1128). Interestingly, mTORC2 phosphorylates PKC and SGKl (serum-and glucocorticoid-induced protein kinase 1), and has also been implicated in controlling cell size (Ikenoue T., et al. EMBO J. (2008) 27: 1919-193; Rosner M., et al. Hum Mol Genet, (2009) 18: 3298-3310).

[008] The mTORCl and mTORC2 complexes are often distinguished by their ability to differentially bind and be inhibited by rapamycin and its analogs (rapalogs), which is in contrast to catalytic inhibitors of mTOR that can equally inhibit mTORCl and mTORC2. Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. The FKBP12-rapamycin complex then binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR enzyme (Jacinto E., et al. Cell (2006) 127: 125-137). As such rapamycin and rapalogs can be considered as allosteric inhibitors regulating the activity of mTORCl only. Furthermore this regulation can be considered incomplete as the ability of these inhibitors to suppress 4EBP1 phosphorylation (an important downstream effect of mTORCl inhibition) is considered to be only partial (Hidalgo, M. J Clin One (2012) Vol 30, 1).

[009] Examples of cell cycle kinases include the Aurora kinases, first identified in yeast (Ipll), Xenopus (Eg2) and Drosophila (Aurora). (Embo J (199$) 17, 5627-5637; Genetics (1993) 135, 677-691; Cell (1995) 81, 95-105; JCellSci (1998) l l l(Pt 5), 557-572). In humans, three isoforms of Aurora kinase exist, including Aurora A, Aurora B and Aurora C (Carmena M, Earnshaw WC. Nat Rev Mol Cell Biol. (2003) 4:842-54). Aurora A and Aurora B play critical roles in the normal progression of cells through mitosis, whereas Aurora C activity is largely restricted to meiotic cells: [010] The Aurora A gene (AURKA) localizes to chromosome 20ql3.2 which is commonly amplified or overexpressed at a high incidence in a diverse array of tumor types. (Embo J (1998) 17, 3052-3065; Int J Cancer (2006) 118, 357-363; J Cell Biol (2003) 161, 267-280; Mol Cancer Ther (2007) 6, 1851-1857; J Natl Cancer Inst (2002) 94, 1320-1329). Increased Aurora A gene expression has been correlated to the etiology of cancer and to a worsened prognosis. (IntJ _^ Oncol (2004) 25, 1631-1639; Cancer Res (2007) 67, 10436-10444; Clin Cancer Res (2004) 10, 2065-2071; Clin Cancer Res (2007) 13, 4098-4104; Int J Cancer (2001) 92, 370-373; Br J Cancer (2001) 84, 824-831; JNatl Cancer Inst (2002) 94, 1320-1329). This concept has been supported in experimental models, demonstrating that Aurora A overexpression leads to oncogenic transformation. {Cancer Res (2002) 62, 4115-4122; Mol Cancer Res (2009) 7, 678- 688; Oncogene (2006) 25, 7148-7158; Cell Res (2006) 16, 356-366; Oncogene (2008) 27, 4305- 4314; Nat Genet (1998) 20, 189-193). Both in vitro and in vivo studies have demonstrated that Aurora A induces tumorigenesis through genome instability. The potential oncogenic role of Aurora A has led to considerable interest in targeting this kinase for the treatment of cancer.

[011] Previous studies have shown that cell signaling cross-talk between Aurora A and other cellular proteins are essential for fully-transformed phenotypes. The cross-talk between Aurora A and the mTOR signaling pathway represents an example of this. In mouse mammary tumor virus (MMTV)- Aurora A transgenic mice, constitutive phosphorylation of mTOR Ser2448 and Akt Ser473 was discovered in developed mammary tumors (Wang X., et al. Oncogene (2006) 25: 7148-7158). Elevated phosphorylation of mTOR Ser2448 and Akt Ser473 in Aurora-A transformed cells suggests that Aurora-A can potentially regulate two mTOR pathways, mTORCl and mTORC2. More evidence suggests that either or both of mTORCl and 2 is important for Aurora-A induced transformation since mTOR inhibition can abolish transformed phenotypes induced by Aurora A (Taga M., et al. Int J Biol Sci (2009) 19: 444-450). Of note, mammary tumor development can be observed only after long latency in MMTV-Aurora A mice.

[012] Given the importance of the protein kinases involved in signal transduction pathways and the cell division cycle, it would be beneficial if more effective treatment regimens, which target these kinases could be developed. In particular, combined treatment regimens could be helpful for patients suffering from disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases, and might potentially even decrease the rate of relapse or overcome the resistance to a particular anticancer agent sometimes seen in these patients.

[013] There is thus a need for new cancer treatment regimens, including combination therapies. SUMMARY

[014] This invention relates to methods for the treatment of disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases. In particular, the invention provides methods for treatment of various disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases, by administering an mTORCl/2 inhibitor in combination with a selective inhibitor of Aurora A kinase. The invention also provides pharmaceutical compositions and kits comprising an mTORC 1/2 inhibitor in combination with a selective Aurora A kinase inhibitor.

[015] The present invention provides new combination therapies for the treatment of disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases. In particular, the present invention provides a method to treat a patient suffering from disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases, comprising administering to said patient an mTORC l/2inhibitor in combination with a selective inhibitor of Aurora A kinase, wherein the amounts of each inhibitor are therapeutically effective when used in combination. The invention also provides an mTORC 1/2 inhibitor in combination with a selective inhibitor of Aurora A kinase for use in the manufacture of a medicament for the treatment of disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases, wherein the amounts of each inhibitor are therapeutically effective when used in combination. The invention also provides pharmaceutical compositions and kits comprising an mTORC 1/2 inhibitor in combination with a selective inhibitor of Aurora A kinase.

[016] While single agent mTORCl/2 inhibitors and single agent selective inhibitors of Aurora A kinase may prove effective in treating a certain number of patients and certain disease conditions including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases and kidney diseases, the present inventors have surprisingly discovered that combined therapy with an mTORCl/2 inhibitor and a selective inhibitor of Aurora A kinase offers benefits not achieved with either agent individually.

[017] Without wishing to be bound by theory, the present inventors believe that overexpression of Aurora A is not a strong driving force, and cell transformation by Aurora A requires additional oncogenic events, such as constitutive activation of mTOR/Akt pathway and loss of PTEN tumor suppressor. Therefore, simultaneous inhibition of Aurora A and mTORCl/2 activity may provide enhanced anti tumor potency and provide an improved treatment paradigm for patients that have tumors impacted by both distinct mechanisms. BRIEF DESCRIPTION OF THE DRAWINGS

[018] FIGURE 1 shows a fitted isobologram for MLNO 128 in combination with MLN8237 in the Calu6 lung cancer cell line. The contours range from 90% to 10% viability, with a separation of 10% in viability.

[019] FIGURE 2 shows a fitted isobologram for MLNO 128 in combination with MLN8237 in the A2780 ovarian cancer cell line. The contours range from 90% to 10% viability, with a separation of 10% in viability.

[020] FIGURE 3 shows the antitumor activity (average tumor volume as a function of time) of MLN0128 in combination with MLN8237 in a PHTX-14B breast cancer xenograft tumor model.

[021] FIGURE 4 shows the antitumor activity (average tumor volume as a function of time) of MLN0128 in combination with MLN8237 in a PHTX-147B breast cancer xenograft tumor model.

[022] FIGURE 5 shows the antitumor activity (average tumor volume as a function of time) of MLNO 128 in combination with MLN8237 in a SUM-149PT breast cancer xenograft tumor model.

DETAILED DESCRIPTION

[023] 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.

[024] Definitions:

[025] Terms used herein shall be accorded the following defined meanings, unless otherwise indicated.

[026] As used herein, the term "mTOR" refers to the catalytic subunit of two complexes, mTORCl and mTORC2.

[027] The term "mTOR inhibitor" or "inhibitor of mTOR" is used to signify a compound which is capable of interacting with mTOR and inhibiting its enzymatic activity. Inhibiting mTOR enzymatic activity means reducing the ability of mTOR to phosphorylate a substrate peptide or protein. In various embodiments, such reduction of mTOR activity is at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various

embodiments, the concentration of mTOR inhibitor required to reduce mTOR enzymatic activity is less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM.

[028] hi some embodiments, such inhibition is selective, i.e., the mTOR inhibitor reduces the ability of mTOR to phosphorylate a substrate peptide or protein at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect, e.g. , reduction of the enzymatic activity of a different kinase, hi some embodiments, the mTOR inhibitor also reduces the enzymatic activity of another kinase, preferably one that is implicated in cancer.

[029] In some embodiments, the mTOR inhibitor selectively inhibits both mTORC 1 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.

[030] The phrase "an mTORC 1/2 inhibitor" when used: herein refers to a catalytic mTOR inhibitor that interacts with and reduces the kinase activity of both mTORC 1 and mTORC2 complexes. In some embodiments of the methods of the invention, the mTOR inhibitor binds to and directly inhibits both mTORC 1 and mTORC2. For example, the mTOR inhibitor inhibits both mTORCl 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 InM or less, as ascertained in an in vitro kinase assay. In another embodiment, the mTOR inhibitor inhibits both mTORCl 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 mTORCl 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.

[031] As used herein, the term "Aurora A kinase" refers to a serine/threonine kinases involved in mitotic progression. Aurora A kinase is also known as AIK, ARK1, AURA, BTAK, STK6, STK7, STK15, AURORA2, MGC34538, and AURKA. A variety of cellular proteins that play a role in cell division are substrates for phosphorylation by the Aurora A kinase enzyme, including, without limitation, p53, TPX-2, XIEg5 (ia Xenop s), and D-TACC (in Drosophila). The Aurora A kinase enzyme is also itself a substrate for autophosphorylation, e.g., at Thr288. Preferably, the Aurora A kinase is a human Aurora A kinase.

[032] The term "inhibitor of Aurora A kinase" or "Aurora A kinase inhibitor" is used to signify a compound that is capable of interacting with Aurora A kinase and inhibiting its enzymatic activity. Inhibiting Aurora A kinase enzymatic activity means reducing the ability of Aurora A kinase to phosphorylate a substrate peptide or protein. In various embodiments, such reduction of Aurora A kinase activity is at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of Aurora A kinase inhibitor required to reduce an Aurora A kinase enzymatic activity is less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM. Preferably, the concentration that is required to inhbit the enzymatic activity of Aurora A kinase is lower than the concentration of the inhibitor that is required to inhibit the enzymatic activity of Aurora B kinase. In various embodiments, the concentration of an Aurora A kinase inhibitor that is required to reduce Aurora A kinase enzymatic activity is at least about 2-fold, at least about 5 -fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 500-fold, or at least about 1000-fold lower than the concentration of the inhibitor that is required to reduce Aurora B kinase enzymatic activity.

[033] Inhibition of Aurora A and inhibition of Aurora B result in markedly different cellular phenotypes. (Proc. Natl. Acad. Sci. (2007) 104: 4106; Mol Cancer Ther (2009) 8(7), 2046-56; Chem Biol. (2008) 15(6) 552-62). For example, inhibition of Aurora A in the absence of Aurora B inhibition results in increased mitotic index as measured by quantifying phosphorylated histone H3 on serine 10 (pHisH3). pHisEB is a unique substrate of Aurora B in physiological systems (e.g. intact cells). By contrast, inhibition of Aurora B or dual inhibition of Aurora A and Aurora B results in a decrease in pHisEB. Accordingly, as used herein, the term "selective inhibitor of Aurora A kinase" or "selective Aurora A kinase inhibitor" refers to an inhibitor that exhibits an Aurora A kinase inhibitor phenotype at effective antitumor concentrations. In some

embodiments, the selective Aurora A kinase inhibitor causes a transient mitotic delay, as measured by quantification of pHisEB, when administered to mice at a dose where the free fraction adjusted concentration (C _ave ) in plasma is equivalent to the free fraction adjusted concentration achieved in plasma in humans at the maximum tolerated dose (MTD). As used herein, "free fraction adjusted concentration" refers to the plasma concentration of free drug (not protein bound).

[034] As used herein, the terms "in combination" or "combination therapy" refer to use of both an mTORCl/2 inhibitor and a selective Aurora A kinase inhibitor in the treatment of the same disease or condition in the same patient. As further described below, unless explicitly specified, the terms "in combination" or "combination therapy" do not restrict the timing of administration of the mTORCl/2 inhibitor and selective Aurora A kinase inhibitor, and thus include both simultaneous and sequential administration of the mTORCl/2 inhibitor and selective Aurora A kinase inhibitor.

[035] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[036] As used herein, the term "comprises" means "includes, but is not limited to."

[037] 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 C _1-4 alkyl has a heteroaryl group connected through a thio sulfur to a alkyl radical that connects to the chemical species bearing the substituent. This condition does not apply where a formula such as, for example "-L-Ci.io alkyl - C3_ ₈ cycloalkyl" is represented. In such case, the terminal group is a C3_ ₈ cycloalkyl group attached to a linking Ci_ ₁₀ alkyl moiety which is attached to an element L, which is itself connected to the chemical species bearing the substituent.

[038] "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 Ci-Cio 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.

[039] The term "aliphatic" or "aliphatic group", as used herein, means a substituted or unsubstituted straight-chain, branched or cyclic Q.n hydrocarbon, which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cylcoalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[040] The terms "alkyl", "alkenyl", and "alkynyl", used alone or as part of a larger moiety, refer to a straight and branched chain aliphatic group having from 1 to 12 carbon atoms. Whenever it appears herein, a numerical range such as "1 to 12" refers to each integer in the given range; e.g., "1 to 12 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 12 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. For purposes of the present invention, the term "alkyl" will be used when the carbon atom attaching the aliphatic group to the rest of the molecule is a saturated carbon atom. However, an alkyl group may include unsaturation at other carbon atoms. Thus, alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, allyl, propargyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl.

[041] For purposes of the present invention, the term "alkenyl" will be used when the carbon atom attaching the aliphatic group to the rest of the molecule forms part of a carbon-carbon double bond. Alkenyl groups include, without limitation, vinyl, 1-propenyl, 1-butenyl, 1- pentenyl, and 1-hexenyl.

[042] For purposes of the present invention, the term "alkynyl" will be used when the carbon atom attaching the aliphatic group to the rest of the molecule forms part of a carbon-carbon triple bond. Alkynyl groups include, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, and 1-hexynyl.

[043] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH ₂ ) _n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. An alkylene chain also may be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.

[044] The terms "aryl" and "ar-", used alone or as part of a larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl", refer to a C ₆ to C _u aromatic hydrocarbon, comprising one to three rings, each of which is optionally substituted. Preferably, the aryl group is a C _6- i ₀ aryl group. Aryl groups include, without limitation, phenyl, naphthyl, and anthracenyl. In some

embodiments, two adjacent substituents on the aryl ring, taken together with the intervening ring atoms, form an optionally substituted fused 5- to 6-membered aromatic or 4- to 8-membered non- aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S. Thus, the term "aryl", as used herein, includes groups in which an aromatic ring is fused to one or more heteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the aromatic ring. Nonlimiting examples of such fused ring systems include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl, benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term "aryl" may be used interchangeably with the terms "aryl group", "aryl moiety", and "aryl ring".

[045] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted. Preferably, the aralkyl group is Ce-io aryl(Ci. ₆ )alkyl, C _6-1 o aryl(Ci _-4 )alkyl, or C _6- io aryl(C _1-3 )alkyl, including, without limitation, 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.

[046] The term "CVioalkylaryl" 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.

[047] "Amino" or "amine" means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include -N¾, -NHCH ₃ , -N(CH ₃ ) ₂ , -NH((Ci.i ₀ )alkyl), -N((C _W0 )alkyl) ₂ , - NH(aryl), -NH(heteroaryl), -N(aryl) ₂ , -N(heteroaryl) ₂ , and the like. Optionally, the two substituents together with the nitrogen may also form a ring. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl,

benzyloxycarbonyl, and the like.

[048] "Amide" or "amido" refers to a chemical moiety with formula -C(0)N(R) ₂ or - HC(0)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 Q-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. The R ² 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, 3 ^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[049] 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, C _r C ₄ alkyl, is an alkyl group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.

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

[051] 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[3.2.1]heptyl ("norbornyl"), bicyclo[2.2.2]octyl, and the like. In particular embodiments, "bicycloalkyl," either alone or represented along with another radical, can be a (C4.i ₅ )bicycloalkyl, a a (C _6- io)bicycloalkyl or a (C _8-10 )bicycloalkyl.

Alternatively, "bicycloalkyl," either alone or represented along with another radical, can be a (Cg)bicycloalkyl, a (C ₉ )bicycloalkyl or a (Ci ₀ )bicycloalkyl.

[052] "Bicycloaryl" means a fused, spiro or bridged bicyclic ring assembly wherein at least one of the rings comprising the assembly is aromatic. (C _x )bicycloaryl and (Cx.Y)bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring. In particular embodiments, "bicycloaryl," either alone or represented along with another radical, can be a (a (C ₄ .i ₅ )bicycloaryl, a (C ₄ . ₁₀ )bicycloaryl, a (C ₆ .io)bicycloaryl or a (C _8- io)bicycloaryl. Alternatively, "bicycloalkyl," either alone or represented along with another radical, can be a (C ₈ )bicycloaryl, a (C ₉ )bicycloaryl or a

(C ₁₀ )bicycloaryl. The term "Ci.io 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-(l-naphthyl)- ethyl. Either portion of the moiety is unsubstituted or substituted.

[053] "Carbonyl" means the radical -C(=0)- and/or -C(=0)R, wherein R is hydrogen or a further substituent. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.

[054] "Carboxy" means the radical -C(=0)-0- and/or -C(=0)-OR, wherein R is hydrogen or a further substituent. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.

[055] The term "carboxylalkyl" refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkyl groups as defined above.

[056] "Cyano" means the radical -CN.

[057] The term "cycloaliphatic", used alone or as part of a larger moiety, refers to a saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 members, wherein the aliphatic ring system is optionally substituted. In some embodiments, the cycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms. Nonlimiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloaliphatic is a bridged or fused bicyclic hydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic ring system has 3-8 members.

[058] In some embodiments, two adjacent substituents on the cycloaliphatic ring, taken together with the intervening ring atoms, form an optionally substituted fused 5- to 6-membered aromatic or 3- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S. Thus, the term "cycloaliphatic" includes aliphatic rings that are fused to one or more aryl, heteroaryl, or heterocyclyl rings. Nonlimiting examples include indanyl, 5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. The term "cycloaliphatic" may be used interchangeably with the terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic". [059] "Cycloalkyl" means a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or polycyclic ring assembly that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. (C _x )cycloalkyl and (C _x . _Y )cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example,

(C3.io)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-l-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like. In particular embodiments, "cycloalkyl," either alone or represented along with another radical, can be a (C _3- i4)cycloalkyl, a (C _3- io)cycloalkyl, a (C _3-7 )cycloalkyl, a (C _8- io)cycloalkyl or a

(C ₅ . ₇ )cycloalkyl. Alternatively, "cycloalkyl," either alone or represented along with another radical, can be a (C ₅ )cycloalkyl, a (C ₆ )cycloalkyl, a (C ₇ )cycloalkyl, a (C _s )cycloalkyl, a

(C9)cycloalkyl or a (Cio)cycloalkyl.

[060] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy", refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14□ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to four heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, two adjacent substituents on the heteroaryl, taken together with the intervening ring atoms, form an optionally substituted fused 5- to 6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S. Thus, the terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. Additional examples of heteroaryls include, but are not limited to, azepinyl, benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzothiadiazolyl, benzo[ >][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, 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[l,2-c]pyridazinyl, dibenzothiophenyl, 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, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxiranyl, 5,6,6a,7,8,9, 10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, quinoxalinyl, 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]pridinyl, and thiophenyl (i.e. thienyl).

[061] A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings ihat are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[062] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered or bridged 6- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a heterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or ^" " ^" NR (as in N-substituted pyrrolidinyl).

[063] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrol inyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

[064] In some embodiments, two adjacent substituents on a heterocyclic ring, taken together with the intervening ring atoms, for an optionally substituted fused 5- to 6-membered aromatic or 3- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S-. Thus, the terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", "heterocycloalkyl" and "heterocyclic radical", are used interchangeably herein, and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[065] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[066] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms. Nonlimiting examples include chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, and 8-chlorononyl. As used herein, the term "halogen" or "halo" means F, CI, Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic wherein the halogen is fluoro.

[067] "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., Ci-C ₄ heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. For example, a -CH ₂ OCH2CH ₃ 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, -OR ^a , -

SR ^a , -OC(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , -C(0)N(R ^a ) ₂ , -N(R ^a )C(0)OR ^a , -N(R ^a )C(0)R ^a , -N( R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), or P0 ₃ (R ^a ) ₂ , where each R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,

carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[068] 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.

[069] 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.

[070] 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.

[071] 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.

[072] The term "heteroalkyl-Cs-gcycloalkyl" refers to a heteroalkyl group as defined above, which is attached to a cyclic alkyl containing 3 to 8 carbons, for example, l-aminobutyl-4- cyclohexyl. Either portion of the moiety is unsubstituted or substituted.

[073] 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.

[074] 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.

[075] "Nitro" means the radical -N0 ₂ .

[076] "Hydroxy" means the radical -OH. [077] "Imino" means the radical -CR(=NR') and/or -C(=NR')-, wherein R and R' are each independently hydrogen or a further substituent.

[078] 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 subststituted onto an aryl or heteroaryl ring, unless it forms part of the aromatic system as a tautomer.

[079] The term "substituted", as used herein, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The phrase "one or more substituents", as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be either the same or different.

[080] An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including the heteroaryl moiety in heteroaralkyl and heteroaralkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group

include -halo, -N0 ₂ ,-CN, -R*, -C(R*)=C(R*) ₂ , -C≡C-R*, -OR*, -SR°, -S(0)R°, -S0 ₂ R°, -S0 ₃ R°, -S0 ₂ N(R ⁺ ) ₂ , -N(R ⁺ ) ₂ , -NR ⁺ C(0)R*, -NR ⁺ C(0)N(R ⁺ ) ₂ , -NR ⁺ C0 ₂ R°, -0-C0 ₂ R*, -OC(0)N(R ⁺ ) ₂ , - 0-C(0)R*, -C0 ₂ R*, -C(0)-C(0)R*, -C(0)R*, -C(0)N(R ⁺ ) ₂ , -C(0)N(R ⁺ )C(=NR ⁺ )-N(R ⁺ ) ₂ , -N(R ⁺ )C(=NR ⁺ )-N(R ⁺ )-C(0)R*, -C(=NR ⁺ )-N(R ⁺ ) ₂ , -C(=NR ⁺ )-OR*, -N(R ⁺ )-N(R ⁺ ) ₂ , -N(R ⁺ )C(=NR ⁺ )-N (R ⁺ ) ₂ , -NR ⁺ S0 ₂ R°, -NR ⁺ S0 ₂ N(R ⁺ ) ₂ , -P(0)(R*) ₂ , -P(0)(OR*) ₂ , -0-P(0)-OR*,

and -P(0)(NR ⁺ )-N(R ⁺ ) ₂ ; or two adjacent substituents, taken together with their intervening atoms, form a 5-6 membered unsaturated or partially unsaturated ring having 0-3 ring atoms selected from the group consisting of N, O, and S.

[081] Each R ⁺ , independently, is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or two R ⁺ on the same nitrogen atom, taken together with the nitrogen atom, form a 5-8 membered aromatic or non-aromatic ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S. Each R* independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group. Each R° is an optionally substituted aliphatic or aryl group.

[082] An aliphatic group or a non-aromatic heterocyclic ring may be substituted with one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include, without limitation, those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =S, =C(R*) ₂ ,

=N-N(R*) ₂ , =N-OR*, =N-NHC(0)R*, =N-NHC0 ₂ R°, =N-NHS0 ₂ R°, or =N-R*, where each R* and R° is as defined above.

[083] Suitable substituents on the nitrogen atom of a non-aromatic heterocyclic ring include -R*, -N(R*) ₂ , -C(0)R*, -C0 ₂ R*, -C(0)-C(0)R* -C(0)CH ₂ C(0)R*, -S0 ₂ R*, -S0 ₂ N(R*) ₂ , -C(=S)N(R*) ₂ , -C(=NH)-N(R*) ₂ , and -NR*S0 ₂ R*; wherein each R* is as defined above.

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

[085] It will be apparent to one skilled in the art that certain compounds described herein may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

Exemplary niTORCl/2 Inhibitor Compounds

[086] Any molecule capable of inhibiting the enzymatic activity of mTORC 1 and mTORC2 may be used in the methods, pharmaceutical compositions, and kits of the present invention. mTORC 1/2 inhibitors can be assayed in vitro or in vivo for their ability to selectively bind to and/or inhibit mTORC 1 and mTORC2. In vitro assays include assays to determine selective inhibition of the ability of mTORC 1 and mTORC2 to phosphorylate a substrate protein or peptide. Alternate in vitro assays quantitate the ability of the compound to selectively bind to mTORC 1 and mTORC2. Selective inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/ mTOR complex and determining the amount of radiolabel bound. Alternatively, selective inhibitor binding may be determined by running a competition experiment in which new inhibitors are incubated with mTOR bound to a known radioligand. The compounds also can be assayed for their ability to affect cellular or physiological functions mediated by mTOR activity. Assays for each of these activities are known in the art. [087] In some embodiments of the methods of the invention, the mTORCl/2 inhibitor inhibits both mTORCl 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 InM or less, as ascertained in an in vitro kinase assay. In another embodiment, the mTORCl/2 inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTORCl/2 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 mTORCl/2 inhibitor inhibits both mTORCl 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.

[088] In some embodiments, the mTORCl/2 inhibitor is a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof , wherein:

Xi is N or C-E ¹ , X ₂ is N or C, X ₃ is N or C, X ₄ is C-R ⁹ or N, X ₅ is N or C-E ¹ , X ₆ is C or N, and X ₇ is C or N; and wherein no more than two nitrogen ring atoms are adjacent;

Ri is H, -L-Q.ioalkyl, -L-C _3-8 cycloalkyl, -L-Ci. ₁₀ alkyl -C ₃ .gcycloalkyl, -L- aryl, -L- heteroaryl, -L-Ci. _]0 alkylaryl, -L- C]-i ₀ alkylhetaryl, -L- Ci.ioalkylheterocylyl, -L-C ₂ -ioalkenyl, -L- C _2- ioalkynyl, -L-C _2- ioalkenyl-C _3-8 cycloalkyl, -L-C _2- i ₀ alkynyl-C ₃ . ₈ cycloalkyl, -L-heteroalkyl, -L- heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl, -L-heteroalkyl-C _3- gcycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -

N(R ³¹ )-;

E ¹ and E ² are independently -(W ¹ ¾ -R ⁴ ;

Mi is a 5, 6, 7, 8, 9, or- 10 membered ring system, wherein the ring system is monocyclic or bicyclic, substituted with 5 and additionally optionally substituted with one or more -{W ² ) _k -

R ² ;

each k is 0 or 1; j in E ¹ or j in E ² , is independently 0 or 1;

W ¹ is -0-, -NR ⁷ -, -S(0)o-2- -C(OH-C(0)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )S(0)-,- N(R ⁷ )S(0) ₂ - -C(0)0-, -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, -CH(R ⁷ )N(S0 ₂ R ⁸ )-, - CH(R ⁷ )N(R ⁸ H -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, -CH(R ⁷ )N(R ⁸ )S(0)-, or - CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

W ² is -0-, -NR ⁷ -, -S(0)o-2- - (O -C(0)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )C(0)N(R ⁸ )-,- N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ -,-C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, - CH(R ⁷ )N(S0 ₂ R ⁸ )-, -CH(R ⁷ )N(R ⁸ )-, -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, - CH(R ⁷ )N(R ⁸ )S(0)-, or -CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

R ² is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , - C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , - C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , - OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , - SC(=0)NR ³¹ R ³² , aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), hetaryl, Ci.ioalkyl, C3.gcycloalkyl, Ci.ioalkyl-C _3-g cycloalkyl, C ₃ _ ₈ cycloalkyl -Ci.ioalkyl, C _3- gcycloalkyl -C2-ioalkenyl, C ₃ .gcycloalkyl- C _2- ioalkynyl, Ci.ioalkyl- C _2- ioalkenyl, Ci_i ₀ alkyl- C ₂ . _l oalkynyl, Ci.i ₀ alkylaryl (e.g. C _2- ioalkyl-monocyclic aryl, Ci.i ₀ alkyl-substituted monocyclic aryl, or Ci.ioalkylbicycloaryl), Ci.ioalkylhetaryl, Ci.ioalkylheterocyclyl, C2-ioalkenyl, C2-ioalkynyl, C ₂ . _l oalkenyl -Ci.ioalkyl, C2-ioalkynyl -Ci.ioalkyl, C ₂ .ioalkenylaryl, C ₂ _i ₀ alkenylhetaryl, C ₂ .

loalkenylheteroalkyl, C ₂ .i ₀ alkenylheterocyclcyl, C2-ioalkenyl-C3.gcycloalkyl, C _2- ioalkynylaryl, C ₂ _ _l oalkynylhetaryl, C _2- i ₀ alkynylheteroalkyl, C ₂ .i ₀ alkynylheterocylyl, C2-ioalkynyl-C3 _-8 cycloalkenyl, Ci_i ₀ alkoxy Ci_i ₀ alkyl, Ci.ioalkoxy-C _2- ioalkenyl, Ci_ioalkoxy-C ₂ .ioalkynyl, heterocyclyl, heteroalkyl, heterocyclyl -Ci.ioalkyl, heterocyclyl-C _2- ioalkenyl, heterocyclyl-C ₂ -ioalkynyl, aryl- Ci.ioalkyl (e.g. monocyclic aryl-C2-ioalkyl, substituted monocyclic aryl- Ci.ioalkyl, or bicycloaryl- -Ci.ioalkyl), aryl-C2-ioalkenyl, aryl-C2_ioalkynyl, aryl-heterocyclyl, hetaryl-Ci.ioalkyl, hetaryl- C2-ioalkenyl, hetaryl-C _2- ioalkynyl, hetaryl-C ₃ _ ₈ cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , - C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , - C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , - OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or- SC(=0) R ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ³ and R ⁴ are independently hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - R ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ R ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , - NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl, hetaryl, C aIkyl. C _1-10 alkyl, C ₃ . ₈ cycloalkyl, C _1-10 alkyl- C ₃ . ₈ cycloalkyl, C _3-8 cycloalkyl -Ci.i ₀ alkyl, C _3-8 cycloalkyl -C ₂ .ioalkenyl, Q.gcycloalkyl- C _2- loalkynyl, Ci.i ₀ alkyl- C ₂ -i ₀ alkenyl, Ci.i ₀ alkyl- C _2-10 alkynyl, Q.^alkylaryl, Ci.i ₀ alkylhetaryl, Ci_ _l oalkylheterocyclyl, C _2- i ₀ alkenyl, C ₂ .i ₀ alkynyl, C _2- i ₀ alkenyl -Ci.i ₀ alkyl, C _2- i ₀ alkynyl -Ci.ioalkyl, C _2-10 alkenylaryl, C _2-10 alkenylhetaryl, C _2- i ₀ alkenylheteroalkyl, C ₂ .ioalkenylheterocyclcyl, C _2- i ₀ alkenyl-C ₃ . _g cycloalkyl, C ₂ -ioalkynyl-C ₃ . ₈ cycloalkyl, C ₂ .i ₀ alkynylaryl, C2-ioalkynylhetaryl, C ₂ . _l oalkynylheteroalkyl, C _2- ioalkynylheterocylyl, C ₂ . ₁₀ alkynyl-C ₃ . ₈ cycloalkenyl, Ci.i ₀ alkoxy Q. loalkyl, C _1-10 alkoxy-C _2-1 oalkenyl, Ci.i ₀ alkoxy-C ₀ alkynyl, heterocyclyl, heterocyclyl heterocyclyl-C ₂ .i ₀ alkenyl, heterocyclyl-C _2- ioalkynyl, aryl- Q.ioalkyl, aryl-C _2- i ₀ alkenyl, aryl-C ₂ . _l oalkynyl, aryl-heterocyclyl, hetaryl-Ci_i ₀ alkyl, hetaryl-C ₂ -i ₀ alkenyl, hetaryl-C ₂ .i ₀ alkynyl, hetaryl-C _3-8 cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , - NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , - C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ⁵ is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , - C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , - C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , - OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² ,or - SC(=0)NR ³¹ R ³² ;

each of R , R , and R is independently H or Q-ioalkyl , wherein the Ci.i ₀ alkyl 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, - Ci.ioalkyl, -CF ₃ , -O-aryl, -OCF ₃ , -OCi.i ₀ alkyl, -NH ₂ , -N(C _M oalkylXC _M oalkyl), - NH(C _1-10 alkyl), - NH( aryl), -NR ³⁴ R ³⁵ , -C(O)(C _1-10 alkyl), - C OXd.ioalkyl-aryl), -C(0)(aryl), -CO ₂ -C _1-10 alkyl, -CO ₂ -C _1-10 alkylaryl, -C0 ₂ -aryl, - C(=O)N(C _1-10 alkyl)( C _1-I0 alkyl), -C(=0)NH( C _1-10 alkyl), -C(=0)NR ³⁴ R ³⁵ , -C(=0)NH ₂ , -OCF ₃ , - O(C _M0 alkyl), -O-aryl, -N(aryl)( C _1-10 alkyl),— 0 ₂ , -CN, -S(O) ₀ - ₂ C _1-10 alkyl, -S(O) ₀ _ ₂ Q.

1 ₀ alkylaryl, -S(O) ₀ _ ₂ aryl, -S0 ₂ N(aryl), -S0 ₂ N(C _1-10 alkyl)( C _1-10 alkyl), -S0 ₂ NH(C _MO alkyl) or - S0 ₂ NR ³⁴ R ³⁵ ;

R ³⁴ and R ³⁵ in - R ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ^3I R ³² , hydroxyl, halogen, oxo, aryl, hetaryl, 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 R ⁷ and R ⁸ is independently hydrogen, Ci.ioalkyl, C ₂ _i ₀ alkenyl, aryl, heteroaryl, heterocyclyl or C3.iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R ⁶ ;

R ⁶ is halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , -NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, - C(=0)NR ³¹ R ³² , C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ C _MO alkyl, -S(O) ₀ - ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , Ci.ioalkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Q.ioalkyl, aryl-C _2- i ₀ alkenyl, aryl-C ₂ . _l oalkynyl, hetaryl-Ci.i ₀ alkyl, hetaryl-C ₂ _i ₀ alkenyl, hetaryl-C ₂ _i ₀ alkynyl, 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, -OCi- _! oalkyl, Ci.ioalkyl, C _2- ioalkenyl, C ₂ .

loalkynyl, haloCi.ioalkyl, haloC _2- i ₀ alkenyl, haloC _2- , ₀ alkynyl, -COOH, -C(=0)NR ³¹ R ³² , - C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , -NR ³¹ R ³² , or -NR ³⁴ R ³⁵ ; and

R ⁹ is H, halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² , C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ Cuoalkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , Q. _l oalkyl, C ₂ .i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Ci.i ₀ alkyl, aryl-C ₂ .i ₀ alkenyl, aryl-C _2- i ₀ alkynyl, hetaryl-Ci_ _l oalkyl, hetaryl-C _2-10 alkenyl, hetaryl-C _2- i ₀ alkynyl, 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, -OQ.ioalkyl, Q.ioalkyl, C ₂ -ioalkenyl, C2-ioalkynyl,

haloC ₂ -i ₀ alkenyl, haloC _2- i ₀ alkynyl, -COOH, -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ R ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , - R ³¹ R ³² , or -NR ³⁴ R ³⁵ .

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

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

[091] In some embodiments, Mi is a moiety having a structure of Formula Ml-A or Formula Ml-B:

Formula Ml-A Formula M 1 -B

wherein W _b W ₂ , and W ₇ are independently N or C-R ⁵ ; W ₄ and Wi ₀ are independently N-R ⁵ , O, or S; W ₆ and W ₈ are independently N or C-R ⁵ ; W ₅ and W ₉ are independently N or C-R ² ; and W ₃ is C or N, provided no more than two N and/or N-R ⁵ are adjacent and no two O or S are adjacent.

[092] In some embodiments of the invention, the M _! moiety of Formula Ml-A is a moiety of Formula Ml-Al, Formula M1-A2, Formula M1-A3, or Formula M1-A4:

Formula Ml -A 1 Formula Ml -A2 Formula Ml -A3 Formula Ml -A4 wherein W ₄ is N-R ⁵ , O, or S; W ₆ is N or C-R ⁵ and W ₅ is N or C-R ² .

[093] Some nonlimiting examples of the Mi moiety of Formula Ml-A include:

wherein R ⁵ is -(W ^! ) _k -R ⁵³ or R ⁵⁵ ; each k is independently 0 or 1, n is 0, 1, 2, or 3, and -(W ¹ ^ - R ⁵³ and R ⁵⁵ are as defined above.

[094] In other embodiments of the invention, the Mi moiety of Formula Ml-B is a moiety of

Formula Ml-Bl Formula Ml -B2 Formula Ml -B3 Formula Ml -B4 wherein Wi ₀ is N-R ⁵ , O, or S, W ₈ is N or C-R ⁵ , and W ₅ is N or C-R ² .

[095] Some nonlimiting examples of the Mi moiety of Formula Ml-B include:

wherein R' ⁵ is -(W' -R ⁵³ or R ⁵⁵ ; k is 0 or 1, n i sO, 1, 2, or 3, and - W ^l \ -R ⁵³ and R ⁵⁵ are as defined above.

[096] i some other embodiments of the invention, the mTORCl/2 inhibitor has the Formula I- A:

Formula I-.

or a pharmaceutically acceptable salt thereof, wherein:

Xi is N or C-E ¹ , X ₂ is N, X ₃ is C, and X ₄ is C-R ⁹ or N; or Xj is N or C-E ¹ , X ₂ is C, X ₃ is N, and X ₄ is C-R ⁹ or N;

Ri is -H, -L-Ci.ioalkyl, -L-C _3-8 cycloalkyl, -L-Ci.i ₀ alkyl -C _3-8 cycloalkyl, -L- aryl, -L-heteroaryl, - L-Q.ioalkylaryl, -L- Ci.ioalkylheteroaryl, -L- Ci.ioalkylheterocyclyl, -L-C2-ioalkenyl, -L- C _2- ioalkynyl, -L-C ₂ .ioalkenyl-C ₃ . ₈ cycloalkyl, -L-C ₂ .i ₀ alkynyl-C ₃ . ₈ cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L- heteroalkyl-C _3- gcycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(0 , -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

Mi is a moiety having the structure of Formula Ml-Fl or M1-F2:

Formula Ml -Fl Formula M1-F2

k is 0 or 1 ;

E ¹ and E ² are independently -(W ¹ ^ -R ⁴ ;

j, in each instance (i.e., in E ¹ or j in E ² ), is independently 0 or 1

W ¹ is -0-, -NR ⁷ -, -S(O) _0-2 - -C(0)-,-C(0)N(RV, -N(R ⁷ )C(0)-, -N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ - -C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ H -CH(R ⁷ )N(C(0)R ⁸ )-, -CH(R ⁷ )N(S0 ₂ R ⁸ )-, - CH(R ⁷ )N(R ⁸ )-, -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, -CH(R ⁷ )N(R ⁸ )S(0)-, or - CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

W ² is -0-, -NR ⁷ -, -S(O) _0-2 -,-C(O)-,-C(O)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )C(0)N(R ⁸ )-,-

N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ -,-C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, - CH(R ⁷ )N(S0 ₂ R ⁸ H -CH(R ⁷ )N(R ⁸ H -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, - CH(R ⁷ )N(R ⁸ )S(OH or -CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

R ² is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ^3I R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ^3I C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Q.ioalkyl, C _3-8 cycloalkyl, Ci,ioalkyl-C _3- gcycloalkyl, C ₃ . ₈ cycloalkyl -Ci _-10 alkyl, C _3-8 cycloalkyl -C _2- i ₀ alkenyl, C ₃ . ₈ cycloalkyl- C ₂ _ loalkynyl, Ci _-10 alkyl- C _2-10 alkenyl, C _1-10 alkyl- C ₂ . ₁₀ alkynyl, C _1-10 alkylaryl (e.g. C _2-10 alkyl- monocyclic aryl, Ci.i ₀ alkyl-substituted monocyclic aryl, or Ci.ioalkylbicycloaryl), Q. loalkylheteroaryl, Ci.i ₀ alkylheterocyclyl, C _2- i ₀ alkenyl, C ₂ -ioalkynyl, C _2-] oalkenyl -Q. loalkyl, C _2- i ₀ alkynyl -Ci _-10 alkyl, C _2- i ₀ alkenylaryl, C _2-10 alkenylheteroaryl, C ₂ .

loalkenylheteroalkyl, C _2- i ₀ alkenylheterocyclcyl, C ₂ .i ₀ alkenyl-C ₃ . ₈ cycloalkyl, C _{2- l} oalkynylaryl, C _2- ioalkynylheteroaryl, C ₂ .i ₀ alkynylheteroalkyl, C ₂ .i ₀ alkynylheterocyclyl, C _2- i ₀ alkynyl-C _3-8 cycloalkenyl, Ci _-10 alkoxy C _1-10 alkyl, Ci.i ₀ alkoxy-C ₂ .i ₀ alkenyl, .

i ₀ alkoxy-C ₂ .i ₀ alkynyl, heterocyclyl, heteroalkyl, heterocyclyl -Ci-i ₀ alkyl, heterocyclyl-C ₂ . loalkenyl, heterocyclyl-C _2- i ₀ alkynyl, aryl- Ci _-10 alkyl (e.g. monocyclic aryl-C ₂ _i ₀ alkyl, substituted monocyclic aryl- C _I-10 alkyl, or bicycloaryl— Ci.i ₀ alkyl), aryl-C _2- i ₀ alkenyl, aryl-C ₂ .i ₀ alkynyl, aryl-heterocyclyl, heteroaryl-Ci-ioalkyl, heteroaryl-C ₂ .i ₀ alkenyl, heteroaryl-C _2- ioalkynyl, heteroaryl-C ₃ . ₈ cycloalkyl, 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, -R ³¹ , -CF ₃ , - OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , - C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³ R ³⁵ , -NR ³¹ C(=0)R ³² , - NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ^3I OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ³ and R ⁴ are independently hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(= R ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl, heteroaryl, C^alkyl, Ci.ioalkyl, C _3-8 cycloalkyl, Ci.ioalkyl-C3. ₈ cycloalkyl, C3- ₈ cycloalkyl - C _1-K) alkyl, C _3-8 cycloalkyl -C _2- i ₀ alkenyl, C _3-8 cycloalkyl- C ₂ .i ₀ alkynyl, C _1-10 alkyl- C _{2- l} oalkenyl, Ci.ioalkyl- C _2- i ₀ alkynyl, Ci.i ₀ alkylaryl, C _1-10 alkylheteroaryl, .

loalkylheterocyclyl, C _2-10 alkenyl, C _2- i ₀ alkynyl, C ₂ .i ₀ alkenyl -Ci.ioalkyl, C ₂ .i ₀ alkynyl -Q. loalkyl, C ₂ . ₁₀ alkenylaryl, C ₂ .ioalkenylheteroaryl, C ₂ . ₁₀ alkenylheteroalkyl, C _{2- l} oalkenylheterocyclcyl, C ₂ .ioalkenyl-C3 _-8 cycloalkyl, C ₂ -ioalkynyl-C3. ₈ cycloalkyl, C ₂ .

loalkynylaryl, C ₂ -ioalkynylheteroaryl, C _2- i ₀ alkynylheteroalkyl, C ₂ .i ₀ alkynylheterocyclyl, C _2- i ₀ alkynyl-C ₃ . ₈ cycloalkenyl, Ci _-10 alkoxy Ci.ioalkyl, Ci.ioalkoxy-C _2- i ₀ alkenyl, Q.

i ₀ alkoxy-C ₂ .i ₀ alkynyl, heterocyclyl, heterocyclyl -Ci.ioalkyl, heterocyclyl-C ₂ .i ₀ alkenyl, heterocyclyl-C _2- i ₀ alkynyl, aryl- .ioalkyl, aryl-C _2- i ₀ alkenyl, aryl-C _2- i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-C ₂ _i ₀ alkenyl, heteroaryl-C _2- i ₀ alkynyl, heteroaryl-C3_ ₈ cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, - S(0)o_ ₂ R ³¹ , -S0 ₂ NR ¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -0C(=0)0R ³³ , - OC(=0)NR ³¹ R ³² , -OC(=p)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ⁵ is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ „ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² ,or -SC(=0) R ³¹ R ³² ;

R ³¹ , R ³² , and R ³³ , in each instance, are independently H or C _1-10 alkyl , wherein the Cj.i ₀ alkyl 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, - Q.ioalkyl, -CF ₃ , -O-aryl, -OCF3, -OC _MO alkyl, -NH ₂ , -N(Ci. ₁₀ alkyl)(Ci _-10 alkyl), - NH(Ci_i ₀ alkyl), - NH( aryl), - NR ³⁴ R ³⁵ , -C(O)(C _1-10 alkyl), -C(O)(C ₁ . ₁₀ alkyl-aryl), -C(0)(aryl), -CO ₂ -C _1-10 alkyl, -CO C _1-10 alkylaryl, -C0 ₂ -aryl, -C(=O)N(C ₁ . ₁₀ alkyl)( C _MO alkyl), ^C(=0)NH( C _1-10 alkyl), - C(=0)NR ³⁴ R ³⁵ , -C(=0)NH ₂ , -OCF ₃ , -O(C _1-10 alkyl), -O-aryl, -N(aryl)( C _MO alkyl),— N0 ₂ , -CN, -S(0)o_ ₂ C^oalkyl, -S(O) ₀ _ ₂ C _1-10 alkylaryl, -S(O) ₀ _ ₂ aryl, -S0 ₂ N(aryl), -S0 ₂ Nid.joalkylX C _MO alkyl), -SOzNH C _L .oalkyl) or -S0 ₂ NR ³⁴ R ³⁵ ;

R ³⁴ and R ³⁵ in - R ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halogen, oxo, aryl, heteroaryl, Q^alkyl, 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;

R ⁷ and R ⁸ are each independently hydrogen, Ci.ioalkyl, C _2- ioalkenyl, aryl, heteroaryl, heterocyclyl or C _3- iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R ⁶ ;

R ⁶ is halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , -NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ^3I R ³² ,

C(=0)NR ³⁴ R ³⁵ , -NO ₂ , -CN, -S(0)o-2 C _1-10 alkyl, -S(O) ₀ - ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ R ³¹ R ³² , Ci _-10 alkyl, C ₂ . ₁₀ alkenyl, C _2- i ₀ alkynyl; aryl-C _1-10 alkyl, aryl-C _2- i ₀ alkenyl, aryl- C _2-10 alkynyl, heteroaryl-Q. _K jalkyl, heteroaryl-C _2- ioalkenyl, heteroaryl-C _2- i ₀ alkynyl, 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, - OQ.ioalkyl, Ci_ ₁₀ alkyl, C _2-10 alkenyl, C _2- ioalkynyl, haloQ.ioalkyl, haloC ₂ _i ₀ alkenyl, haloC ₂ . I ₀ alkynyl, -COOH, -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , - NR ³¹ R ³² , or -NR ³⁴ R ³⁵ ; and

R ⁹ is H, halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² , C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ - ₂ Ci _-10 alkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , C _! . ₁₀ alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Ci_i ₀ alkyl, aryl-C ₂ .i ₀ alkenyl, aryl- C ₂ .i ₀ alkynyl, heteroaryl-C _MO alkyl, heteroaryl-C _2- i ₀ alkenyl, heteroaryl-C _2-10 alkynyl, 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, - OCi _-10 alkyl, Ci.i ₀ alkyl, C _2- ioalkenyl, C _2- ioalkynyl, haloCi.i ₀ alkyl, haloC _2- ioalkenyl, haloC _{2- 10} alkynyl, -COOH, -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , - NR ³¹ R ³² , or -NR ³⁴ R ³⁵ .

[097] In some embodiments, X ₄ is C-R ⁹ .

[098] In some other embodiments of the invention, the mTORCl/2 inhibitor is as defined above, wherein the compound is of Formula I-B:

Formula I-B

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

[099] In various embodiments the compound of Formula I-B or its pharmaceutically acceptable salt thereof, is a c la I-B2:

Formula I-Bl Formula I-B2

harmaceutically acceptable salt thereof.

[0100] In various embodiments of Formula I-Bl, Xi is N and X ₂ is N. In other embodiments, Xi is C-E ¹ and X ₂ is N. In yet other embodiments, Xi is NH and X ₂ is C.

[0101] In further embodiments, Xi is CH-E ¹ and X ₂ is C.

[0102] In various embodiments of Formula I-B2, Xi is N and X ₂ is C. In further embodiments, Xi is C-E ¹ and X ₂ is C.

[0103] In various embodiments, Xi is C-iW ¹ ^ -R ⁴ , where j is 0. [0104] In another embodiment, Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.

[0105] In various embodiments of X _l5 it is C -{W ¹ ^ -R ⁴ . In various embodiments of Xi, j is 1, and W ¹ is -0-. In various embodiments of X _l5 j is 1, and W ¹ is— NR ⁷ -. In various embodiments of Xi, j is 1, and W ¹ is— NH-. In various embodiments of Xi, j is 1, and W ¹ is— S(O) _0- 2-. hi various embodiments of Xj, j is 1, and W ¹ is— C(O)-. In various embodiments of Xj, j is 1, and W ¹ is— C(0)N(R ⁷ )-. hi various embodiments of X _b j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of X _ls j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments of X _l5 j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ -. In various embodiments of Xi, j is 1, and W ¹ is -C(0)0-. In various embodiments of Xi, j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments ofX j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. h various embodiments of X _b j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )- In various embodiments of X _b j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-- In various embodiments of X j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of X _l5 j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of ¾, j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments of X _I; j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0106] In another embodiment, X] is CH ₂ . In yet another embodiment, Xi is CH-halogen, where halogen is CI, F, Br, or I.

[0107] In another embodiment, Xj is N.

[0108] In various embodiments, X ₂ is N. In other embodiments, X ₂ is C.

[0109] In various embodiments, E ² is -(W ¹ ^ -R ⁴ , where j is 0.

[0110] In another embodiment, E ² is CH. In yet another embodiment, E ² is C-halogen, where halogen is CI, F, Br, or I.

[01 11] In various embodiments of E ² , it is -(W ¹ ^ -R ⁴ . In various embodiments of E ² , j is 1, and W ¹ is -O-. In various embodiments of E ² , j is 1, and W ¹ is— NR ⁷ -. i various embodiments of E ² , j is 1 , and W ¹ is— NH-. In various embodiments of E ² , j is 1 , and W ¹ is— S(0)o_2-. In various embodiments of E ² , j is 1, and W ¹ is— C(O)-. In various embodiments of E ² , j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )S(0)-. i various embodiments of E ² , j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ - In various embodiments of E ² , j is 1, and W ¹ is -C(0)0- In various embodiments of E ² , j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. i various embodiments of E ² , j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-- In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0112] In various embodiments when M _\ is a moiety of Formula Ml-Fl, Mj is benzoxazolyl substituted with -(W2) _k -R ₂ - hi some embodiments, Mi is a benzoxazolyl substituted at the 2- position with -(W ² ) _j -R ² . In some embodiments, Mi is either a 5- benzoxazolyl or a 6- benzoxazolyl moiety, optionally substituted at the 2-position with -(W ² ) _j -R ² . Exemplary Formula Ml-Fl Mi moieties include but are not limited to the following:

^■ > , and r .

[0113] In various embodiments when Mi 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:

-32- [0115] In various embodiments of Mi, k is 0. In other embodiments of Mi, k is 1, and W ² is selected from one of the following: -0-, -NR ⁷ -, -S(O) _0-2 - -C(O)-, -C(0)N(R ⁷ )-, - N(R ⁷ )C(0)-, or -N(R ⁷ )C(0)N(R ⁸ )-. hi yet another embodiment of M k is 1, and W ² is - N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ - -C(0)0-, -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, or - CH(R ⁷ )N(S0 ₂ R ⁸ )-. i a further embodiment of M _b k is 1, and W ² is -CH(R ⁷ )N(R ⁸ )-, - CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, or -CH(R ⁷ )N(R ⁸ )S(0)-. In yet another embodiment of Mi, k is 1, and W ² is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0116] In some other embodiments, the mTORCl/2 inhibitor is a compound of Formula I-C or Formula I-D:

Formula I-C Formula I-D or a pharmaceutically acceptable salt thereof, wherein X _x is N or C-E ¹ , X ₂ is N, and X ₃ is C; or Xi is N or C-E ¹ , X ₂ is C, and X ₃ is N;

Ri is -H, -L-Ci_i ₀ alkyl, -L-C3_gcycloalkyl, -L- Q.ioalkyl -Ca-gcycloalkyl, -L- aryl, -L-heteroaryl, - L-Ci.ioalkylaryl, -L- Ci.ioalkylheteroaryl, -L- Ci_i ₀ alkylheterocyclyl, -L-C _2- ioalkenyl, -L- C ₂ _i ₀ alkynyl, -L-C2-ioalkenyl-C ₃ _ ₈ cycloalkyl, -L-C _2- ioalkynyl-C3_ ₈ cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L- heteroalkyl-C _3-8 cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

E ¹ and E ² are independently -(W ¹ ^ -R ⁴ ;

j in E ¹ or j in E ² , is independently 0 or 1;

W ¹ is -0-, -NR ⁷ -, -S(O) _0-2 -,-C(O)-,-C(O)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ - -C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, -CH(R ⁷ )N(S0 ₂ R ⁸ )-, - CH(R ⁷ )N(R ⁸ )-, -CH(R ⁷ )C(0)N(R ⁸ H -CH(R ⁷ )N(R ^g )C(0)-, -CH(R ⁷ )N(R ⁸ )S(0)-, or - CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

W ² is -0-, -NR ⁷ -, -S(0)o _-2 - -C(0)-,-C(0)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )C(0)N(R ⁸ )-, -

N(R ⁷ )S(Q)-, -N(R ⁷ )S(0) ₂ -, -C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, - CH(R ⁷ )N(S0 ₂ R ⁸ )-, -CH(R ⁷ )N(R ⁸ )-, -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, - CH(R ⁷ )N(R ⁸ )S(OH or -CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

k is 0 or 1 ;

R ² is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ R ³¹ R ³² , - S0 ₂ R ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)0R ³² , -NR ³¹ C(=0)NR ³ R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ^3I OR ³² , -SC(=0)NR ³¹ R ³² , aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci.i ₀ alkyl, C ₃ .gcycloalkyl, Ci.i ₀ alkyl-C _3- gcycloalkyl, C _3-8 cycloalkyl -Ci.i ₀ alkyl, C _3-8 cycloalkyl -C _2- i ₀ alkenyl, C ₃ . ₈ cycloalkyl- C ₂ . loalkynyl, C _1-10 alkyl- C ₂ _ ₁₀ alkenyl, Ci.i ₀ alkyl- C _2- i ₀ alkynyl, Ci. ₁₀ alkylaryl (e.g. C _2-10 alkyl- monocyclic aryl, Ci.i ₀ alkyl-substituted monocyclic aryl, or Ci.ioalkylbicycloaryl), Ci_ loalkylheteroaryl, Ci.i ₀ alkylheterocyclyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _2- i ₀ alkenyl -Ci_ ioalkyl, C _2- i ₀ alkynyl -Ci.i ₀ alkyl, C _2-10 alkenylaryl, C ₂ -ioalkenylheteroaryl, C ₂ .

1 ₀ alkenylheteroalkyl, C _2- i ₀ alkenylheterocyclcyl, C ₂ -ioalkenyl-C ₃ . ₈ cycloalkyl, C _{2- l} oalkynylaryl, C ₂ .i ₀ alkynylheteroaryl, C _2- ioalkynylheteroalkyl, C _2- ioalkynylheterocyclyl, C _2- i ₀ alkynyl-C _3-8 cycloalkenyl, Ci.i ₀ alkoxy Q.ioalkyl, Ci.ioalkoxy-C _2- i ₀ alkenyl, Ci.

i ₀ alkoxy-C _2- i ₀ alkynyl, heterocyclyl -Ci _-10 alkyl, heterocyclyl-C _2- ioalkenyl, heterocyclyl-C _{2- l} oalkynyl, aryl- Ci.i ₀ alkyl (e.g. monocyclic aryl-C _2- i ₀ alkyl, substituted monocyclic aryl- Ci.ioalkyl, or bicycloaryl— Ci.i ₀ alkyl), aryl-C _2- i ₀ alkenyl, aryl-C _2- i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-Ci.ioalkyl, heteroaryl-C _2- i ₀ alkenyl, heteroaryl-C _2- i ₀ alkynyl, heteroaryl-C _3- gcycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o- ₂ R ³² , -C(=S)OR ³¹ , -€(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ³ and R ⁴ are independently hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ¹ C(=NR ³² )NR ³³ R ³² , -NR ¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl, heteroaryl, Ci.i ₀ alkyl, C3 _-8 cycloalkyl, C _! -ioalkyl-Ca-gcycloalkyl, C _3-8 cycloalkyl -Ci.i ₀ alkyl, C _3-8 cycloalkyl -C _2- i ₀ alkenyl, C ₃ . _g cycloalkyl- C _2- i ₀ alkynyl, Ci.i ₀ alkyl- C .i ₀ alkenyl, Ci. loalkyl- C _2- i ₀ alkynyl, Ci.ioalkylaryl, Ci.ioalkylheteroaryl, Q.ioalkylheterocyclyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _2- i ₀ alkenyl -Ci.ioalkyl, C _2-10 alkynyl -Ci.i ₀ alkyl, C _2- i ₀ alkenylaryl, C -i ₀ alkenylheteroaryl, C _2- i ₀ alkenylheteroalkyl, C _2- i ₀ alkenylheterocyclcyl, C _2- i ₀ alkenyl- C _3-8 cycloalkyl, C ₂ .i ₀ alkynylaryl, C2-ioalkynylheteroaryl, C ₂ .i ₀ alkynylheteroalkyl, C ₂ . loalkynylheterocyclyl, C2-ioalkynyl-C ₃ . ₈ cycloalkenyl, Ci.i ₀ alkoxy Q.ioalkyl, Ci _-10 alkoxy- C _2- i ₀ alkenyl, Ci _-10 alkoxy-C _2- ioalkynyl, heterocyclyl -Ci.i ₀ alkyl, heterocyclyl-C _2- ioalkenyl, heterocyclyl-C ₂ -ioalkynyl, aryl- Ci.i ₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl-C _2- i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-Ci _-10 alkyl, heteroaryl-C _2- i ₀ alkenyl, heteroaryl-C ₂ .i ₀ alkynyl, heteroaryl-C ₃ .gcycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ - 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o- ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ^3I C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, - R ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ⁵ is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(0)o_ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ^3, C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³ )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ^3, R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² ,or -SC(=0)NR ³¹ R ³² ;

R ³¹ , R ³² , and R ³³ , in each instance, are independently H or Ci.i ₀ alkyl , wherein the Ci.i ₀ alkyl 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, - Ci-ioalkyl, -CF ₃ , -O-aryl, -OCF ₃ , -OC _MO alkyl, -NH ₂ , - NCC _M oalkylXQ.ioalkyl), - NH(C _I-10 alkyl), - NH( aryl), - NR ³⁴ R ³⁵ , -C(O)(C _1-10 alkyl), -C(O)(C _1-10 alkyl-aryl), -C(0)(aryl), -CO ₂ -C _1-10 alkyl, -C0 ₂ - C _1-10 alkylaryl, -C0 ₂ -aryl, -C(=O)N(C _W0 alkyl)( C _1-10 alkyl), -C(=0)NH( C _1-10 alkyl), - C(=0)NR ³⁴ R ³⁵ , -C(=0)NH ₂ , -OCF ₃ , -O(C _1-10 alkyl), -O-aryl, -N(aryl)( Ci.joalkyl),— N0 ₂ , -CN, C _MO alkyl, -S(O) ₀ _ ₂ Q.joalkylaryl, -S(O) ₀ _ ₂ aryl, -S0 ₂ N(aryl), -S0 ₂ NiQ-!oalkylX C _1-10 alkyl), -S0 ₂ NH(C ₁ oalkyl) or -S0 ₂ NR ³⁴ R ³⁵ ;

R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halo gen, oxo, aryl, heteroaryl, C^alkyl, 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

R ⁷ and R ⁸ are each independently hydrogen, Ci_i ₀ alkyl, C _2- i ₀ alkenyl, aryl, heteroaryl, heterocyclyl or C _3- iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R ⁶ ; and R ⁶ is halo, -OR ³¹ , -SH, NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , - C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² , C(=0) NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ Ci. ₁₀ alkyl, - S(0) o- ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , C _MO alkyl, C ₂ . ₁₀ alkenyl, or C _2-10 alkynyl; or R ⁶ is aryl-Ci _-10 alkyl, aryl-C ₂ . ₁₀ alkenyl, aryl-C ₂ _i ₀ alkynyl, heteroaryl-Ci.i ₀ alkyl, heteroaryl-C _2- loalkenyl, heteroaryl-C _2-10 alkynyl, each of which is unsubstituted or is substituted with one or more independent halo, cyano, nitro, -OCi.i ₀ alkyl, Ci.i ₀ alkyl, C _2- i ₀ alkenyl, C _2- W

₁₀ alkynyl, haloC _MO alkyl, haloC ₂ .i ₀ alkenyl, haloC _2- i ₀ alkynyl, -COOH, -C(=0)NR ³¹ R , - C(=0) NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , -NR ³¹ R ³² , or -NR ³⁴ R ³⁵ .

[0117] In various embodiments of the compound of Formula I-C, the compound has a structure of Formula I-Cl or Formula I-C2:

Formula I-C 1 Formula I-C2

larnaceutically acceptable salt thereof.

[0118] In some embodiments of Formula I-Cl, Xi is N and X ₂ is N. In other embodiments, Xi is C-E ¹ and X ₂ is N. In yet other embodiments, Xi is NH and X ₂ is C. In further embodiments, Xj is CH-E ¹ and X ₂ is C.

[01 19] In several embodiments of Formula I-C2, X[ is N and X ₂ is C. In yet other embodiments, Xi is NH and X ₂ is C. In further embodiments, Xi is CH-E ¹ and X ₂ is C.

[0120] In various embodiments of the compound of Formula I-D, the compound has a structure of Formula I-Dl or Formula I-D2:

Formula I-Dl Formula I-D2

larmaceutically acceptable salt thereof.

[0121] In some embodiments of Formula I-Dl, X _t is N and X ₂ is N. In other embodiments, X] is C-E ¹ and X ₂ is N. i yet other embodiments, Xi is NH and X ₂ is C. In further embodiments, X] is CH-E ¹ and X ₂ is C. [0122] In several embodiments of Formula I-D2, Xj is N and X ₂ is C. In further embodiments,

[0123] In various embodiments, Xi is C-iW^ _j -R ⁴ , where j is 0.

[0124] In another embodiment, Xj is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.

[0125] In various embodiments of X], it is C -(W ¹ ^ -R ⁴ . In various embodiments of X _l5 j is 1, and W ¹ is -0-. In various embodiments of X _l5 j is 1, and W ¹ is— NR ⁷ -. In various embodiments of Xi, j is 1, and W ¹ is— NH-. In various embodiments of X _ls j is 1, and W ¹ is— S(O) _0- 2-. In various embodiments of X _ls j is 1, and W ¹ is— C(O)-. In various embodiments of X _l5 j is 1 , and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of X j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of X _u j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments of Xi, j is 1 , and W ¹ is— N(R ⁷ )S(0) ₂ -. In various embodiments of X _l5 j is 1, and W ¹ is -C(0)0-. In various embodiments of X _ls j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of Xi, j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments of X j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In various embodiments of X _l5 j is 1 , and W ¹ is -CH(R ⁷ )N(R ⁸ }- In various embodiments of X _l5 j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of Xi, j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of X j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments of ¾, j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0126] i various embodiments, Xi is CH-^W ¹ ^ -R ⁴ , where j is 0.

[0127] In another embodiment, Xi is CH ₂ . In yet another embodiment, Xi is CH-halogen, where halogen is CI, F, Br, or I.

[0128] In various embodiments of Xj, it is CH -(W ¹ ^ -R ⁴ . In various embodiments of X _ls j is 1 , and W ¹ is -0-. i various embodiments of X _ls j is 1, and W ¹ is— NR ⁷ -. In various embodiments of X], j is 1, and W ¹ is— NH-. In various embodiments of Xi, j is 1, and W ¹ is— S(0)o_2- i various embodiments of X _l9 j is 1, and W ¹ is— C(O)-. In various embodiments of X _l5 j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of X j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of X _t , j is 1, and W ¹ is -N(R ⁷ )S(0)-. hi various embodiments of Xi, j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ - In various embodiments of Xi, j is 1, and W ¹ is -C(0)0-. In various embodiments of X _b j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of Xi, j is 1 , and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. hi various embodiments of X _ls j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. hi various embodiments of X _h j is 1 , and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of X _ls j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of Xi, j is 1 , and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of X _1; j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0}-. In various embodiments of X _h j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0129] In another embodiment, Xi is N.

[0130] In various embodiments, X ₂ is N. In other embodiments, X ₂ is C.

[0131] In various embodiments, E ² is -(W ¹ ^ -R ⁴ , where j is 0.

[0132] Γη another embodiment, E ² is CH. In yet another embodiment, E ² is C-halogen, where halogen is CI, F, Br, or I.

[0133] In various embodiments of E ² , it is -{W ¹ ), -R ⁴ . In various embodiments of E ² , j is 1, and W ¹ is -0-. In various embodiments of E ² , j is 1, and W ¹ is— NR ⁷ -. In various embodiments of E ² , j is 1, and W ¹ is— NH-. In various embodiments of E ² , j is 1, and W ¹ is— S(O) _0- 2-. In various embodiments of E ² , j is 1, and W ¹ is— C(O)-. In various embodiments of E ² , j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments of E ² , j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ -. In various embodiments of E ² , j is 1, and W ¹ is -C(0)0- In various embodiments of E ² , j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of E ² , j is 1 , and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-.

[0134] In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0135] In various embodiments, k is 0. In other embodiments, k is 1 and W ² is -0-. In another embodiment, k is 1 and W ² is -NR ⁷ -. In yet another embodiment of, k is 1, and W ² is -S(O) ₀ . ₂ -. In another embodiment of, k is 1 and W ² is -C(O)-. In a further embodiment, k is 1 and W ² is - C(0)N(R ⁷ )-. In another embodiment, k is 1, and W ² is -N(R ⁷ )C(0)-. In another embodiment, k is 1 and W ² is -N(R ⁷ )C(0)N(R ⁸ )-. In yet another embodiment, k is 1 and W ² is -N(R ⁷ )S(0)-. In still yet another embodiment, k is 1 and W ² is -N(R ⁷ )S(0) ₂ - In a further embodiment, k is 1 and W ² is -C(0)0-. In another embodiment, k is 1 and W ² is -CH(R ⁷ )N(C(0)OR ⁸ )-. In another embodiment, k is 1 and W ² is -CH(R ⁷ )N(G(0)R ⁸ )-. In another embodiment, k is 1 and W ² is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In a further embodiment, k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )-. In another embodiment, k is 1 and W ² is -CH(R ⁷ )C(0)N(R ⁸ )-. In yet another embodiment, k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )C(0)-. In another embodiment, k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )S(0)-. In yet another embodiment, k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0136] In some other embodiments, the mTORCl/2 inhibitor is a compound of Formula I-E:

Formula I-E

or a pharmaceutically acceptable salt thereof, wherein: X _! is N or C-E ¹ , X ₂ is N, and X ₃ is C; or Xi is N or C-E ¹ , X ₂ is C, and X ₃ is N;

Ri is -H, -L-Ci.ioalkyl, -L-C _3-8 cycloalkyl, -L-Ci.i ₀ alkyl -C ₃ .gcycloalkyl, -L- aryl, -L-heteroaryl, - L-Ci.ioalkylaryl, -L- C _1-10 alkylheteroaryl, -L- Ci.i ₀ alkylheterocyclyl, -L-C _2- ioalkenyl, -L- C _2- ioalkynyl, -L-C ₂ _ioalkenyl-C3, ₈ cycloalkyl, -L-C ₂ .ioalkynyl-C3_ ₈ cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L- heteroalkyl-C _3-8 cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

M! is a moiety having the structure of Formula Ml-Fl or Formula M1-F2:

Formula Ml-Fl Formula M1-F2

k is 0 or 1;

E ¹ and E ² are independently -(W ¹ ^ -R ⁴ ;

j in E ¹ or j in E ² , is independently 0 or 1;

W ¹ is -0-, -NR ⁷ -, -S(O) _0-2 -,-C(O)-,-C(O)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )S(0)-,-N(R ⁷ )S(0) ₂ - -C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, -CH(R ⁷ )N(S0 ₂ R ⁸ )-, - CH(R ⁷ )N(R ⁸ K -CH(R ⁷ )C(0)N(R ⁸ }-, -CH(R ⁷ )N(R ⁸ )C(0)-, -CH(R ⁷ )N(R ⁸ )S(0)-, or - CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

W ² is -0-, -NR ⁷ -, -S(0)o-2-,-C(0)- -C(0)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )C(0)N(R ⁸ - -

N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ -,-C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, - CH(R ⁷ )N(S0 ₂ R ⁸ H -CH(R ⁷ )N(R ⁸ H -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, - CH(R ⁷ )N(R ⁸ )S(0)-, or -CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

R ² is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci_i ₀ alkyl, C ₃ _ ₈ cycloalkyl, Ci.ioalkyl-C _3- gcycloalkyl, C _3-8 cycloalkyl -Ci.i ₀ alkyl, C _3-8 cycloalkyl -C _2- ioalkenyl, C ₃ . ₈ cycloalkyl- C _{2- l} oalkynyl, Ci _-10 alkyl- C _2- i ₀ alkenyl, Ci.ioalkyl- C _2- i ₀ alkynyl, Ci.i ₀ alkylaryl (e.g. C _2-10 alkyl- monocyclic aryl, Ci.i ₀ alkyl-substituted monocyclic aryl, or Ci.i ₀ alkylbicycloaryl), Q. loalkylheteroaryl, Ci.ioalkylheterocyclyl, C _2- ioalkenyl, C _2- ioalkynyl, C _2- ioalkenyl -Q. loalkyl, C _2- ioalkynyl -Ci.ioalkyl, C _2- ioalkenylaryl, C _2-10 alkenylheteroaryl, C ₂ _

loalkenylheteroalkyl, C ₂ _i ₀ alkenylheterocyclcyl, C _2- ioalkenyl-C _3-8 cycloalkyl, C ₂ _ loalkynylaryl, C _2- ioalkynylheteroaryl, C _2- ioalkynylheteroalkyl, C _2- ioalkynylheterocyclyl, C _2- ioalkynyl-C ₃ .gcycloalkenyI, Ci_i ₀ alkoxy Ci_i ₀ alkyl, Ci.ioalkoxy-C ₂ .ioalkenyl, Ci_ ioalkoxy-C2-ioalkynyl, heterocyclyl -Ci.ioalkyl, heterocyclyl-C ₂ _i ₀ alkenyl, heterocyclyl-C ₂ _ loalkynyl, aryl- Ci_i ₀ alkyl (e.g. monocyclic aryl-C _2- ioalkyl, substituted monocyclic aryl- Ci.ioalkyl, or bicycloaryl— Ci_i ₀ alkyl), aryl-C _2- ioalkenyl, aryl-C _2- i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-Ci.ioalkyl, heteroaryl-C _2- ioalkenyl, heteroaryl-C _2- i ₀ alkynyl, heteroaryl-C _3-8 cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(OV 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³ )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, - R ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ³ and R ⁴ are independently hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ - 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - R ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )0R ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl, heteroaryl, Q^alkyl, d.ioalkyl, C _3-8 cycloalkyl, C].ioalkyl-C _3-8 cycloalkyl, C _3- scycloalkyl -Ci.ioalkyl, C ₃ _ ₈ cycloalkyl -C ₂ _ioalkenyl, C _3-8 cycloalkyl- C ₂ _ioalkynyl, . loalkyl- C ₂ .] ₀ alkenyl, Ci _-10 alkyl- C _2- i ₀ alkynyl, Ci.i ₀ alkylaryl, Ci. loalkylheterocyclyl, C _2- i ₀ alkenyl, C ₂ -ioalkynyl, C ₂ .i ₀ alkenyl -Q.ioalkyl, C ₂ .i ₀ alkynyl - . loalkyl, C _2- ioalkenylaryl, C ₂ _ioalkenylheteroaryl, C _2- ioalkenylheteroalkyl, C _2- loalkenylheterocyclcyl, C ₂ .ioalkenyl-C ₃ . _g cycloalkyl, C ₂ . _I0 alkynyl-C ₃ . ₈ cycloalkyl, C _{2- l} oalkynylaryl, C _2-10 alkynylheteroaryl, C ₂ .i ₀ alkynylheteroalkyl, C ₂ .i ₀ alkynylheterocyclyl, C ₂ . ₁₀ alkynyl-C _3-8 cycloalkenyl, Q.ioalkoxy Ci.i ₀ alkyl, Ci.ioalkoxy-C _2- i ₀ alkenyl, Ci.

i ₀ alkoxy-C ₂ .i ₀ alkynyl, heterocyclyl, heterocyclyl -C _1-10 alkyl, heterocyclyl-C ₂ .i ₀ alkenyl, heterocyclyl-C _2- i ₀ alkynyl, aryl- Ci_ ₁₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl-C ₂ ,i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-Ci.joalkyl, heteroaryl-C ₂ .i ₀ alkenyl, heteroaryl-C _2- i ₀ alkynyl, heteroaryl-C ₃ . ^' ₈ cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, - S(0)o_ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ R ³ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0) R ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ; R ⁵ is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² ,or -SC(=0)NR ³¹ R ³² ;

R ³¹ , R ³² , and R ³³ , in each instance, are independently H or Ci_i ₀ alkyl , wherein the Ci.ioalkyl 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, - Ci. ₁₀ alkyl, -CF ₃ , -O-aryl, -OCF3, -OCi.ioalkyl, -NH ₂ , - - H(Ci.i ₀ alkyl), - NH( aryl), - NR ³⁴ R ³⁵ , - OXC _M oalkyl), -C(O)(C,. ₁₀ alkyl-aryl), -C(0)(aryl), -CO ₂ -C _M0 alkyl, -C0 ₂ - C _1-10 alkylaryl, -C0 ₂ -aryl, -C(=O)N(Ci _-10 alkyl)( Ci.ioalkyl), -C(=0)NH( Ci.ioalkyl), - C(=0)NR ³⁴ R ³⁵ , -C(=0)NH ₂ , -OCF ₃ , -O(C ₀ alkyl), -O-aryl, -N(aryl)( C _MO alkyl),— N0 ₂ , -CN, -S(0)o_ ₂ Cj.joalkyl, -S(O) ₀ _ ₂ C _1-10 alkylaryl, -S(O) ₀ _ ₂ aryl, -S0 ₂ N(aryl), -S0 ₂ N(Ci., ₀ alkyl)( C _1-10 alkyl), -S0 ₂ NH(C _MO alkyl) or -S0 ₂ NR ³⁴ R ³⁵ ;

R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halo gen, oxo, aryl, heteroaryl, Ci_ ₆ alkyl, 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;

R ⁷ and R ⁸ are each independently hydrogen, Ci.ioalkyl, C _2- ioalkenyl, aryl, heteroaryl, heterocyclyl or C3.iocycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R ⁶ ;

R ⁶ is halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² ,

C(=0)NR ³⁴ R ³⁵ , -NO ₂ , -CN, -5(0) ₀ -2 Ci.ioalkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , C ₂ _i ₀ alkenyl, C ₂ .i ₀ alkynyl; aryl-Ci_i ₀ alkyl, aryl-C ₂ .i ₀ alkenyl, aryl- C _2- i ₀ alkynyl, tieteroaryl-Ci_i ₀ alkyl, heteroaryl-C _2- i ₀ alkenyl, heteroaryl-C ₂ .i ₀ alkynyl, 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, - OCi.ioalkyl, Ci_ ₁₀ alkyl, C _2- i ₀ alkenyl, C ₂ .i ₀ alkynyl, haloCi.i ₀ alkyl, haloC ₂ .ioalkenyl, haloC ₂ . loalkynyl, -COOH, -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , - NR ³¹ R ³² , or -NR ³⁴ R ³⁵ ; and R ⁹ is H, halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² , C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ C _1-10 alkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ^3I R ³² , C _2- i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Ci _-10 alkyl, aryl-C _2-10 alkenyl, aryl- C _2-10 alkynyl, heteroaryl-Ci. ₁₀ alkyl, heteroaryl-C _2- ioalkenyl, heteroaryl-C ₂ .i ₀ alkynyl, 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, - OCj.ioalkyl, C oalkyl, C ₂ .] ₀ alkenyl, C ₂ _i ₀ alkynyl, haloCi.ioalkyl, haloC _2- i ₀ alkenyl, haloC ₂ . loalkynyl, -COOH, -C(=0)NR ^3I R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³ R ³⁵ , -S0 ₂ NR ^3I R ³² , -

[0137] In various embodiments of the compound of Formula I-E, the compound has a structure of Formula I-El or Formula I-E2:

Formula I-El Formula I- or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments of Formula I-El, Xi is N and X ₂ is ^' N. In other embodiments, Xi is C-E ¹ and X ₂ is N. In yet other embodiments, Xj is NH and X ₂ is C. In further embodiments, Xi is CH-E ¹ and X ₂ is C.

[0139] In several embodiments of Formula I-E2, X] is N and X ₂ is C. In further embodiments, Xi is C-E ¹ and X ₂ is C.

[0140] In various embodiments, X _! is C-fW^ _j -R ⁴ , where j is 0.

[0141] In another embodiment, Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.

[0142] In various embodiments of Xi, it is C -(W ¹ ^ -R ⁴ . In various embodiments of Xi, j is 1, and W ¹ is -0-. hi various embodiments of Xi, j is 1, and W ¹ is— NR ⁷ -. In various embodiments of Xi, j is 1, and W ¹ is— NH-. In various embodiments of Xi, j is 1, and W ¹ is— S(O) _0-2 -. In various embodiments of Xj, j is 1, and W ¹ is— C(O)-. In various embodiments of Xi, j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments ofX _h j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of X _b j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments ofX _h j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ - In various embodiments of X _ls j is 1, and W ¹ is -C(0)0-. In various embodiments of X,, j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of Xi, j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments ofX j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In various embodiments of X _h j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of X _b j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of Xi, j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of X j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments ofX j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0143] In another embodiment, X] is N.

[0144] In various embodiments, X ₂ is N. In other embodiments, X ₂ is C.

[0145] In various embodiments, E ² is -(W ¹ ^ -R ⁴ , where j is 0.

[0146] In another embodiment, E ² is CH. In yet another embodiment, E ² is C-halogen, where halogen is CI, F, Br, or I.

[0147] In various embodiments of E ² , it is -(W ¹ ^ -R ⁴ . In various embodiments of E ² , j is 1, and W ¹ is -0-. In various embodiments of E ² , j is 1, and W ¹ is— R ⁷ -. In various embodiments of E ² , j is 1, and W ¹ is— NH-. In various embodiments of E ² , j is 1, and W ¹ is— S(O) _0-2 -. In various embodiments of E ² , j is 1, and W ¹ is— C(O)-. In various embodiments of E ² , j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments of E ² , j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ -. In various embodiments of E ² , j is 1, and W ¹ is -C(0)0- In various embodiments of E ² , j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of E , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0148] In various embodiments when Mi is a moiety of Formula I-El, Mi is benzoxazolyl substituted with -(W ₂ ) _k -R ₂ . In some embodiments, Mi is a benzoxazolyl moiety, substituted at the 2-position with -(W ₂ ) _k -R ₂ . In some embodiments, Mi is either a 5- benzoxazolyl or a 6- benzoxazolyl moiety, optionally substituted with -(W ₂ ) _k -R ₂ . Exemplary Formula I-El Mi moieties include but are not limited to the following:

[0149] In various embodiments when Mj is a moiety of Formula I-E2, Formula I-E2 is an aza-

[0150] Exemplary Formula I-E2 Mi moieties include but are not limited to the following:

[0151] In various embodiments of Mi, k is 0. In other embodiments of Mi, k is 1 and W ² is -0-. In another embodiment of Mi, k is 1 and W ² is -NR ⁷ -. In yet another embodiment of Mi, k is 1 and W ² is -S(0)o-2- In another embodiment of Mi, k is 1 and W ² is -C(O)-. In a further embodiment of Mi, k is 1 and W ² is -C(0)N(R ⁷ )-. In another embodiment of Mi, k is 1 and W ² is -N(R ⁷ )C(0)-. In another embodiment, k is 1 and W ² is -N(R ⁷ )C(0)N(R ⁸ )-. hi yet another embodiment of M], k is 1 and W ² is -N(R ⁷ )S(0)-. In still yet another embodiment of Mi, k is 1 and W ² is -N(R ⁷ )S(0) ₂ -. In a further embodiment of M k is 1 and W ² is -C(0)0-. another embodiment of M _b k is 1 and W ² is -CH(R ⁷ )N(C(0)OR ⁸ )-- hi another embodiment of M _b k is 1 and W ² is -CH(R ⁷ )N(C(0)R ⁸ )-. In another embodiment of M,, k is 1 and W ² is - CH(R ⁷ )N(S0 ₂ R ⁸ )-. In a further embodiment of M _h k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )-. In another embodiment of M _u k is 1 and W ² is -CH(R ⁷ )C(0)N(R ⁸ )-. In yet another embodiment of M _b k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )C(0)-. In another embodiment of M,, k is 1 and W ² is - CH(R ⁷ )N(R ⁸ )S(0)-. In yet another embodiment of M k is 1 and W ² is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0152] Additional embodiments of compounds of Formula I, including I-A, I-B, I-C, I-D, I-E and others are described below.

[0153] i various embodiments of compounds of Formula I, L is absent. In another

embodiment, L is -(C=0)-. In another embodiment; L is C(=0)0-. In a further embodiment, L is -C(=0) NR -. In yet another embodiment, L is -S-. In one embodiment, L is -S(O)-. In another embodiment, L is -S(0) ₂ -. In yet another embodiment, L is -S(0) ₂ NR ³¹ -. In another

embodiment, L is -NR ³¹ - .

[0154] In various embodiments of compounds of Formula I, Ri is -L-Ci_i ₀ alkyl, which is unsubstituted. In another embodiment, R _! is -L-Ci.i ₀ alkyl, which is substituted by one or more independent R ³ . In yet another embodiment, Ri is -L- unsubstituted Ci. ₁₀ alkyl, where L is absent. In another embodiment, Ri is -L-Ci.i ₀ alkyl, which is substituted by one or more independent R ³ , and L is absent.

[0155] In various embodiments of compounds of Formula I, Ri is -L-C _3-8 cycloalkyl, which is unsubstituted. In another embodiment, Ri is L-C _3-8 cycloalkyl, which is substituted by one or more independent R ³ . In yet another embodiment, Ri is -L-C ₃ . ₈ cycloalkyl, which is unsubstituted, and L is absent. In a further embodiment, Rj is -L-C3.gcycloalkyl which is substituted by one or more independent R ³ , and L is absent.

[0156] In various embodiments of compounds of Formula I, Ri is H.

[0157] In various embodiments of compounds of Formula I, Ri is -L- aryl, which is

unsubstituted. In another embodiment, Ri is -L- aryl, which is substituted by one or more independent R ³ . In another embodiment, Ri is -L- aryl which is unsubstituted, and L is absent. In yet another embodiment, Ri is -L- aryl, which is substituted by one or more independent R ³ , and L is absent.

[0158] In various embodiments of compounds of Formula I, Ri is -L-heteroaryl, which is unsubstituted. In another embodiment, Ri is -L-heteroaryl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroaryl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L- heteroaryl, which is substituted by one or more independent R ³ , and L is absent.

[0159] In various embodiments of compounds of Formula I, Ri is - L- Ci _-10 alkyl -C ₃ „gcycloalkyl, which is unsubstituted. In another embodiment, Ri is - L- Q.ioalkyl -C3_ ₈ cycloalkyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is - L- Ci _-10 alkyl -C ₃ _ gcycloalkyl which is unsubstituted and L is absent. In yet another embodiment, Ri is - L- Q. _l oalkyl -C ₃ .gcycloalkyl, which is substituted by one or more independent R ³ , and L is absent.

[0160] In various embodiments of compounds of Formula I, Ri is - L-Q.ioalkylaryl, which is unsubstituted. In another embodiment, Ri is - L-Ci_i ₀ alkylaryl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is - L-Ci.i ₀ alkylaryl which is unsubstituted and L is absent. Γη yet another embodiment, ¾ is - L-Ci.i ₀ alkylaryl, which is substituted by one or more independent R ³ , where L is absent.

[0161] In various embodiments of compounds of Formula I, Ri is -L- Ci _-10 alkylheteroaryl, which is unsubstituted. In another embodiment, Ri is -L- Ci.ioalkylheteroaryl, which is substituted by one or more independent R ³ . i a further embodiment, Ri is -L- Ci.ioalkylheteroaryl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L- Ci.ioalkylheteroaryl, which is substituted by one or more independent R ³ , where L is absent.

[0162] hi various embodiments of compounds of Formula I, Ri is -L- Ci.ioalkylheterocyclyl, which is unsubstituted. In another embodiment, Ri is -L- Ci.ioalkylheterocyclyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L- Q.

loalkylheterocyclyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L- Ci.ioalkylheterocyclyl, which is substituted by one or more independent R ³ , where L is absent.

[0163] In various embodiments of compounds of Formula I, Ri is -L-C ₂ .ioalkenyl, which is unsubstituted. In another embodiment, Ri is -L-C ₂ -ioalkenyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-C _2- i ₀ alkenyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-C ₂ -ioalkenyl, which is substituted by one or more independent R ³ , where L is absent.

[0164] In various embodiments of compounds of Formula I, Ri is -L-C ₂ .i ₀ alkynyl, which is unsubstituted. In another embodiment, Rj is -L-C ₂ .i ₀ alkynyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-C ₂ .ioalkynyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-C ₂ .i ₀ alkynyl, which is substituted by one or more independent R ³ , where L is absent.

[0165] In various embodiments of compounds of Formula I, Ri is -L-C ₂ .ioalkenyl-C ₃ . ₈ cycloalkyl, which is unsubstituted. In another embodiment, Ri is -L-C ₂ _i ₀ alkenyl-C ₃ .gcycloalkyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-C ₂ .ioalkenyl-C ₃ . gcycloalkyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-C ₂ . ioalkenyl-C3_ ₈ cycloalkyl, which is substituted by one or more independent R ³ , where L is absent.

[0166] In various embodiments of compounds of Formula I, Ri is -L-C ₂ .ioalkynyl-C ₃ .gcycloalkyl, which is unsubstituted. In another embodiment, Ri is -L-C ₂ .ioalkynyl-C ₃ .gcycloalkyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-C ₂ .i ₀ alkynyl-C ₃ . scycloalkyl which is unsubstituted and L is absent, hi yet another embodiment, Ri is -L-C ₂ . ioalkynyl-C ₃ . ₈ cycloalkyl, which is substituted by one or more independent R ³ , where L is absent. [0167] In various embodiments of compounds of Formula I, Ri is -L-C ₂ -ioalkynyl-C3.gcycloalkyl, which is unsubstituted. In another embodiment, Ri is -L-C _2- ioalkynyl-C3. ₈ cycloalkyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-C ₂ .i ₀ alkynyl-C _{3- 8} cycloalkyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-C _2- ioalkynyl-C _3-8 cycloalkyl, which is substituted by one or more independent R ³ , where L is absent.

[0168] In various embodiments of compounds of Formula I, Ri is -L-heteroalkyl, which is unsubstituted. In another embodiment, Ri is -L-heteroalkyl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroalkyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-heteroalkyl, which is substituted by one or more independent R ³ , where L is absent.

[0169] In various embodiments of compounds of Formula I, Ri is -L-heteroalkylaryl, which is unsubstituted. In another embodiment, Ri is -L-heteroalkylaryl which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroalkylaryl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L-heteroalkylaryl, which is substituted by one or more independent R ³ , where L is absent.

[0170] In various embodiments of compounds of Formula I, Ri is -L-heteroalkylheteroaryl, which is unsubstituted. In another embodiment, Ri is -L-heteroalkylheteroaryl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L- heteroalkylheteroaryl which is unsubstituted and L is absent. In yet another embodiment, Ri is - L-heteroalkylheteroaryl, which is substituted by one or more independent R ³ , where L is absent.

[0171] In various embodiments of compounds of Formula, Ri is -L-heteroalkyl-heterocyclyl, which is unsubstituted. In another embodiment, Ri is -L-heteroalkyl-heterocyclyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroalkyl- heterocyclyl which is unsubstituted, and L is absent. In yet another embodiment, Ri is -L- heteroalkyl-heterocyclyl, which is substituted by one or more independent R ³ , where L is absent.

[0172] In various embodiments of compounds of Formula I, Ri is -L-heteroalkyl-C _3-8 cycloalkyl, which is unsubstituted. In another embodiment, Ri is -L-heteroalkyl-C ₃ . ₈ cycloalkyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroalkyl-C ₃ _ scycloalkyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L- heteroalkyl-C _3-8 cycloalkyl, which is substituted by one or more independent R ³ , where L is absent. [0173] In various embodiments of compounds of Formula I, R _t is -L-aralkyl, which is unsubstituted. In another embodiment, Ri is -L-aralkyl, which is substituted by one or more independent R ³ . In a further embodiment, Rj is -L-aralkyl which is unsubstituted. In yet another embodiment, R _! is -L-aralkyl, which is substituted by one or more independent R ³ , where L is absent.

[0174] In various embodiments of compounds of Formula I, Ri is -L-heteroaralkyl, which is unsubstituted. In another embodiment, R _! is -L-heteroaralkyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heteroaralkyl which is unsubstituted and L is absent. In yet another embodiment, R _! is -L-heteroaralkyl, which is substituted by one or more independent R ³ , where L is absent.

[0175] In various embodiments of compounds of Formula I, Rj is -L-heterocyclyl, which is unsubstituted. In another embodiment, R _x is -L-heterocyclyl, which is substituted by one or more independent R ³ . In a further embodiment, Ri is -L-heterocyclyl which is unsubstituted and L is absent. In yet another embodiment, Ri is -L- heterocyclyl, which is substituted by one or more inde endent R ³ , where L is absent.

[0177] In various embodiments of compounds of Formula I, R ² is hydrogen. In another embodiment, R ² is halogen. In another embodiment, R ² is -OH. In another embodiment, R ² is - R ³¹ . In another embodiment, R ² is -CF ₃ . In another embodiment, R ² is -OCF ₃ . In another embodiment, R is -OR . In another embodiment, R is -NR R . In another embodiment, R ^" is -NR ³⁴ R ³⁵ . In another embodiment, R ² is -C(0)R ³¹ . In another embodiment, R ² is -C0 ₂ R ³¹ . In another embodiment, R ² is -C(=0)NR ³¹ R ³² . In another embodiment, R ² is -C(=0)NR ³⁴ R ³⁵ . In another embodiment, R ² is -N0 ₂ . In another embodiment, R ² is -CN. In another embodiment, R ² is -S(0)o-2R ³ hi another embodiment, R ² is -S0 ₂ NR ³¹ R ³² . In another embodiment, R ² is - S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ² is -NR ³¹ C(=0)R ³² . i another embodiment, R ² is - NR ³¹ C(=0)OR ³² . In another embodiment, R ² is -NR ³¹ C(=0)NR ³² R ³³ . In another embodiment, R ² is - R ³¹ S(0)o¾R ³² . In another embodiment, R ² is -C(=S)OR ³¹ . In another embodiment, R ² is -C(=0)SR ³¹ . In another embodiment, R ² is -NR ³¹ C(=NR ³² )NR ³³ R ³² . In another embodiment, R ² is -NR ^3, C(=NR ³² )OR ³³ . In another embodiment, R ² is -NR ³¹ C(=NR ³ )SR ³³ . In another embodiment, R ² is -OC(=0)OR ³³ . In another embodiment, R ² is -OC(=0)NR ³¹ R ³² . In another embodiment, R ² is -OC(=0)SR ³¹ . hi another embodiment, R ² is -SC(=0)OR ³¹ . In another embodiment, R ² is -P(0)OR ^3I OR ³² . In another embodiment, R ² is -SC(=0)NR ³¹ R ³² . In another embodiment, R ² is monocyclic aryl. In another embodiment, R ² is bicyclic aryl. In another embodiment, R ² is substituted monocyclic aryl. In another embodiment, R ² is heteroaryl. In another embodiment, R ² is Ci_ ₄ alkyl. In another embodiment, R ² is Cj.ioalkyl. In another embodiment, R ² is C _3-8 cycloalkyl. In another embodiment, R ² is C _3-8 cycloalkyl- Ci _-10 alkyl. In another embodiment, R ² is Ci.i ₀ alkyl -C _3-8 cycloalkyl. In another embodiment, R ² is Q.ioalkyl- monocyclic aryl. In another embodiment, R ² is C2-ioalkyl-monocyclic aryl. In another embodiment, R ² is monocyclic aryl- C _2- ioalkyl. In another embodiment, R ² is Ci-ioalkyl- bicyclicaryl. In another embodiment, R ² is bicyclicaryl- Ci.i ₀ alkyl. In another embodiment, R ² is - Ci.ioalkylheteroaryl. In another embodiment, R ² is - Ci.ioalkylheterocyclyl. In another embodiment, R ² is -C2-ioalkenyl. In another embodiment, R ² is -C _2- ioalkynyl. In another embodiment, R ² is C2-ioalkenylaryl. In another embodiment, R ² is C2-ioalkenylheteroaryl. In another embodiment, R ² is C ₂ -ioalkenylheteroalkyl. In another embodiment, R ² is C _{2- 10} alkenylheterocyclcyl. In another embodiment, R ² is -C ₂ .ioalkynylaryl. In another embodiment, R ² is -C ₂ -ioalkynylheteroaryl. In another embodiment, R ² is -C ₂ -ioalkynylheteroalkyl. In another embodiment, R ² is -C _2- i ₀ alkynylheterocyclyl. In another embodiment, R ² is -C2-ioalkynylC ₃ . gcycloalkyl. In another embodiment, R ² is -C ₂ .ioalkynylC _3-8 cycloalkenyl. In another embodiment, R ² is - Ci.ioalkoxy-Ci.ioalkyl. In another embodiment, R ² is - In another embodiment, R ² is - Ci.ioalkoxy-C ₂ -ioalkynyl. In another embodiment, R ² is - heterocyclyl Q.ioalkyl. In another embodiment, R ² is heterocyclylC ₂ _ioalkenyl. In another embodiment, R ² is heterocyclylC2-ioalkynyl. In another embodiment, R ² is aryl-C ₂ _ioalkyl. In another embodiment, R ² is aryl-Ci.ioalkyl. In another embodiment, R ² is aryl-C ₂ .i ₀ alkenyl. In another embodiment, R ² is aryl-C2-ioalkynyl. In another embodiment, R ² is aryl-heterocyclyl. In another embodiment, R ² is heteroaryl- Ci _-10 alkyl. In another embodiment, R ² is heteroaryl-C ₂ . _l oalkenyl. In another embodiment, R ² is heteroaryl-C2_ioalkynyl. . In another embodiment, R ² is heteroaryl- CVscycloalkyl. In another embodiment, R ² is heteroaryl- heteroalkyl. In another embodiment, R ² is heteroaryl- heterocyclyl.

[0178] In various embodiments of compounds of Formula I, R ³ is hydrogen. In another embodiment, R ³ is halogen. In another embodiment, R ³ is -OH. In another embodiment, R ³ is - R ³¹ . In another embodiment, R ³ is -CF ₃ . In another embodiment, R ³ is -OCF ₃ . In another embodiment, R is -OR . In another embodiment, R is -NR R . In another embodiment, R is -NR ³⁴ R ³⁵ . In another embodiment, R ³ is -C(0)R ³¹ . In another embodiment, R ³ is -C0 ₂ R ³¹ . In another embodiment, R ³ is -C(=0)NR ³¹ R ³² . In another embodiment, R ³ is -C(=0)NR ³⁴ R ³⁵ . In another embodiment, R ³ is -N0 ₂ . In another embodiment, R ³ is -CN. In another embodiment, R ³ is -S(0)o_ ₂ R ³ In another embodiment, R ³ is -S0 ₂ NR ³¹ R ³² . In another embodiment, R ³ is - S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ³ is -NR ³¹ C(=0)R ³² . In another embodiment, R ³ is - NR ^3I C(=0)OR ³² . In another embodiment, R ³ is - R ³¹ C(=0)NR ³² R ³³ . In another embodiment, R ³ is -NR ³¹ S(0)o- ₂ R ³² . In another embodiment, R ³ is -C(=S)OR ³¹ . In another embodiment, R ³ is -C(=0)SR ³¹ . In another embodiment, R ³ is -NR ³¹ C(=NR ³² )NR ³³ R ³² . In another embodiment, R ³ is -NR ³¹ C(=NR ³² )OR ³³ . In another embodiment, R ³ is -NR ¹ C(=NR ³² )SR ³³ . In another embodiment, R ³ is -OC(=0)OR ³³ . In another embodiment, R ³ is -OC(=0)NR ³¹ R ³² . In another embodiment, R ³ is -OC(=0)SR ³¹ . In another embodiment, R ³ is -SC(=0)OR ³¹ . hi another embodiment, R ³ is -P(0)OR ³¹ OR ³² . In another embodiment, R ³ is -SC(=0)NR ³¹ R ³² . In another embodiment, R ³ is aryl. In another embodiment, R ² is heteroaryl. In another embodiment, R ³ is C _1-4 alkyl. In another embodiment, R ³ is Ci.i ₀ alkyl. In another embodiment, R ³ is C ₃ . ₈ cycloalkyl. In another embodiment, R ³ is C _3-8 cycloalkyl- Ci.i ₀ alkyl. In another embodiment, R ³ is - C . _l oalkyl -C ₃ .gcycloalkyl. In another embodiment, R ³ is C _2- i ₀ alkyl-monocyclic aryl. In another embodiment, R ³ is monocyclic aryl- C _2-]0 alkyl. In another embodiment, R ³ is C _1-10 alkyl- bicyclicaryl. In another embodiment, R ³ is bicyclicaryl- Ci.ioalkyl. In another embodiment, R ³ is Ci.i ₀ alkylheteroaryl. In another embodiment, R ³ is Ci.i ₀ alkylheterocyclyl. In another

embodiment, R ³ is C _2-10 alkenyl. In another embodiment, R ³ is C _2- i ₀ alkynyl. In another embodiment, R ³ is C ₂ _i ₀ alkenylaryl. In another embodiment, R ³ is C ₂ . ₁₀ alkenylheteroaryl. In another embodiment, R ³ is C ₂ .i ₀ alkenylheteroalkyl. In another embodiment, R ³ is C ₂ .

loalkenylheterocyclcyl. In another embodiment, R ³ is -C ₂ _ioalkynylaryl. In another embodiment, R ³ is -C _2- ioalkynylheteroaryl. In another embodiment, R ³ is -C _2- ioalkynylheteroalkyl. In another embodiment, R ³ is C ₂ .i ₀ alkynylheterocyclyl. In another embodiment, R ³ is -C ₂ .i ₀ alkynylC _3- gcycloalkyl. In another embodiment, R ³ is C ₂ _ioalkynylC _3-8 cycloalkenyl. In another embodiment, R ³ is - Ci.ioalkoxy-Q.ioalkyl. In another embodiment, R ³ is Ci_i ₀ alkoxy-C ₂ .i ₀ alkenyl. In another embodiment, R ³ is - Ci_ioalkoxy-C _2- ioalkynyl. In another embodiment, R ³ is heterocyclyl- Ci_ _l oalkyl. In another embodiment, R ³ is -heterocyclylC ₂ .i ₀ alkenyl. In another embodiment, R ³ is heterocyclyl-C _2- i ₀ alkynyl. In another embodiment, R ³ is aryl-Ci.ioalkyl. In another embodiment, R ³ is aryl-C _2- ioalkenyl. In another embodiment, R ³ is aryl-C ₂ _i ₀ alkynyl. In another embodiment, R ³ is aryl-heterocyclyl. In another embodiment, R ³ is heteroaryl- Ci _-10 alkyl. In another embodiment, R ³ is heteroaryl-C _2- i ₀ alkenyl. In another embodiment, R ³ is heteroaryl-C _2- i ₀ alkynyl. In another embodiment, R ³ is heteroaryl- C ₃ . ₈ cycloalkyl. In another embodiment, R ³ is heteroaryl- heteroalkyl. In another embodiment, R ³ is heteroaryl- heterocyclyl.

[0179] In various embodiments of compounds of Formula I, R ⁴ is hydrogen. In another embodiment, R ⁴ is halogen. In another embodiment, R ⁴ is -OH. In another embodiment, R ⁴ is - R ³¹ . In another embodiment, R ⁴ is -CF ₃ . In another embodiment, R ⁴ is -OCF ₃ . In another embodiment, R ⁴ is -OR ³¹ . In another embodiment, R ⁴ is -NR ³¹ R ³² . In another embodiment, R ⁴ is -NR ³⁴ R ³⁵ . In another embodiment, R ⁴ is -C(0)R ³¹ . In another embodiment, R ⁴ is -C0 ₂ R ³¹ . In another embodiment, R ⁴ is -C(=0)NR ³¹ R ³² . In another embodiment, R ⁴ is -C(=0)NR ³⁴ R ³⁵ . In another embodiment, R ⁴ is -N0 ₂ . In another embodiment, R ⁴ is -CN. In another embodiment, R ⁴ is -S(O) ₀ _ ₂ R ³ In another embodiment, R ⁴ is -S0 ₂ NR ³¹ R ³² . In another embodiment, R ⁴ is - S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ⁴ is -NR ³¹ C(=0)R ³² . In another embodiment, R ⁴ is - NR ³¹ C(=0)0R ³² . In another embodiment, R ⁴ is -NR ³¹ C(=0)NR ³² R ³³ . In another embodiment, R ⁴ is -NR ³¹ S(OV ₂ R ³² . In another embodiment, R ⁴ is -C(=S)OR ³¹ . In another embodiment, R ⁴ is -C(=0)SR ³¹ . In another embodiment, R ⁴ is -NR ³¹ C(=NR ³ )NR ³³ R ³² . In another embodiment, R ⁴ is -NR ³¹ C(=NR ³² )OR ³³ . In another embodiment, R ⁴ is -NR ³¹ C(=NR ³² )SR ³³ . In another embodiment, R ⁴ is -OC(=0)OR ³³ . In another embodiment, R ⁴ is -OC(=0)NR ³¹ R ³² . In another embodiment, R ⁴ is -OC(=0)SR ³¹ . In another embodiment, R ⁴ is -SC(=0)OR ³¹ . In another embodiment, R ⁴ is -P(0)OR ^3I OR ³² . In another embodiment, R ⁴ is -SC(=0)NR ^3I R ³² . In another embodiment, R ⁴ is aryl. In another embodiment, R ⁴ is heteroaryl. In another embodiment, R ⁴ is Ci_ ₄ alkyl. In another embodiment, R ⁴ is C _1-10 alkyl. In another embodiment, R ⁴ is C _3-8 cycloalkyl. In another embodiment, R ⁴ is Ci-ioalkyl -C ₃ . _g cycloalkyl. In another embodiment, R ⁴ is Q.

loalkylaryl. In another embodiment, R ⁴ is Ci.ioalkylheteroaryl. In another embodiment, R ⁴ is Ci_ _l oalkylheterocyclyl. In another embodiment, R ⁴ is C ₂ _i ₀ alkenyl. In another embodiment, R ⁴ is C ₂ . _l oalkynyl. In another embodiment, R ⁴ is C _i ₀ alkynyl- C _3-8 cycloalkyl. R ⁴ is C _2- i ₀ alkenyl- C _3- scycloalkyl. In another embodiment, R ⁴ is C _2- ioalkenylaryl. In another embodiment, R ⁴ is C _{2- l} oalkenyl-heteroaryl. In another embodiment, R ⁴ is C ₂ .i ₀ alkenylheteroalkyl. In another embodiment, R ⁴ is C _2- i ₀ alkenylheterocyclcyl. In another embodiment, R ⁴ is -C _2- i ₀ alkynylaryl. In another embodiment, R ⁴ is C ₂ _ioalkynylheteroaryl. In another embodiment, R ⁴ is C _{2- l} oalkynylheteroalkyl. In another embodiment, R ⁴ is C ₂ _ioalkynylheterocyclyl. In another embodiment, R ⁴ is C ₂ _ioalkynylC ₃ _ ₈ cycloalkyl. In another embodiment, R ⁴ is heterocyclyl Ci_ _l oalkyl. In another embodiment, R ⁴ is heterocyclylC _2- i ₀ alkenyl. In another embodiment, R ⁴ is heterocyclyl-C _2- ioalkynyl. In another embodiment, R ⁴ is aryl- Ci.ioalkyl. In another embodiment, R ⁴ is aryl-C _2- i ₀ alkenyl. In another embodiment, R ⁴ is aryl-C ₂ .i ₀ alkynyl. In another embodiment, R ⁴ is aryl-heterocyclyl. In another embodiment, R ⁴ is heteroaryl- Ci.ioalkyl. In another embodiment, R ⁴ is heteroaryl-C2_ioalkenyl. In another embodiment, R ⁴ is heteroaryl-C2-ioalkynyl. In another embodiment, R ⁴ is C ₃ . ₈ cycloalkyl- Ci.i ₀ alkyl. In another embodiment, R ⁴ is C ₃ .

gcycloalkyl- C _2- ioalkenyl. In another embodiment, R ⁴ is C _3-8 cycloalkyl- C ₂ _ioalkynyl.

[0180] In various embodiments of compounds of Formula I, R ^s is hydrogen. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is -OH. In another embodiment, R ⁵ is - R ³¹ . In another embodiment, R ⁵ is -CF ₃ . In another embodiment, R ⁵ is -OCF ₃ . hi another embodiment, R ⁵ is -OR ³¹ . In another embodiment, R ⁵ is -NR ³¹ R ³² . In another embodiment, R ⁵ is -NR ³⁴ R ³⁵ . In another embodiment, R ⁵ is -C(0)R ³¹ . In another embodiment, R ⁵ is -C0 ₂ R ³¹ . In another embodiment, R ⁵ is -C(=0)NR ³¹ R ³² . In another embodiment, R ⁵ is -C(=0)NR ³⁴ R ³⁵ . In another embodiment, R ⁵ is -N0 ₂ . In another embodiment, R ⁵ is -CN. In another embodiment, R ⁵ is -S(0)o- ₂ R ³¹ . In another embodiment, R ⁵ is -S0 ₂ NR ³¹ R ³² . hi another embodiment, R ⁵ is - S0 ₂ NR ³ R ³⁵ . In another embodiment, R ⁵ is -NR ³¹ C(=0)R ³² . In another embodiment, R ⁵ is - NR ³¹ C(=0)0R ³² . In another embodiment, R ⁵ is -NR ^I C(=0)NR ³² R ³³ . In another embodiment, R ⁵ is -NR ³¹ S(0)o ₂ R ³² . In another embodiment, R ⁵ is -C(=S)OR ³¹ . In another embodiment, R ⁵ is -C(=0)SR ³¹ . In another embodiment, R ⁵ is - R ^3I C(=NR ³² )NR ³³ R ³² . In another embodiment, R ⁵ is -NR ³¹ C(=NR ³ )0R ³³ . In another embodiment, R ⁵ is -NR ³¹ C(=NR ³² )SR ³³ . In another embodiment, R ⁵ is -0C(=0)0R ³³ . In another embodiment, R ⁵ is -0C(=0)NR ³¹ R ³² . In another embodiment, R ⁵ is -OC(=0)SR ³¹ . In another embodiment, R ⁵ is -SC(=0)OR ³¹ . In another embodiment, R ⁵ is -P(0)OR ³¹ OR ³² . In another embodiment, R ⁵ is or -SC(=0)NR ³¹ R ³² .

[0181] In various embodiments of compounds of Formula I, R ⁷ is hydrogen. In another embodiment, R ⁷ is unsubstituted Q.ioalkyl. In another embodiment, R ⁷ is unsbustituted C _{2- l} oalkenyl. In another embodiment, R ⁷ is unsubstituted aryl. In another embodiment, R ⁷ is unsubstituted heteroaryl. In another embodiment, R ⁷ is unsubstituted heterocyclyl. In another embodiment, R ⁷ is unsubstituted C _3- i ₀ cycloalkyl. In another embodiment, R ⁷ is Ci.i ₀ alkyl substituted by one or more independent R ⁶ . In another embodiment, R ⁷ is C _2- i ₀ alkenyl substituted by one or more independent R ⁶ . In another embodiment, R ⁷ is aryl substituted by one or more independent R ⁶ . In another embodiment, R ⁷ is heteroaryl substituted by one or more independent R ⁶ . In another embodiment, R ⁷ is heterocycly substituted by one or more independent R ⁶ . In another embodiment, R ⁷ is C ₃ _iocycloalkyl substituted by one or more independent R ⁶ .

[0182] In various embodiments of compounds of Formula I, R ⁸ is hydrogen. In another embodiment, R ⁸ is unsubstituted C^oalkyl. hi another embodiment, R ⁸ is unsubstituted C ₂ _ _l oalkenyl. In another embodiment, R ⁸ is unsubstituted aryl. In another embodiment, R ⁸ is unsubstituted heteroaryl. In another embodiment, R ⁸ is unsubstituted heterocyclyl. In another embodiment, R is unsubstituted C3.iocycloalkyl. In another embodiment, R is Ci_ ₁₀ alkyl substituted by one or more independent R ⁶ . In another embodiment, R ⁸ is C _2- ioalkenyl substituted by one or more independent R ⁶ . In another embodiment, R ⁸ is aryl substituted by one or more independent R ⁶ . In another embodiment, R ⁸ is heteroaryl substituted by one or more independent R ⁶ . In another embodiment, R ⁸ is heterocyclyl substituted by one or more independent R ⁶ . In another embodiment, R ⁸ is Q-iocycloalkyl substituted by one or more independent R ⁶ .

[0183] In various embodiments of compounds of Formula I, R ⁶ is halo. In another embodiment, R ⁶ is-OR ³¹ . i another embodiment, R ⁶ is -SH. In another embodiment, R ⁶ is NH ₂ . In another embodiment, R ⁶ is -NR ³⁴ R ³⁵ . In another embodiment, R ⁶ is - NR ³¹ R ³² . In another embodiment, R ⁶ is -CO2R ³¹ . In another embodiment, R ⁶ is -C0 ₂ aryl. In another embodiment, R ⁶ is - C(=0)NR ³¹ R ³² . In another embodiment, R ⁶ is C(=0) NR ³⁴ R ³⁵ . In another embodiment, R ⁶ is - N0 ₂ . In another embodiment, R ⁶ is -CN. In another embodiment, R ⁶ is -S(O) ₀ _2 Ci.ioalkyl. In another embodiment, R ⁶ is -S(O) ₀ 2aryl. In another embodiment, R ⁶ is -S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ⁶ is -S0 ₂ NR ³¹ R ³² . In another embodiment, R ⁶ is Ci.ioalkyl. In another embodiment, R ⁶ is C ₂ .ioalkenyl. In another embodiment, R ⁶ is C2-ioalkynyl. In another embodiment, R ⁶ is unsubstituted aryl-Ci.ioalkyl. In another embodiment, R ⁶ is unsubstituted aryl- C2-ioalkenyl. In another embodiment, R ⁶ is unsubstituted aryl-C _2- ioalkynyl. In another embodiment, R ⁶ is unsubstituted heteroaryl-Ci.i ₀ alkyl. In another embodiment, R ⁶ is unsubstituted heteroaryl-C _2- ioalkenyl. In another embodiment, R ⁶ is aryl-Ci_i ₀ alkyl, aryl-Q. _l oalkenyl, aryl-C ₂ .ioalkynyl, heteroaryl-Q_i ₀ alkyl, or heteroaryl-C _2- ioalkenyl substituted by one or more independent halo. In another embodiment, R ⁶ is aryl-Q.i ₀ alkyl, aryl-C _2- ioalkenyl, aryl-C _2- i ₀ alkynyl, heteroaryl-Ci.i ₀ alkyl, or heteroaryl-C _2- ioalkenyl substituted by one or more independent cyano. In another embodiment, R ⁶ is aryl-Q.ioalkyl, aryl-C2_ioalkenyl, aryl-C ₂ .ioalkynyl, heteroaryl-Ci-ioalkyl, or heteroaryl-C _2- ioalkenyl substituted by one or more independent nitro. In another embodiment, R ⁶ is aryl-Ci.ioalkyl, aryl-C2-ioalkenyl, aryl-C2-ioalkynyl, heteroaryl-Q_ _l oalkyl, or heteroaryl-Q.ioalkenyl substituted by one or more independent -OQ.ioalkyl. In another embodiment, R ⁶ is aryl-Q.ioalkyl, aryl-Q-ioalkenyl, aryl-C2-ioalkynyl, heteroaryl-Ci. _l oalkyl, or heteroaryl-Q-ioalkenyl substituted by one or more independent -Q.^alkyl. In another embodiment, R ⁶ is aryl-Ci.i ₀ alkyl, aryl-Q-ioalkenyl, aryl-C ₂ -ioalkynyl, heteroaryl-Ci.i ₀ alkyl, or heteroaryl-C2-ioalkenyl substituted by one or more independent - Q-ioalkenyl. In another embodiment, R ⁶ is aryl-Q.i ₀ alkyl, aryl-C ₂ .ioalkenyl, aryl-Q-ioalkynyl, heteroaryl-Q.i ₀ alkyl, or heteroaryl-C _2- ioalkenyl substituted by one or more independent - Q-ioalkynyl. In another embodiment, R ⁶ is aryl-Q.i ₀ alkyl, aryl-C _2- ioalkenyl, aryl-C _2- ioalkynyl, heteroaryl-Q.i ₀ alkyl, or heteroaryl-C2-ioalkenyl substituted by one or more independent -(halo)Q_i ₀ alkyl. In another embodiment, R ⁶ is aryl-Q.ioalkyl, aryl-C _2- ioalkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ -ioalkenyl substituted by one or more independent - (halo)C ₂ -ioalkenyl. In another embodiment, R ⁶ is aryl-Ci.i ₀ alkyl, aryl-C _2- ioalkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ .ioalkenyl substituted by one or more independent - (halo)C _2- ioalkynyl. In another embodiment, R ⁶ is aryl-Ci.ioalkyl, aryl-C ₂ _ioalkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C _2- i ₀ alkenyl substituted by one or more independent -COOH. In another

embodiment, R ⁶ is aryl-Ci.i ₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ _i ₀ alkenyl substituted by one or more independent -C(=0)NR ³¹ R ³² . In another embodiment, R ⁶ is aryl-Ci_i ₀ alkyl, aryl-C ₂ .i ₀ alkenyl, aryl-C ₂ _ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ -ioalkenyl substituted by one or more independent -C(=0) NR ³⁴ R ³⁵ . In another embodiment, R ⁶ is aryl-Ci.i ₀ alkyl, aryl-C ₂ -ioalkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ .ioalkenyl substituted by one or more independent -S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ⁶ is aryl-Ci.i ₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl-C _2- ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ -ioalkenyl substituted by one or more independent -SO ₂ R ³¹ R ³² . In another embodiment, R ⁶ is aryl-Ci_i ₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl-C _2- i ₀ alkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ -ioalkenyl substituted by one or more independent -NR ³¹ R ³² . In another embodiment, R ⁶ is aryl-Ci-i ₀ alkyl, aryl-C ₂ -ioalkenyl, aryl-C ₂ _i ₀ alkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ .i ₀ alkenyl substituted by one or more independent -NR ³⁴ R ³⁵ .

[0184] In various embodiments of compounds of Formula I, R ⁹ is H. In another embodiment, R ⁹ is halo. In another embodiment, R ⁹ is-OR ³¹ . hi another embodiment, R ⁹ is -SH. In another embodiment, R ⁹ is NH ₂ . In another embodiment, R ⁹ is -NR ³⁴ R ³⁵ . In another embodiment, R ⁹ is - NR ³¹ R ³² . In another embodiment, R ⁹ is -C0 ₂ R ³¹ . In another embodiment, R ⁹ is -C0 ₂ aryl. In another embodiment, R ⁹ is -C(=0)NR ³¹ R ³² . In another embodiment, R ⁹ is C(=0) NR ³⁴ R ³⁵ . In another embodiment, R ⁹ is -N0 ₂ . In another embodiment, R ⁹ is -CN. In another embodiment, R ⁹ is -S(O) ₀ - ₂ Ci-ioalkyl. In another embodiment, R ⁹ is -S(O) o- ₂ aryl. In another embodiment, R ⁹ is -S0 ₂ NR ³⁴ R ³⁵ . In another embodiment, R ⁹ is -S0 ₂ NR ³¹ R ³² . In another embodiment, R ⁹ is Ci_ _l oalkyl. In another embodiment, R ⁹ is C _2- i ₀ alkenyl. In another embodiment, R ⁹ is C _2- i ₀ alkynyl. In another embodiment, R ⁹ is unsubstituted aryl-Ci.i ₀ alkyl. In another embodiment, R ⁹ is unsubstituted aryl-C _2- i ₀ alkenyl. In another embodiment, R ⁹ is unsubstituted aiyl-C _2- i ₀ alkynyl. In another embodiment, R ⁹ is unsubstituted heteroaryl-Ci.ioalkyl. hi another embodiment, R ⁹ is unsubstituted heteroaryl-C ₂ .i ₀ alkenyl. In another embodiment, R ⁹ is aryl-Q.ioalkyl, aryl-C ₂ . _l oalkenyl, aryl-C ₂ -ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ . ₁₀ alkenyl substituted by one or more independent halo. In another embodiment, R ⁹ is aryl-Ci.i ₀ alkyl, aryl-C ₂ .i ₀ alkenyl, aryl-C ₂ . _l oalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C ₂ _i ₀ alkenyl substituted by one or more independent cyano. In another embodiment, R ⁹ is aryl-Ci.i ₀ alkyl, aryl-C2-ioalkenyl, aryl-C ₂ -ioalkynyl, heteroaryl-Ci.ioalkyl, or heteroaryl-C2-ioalkenyl substituted by one or more independent nitro. In various embodiments of compounds of Formula I, R ³¹ is H. In some embodiments, R ³¹ is unsubstituted Ci.ioalkyl. In some embodiments, R ³¹ is substituted Ci_i ₀ alkyl. In some

embodiments, R ^3I is Ci_i ₀ alkyl substituted with one or more aryl. In some embodiments, R ¹ is Q. _l oalkyl substituted with one or more heteroalkyl. In some embodiments, R ³¹ is Ci.ioalkyl substituted with one or more heterocyclyl. In some embodiments, R ³¹ is Ci.ioalkyl substituted with one or more heteroaryl.

[0185] In various embodiments of compounds of Formula I, R ³² is H. In some embodiments, R ³² is unsubstituted Ci.ioalkyl. In some embodiments, R ³² is substituted Ci.ioalkyl. In some embodiments, R ³² is Ci.ioalkyl substituted with one or more aryl. In some embodiments, R ³² is Q. _l oalkyl substituted with one or more heteroalkyl. In some embodiments, R ³² is Ci.ioalkyl substituted with one or more heterocyclyl. In some embodiments, R ³² is Ci.ioalkyl substituted with one or more heteroaryl.

[0186] In various embodiments of compounds of Formula I, R ³³ is unsubstituted Ci.ioalkyl. In some embodiments, R ³³ is substituted Ci.ioalkyl. In some embodiments, R ³³ is Ci.ioalkyl substituted with one or more aryl. In some embodiments, R ³³ is Ci.ioalkyl substituted with one or more heteroalkyl. In some embodiments, R ³³ is Ci.ioalkyl substituted with one or more heterocyclyl. In some embodiments, R ³³ is Ci.ioalkyl substituted with one or more heteroaryl.

[0187] In various embodiments of compounds of Formula I, R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , - C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halogen, oxo, aryl, heteroaryl, Ci^alkyl, 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.

[0188] In some embodiments, the R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ R ³⁴ R ³⁵ , are taken to ether with the nitro en atom to which the are attached to form:

[0189] In another embodiment, X _x is C— NH ₂ .

[0190 In various embodiments Xj is C— NH -R ⁴ ,where -NH-R ⁴ is:

[0191] In one embodiment, the invention provides an inhibitor of Formula I-Cl where R ⁵ is H. In another embodiment, the invention provides an inhibitor of Formula I-C2 where R ⁵ is H.

[0192] In some embodiments of the invention, the mTORCl/2 inhibitor is a compound of Formula I-Cl a:

Formula I-Cla

or a pharmaceuctically acceptable salt thereof wherein:

E ² is -H;

Ri is -L-Ci_i ₀ alkyl, -L-C3. ₈ cycloalkyl, -L- Ci.ioalkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

R ³ is hydrogen, -OH, -OR ³¹ , -NR ^3I R ³² , -C(0)R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , aryl,

heteroaryl, Q^alkyl, Q-ioalkyl, C ₃ ,gcycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ R ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , - R ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , - R ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

-(W ² ) _k - is -NH-, -N(H)C(0)- or -N(H)S(0) ₂ -;

R ² is hydrogen, halogen, -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , - C(=0)NR ³⁴ R ³⁵ ,-S(0)o- ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , bicyclic aryl, substituted monocyclic aryl, heteroaryl, Ci.ioalkyl, C _3-8 cycloalkyl, Ci.ioalkyl-C _3- gcycloalkyl, C ₃ _ gcycloalkyl- Q.ioalkyl, C _3-8 cycloalkyl- C _2- ioalkenyl, C _3-8 cycloalkyl- C _2- ioalkynyl, C _{2- l} oalkyl-monocyclic aryl, monocyclic aryl-C ₂ _ioalkyl, Ci.ioalkylbicycloaryl, bicycloaryl— Q.ioalkyl, substituted Ci.ioalkylaryl, substituted aryl-Ci.ioalkyl, Q.ioalkylheteroaryl, Q. loalkylheterocyclyl, C _2- ioalkenyl, C ₂ -ioalkynyl, C ₂ -ioalkenylaryl, C _2- ioalkenylheteroaryl, C ₂ .i ₀ alkenylheteroalkyl, C _2-10 alkenylheterocyclcyl, C ₂ .i ₀ alkynylaryl, C _{2- l} oalkynylheteroaryl, C2-ioalkynylheteroalkyl, C ₂ -ioalkynylheterocyclyl, C ₂ .i ₀ alkenyl-C _3- gcycloalkyl, Q_i ₀ alkynyl-Q _-8 cycloalkenyl, Q.ioalkoxy Ci.i ₀ alkyl, Ci.ioalkoxyC _2- ioalkenyl, Ci.ioalkoxyC _2- ioalkynyl, heterocyclyl, heterocyclyl .ioalkyl, heterocyclylC ₂ .i ₀ alkenyl, heterocyclyl-C _2- i ₀ alkynyl, aryl-C _2- ioalkenyl, aryl-C ₂ .ioalkynyl, aryl-heterocyclyl, heteroaryl-Ci-ioalkyl, heteroaryl-C _2- ioalkenyl, heteroaryl-C _2- ioalkynyl, heteroaryl-Q_ gcycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , - NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³ R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , - OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or- SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or - C(=0)NR ³¹ R ³² ;

R , R , and R , in each instance, are independently H or Q.ioalkyl, wherein the Q.ioalkyl is unsubstituted; and

R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halo gen, oxo, aryl, heteroaryl, Q_ ₆ alkyl, 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.

[0193] In another aspect, the mTORCl/2 inhibitor of Formula I-Cl is a compound of Formula I- Cla:

Formula I-Cla

or a pharmaceutically acceptable salt thereof, wherein: E ² is -H; Xi is CH and X ₂ is N;

Ri is -L-Ci.ioalkyl, -L-C _3-8 cycloalkyl, -L- Ci.ioalkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0)-, -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

R ³ is hydrogen, -OH, -OR ³¹ , - R ³¹ R ³² , -C(0)R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , aryl,

heteroaryl, C _1-4 alkyl, Ci_i ₀ alkyl, C _3-8 cycloalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ R ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

-(W ² ) _k - is -NH-, -N(H)C(0)- or -N(H)S(0) ₂ -;

R ² is hydrogen, halogen, -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , - C(=0)NR ³⁴ R ³⁵ ,-S(0)o_ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , bicyclic aryl, substituted monocyclic aryl, heteroaryl, Ci.i ₀ alkyl, C _3-8 cycloalkyl, Ci.ioalkyl-C _3-8 cycloalkyl, C ₃ _ gcycloalkyl- Ci.ioalkyl, C _2- ioalkyl-monocyclic aryl, monocyclic aryl-C _2- ioalkyl, Ci_ loalkylbicycloaryl, bicycloaryl— Ci.ioalkyl, substituted Ci_i ₀ alkylaryl, substituted aryl-Ci. loalkyl, Ci.i ₀ alkylheteroaryl, Ci.ioalkylheterocyclyl, C ₂ .i ₀ alkenyl, C ₂ .i ₀ alkynyl, heterocyclyl, heterocyclyl Ci_i ₀ alkyl, heterocyclyl-C ₂ _i ₀ alkenyl, heterocyclyl-C ₂ _ioalkynyl, aryl-heterocyclyl, heteroaryl-Ci.ioalkyl, 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0) R ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

31 32 33 *

R , R , and R , in each instance, are independently H or Ci_i ₀ alkyl, wherein the Ci.ioalkyl is unsubstituted; and

R ³⁴ and R ³⁵ in -NR ⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halogen, oxo, aryl, heteroaryl, 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.

[0194] In some other embodiments, the mTORCl/2 inhibitor is a compound of Formula I-A:

Formula I-A

or a pharmaceutically acceptable salt thereof, wherein:

Xi is N or C-E ¹ , X ₂ is N, X ₃ is C, and X ₄ is C-R ⁹ or N; or Χ _λ is N or C-E ¹ , X ₂ is C, X ₃ is N, and X ₄ is C-R ⁹ or N;

Ri is -H, -L-Ci_i ₀ alkyl, -L-C _3-8 cycloalkyl, -L-Ci_ ₁₀ alkyl -C ₃ _ ₈ cycloalkyl, -L- aryl, -L-heteroaryl, - L-Ci.ioalkylaryl, -L- Ci.ioalkylheteroaryl, -L- Ci.i ₀ alkylheterocyclyl, -L-C _2- ioalkenyl, -L- C _2- i ₀ alkynyl, -L-C _2- i ₀ alkenyl-C _3-8 cycloalkyl, -L-C _2- ioalkynyl-C _3-8 cycloalkyl, -L- heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl, -L-heteroalkyl-heterocyclyl, -L- heteroalkyl-C3.gcycloalkyl, -L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R ³ ;

L is absent, -(C=0 , -C(=0)0-, -C(=0) N(R ³¹ )-,-S-, -S(O)-, -S(0) ₂ -, -S(0) ₂ N(R ³¹ )-, or -N(R ³¹ )-;

Mi is benzothiazolyl substituted with -(W ² ) _k -R ² ;

k is 0 or 1;

E ¹ and E ² are independently -(W^ _j -R ⁴ ;

j, in each instance (i.e., in E ¹ or j in E ² ), is independently 0 or 1

W ¹ is -O- -NR ⁷ -, -S(0)o-2- -C(0)-,-C(0)N(RV, -N(R ⁷ )C(0)-, -N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ -

-C(0)0-, -CH(R ⁷ )N(C(0)OR ⁸ H -CH(R ⁷ )N(C(0)R ⁸ H -CH(R ⁷ )N(S0 ₂ R ⁸ H - CH(R ⁷ )N(R ⁸ K -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, -CH(R ⁷ )N(R ⁸ )S(0)-, or - CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

W ² is -0-, -NR ⁷ -, -S(0)o- ₂ -,-C(0)-,-C(0)N(R ⁷ )-, -N(R ⁷ )C(0)-, -N(R ⁷ )C(0)N(R ⁸ )-,-

N(R ⁷ )S(0)-, -N(R ⁷ )S(0) ₂ -,-C(0)0- -CH(R ⁷ )N(C(0)OR ⁸ )-, -CH(R ⁷ )N(C(0)R ⁸ )-, - CH(R ⁷ )N(S0 ₂ R ⁸ }-, -CH(R ⁷ )N(R ⁸ >-, -CH(R ⁷ )C(0)N(R ⁸ )-, -CH(R ⁷ )N(R ⁸ )C(0)-, - CH(R ⁷ )N(R ⁸ )S(OH or -CH(R ⁷ )N(R ⁸ )S(0) ₂ -;

R ² is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ - ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclic aryl), heteroaryl, Ci_i ₀ alkyl, C3.scycloalkyl, Ci.ioalkyl-C ₃ _ gcycloalkyl, C ₃ .gcycloalkyl -C _MO alkyl, C ₃ . ₈ cycloalkyl -C _2-10 alkenyl, C _3-8 cycloalkyl- C ₂ . loalkynyl, Q.ioalkyl- C _2-10 alkenyl, C _1-10 alkyl- C _2-10 alkynyl, Ci.i ₀ alkylaryl (e.g. C _2-10 alkyl- monocyclic aryl, Ci.ioalkyl-substituted monocyclic aryl, or Ci.ioalkylbicycloaryl), Q. loalkylheteroaryl, Ci.i ₀ alkylheterocyclyl, C _2- i ₀ alkenyl, C ₂ .i ₀ alkynyl, C ₂ . ₁₀ alkenyl -Q. i ₀ alkyl, C ₂ .ioalkynyl -Ci.ioalkyl, C ₂ _i ₀ alkenylaryl, C ₂ .i ₀ alkenylheteroaryl, C ₂ _

loalkenylheteroalkyl, C _2- ioalkenylheterocyclcyl, C ₂ _ioalkenyl-C ₃ _ ₈ cycloalkyl, C _{2- l} oalkynylaryl, C ₂ .i ₀ alkynylheteroaryl, C ₂ -ioalkynylheteroalkyl, C _2- i ₀ alkynylheterocyclyl, C ₂ .i ₀ alkynyl-C _3-8 cycloalkenyl, Ci.i ₀ alkoxy Ci.ioalkyl, Ci.i ₀ alkoxy-C ₂ .i ₀ alkenyl, Ci_ i ₀ alkoxy-C _2- i ₀ alkynyl, heterocyclyl, heteroalkyl, heterocyclyl -Ci_i ₀ alkyl, heterocyclyl-C _2- i ₀ alkenyl, heterocyclyl-C _2- ioalkynyl, aryl- (e.g. monocyclic aryl-C _2- ioalkyl, substituted monocyclic aryl- Ci.ioalkyl, or bicycloaryl— Ci.ioalkyl), aryl-C _2- ioalkenyl, aryl-C _2- ioalkynyl, aryl-heterocyclyl, heteroaryl-Ci.ioalkyl, heteroaryl-C ₂ -ioalkenyl, heteroaryl-C2-ioalkynyl, heteroaryl-C _3- gcycloalkyl, 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, -R ³¹ , -CF ₃ , - OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - R ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , - C(=0)NR ³⁴ R ³⁵ , -NO ₂ , -CN, -S(0)o_ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , - NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , 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, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , - C(=0)NR ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ;

R ⁴ are independently hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , - NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³ R ³⁵ , -N0 ₂ , -CN, -S(0)o- 2R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , -SC(=0)NR ³¹ R ³² , aryl, heteroaryl, Ci.i ₀ alkyl, C _3-8 cycloalkyl, Ci _-10 alkyl-C _3-8 cycloalkyl, C ₃ . ₈ cycloalkyl - Ci.ioalkyl, C ₃ _ ₈ cycloalkyl -C _2- ioalkenyl, C _3-8 cycloalkyl- C _2- ioalkynyl, Ci.ioalkyl- C ₂ _ loalkenyl, Ci.ioalkyl- C _2- i ₀ alkynyl, Ci.i ₀ alkylaryl, Ci.ioalkylheteroaryl, Ci.

loalkylheterocyclyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, C _2- ioalkenyl - .ioalkyl, C ₂ _i ₀ alkynyl -Ci_ loalkyl, C ₂ _ioalkenylaryl, C ₂ .ioalkenylheteroaryl, C _2- ioalkenylheteroalkyl, C _2- i ₀ alkenylheterocyclcyl, C ₂ -ioalkenyl-C ₃ _ ₈ cycloalkyl, C ₂ .ioalkynyl-C _3- gcycloalkyl, C ₂ . loalkynylaryl, C _2- ioalkynylheteroaryl, C2-ioalkynylheteroalkyl, C2-ioalkynylheterocyclyl, C _2- ioalkynyl-C _3-8 cycloalkenyl, Ci.i ₀ alkoxy Ci.ioalkyl, Ci-i ₀ alkoxy-C _2- i ₀ alkenyl, Q.

ioalkoxy-C ₂ .ioalkynyl, heterocyclyl, heterocyclyl heterocyclyl-C ₂ .i ₀ alkenyl, heterocyclyl-C _2- ioalkynyl, aryl- Ci _-10 alkyl, aryl-C ₂ -ioalkenyl, aryl-C ₂ .i ₀ alkynyl, aryl- heterocyclyl, heteroaryl-Ci_i ₀ alkyl, heteroaryl-C ₂ .ioalkenyl, heteroaryl-C2-ioalkynyl, heteroaryl-C _3-8 cycloalkyl, 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, ^' -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, - S(0)o_ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , -S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , - NR ³¹ C(=0)NR ³² R ³³ , -NR ³¹ S(0)o_ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , - NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , -NR ³¹ C(=NR ³² )SR ³³ , -OC(=0)OR ³³ , - OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , -P(0)OR ³¹ OR ³² , or-SC(=0)NR ³¹ R ³² , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , - O-aryl, -NR ³¹ R ³² , -NR ³⁴ R ³⁵ ,-C(0)R ³¹ , -C0 ₂ R ³¹ , -C(=0) R ³⁴ R ³⁵ , or -C(=0)NR ³¹ R ³² ; R ⁵ is hydrogen, halogen, -OH, -R ³¹ , -CF ₃ , -OCF ₃ , -OR ³¹ , -NR ³¹ R ³² , -NR ³⁴ R ³⁵ , -C(0)R ³¹ , - C0 ₂ R ³¹ , -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ ^ ₂ R ³¹ , -S0 ₂ NR ³¹ R ³² , - S0 ₂ NR ³⁴ R ³⁵ , -NR ³¹ C(=0)R ³² , -NR ³¹ C(=0)OR ³² , -NR ³¹ C(=0)NR ³² R ³³ , -NR ^3I S(O) ₀ _ ₂ R ³² , -C(=S)OR ³¹ , -C(=0)SR ³¹ , -NR ³¹ C(=NR ³² )NR ³³ R ³² , -NR ³¹ C(=NR ³² )OR ³³ , - NR ³¹ C(=NR ³² )SR ³³ , -0C(=0)0R ³³ , -OC(=0)NR ³¹ R ³² , -OC(=0)SR ³¹ , -SC(=0)OR ³¹ , - P(0)OR ³¹ OR ³² ,or -SC(=0)NR ³¹ R ³² ;

R 31 , R 32 , and R 33 , in each instance, are independently H or d-ioalkyl , wherein the Ci_ ₁₀ alkyl 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, - Ci.i ₀ alkyl, -CF ₃ , -O-aryl, -OCF ₃ , -OCwoalkyl, -NH ₂ , - NiQ.joalkylXd.ioalkyl), - NH(C _1-10 alkyl), -NH( aryl), - NR ³⁴ R ³⁵ , -C(O)(C _1-10 alkyl), -C(O)(Ci _-10 alkyl-aryl), -C(0)(aryl), -CO ₂ -C _1-10 alkyl, -C0 ₂ - C _1-10 alkylaryl, -C0 ₂ -aryl, -C(=O)N(d. ₁₀ alkyl)( C _O alkyl), -C(=0)NH( d_ ₁₀ alkyl), - C(=0)NR ³⁴ R ³⁵ , -C(=0)NH ₂ , -OCF ₃ , -O(C _1-10 alkyl), -O-aryl, -N(aryl)( C _1-10 alkyl),— N0 ₂ , -CN, -S(0)o_ ₂ C _1-10 alkyl, -S(O) _{0 2} d.joalkylaryl, -S(O) ₀ _ ₂ aryl, -S0 ₂ N(aryl), -S0 ₂ N(C _MO alkyl)( C _1-10 alkyl), -S0 ₂ NH(C _MO alkyl) or -S0 ₂ NR ³⁴ R ³⁵ ;

R ³⁴ and R ³⁵ in -NR ³⁴ R ³⁵ , -C(=0)NR ³⁴ R ³⁵ , or -S0 ₂ NR ³⁴ R ³⁵ , 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— NR ³¹ R ³² , hydroxyl, halogen, oxo, aryl, heteroaryl, C^alkyl, 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; R and R* are each independently hydrogen, Ci.i ₀ alkyl, C _2- ioalkenyl, aryl, heteroaryl, heterocyclyl or C _3- i ₀ cycloalkyl, each of which except for hydrogen is unsubstituted or is substituted by one or more independent R ⁶ ;

R ⁶ is halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , -NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² ,

C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ Ci _-10 alkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , Ci.ioalkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Ci.i ₀ alkyl, aryl-C _2- i ₀ alkenyl, aryl- C _2-10 alkynyl, heteroaryl-Ci.i ₀ alkyl, heteroaryl-C _2- i ₀ alkenyl, heteroaryl-G _2- i ₀ alkynyl, 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, - OCi.ioalkyl, Ci.i ₀ alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, haloCi.i ₀ alkyl, haloC _2- i ₀ alkenyl, haloC ₂ . 1 ₀ alkynyl, -COOH, -C(=0)NR ^3I R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ¹ R ³² , - NR ³¹ R ³² , or -NR ³⁴ R ³⁵ ; and

R ⁹ is H, halo, -OR ³¹ , -SH, -NH ₂ , -NR ³⁴ R ³⁵ , - NR ³¹ R ³² , -C0 ₂ R ³¹ , -C0 ₂ aryl, -C(=0)NR ³¹ R ³² , C(=0)NR ³⁴ R ³⁵ , -N0 ₂ , -CN, -S(O) ₀ _ ₂ C _1-10 alkyl, -S(O) ₀ _ ₂ aryl, -S0 ₂ NR ³⁴ R ³⁵ , - S0 ₂ NR ³¹ R ³² , Ci _-10 alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl; aryl-Ci.ioalkyl, aryl-C _2- i ₀ alkenyl, aryl- C _2-10 alkynyl, heteroaryl-Ci.i ₀ alkyl, heteroaryl-C ₂ .i ₀ alkenyl, heteroaryl-C ₂ .i ₀ alkynyl, 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, - OCi.ioalkyl, Ci.i ₀ alkyl, C _2- i ₀ alkenyl, C _2- i ₀ alkynyl, haloCi.i ₀ alkyl, haloC _2- i ₀ alkenyl, haloC ₂ . loalkynyl, -COOH, -C(=0)NR ³¹ R ³² , -C(=0)NR ³⁴ R ³⁵ , -S0 ₂ NR ³⁴ R ³⁵ , -S0 ₂ NR ³¹ R ³² , - NR ³¹ R ³² , or -NR ³⁴ R ³⁵ .

[0195] In some embodiments, X4 is C-R ⁹ .

[0196] In some other embodiments of the invention, the mTORCl/2 inhibitor as defined above is a compound of Formula I-B:

Formula I-B

or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined above. [0197] In various embodiments the compound of Formula I-B or its pharmaceutically acceptable salt thereof, is an inhibitor having the structure of Formula I-Bl or Formula I-B2:

Formula I-B 1 Formula I-B2

or a pharmaceutically acceptable salt thereof.

[0198] In various embodiments of Formula I-Bl, Xi is N and X ₂ is N. In other embodiments, Xj is C-E ¹ and X ₂ is N. In yet other embodiments, Xi is NH and X ₂ is C. In further embodiments, Xi is CH-E' and Xz is C.

[0199] In various embodiments of Formula I-B2, Xi is N and X ₂ is C. In further embodiments, Xi is C-E ¹ and X ₂ is C.

[0200] In various embodiments, Xj is CH W ¹ ^ -R ⁴ , where j is 0.

[0201] In another embodiment, Xi is CH. In yet another embodiment, Xi is C-halogen, where halogen is CI, F, Br, or I.

[0202] In various embodiments of Xi, it is C -(W ¹ ^ -R ⁴ . In various embodiments of X _l9 j is 1, and W ¹ is -0-. In various embodiments of X _l5 j is 1, and W ¹ is— NR ⁷ -. In various embodiments of Xi, j is 1, and W ¹ is— H-. In various embodiments of X _l5 j is 1, and W ¹ is— S(O) _0-2 - In various embodiments of X _l5 j is 1, and W ¹ is— C(O)-. In various embodiments of Xj, j is 1, and W ¹ is— C(0)N(R ⁷ )-. In various embodiments of X _1? j is 1, and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of X _b j is 1, and W ¹ is -N(R ⁷ )S(0)-. i various embodiments of X _ls j is 1, and W ¹ is— (R ⁷ )S(0) ₂ -. In various embodiments of Xi, j is 1, and W ¹ is -C(0)0-. In various embodiments of X j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of Xi, j is 1, and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments of X _h j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ )- In various embodiments ofX j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. I various embodiments ofX j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of X _ls j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments ofX j is 1, and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-. In various embodiments of ¾, j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -. [0203] In another embodiment, Xi is CH ₂ . In yet another embodiment, Xi is CH-halogen, where halogen is CI, F, Br, or I.

[0204] In another embodiment, Xi is N.

[0205] In various embodiments, X2 is N. In other embodiments, X ₂ is C.

[0206] In various embodiments, E ² is -(W ^! ) _j -R ⁴ , where j is 0.

[0207] In another embodiment, E ² is CH. In yet another embodiment, E ² is C-halogen, where halogen is CI, F, Br, or I.

[0208] In various embodiments of E ² , it is -(W ¹ ^ -R ⁴ . In various embodiments of E ² , j is 1, and W ¹ is -O-. In various embodiments of E ² , j is 1, and W ¹ is— NR ⁷ -. In various embodiments of E ² , j is 1, and W ¹ is— NH-. In various embodiments of E ² , j is 1 , and W ¹ is— S(0)o_ ₂ -. In various embodiments of E ² , j is 1, and W ¹ is— C(0)-. In various embodiments of E ² , j is 1 , and W ¹ is— C(0)N(R ⁷ >- hi various embodiments of E ² , j is 1 , and W ¹ is -N(R ⁷ )C(0)-. In various embodiments of E ² , j is 1, and W ¹ is -N(R ⁷ )S(0)-. In various embodiments of E ² , j is 1, and W ¹ is— N(R ⁷ )S(0) ₂ -. In various embodiments of E ² , j is 1, and W ¹ is -C(0)0- In various embodiments of E ² , j is 1, and W ¹ is CH(R ⁷ )N(C(0)OR ⁸ )-. In various embodiments of E ² , j is 1 , and W ¹ is -CH(R ⁷ )N(C(0)R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is - CH(R ⁷ )N(S0 ₂ R ⁸ }- In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )C(0)N(R ⁸ )-. In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )C(0)-. In various embodiments of E ² , j is 1 , and W ¹ is—

CH(R ⁷ )N(R ⁸ )S(0)-.

[0209] In various embodiments of E ² , j is 1, and W ¹ is -CH(R ⁷ )N(R ⁸ )S(0) ₂ -.

[0210] In various embodiments of Formula I- A, I-B, I-B l and I-B2, Mi is :

[0211] In some embodiments of the invention, Mi is benzothiazolyl substituted with -(W ² ) _k -R ² . W ² can be -0-, -S(O) _0-2 -<including but not limited to -S-, -S(O)-, and -S(0) ₂ -),-C(0)- , or - C(0)0-. In other embodiments, W ¹ is -NR ⁶ - or -CH(R ⁶ )N(R ⁷ )-, wherein R ⁶ and R ⁷ are each independently hydrogen, unsubstituted or substituted Ci-Ci ₀ alkyl (which includes but is not limited to -CH ₃ , -CH2CH ₃ , n-propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl, and heptyl), unsubstituted or substituted C ₂ -Cioalkenyl (including but not limited to alkenyl such as, for example, vinyl, allyl, 1 -methyl propen-l-yl, butenyl, or pentenyl). Additionally when W ² is - NR ⁶ - or -CH(R ⁶ )N(R ⁷ )-, R ⁶ and R ⁷ are each independently unsubstituted or substituted aryl (including phenyl and naphthtyl). In yet other embodiments, when W ² is -NR ⁶ - or - CH(R ⁶ )N(R ⁷ )-, R ⁶ and R ⁷ are each independently heteroaryl, wherein the heteroaryl is unsubstituted or substituted. R ⁶ and R ⁷ heteroaryl is monocyclic heteroaryl, and includes but is not limted to imidazolyl, pyrrolyl, oxazolyl, thiazolyl, and pyridinyl. In some other

embodiments, when W ² is -NR ⁶ - or -CH(R ⁶ )N(R ⁷ )-, R ⁶ and R ⁷ 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 C _3-8 cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl). Non limiting exemplary W ² include -NH-, - N(cyclopropyl), and -N(4-N-piperidinyl).

[0212] For example, exemplary mTORCl/2 inhibitors of the invention have the Formulas:

[0213] Some illustrative mTORCl/2 inhibitor compounds are described below. The mTORCl/2 inhibitor compounds that may be used in the present invention are not limited in any way to the compounds illustrated herein.

Subclass la Subclass lb

Subclass 6a Subclass 6b

Subclass 9a Subclass 9b

Subclass 10a Subclass 10b

[0214] Illustrative compounds of the invention include those of subclass la, lb, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 1 1a, l ib, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b, where the substituents Ri, Xj, and V are as described below.

[0215] In other embodiments, when Ri is H, CH ₃ , Et, iPr, cyclobutyl, cyclopentyl, phenyl, pyridin-2-yl, N-methylaminocyclohex-4-yl, N-methylpiperidin-4- -methylaminocyclobut-3- yl, tert-butyl, l-cyano-but-4-yl, l-cyano-prop-3-yl, 3-azetidinyl,

O O , O . H , O . H , C , ONH e, ,

phenylamino, benzyl, phenyl, NHMe, NH ₂ , NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHS0 ₂ Me. In one embodiment, ¾ is iPr, X _! is N, and V is NH ₂ . In another embodiment, Ri is iPr, Xi is N, and V is NHCOMe.

[0216] In other embodiments, when Rj is H, CH ₃ , Et, iPr, cyclobutyl, cyclopentyl, phenyl, pyridin-2- l, N-meth laminoc clohex-4- l, N-meth l i eridin-4- -meth laminoc clobut-3-

cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N- morpholino. In other embodiments, when Ri is iPr and Xi is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. d embodiments above, ridin-2-yl is V) N-methylaminocyclohex-4-yl is

and N-methylaminocyclobut-3-yl is

[0218] Illustrative compounds of the invention include those of subclass la, lb, 2a, 2b, 3 a, 3 b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, l ib, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b, where the substituents Rj, Xi, and V are as described below. In other embodiments, when Ri is iPr and Xi is N, V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino.

[0219] Table 1. Several illustrative mTORCl/2 inhibitor compounds

[0221] Additional compounds which are mTORCl/2 inhibitors are shown in Table 2.

[0222] Table 2. mTORCl/2 inhibitors

[0223] In other embodiments, the mTORCl/2 inhibitor is CC223 (Celgene), OSI027 (OSI Pharmaceuticals), DS3078 (Daiichi), AZD8055 (Astra Zeneca), or AZD2014 (Astra Zeneca).

[0224] Structures of exemplary mTORCl/2 inhibitors are shown below:

[0225] In some embodiments, the mTORCl/2 inhibitor is a compound as described in U.S. Patent 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. Compounds of Formulas I, I- A, I-B, I-Bl, I-B2, 1-C, I-D, I-Cl, I-C2, 1-Dl, I-D2, 1-E, I-El, I-E2, 1-Cla are known in the art and can be prepared by the methods of the above referenced patents and patent applications. In one embodiment, the mTORCl/2 inhibitor is 3-(2-amino-l,3-benzoxazol-5-yl)-l-(propan-2-yl)-lH- pyrazolo [3, 4-d] pyrimidin-4-amine (MLN0128), or a pharmaceutically acceptable salt thereof.

Exemplary Aurora A kinase Inhibitor Compounds

[0226] Any molecule capable of selectively inhibiting the enzymatic activity of Aurora A kinase may be used in the methods, pharmaceutical compositions, and kits of the present invention. Aurora A kinase inhibitors can be assayed in vitro or in vivo for their ability to selectively bind to and/or inhibit an Aurora A kinase. In vitro assays include assays to determine selective inhibition of the ability of an Aurora A kinase to phosphorylate a substrate protein or peptide. Alternate in vitro assays quantitate the ability of the compound to selectively bind to an Aurora A kinase. Selective inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/Aurora A kinase complex and determining the amount of radiolabel bound. Alternatively, selective inhibitor binding may be determined by running a competition experiment in which new inhibitors are incubated with Aurora A kinase bound to a known radioligand. The compounds also can be assayed for their ability to affect cellular or physiological functions mediated by Aurora A kinase activity. In order to assess selectivity for Aurora A kinase over Aurora B kinase, inhibitors can also be assayed in vitro and in vivo for their ability to selectively bind to and/or inhibit an Aurora B kinase, using assays analogous to those described above for Aurora A kinase. Inhibitors can be assayed in vitro and in vivo for their ability to inhibit Aurora A kinase in the absence of Aurora B kinase inhibition, by immunofluorescent detection of pHisH3. {Proc. Natl. Acad. Sci. (2007) 104, 4106). Assays for each of these activities are known in the art.

[0227] In some embodiments the selective Aurora A kinase inhibitor is a small molecular weight compound. In particular, selective inhibitors of Aurora A kinase include the compounds described herein, as well as compounds disclosed in, for example, US Publication No.

2008/0045501, US Patent No. 7,572,784, WO 05/111039, WO 08/021038, US Patent No.

7,718,648, WO 08/063525, US Publication No. 2008/0167292, US Patent No. 8,026,246, WO 10/134965, US Publication No. 2010/0310651, WO 11/014248, US Publication No.

2011/0039826, and US Publication No. 2011/0245234, each of which is hereby incorporated by reference in its entirety, as well as the compounds sodium 4-{[9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-£/] [2]benzazepin-2-yl] amino } -2-methoxybenzoate, ENMD- 2076 (EntreMed), and MK-5108 (Vertex Merck). Also suitable for use in the methods, pharmaceutical compositions, and kits of the invention are solvated and hydrated forms of any of these compounds. Also suitable for use in the methods, pharmaceutical compositions, and kits of the invention are pharmaceutically acceptable salts of any of the compounds, and solvated and hydrated forms of such salts. These selective Aurora A kinase inhibitors can be prepared in a number of ways well known to one skilled in the art of organic synthesis, including, but not limited to, the methods of synthesis described in detail in the references referred to herein.

[0228] In some embodiments, the selective Aurora A kinase inhibitor is a compound represented by formula (III):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is a substituted or unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;

Ring B is a substituted or unsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring; Ring C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; R ^e is hydrogen, -OR ⁵ , -N(R ⁴ ) ₂ , -SR ⁵ , or a C _1-3 aliphatic optionally substituted with R ³ or R ⁷ ; each of R ^x and R ^y independently is hydrogen, fluoro, or an optionally substituted

Ci_6 aliphatic; or R and R , taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloaliphatic ring;

each R ³ independently is selected from the group consisting

of -halo, -OH, -0(C _1-3 alkyl), -CN, -N(R ⁴ ) ₂ , -C(0)(C _1-3 alkyl), -C0 ₂ H, -C0 ₂ (C _1-3 alkyl), - C(0)NH ₂ , and -C(0)NH(C _1-3 alkyl);

each R ⁴ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R ⁴ on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;

each R ⁵ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and

each R ⁷ independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group.

[0229] Ring A is a substituted or unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Examples of Ring A include furano, dihydrofurano, thieno, dihydrothieno, cyclopenteno, cyclohexeno, 2H-pyrrolo, pyrrolo, pyrrolino, pyrrolidino, oxazolo, thiazolo, imidazolo, imidazolino, imidazolidino, pyrazolo, pyrazolino, pyrazolidino, isoxazolo, isothiazolo, oxadiazolo, triazolo, thiadiazolo, 2H-pyrano, 4H-pyrano, benzo, pyridino, piperidino, dioxano, morpholino, dithiano, thiomorpholino, pyridazino, pyrimidino, pyrazino, piperazino, and triazino, any of which groups may be substituted or unsubstituted. Preferred values for Ring A include, without limitation, substituted or unsubstituted rings selected from the group consisting of furano, thieno, pyrrolo, oxazolo, thiazolo, imidazolo, pyrazolo, isoxazolo, isothiazolo, triazolo, benzo, pyridino, pyridazino, pyrimidino, and pyrazino.

[0230] Ring A may be substituted or unsubstituted. In some embodiments, each substitutable saturated ring carbon atom in Ring A is unsubstituted or is substituted with =0, =S, =C(R ⁵ ) , =N-N(R ⁴ ) ₂ , =N-OR ⁵ , =N-NHC(0)R ⁵ , =N-NHC0 ₂ R ⁶ , =N-NHS0 ₂ R ⁶ , =N-R ⁵ or -R ^b , where R ^b , R ⁴ , R ⁵ , and R ⁶ are as defined below. Each substitutable unsaturated ring carbon atom in Ring A is unsubstituted or substituted with -R ^b . Each substitutable ring nitrogen atom in Ring A is unsubstituted or is substituted with -R ^9b , and one ring nitrogen atom in Ring A optionally is oxidized. Each R ⁹ independently is -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C0 ₂ R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , or a CM aliphatic optionally substituted with R ³ or R ⁷ .

[0231] Each R ^b independently is R ^2b , an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two adjacent R ^b , taken together with the intervening ring atoms, form an optionally substituted fused 4- to 8-membered aromatic or non- aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S.

[0232] Each R ^2b independently

is -halo, -N0 ₂ , -CN, -C(R ⁵ )=C(R ⁵ ) ₂ , -C(R ⁵ )=C(R ⁵ )(R ¹⁰ ), -C≡C-R ⁵ , -C≡C-R ¹⁰ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶

, -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , -NR ⁴ C(0)N(R ⁴ ) ₂ , -NR ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(0)N

(R ⁴ ) ₂ , -0-C(0)R ⁵ , -C0 ₂ R ⁵ , -C(0)-C(0)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N(R ⁴ ) ₂ , -C(=NR ⁴ )-0

R ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , N(R ⁴ )C(=NR ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N(R ⁴ )S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ , where the variables R ⁴ , R ⁵ , and R ⁷ have the values described above; each R ⁶ independently is an optionally substituted aliphatic or aryl group; and each R ¹⁰ independently is -

C0 ₂ R ⁵ or -C(0)N(R ⁴ ) ₂ .

[0233] In some embodiments, Ring A is substituted by 0-2 substituents R ^b . In some such embodiments, each R ^b independently is Ci _-3 aliphatic or R ^2b , and each R ^2b independently is selected from the group consisting of -halo, -N0 ₂ , -C(R ⁵ )=C(R ⁵ ) ₂ , -C≡C-R ⁵ , -OR ⁵ , and -N(R ) ₂ . In some embodiments, each R ^b independently is selected from the group consisting of -halo, Ci_3 aliphatic, Ci_ ₃ fluoroaliphatic, and -OR ⁵ , where R ⁵ is hydrogen or C _1-3 aliphatic. In certain preferred embodiments, Ring A is substituted with 0, 1 , or 2 substituents, preferably 0 or 1 substituents, independently selected from the group consisting of chloro, fluoro, bromo, methyl, trifluoromethyl, and methoxy. [0234] In some embodiments, Ring B is a substituted or unsubstituted mono- or bicyclic aryl or heteroaryl ring selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzo[b]furanyl, benzo[b]thienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,

naphthyridinyl, and pteridinyl.

[0235] Each substitutable saturated ring carbon atom in Ring B is unsubstituted or is substituted with =0, =S, =C(R ⁵ ) ₂ , =N-N(R ⁴ ) ₂ , =N-OR ⁵ , =N-NHC(0)R ⁵ , =N-NHC0 ₂ R ⁶ , =N-NHS0 ₂ R ⁶ , =N-R ⁵ or -R°. Each substitutable unsaturated ring carbon atom in Ring B is unsubstituted or substituted with -R ^c . Each substitutable ring nitrogen atom in Ring B is unsubstituted or is substituted with -R ^9c , and one ring nitrogen atom in Ring B optionally is oxidized. Each R ⁹ ° independently is -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C0 ₂ R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , or a C _1-4 aliphatic optionally substituted with R ³ or R ⁷ . Ring B may be unsubstituted or may be substituted on any one or more of its component rings, wherein the substituents may be the same or different. In some embodiments, Ring B is substituted with 0-2 independently selected R° and 0-3 independently selected R ^2c or Ci _-6 aliphatic groups. The variables R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined above for Ring A, and R° and R ^2c are defined below.

[0236] Each R° independently is R ^2c , an optionally substituted Ci_6 aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl group.

[0237] Each R ^2c independently is -halo, -N0 ₂ , -CN, -

C(R ⁵ )=C(R ⁵ ) ₂ , -C(R ⁵ )=C(R ⁵ )(R ¹⁰ ), -C≡C-R ⁵ , -C≡C-R ¹⁰ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , -NR ⁴ C(0)N(R ⁴ ) ₂ , -NR ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(0)N(R ⁴ ) ₂ , -0-C(0)R ⁵ , -C 0 ₂ R ⁵ , -C(0)-C(0)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N(R ⁴ ) ₂ , -C(=NR ⁴ )-OR ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , - N(R ⁴ )C(=NR ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N(R ⁴ )S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ .

[0238] In some embodiments, Ring B is a monocyclic 5- or 6-membered aryl or heteroaryl ring, substituted with 0-2 independently selected R° and 0-2 independently selected R ^2c or C _\ . aliphatic groups. In certain such embodiments, Ring B is a substituted or unsubstituted phenyl or pyridyl ring.

[0239] In some embodiments, Ring B is substituted with 0-2 substituents R ^c . In some such embodiments, each R° independently is Ci _-3 aliphatic or R ^2c , and each R ^2c independently is selected from the group consisting of -halo, -N0 ₂ , -C(R ⁵ )=C(R ⁵ ) ₂ , -C≡C-R ⁵ , -OR ⁵ , and -N(R ⁴ ) ₂ . In some embodiments, each R° independently is selected from the group consisting of -halo, Ci _-3 aliphatic, Ci _-3 haloaliphatic, and -OR ⁵ , where R ⁵ is hydrogen or Ci_ ₃ aliphatic. In certain preferred embodiments, Ring B is substituted with 0, 1 , or 2 substituents, independently selected from the group consisting of chloro, fluoro, bromo, methyl, trifluoromethyl, and methoxy.

[0240] Each substitutable saturated ring carbon atom in Ring C is unsubstituted or is substituted with =0, =S, =C(R ⁵ ) ₂ , =N-N(R ⁴ ) ₂ , =N-OR ⁵ , =N-NHC(0)R ⁵ , =N-NHC0 ₂ R ⁶ , =N-NHS0 ₂ R ⁶ , =N-R ⁵ or -R ^d . Each substitutable unsaturated ring carbon atom in Ring C is unsubstituted or substituted with -R ^d . Each substitutable ring nitrogen atom in Ring C is unsubstituted or is substituted with -R ^9d , and one ring nitrogen atom in Ring C optionally is oxidized. Each R ^9d independently is -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C0 ₂ R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , or a C _1-4 aliphatic optionally substituted with R ³ or R ⁷ . Ring C may be unsubstituted or may be substituted on any one or more of its component rings, wherein the substituents may be the same or different. In some embodiments, Ring C is substituted with 0-2 independently selected R ^d and 0-3 independently selected R ^2d or Ci_ ₆ aliphatic groups. The variables R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as described above for Rings A and B. The variables R ^d and R ^2d are described below.

[0241] Each R ^d independently is R ^2d , an optionally substituted aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl group.

[0242] Each R ^2d independently is -halo, -N0 ₂ , -CN, -C(R ⁵ )=C(R ⁵ ) ₂ , -

C(R ⁵ )=C(R ⁵ ) ₂ (R ¹⁰ ), -OC-R ⁵ , -C≡C-R ¹⁰ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , - R ⁴ C(0)N(R ⁴ ) ₂ , - R ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(0)N(R ) ₂ , -0-C(0)R ⁵ , -C0 ₂ R ⁵ , -C(0)-C (O)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N(R ⁴ ) ₂ , -C(=NR ⁴ )-OR ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )C(=NR ⁴ )- N(R ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N(R ⁴ )S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ . Additionally, R ^2d can

[0243] In some embodiments, Ring C is a monocyclic 5- or 6-membered aryl or heteroaryl ring, which is substituted with 0-2 independently selected substituents R ^d and 0-2 independently selected R ^2d or aliphatic groups. In some such embodiments, Ring C is an optionally substituted heteroaryl ring selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, and oxazolyl. In some other embodiments, Ring C is a substituted or unsubstituted phenyl ring. In some embodiments, Ring C is a monocyclic 5- or 6- membered aryl or heteroaryl ring, which is substituted with 0, 1, or 2 substituents R ^d , as defined above.

[0244] In some other embodiments, Ring C is a monocyclic 5- or 6-membered heterocyclyl or cycloaliphatic ring, which is substituted with 0-2 independently selected substituents R ^d and 0-2 independently selected R ^2d or Ci_ ₆ aliphatic groups.

[0245] In some embodiments, the selective Aurora A kinase inhibitor is a compound represented by formula {IV):

or a pharmaceutically acceptable salt thereof;

wherein:

R ^e is hydrogen or a C1.3 aliphatic optionally substituted with R ³ or R ⁷ ;

Ring A is substituted with 0-3 R ^b ;

each R ^b independently is selected from the group consisting of Ci_6 aliphatic, R ^2b , R ^7b , -Τ ¹ ^, and -T ¹ -R ^7b ;

each R ^2b independently

is -halo, -N0 ₂ , -CN, -C(R ⁵ )=C(R ⁵ ) ₂ , -OC-R ⁵ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , -NR ⁴ C(0)N(R ⁴ ) ₂ , -NR ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(0 )N(R ) ₂ , -0-C(0)R ⁵ , -C0 ₂ R ⁵ , -C(0)-C(0)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N (R ⁴ ) ₂ , -C(=NR ⁴ )-OR ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )C(=NR ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N( R ⁴ )S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ ;

each R ^7b independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

Ring B is substituted with 0-2 independently selected R° and 0-2 independently selected R ^2c or Ci_6 aliphatic groups;

each R° independently is selected from the group consisting of aliphatic, R ^2c , R ^7c , -T'-R ²⁰ , and -T'-R ⁷⁰ ;

each R ^2c independently

is -halo, -N0 ₂ , -CN, -C(R ⁵ )=C(R ⁵ ) ₂ , -C≡C-R ⁵ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , -NR ⁴ C(0)N(R ⁴ ) ₂ , -NR ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(0 )N(R ⁴ ) ₂ , -0-C(0)R ⁵ , -C0 ₂ R ⁵ , -C(0)-C(0)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N (R ⁴ ) ₂ , -C(=NR ⁴ )-OR ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )C(=NR ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N( R ⁴ )S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ ;

each R ^7c independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group; T ¹ is a Ci _-6 alkylene chain optionally substituted with R ³ or R ^3b , wherein T ¹ or a portion thereof optionally forms part of a 3- to 7 -membered ring;

Ring C is substituted with 0-2 independently selected R ^d and 0-3 independently selected R ^2d or Ci_6 aliphatic groups;

each R ^d independently is selected from the group consisting of Ci _-6 aliphatic, R ^2d ,

R ^7d , -T ² -R ^2d , -T ² -R ^7d , -V-T ³ -R ^2d , and -V-T ³ -R ^7d ;

T ² is a Ci_6 alkylene chain optionally substituted with R ³ or R ^3b , wherein the alkylene chain optionally is interrupted

by -C(R ⁵ )=C(R ⁵ )-, -C≡C-, -0-, -S-, -S(O)-, -S(0) ₂ -, -S0 ₂ N(R ⁴ )-, -N(R ⁴ )-, -N(R ⁴ ) C(O)-, -NR ⁴ C(0)N(R ⁴ )-, -N(R ⁴ )C0 ₂ -, -C(0)N(R ⁴ )-, -C(O)-, -C(0)-C(0)-, -C0 ₂ -, -OC(O)-, -OC(0)0-, -OC(0)N(R ⁴ )-, -N(R ⁴ )-N(R ⁴ )-, -N(R ⁴ )S0 ₂ -, or -S0 ₂ N(R ⁴ )-, and wherein T ² or a portion thereof optionally forms part of a 3-7 membered ring;

T ³ is a Ci-6 alkylene chain optionally substituted with R ³ or R ^3b , wherein the alkylene chain optionally is interrupted

by -C(R ⁵ )=C(R ⁵ )-, -C≡C-, -0-, -S-, -S(O)-, -S(0) ₂ -, -S0 ₂ N(R ⁴ )-, -N(R ⁴ )-, -N(R ⁴ ) C(O)-, -NR ⁴ C(0)N(R ⁴ )-, -N(R ⁴ )C0 ₂ -, -C(0)N(R ⁴ )-, -C(O)-, -C(0)-C(0)-, -C0 ₂ -, -OC(O)-, -OC(0)0-, -OC(0)N(R ⁴ )-, -N(R ⁴ )-N(R ⁴ )-, -N(R ⁴ )S0 ₂ -, or -S0 ₂ N(R ⁴ )-, and wherein T ³ or a portion thereof optionally forms part of a 3-7 membered ring;

V

is -C(R ⁵ )=C(R ⁵ )-, -C≡C-, -0-, -S-, -S(O)-, -S(0) ₂ -, -S0 ₂ N(R ⁴ )-, -N(R ⁴ )-, -N(R ⁴ )C (O)-, -NR ⁴ C(0)N(R ⁴ )-, -N(R ⁴ )C0 ₂ -, -C(0)N(R ⁴ )-, -C(O)-, -C(0)-C(0)-, -C0 ₂ -, - OC(O)-, -OC(0)0-, -OC(0)N(R ⁴ )-, -C( R ⁴ )=N-, -C(OR ⁵ )=N-, -N(R ⁴ )-N(R ⁴ )-, - N(R ⁴ )S0 ₂ -, -N(R ⁴ )S0 ₂ N(R ⁴ )-, -P(0)(R ⁵ )-, -P(0)(OR ⁵ )-0-, -P(0)-0-, or -P(0)(NR ⁵ )-N(R ⁵ )-;

R ^2d

is -halo, -N0 ₂ , -CN, -C(R ⁵ )=C(R ⁵ ) ₂ , -OC-R ⁵ , -OR ⁵ , -SR ⁶ , -S(0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ N(R ⁴ ) ₂ , -N(R ⁴ ) ₂ , -NR ⁴ C(0)R ⁵ , -NR ⁴ C(0)N(R ⁴ ) ₂ , -N ⁴ C0 ₂ R ⁶ , -0-C0 ₂ R ⁵ , -OC(O) N(R ⁴ ) ₂ , -0-C(0)R ⁵ , -C0 ₂ R ⁵ , -C(0)-C(0)R ⁵ , -C(0)R ⁵ , -C(0)N(R ⁴ ) ₂ , -C(=NR ⁴ )-N( R ⁴ ) ₂ , -C(=NR ⁴ )-OR ⁵ , -N(R ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )C(=NR ⁴ )-N(R ⁴ ) ₂ , -N(R ⁴ )S0 ₂ R ⁶ , -N(R 4)S0 ₂ N(R ⁴ ) ₂ , -P(0)(R ⁵ ) ₂ , or -P(0)(OR ⁵ ) ₂ ; and

each R ^7d independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group. each R ³ independently is selected from the group consisting

of -halo, -OH, -0(C _1-3 alkyl), -CN, -N(R ⁴ ) ₂ , -C(0)(C _1-3 alkyl), -C0 ₂ H, -C0 ₂ (C _1-3 alkyl), -

C(0)NH ₂ , and -C(0)NH(C _1-3 alkyl);

each R ^3b independently is a Ci _-3 aliphatic optionally substituted with R ³ or R ⁷ , or two

substituents R ^3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;

each R ⁴ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R ⁴ on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 8-membered heteroaryl or heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;

each R ⁵ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

each R ⁶ independently is an optionally substituted aliphatic or aryl group; and

each R ⁷ independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group.

[0246] Table 3 provides the chemical names for specific examples of compounds of formula

ylamino] -phenyl } -piperazin- 1 -yl-methanone

rv-9 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } -(4-methy 1-piperazin- 1 -yl)-methanone

IV- 10 {4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -(4-metbyl-piperazin- 1 -yl)-methanone

IV-l l [4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amino)-phenyl]- (4-methyl-piperazin- 1 -yl)-methanone

IV-12 {4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e] azepin-2- ylamino] -phenyl } -(4-methy 1-piperazin- 1 -yl)-methanone

IV- 13 {4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl} -(4-methyl-piperazin- 1 -yl)-methanone

IV-14 {4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } -(4-methyl-piperazin- 1 -yl)-methanone

IV-15 2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino] -phenyl } - 1 -(4-methyl-piperazin- 1 -yl)-ethanone

IV-16 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-piperidin-4-yl-benzamide

IV-17 (4-Amino-piperidin- 1 -yl)- {4-[9-chloro-7-(2-fluoro-phenyl)-5H- benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] -phenyl } -methanone

IV-18 {4-[9-Chloro-7-(2-£luoro-phenyl)-5H-benzo[c]pyrimido[4,5-e] azepin-2- ylamino] -phenyl} -(4-dimethylamino-piperidin- 1 -yl)-methanone

IV- 19 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-[3 -(4-methyl-piperazin- 1 -yl)-propyl]-benzamide

IV-20 4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-[3 -(4-methyl-piperazin- 1 -yl)-propyl]-benzamide

IV-21 4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla mino)-N-[3-(4- methy 1-piperazin- 1 -yl)-propyl] -benzamide

IV-22 4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-N-[3-(4-methyl-piperazin- 1 -yl)-propyl] -benzamide

IV-23 4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N- [3 -(4-methyl-piperazin- 1 -yl)-propy l]-benzamide

rV-24 4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]az epin-2- ylamino] -N- [3 -(4-methyl-piperazin- 1 -yl)-propy 1] -benzamide

IV-25 2- {3 - [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c] pyrimido[4, 5 -e] azepin-2- ylamino]-phenyl} -N-[3-(4-methyl-piperazin- 1 -yl)-propyl]-acetamide

IV-26 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl}-morpholin-4-yl-methanone

IV-27 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- NN-bis-(2-hydroxy-ethyl)-benzamide

IV-28 {4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -morpholin-4-yl-methanone

IV-29 4- [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] - N-(2-morpholin-4-yl-ethyl)-benzamide

IV-30 4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-morpholin-4-yl-ethyl)-benzamide

IV-31 4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yla mino)-N-(2- mo holin-4-yl-ethyl)-benzamide

IV-32 4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -N-(3 -moφholin-4-yl-propyl)-benzamide

IV-33 4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-morpholin-4-yl-ethyl)-benzamide

IV-34 4- [9-Chloro-7-(2-chloro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] - 2-hydroxy-N-(2-morpholin-4-yl-ethyl)-benzamide

IV-35 [9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-pyridin- 2-yl-amine

IV-36 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido[4, 5 -e] azepin-2-yl] -(3,5- dichloro-phenyl)-amine

IV-37 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-yl] -(4- methoxy-phenyl)-amine

IV-38 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(4- ethoxy-phenyl)-amine

IV-39 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(3- methoxy-phenyl)-amine

IV-40 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(2- methoxy-phenyl)-amine

IV-41 [9-Chloro-7-(2-fluoro-pheny l)-5H-benzo [c]pyrimido [4, 5 -e] azepin-2-yl] -(4- chloro-phenyl)-amine

IV-42 [9-Chloro-7-(2-chloro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-yl] -(4- chloro-phenyl)-amine

IV-43 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(3- chloro-phenyl)-amine

IV-44 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(2- chloro-phenyl)-amine

IV-45 4- [9-Chloro-7-(2-chloro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] - phenol

IV-46 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(4- mo holi -4-yl-phenyl)-amine

IV-47 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-[4-(4- methyl-piperazin- 1 -yl)-phenyl] -amine

IV-48 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(4- pyridin-4-ylmethyl-phenyl)-amine

IV-49 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzonitrile

IV-50 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(4-nitro- phenyl)-amine

IV-51 4- [7-(2-Fluoro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] -benzoic acid

IV-52 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzoic acid

IV-53 4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzoic acid

IV-54 4-(9-Chloro-7-o-tolyl-5H-benzo [c] pyrimido [4,5 -e] azepin-2-ylamino)-benzoic acid

IV-55 4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -benzoic acid

IV-56 4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzoic acid

IV-57 4-[9-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzoic acid

IV-58 4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]az epin-2- ylamino] -benzoic acid

IV-59 4- [ 10-Fluoro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido [4, 5-e] azepin-2- benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine

IV-77 (3 ,4-Dimethoxy-phenyl)- [ 10-fluoro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido- [4,5-e]azepin-2-yl]-amine

IV-78 [10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(3,4- dimethoxy-phenyl)-amine

IV-79 (3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-trifluoroniet hyl-5H- benzo [c]pyrimido [4,5 -e] azepin-2-yl] -amine

IV-80 (3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methyl-5H-ben zo[c]pyrimido- [4,5-e]azepin-2-yl]-amine

IV-81 (3 ,4-Dimethoxy-pheny I)- [7-(2-fluoro-phenyl)- 10-methoxy-5H- benzo [c]pyrimido [4,5 -e] azepin-2-yl] -amine

IV-82 (3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)- 11 -methyl-5H-benzo[c]pyrimido- [4, 5 -e] azepin-2-yl] -amine

IV-83 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(2,3- dihydro-benzo[l,4]dioxin-6-yl)-amine

IV-84 [9-Chloro-7-(2-fluoro-pheny l)-5H-benzo [c]pyrimido[4, 5 -e] azepin-2-yl] -(4- fluoro-3 -methoxy-phenyl)-amine

IV-85 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-hydroxy-benzoic acid

IV-86 4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-hydroxy-benzoic acid

IV-87 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(3,4- dichloro-phenyl)-amine

IV-88 [9-Chloro-7-(2-chloro-phenyl)-5H-benzo [c]pyrimido [4, 5 -e] azepin-2-yl] -(3,5- dimethoxy-phenyl)-amine

IV-89 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-(3,5- dimethyl-phenyl)-amine

IV-90 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azep in-2-yl]-phenyl- amine

IV-91 4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid

IV-92 4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid

IV-93 (3 -Dimethylamino-pyrrolidin- 1 -yl)- {4-[7-(2-fluoro-phenyl)-9-methoxy-5H- benzo [c]pyrimido [4,5 -e] azepin-2-ylamino] -phenyl } -methanone

IV-94 4-[9-Chloro-7-(2,5-dimethoxy-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino] -benzoic acid

IV-95 4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-N,N-bis-(2-hydroxy-ethyl)-benzamide

IV-96 4-[9-Chloro-7-(2,4-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid

IV-97 4- [9-Chloro-7-(2,4-difluoro-phenyl)-7H-benzo [cjpyrimido [4, 5 -e] azepin-2- ylamino] -benzoic acid

IV-98 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl} -(3-dimethylamino-azetidin- 1 -yl)-methanone

IV-99 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-methyl-N-( 1 -methy l-pyrrolidin-3 -y l)-benzamide

rv-ioo {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c] pyrimido [4,5 -e] azepin-2- ylamino] -phenyl } -(3 -dimethylamino-pyrrolidin- 1 -yl)-methanone

IV-101 4-[9-Chloro-7-(2,4-dimethoxy-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylaraino] -benzoic acid

IV- 102 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl} -(3-methylamino-pyrrolidin- 1 -yl)-methanone

IV- 103 (3-Amino-pyrrolidin- 1 -yl)- {4-[9-chloro-7-(2-fluoro-phenyl)-5H- benzo [c]pyrimido[4,5 -e] azepin-2-ylamino] -phenyl } -methanone

IV-104 4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid methyl ester

IV-105 4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid methyl ester

IV- 106 {4-[9-Ghloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -phosphonic acid

IV-107 N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino] -phenyl } -methanesulfonamide

IV-108 N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino] -phenyl } -N-methyl-acetamide

IV- 109 2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino]-benzoylamino} -succinic acid

IV-110 [9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido[4 ,5-e]azepin-2- yl] -(3 ,4-dimethoxy-phenyl)-amine

rv-i i i {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl} -(3 ,5-dimethyl-piperazin- 1 -yl)-methanone

IV-112 l-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino] -benzoyl } -pyrrolidine-2-carboxylic acid

IV-113 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } -(3 -methy 1-piperazin- 1 -y l)-methanone

IV-114 [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyriniido[4,5-e]aze pin-2-yl]-[4-(2H- tetrazol-5 -yl)-phenyl] -amine

IV-115 N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino]-phenyl} -acetamide

IV-116 5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-fluoro-benzoic acid

IV-117 N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[ c]pyrimido- [4,5 -e] azepin-2-ylamino] -N-methyl-benzamide

IV-118 2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino]-benzoylamino} -propionic acid

IV-119 5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- pyridine-2-carboxylic acid

IV-120 2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2- ylamino] -phenyl} -N-(2-morpholin-4-yl-ethyl)-acetamide

IV-121 5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-methoxy-benzoic acid

IV- 122 5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-methyl-benzoic acid

rv-123 6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- nicotinic acid

IV- 124 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide

rv-125 2-Ghloro-5-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido [4,5-e]azepin-2- ylamino] -benzoic acid ^■ . .

IV- 126 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -acetic acid

IV-127 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylaminol- 2-trifluoromethyl-benzoic acid

IV- 128 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-methyl-N-( 1 -methyl-piperidin-4-yl)-benzamide

IV- 129 N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[ c]pyrimido- [4,5-e]azepin-2-ylamino]-benzamide

IV-130 4- [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c] pyrimido [4, 5-e] azepin-2-ylamino] - N-(3-methylamino-propyl)-benzamide

IV-131 N-(2-Amino-2-methyl-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)- 5H- benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide

IV-132 2-(3,4-Dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5H-benzo[c ]pyrimido- [4,5-e]azepine- 10-carboxylic acid

IV-133 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-methyl-benzoic acid

IV- 134 2-Chloro-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido [4,5-e]azepin-2- ylamino] -benzoic acid

IV-135 4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -benzoic acid

IV-136 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-fluoro-benzoic acid

IV-137 4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylaminoj-benzoic acid

IV-138 (3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methoxy-5H-ben zo[c]pyrimido- [4,5-e]azepin-2-yl]-amine

IV-139 [9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e ]azepin-2-yl]- (3 ,4-dimethoxy-pheny l)-amine

IV- 140 4-[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino] -benzoic acid

IV-141 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- 2-methoxy-benzoic acid

IV- 142 N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c ]pyrimido- [4,5 -e] azepin-2-ylamino] -benzamide

IV-143 4-(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylam ino)-benzoic acid

IV- 144 [7-(2-Bromo-phenyl)-9-chloro-5H-benzo [c]pyrimido [4, 5 -e] azepin-2-yl] -(3,4- dimethoxy-phenyl)-amine

IV- 145 2- {4- [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido [4,5 -e] azepin-2- ylamino] -phenyl } - 1 -(4-methyl-piperazin- 1 -yl)-ethanone

IV- 146 3 - [9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido[4, 5 -e] azepin-2-ylamino] - benzoic acid

IV- 147 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-[2-(lH-imidazol-4-yl)-ethyl]-benzamide

IV- 148 4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]az epin-2- ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide

IV- 149 {3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -acetic acid

IV-150 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo [c]pyrimido [4, 5 -e] azepin-2-ylamino] - N-(2-pyridin-4-yl-ethyl)-benzamide

IV-151 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-pyridin-3-yl-ethyl)-benzamide

IV-152 (9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3 ,4-dimethoxy- phenyl)-amine

IV-153 4-[7-(2-Fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -benzoic acid

IV- 154 (3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-5H-benzo[c]pyrim ido- [4,5 -e] azepin-2-yl] -amine

IV-155 4-[9-Chloro-7-(4-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -benzoic acid

IV-156 4- [9-Chloro-7-(3 -methoxy-phenyl)-5H-benzo [c]pyrimido [4, 5 -e] azepin-2- ylamino] -benzoic acid

IV-157 4- [9-Chloro-7-(3 -fluoro-phenyl)-5H-benzo [cjpyrimido [4,5 -e] azepin-2-ylamino] - N- [3 -(4-methyl-piperazin- 1 -yl)-propy 1] -benzamide

IV-158 4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-morpholin-4-yl-ethyl)-benzamide

IV-159 {4- [9-Chloro-7-(3 -fluoro-phenyl)-5H-benzo [cjpyrimido [4, 5 -e] azepin-2- ylamino] -phenyl} -(4-methyl-piperazin- 1 -yl)-methanone

IV- 160 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamide

IV-161 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- N-(2-pyridin-2-yl-ethyl)-benzamide

IV- 162 4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- benzoic acid

IV- 163 {3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } -(4-methy 1-piperazin- 1 -yl)-methanone

IV- 164 9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyridin-2-ylpiperazin-l - yl)carbonyl]phenyl} -5H-pyrimido[5,4-c/] [2]benzazepin-2-amine

IV-165 9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-mo holin-4-yl-2-oxoethyl)piperazin- l-yl]carbonyl}phenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-166 9-Chloro-7-(2-fluorophenyl-N-(4-{[4-(2-furoyl)piperazin-l-yl ]carbonyl}phenyl)- 5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-167 Benzyl-4-(4- { [9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-^ [2]benzazepin-2- yl] amino } benzoyl)piperazine- 1 -carboxylate

IV-168 Ethyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yljamino} benzoyl)piperazine- 1 -carboxylate

IV-169 2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-£ l[2]benzazepin-2- yl] amino } benzoyl)piperazin- 1 -yl] benzoic acid

IV- 170 2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } benzoyl)piperazin- 1 -yl] -N-isopropylacetamide

IV-171 9-Chloro-7-(2-fluorophenyl)-N-(4- { [4-(2-pyrrolidin- 1 -ylethyl)piperazin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-i l[2]benzazepin-2-amine

IV- 172 N-[2-(aminocarbonyl)phenyl]-4-{[9-chloro-7-(2-fluorophenyl)- 5H-pyrimido- [5 ,4-d] [2] benzazep in-2-y 1] amino } benzamide

IV- 173 9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyrimidin-2-ylpiperazin -l- yl)carbonyl]phenyl}-5H-pyrimido[5,4-cT][2]benzazepin-2-amine

IV-174 4-{[9-Chloro-7-(2-chloro-6-fluorophenyl)-5H-pyrimido[5,4-c ][2]benzazepin-2- yl]amino}benzoic acid

IV- 175 9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin -l- yl)carbonyl]phenyl}-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV- 176 9-Chloro-7-(2,6-difluorophenyl)-N-(4- { [3 -(dimethylamino)pyrrolidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-cf][2]benzazepin-2-amine

IV- 177 9-Chloro-N-{4-[(3,5-dimethylpiperazin-l-yl)carbonyl]phenyl}- 7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-c ][2]benzazepin-2 -amine IV- 178 9-Chloro-N-(4- { [3 -(dimethylamino)pyrrolidin- 1 -yl] carbonyl } phenyl)-7-(2- fluoro-6-methoxyphenyl)-5H-pyrimido[5,4- ][2]benzazepin-2-amine

IV- 179 9-Chloro-N-(4- { [3 -(dimethylamino)azetidin- 1 -yl]carbonyl } phenyl)-7-(2-fluoro- 6-methoxyphenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-180 9-Chloro-7-(2,6-difluorophenyl)-N-(4- { [3 -(dimethylamino)azetidin- 1 - yl] carbonyl} phenyl)-5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-181 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } - [4-(3 -piperidin- 1 -yl-propy l)-piperazin- 1 -yl] -methanone

IV- 182 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl} -[4-(2 -piperidin- 1 -yl-ethyl)-piperazin- 1-yl] -methanone

IV- 183 {4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino] -phenyl } -(4-dimethylamino-piperidin- 1 -yl)-methanone

IV- 184 {4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino]-phenyl}-(4-methyl-piperazin-l-yl)-methanone

IV- 185 4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -N-(3 -dimethylamino-propyl)-N-methyl-benzamide

IV- 186 {4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimi do-

[4, 5 -e] azepin-2-ylamino] -phenyl } -(4-dimethylamino-piperidin- 1 -yl)-methanone

IV- 187 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino]-phenyl}-[4-(2-dipropylamino-ethyl)-piperazin-l-yl]- methanone

IV-188 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl } - [4-(3 -pyrrolidin- 1 -yl-propy l)-piperazin- 1 -yl] -methanone

IV- 189 {4-[9-Chloro-7-(2-£luoro-phenyl)-5H-benzo[c]pyrimido[4,5-e] azepin-2- ylamino]-phenyl}-[4-(2-moφholin-4-yl-ethyl)-piperazin-l-yl] -methanone

IV-190 4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimid o[4,5-e]azepin- 2-ylamino] -benzoic acid

IV-191 {4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino] -phenyl} -(3(S)-methyl-piperazin- 1 -yl)-methanone

IV- 192 (3 -Amino-azetidin- 1 -yl)- {4-[9-chloro-7-(2-fluoro-phenyl)-5H- benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone

IV-193 {4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]a zepin-2- ylamino] -phenyl} -(3 -dimethylaminomethyl-azetidin- 1 -yl)-methanone

IV- 194 {4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino]-phenyl} -(3 (R)-methyl-piperazin- 1 -yl)-methanone IV- 195 {4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5 -e]azepin-2- ylamino]-phenyl}-piperazin-l-yl-methanone

IV- 196 (3 -Amino-pyrrolidin- 1 -yl)- {4-[9-chloro-7-(2,6-difluoro-phenyl)-5H- benzo [cjpyrimido [4,5 -e] azepin-2-ylamino] -phenyl } -methanone

IV- 197 {4- [9-Chloro-7-(2,6-difluoro-pheny l)-5H-benzo [c] pyrimido [4,5 -e] azepin-2- ylamino] -phenyl} -(3 -methylamino-pyrrolidin- 1 -yl)-methanone

IV-198 4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5- e]azepin-2- ylamino] -N-methyl-N-(3 -methylamino-propyl)-benzamide

IV- 199 {4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimi do[4,5- e] azepin-2-ylamino] -phenyl } -(3 -methylamino-pyrrolidin- 1 -yl)-methanone

IV-200 4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]az epin-2-ylamino]- cyclohexanecarboxylic acid

rV-201 9-chloro-N-(4- { [4-(2-ethoxyphenyl)piperazin- 1 -yl] carbonyl } phenyl)-7-(2- fluorophenyl)-5H-pyrimido[5,4- ][2]benzazepin-2-amine

IV-202 N-[amino(imino)methyl]-4-{[9-chloro-7-(2,6-difluorophenyl)-5 H-pyrimido[5,4- d] [2]benzazepin-2-yl] amino } benzamide

IV-203 3- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d] [2]benzazepin-2- yl] amino} benzoic acid

IV-204 9-chloro-7-(2,6-difluorophenyl)-N-(3 - { [3 -(dimethylamino)azetidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2 -amine

IV-205 9-chloro-7-(2,6-difluorophenyl)-N-(3 - { [4-(dimethylamino)piperidin- 1 - yl] carbonyl } phenyl)-5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-206 9-chloro-7-(2,6-difluorophenyl)-N-(3 - { [3 -(dimethylamino)pyrrolidin- 1 - yl] carbonyl } phenyl)-5H-pyrimido [5 ,4-d\ [2]benzazepin-2-amine

IV-207 N-[2-(aminomethyl)-l,3-benzoxazol-5-yl]-9-chloro-7-(2,6-difl uorophenyl)-5H- pyrimido[5,4-t/][2]benzazepin-2 -amine

IV-208 9-chloro-N-[4-({4-[3-(diethylamino)propyl]piperazin-l-yl}car bonyl)phenyl]-7- (2-fluorophenyl)-5H-pyrimido [5,4-c?][2] benzazepin-2-amine

IV-209 9-chloro-N-[4-({4-[2-(diethylamino)ethyl]piperazin-l-yl}carb onyl)phenyl]-7-(2- fluorophenyl)-5H-pyrimido[5,4-(i][2]benzazepin-2-amine

IV-210 9-chloro-N-[4-( {4-[3 -(dimethylamino)propyl]piperazin- 1 -yl} carbonyl)phenyl] -7- (2-fluorophenyl)-5H-pyrimido[5,4-if|[2]benzazepin-2-amine

IV-21 1 9-chloro-7-(2-fluorophenyl)-N- [4-( { 4- [( 1 -methylpiperidin-3 - yl)methyl]piperazin- 1 -yl} carbonyl)phenyl]-5H-pyrimido[5,4-cf] [2]benzazepin-2-

- I l l - amine rv-212 9-chloro-7-(2,6-difluorophenyl)-N-(4-nitrophenyl)-5H-pyrimid o[5,4- d] [2]benzazepin-2-amine

IV-213 9-chloro-N-(3 -chloro-4- { [4-(2-pyrrolidin- 1 -ylethyl)piperazin- 1 - yl]carbonyl}phenyl)-7-(2-fluorophenyl)-5H-pyrimido[5,4-i/][2 ]benzazepin-2- amine

IV-214 9-chloro-N- {3 -chloro-4-[(3 -methylpiperazin- 1 -yl)carbonyl]phenyl} -7-(2- fluorophenyl)-5H-pyrimido[5,4-i/][2]benzazepin-2 -amine

IV-215 9-chloro-N-(3 -chloro-4- { [3 -(dimethylamino)pyrrolidin- 1 -yl] carbonyl } pheny l)-7- (2,6-difluorophenyl)-5H-pyrimido[5,4-t ][2]benzazepin-2-amine

IV-216 9-chloro-N- {3 -chloro-4-[(3 -methylpiperazin- 1 -yl)carbonyl]phenyl} -7-(2,6- difluorophenyl)-5H-pyrimido[5,4-i/][2]benzazepin-2-amine

IV-217 N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yljbenzene- 1 ,4-diamine

IV-218 methyl 2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4 - i ][2]benzazepin-2-yl]amino}benzoate

IV-219 l-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino }benzoyl)piperazine-2-carboxylic acid

rV-220 9-chloro-7-(2,6-difluorophenyl)-N-(4- { [4-(methylamino)piperidin- 1 - yl] carbonyl } phenyl)-5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-221 N- {4-[(3 -aminopiperidin- 1 -yl)carbonyl]phenyl} -9-chloro-7-(2,6- difluorophenyl)-5H-pyrimido[5,4-if][2]benzazepin-2-amine

IV-222 9-chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin -l- yl)carbonyl]phenyl}-5H-pyrimido[5,4-(3i][2]benzazepin-2-amin e

IV-223 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-c ][2]benzazepin-2- yl]amino}-N-[[4-(dimethylamino)piperidin-l-yl](imino)methyl] benzamide

IV-224 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } -N- [imino(piperazin- 1 -yl)methyl]benzamide

IV-225 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-&l t; ][2]benzazepin- 2-yl] amino } -N- [3 -(dimethylamino)propyl] -N-methylbenzamide

IV-226 3-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-i/ ][2]benzazepin- 2-yl] amino } -N- [3 -(dimethylamino)propyl] -N-methylbenzamide IV-227 9-chloro-N-(3 - { [3 -(dimethylamino)azetidin- 1 -yl]carbonyl} phenyl)-7-(2-fluoro- 6-methoxyphenyl)-5H-pyrimido[5,4-^[2]benzazepin-2-amrne

IV-228 9-chloro-N- {3 -[(3 ,5-dimethylpiperazin- 1 -yl)carbonyl]phenyl} -7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-<¾[2]benzazepin-2-amine rv-229 9-chloro-N-(3 - { [4-(dimethylamino)piperidin- 1 -yl]carbonyl} phenyl)-7-(2-fluoro- 6-methoxyphenyl)-5H-pyrimido [5 ,4-d [2]benzazepin-2-amine

IV-230 N-(4- { [3 -(aminomethyl)azetidin- 1 -yl] carbonyl } phenyl)-9-chloro-7-(2- fluorophenyl)-5H-pyrimido[5,4-<fl[2]benzazepin-2-amine

IV-231 9-chloro-N-(3 - { [3 -(dimethy lamino)pyrrolidin- 1 -yl]carbonyl}phenyl)-7-(2- fluoro-6-methoxypheny l)-5 H-pyrimido [5 ,4-d\ [2] benzazepin-2-amine

IV-232 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(3-methylpiperaz in-l- yl)carbonyl]phenyl } -5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-233 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(4-methylpiperaz in-l- yl)carbonyl]phenyl}-5H-pyrimido[5,4-ii][2]benzazepin-2-amine

IV-234 9-chloro-7-(2,6-difluorophenyl)-N-(4- { [3 -(methylamino)azetidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-235 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4- { [3 -(methylamino)azetidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-if][2]benzazepin-2 -amine

IV-236 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } benzonitrile

IV-237 4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-flf] [2]benzazepin-2- yl] amino } -N- [[3 -(dimethylamino)pyrrolidin- 1 -yl](imino)methyl] benzamide

IV-238 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-c/][2]be nzazepin-2- yl] amino } -N- [(3 ,5 -dimethy lpiperazin- 1 -yl)(imino)methyl]benzamide

IV-239 N-{4-[(4-aminopiperidin-l-yl)carbonyl]phenyl}-9-chloro-7-(2, 6- difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-240 N-{4-[(3-aminopyrrolidin-l-yl)carbonyl]phenyl}-9-chloro-7-(2 -fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-<fJ[2]benzazepin-2 -amine

IV-241 N- {4-[(4-aminopiperidin- 1 -yl)carbonyl]phenyl} -9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-(3i][2]benzazepin-2-amine

IV-242 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4- { [4-(methylamino)piperidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-243 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-[4-(piperazin-l-ylca rbonyl)phenyl]- 5H-pyrimido[5,4-i/][2]benzazepin-2-amine IV-244 9-chloro-7-(2,6-difluorophenyl)-N- {4-[[4-(dimethylamino)piperidin- 1 - yl](imino)methyl]phenyl}-5H-pyrimido[5,4-i/][2]benzazepin-2- amine

IV-245 N-(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i/] [2]benzazepin-2- yl] amino } phenyl)guanidine

IV-246 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i/][2]be nzazepin-2- yl] amino } -N-methyl-N- [2-(methylamino)ethyl]benzamide

IV-247 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } -N- [2-(dimethylamino)ethyl] -N-methylbenzamide

IV-248 methyl 4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4- d][2]benzazepin-2-yl]amino}benzoyl)piperazme-2-carboxylate

IV-249 2-[(4-carboxyphenyl)amino]-7-(2-fluorophenyl)-5H-pyrimido[5, 4- d] [2]benzazepine-9-carboxylic acid

rv-250 9-chloro-7-(2,6-difluorophenyl)-N- {4-[[3 -(dimethylamino)pyrrolidin- 1 - yl](imino)methyl]phenyl}-5H-pyrimido[5,4-<5 ][2]benzazepin-2 -amine

IV-251 9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin -l- yl)(imino)methyl]phenyl}-5H-pyrimido[5,4-(s ][2]benzazepin-2-amine

IV-252 N-(2-aminoethyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri mido[5,4- i/][2]benzazepin-2-yl]amino}-N-methylbenzamide

IV-253 9-chloro-7-(2,6-difluorophenyl)-N-(4- { [3-(methylamino)piperidin- 1 - yl] carbonyl } phenyl)-5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-254 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-i/ |[2]benzazepin- 2-yl]amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide

IV-255 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-i ][2]benzazepin- 2-yl]amino} -N-[2-(dimethylamino)ethyl]-N-methylbenzamide

IV-256 7-(2-fluorophenyl)-2- [(3 -methoxyphenyl)amino] -5H-pyrimido [5 ,4- d] [2]benzazepine-9-carboxylic acid

IV-257 N-(3 -aminopropyl)-4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido [5 ,4- ][2]benzazepin-2-yl]amino}-N-methylbenzamide

IV-258 2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4 -< j[2]benzazepin- 2-yl]amino}benzoic acid

IV-259 4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5 ,4-d] [2]benzazepin-2- yl]amino}-N-[[3-(dimethylamino)azetidin-l-yl](imino)methyl]b enzamide

IV-260 N-(2-amino-2-methylpropyl)-4-{[9-chloro-7-(2,6-difluoropheny l)-5H- pyrimido [5 ,4-d [2]benzazepin-2-yl] amino } benzamide IV-261 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-(5 i][2]benzazepin- 2-yl]amino}-N-methyl-N-[3-(methylamino)propyl]benzamide

IV-262 N- {4- [(3 -aminopiperidin- 1 -yl)carbonyl]phenyl } -9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-<5 ] [2]benzazepin-2-amine

IV-263 9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino) piperidin-l- yl]carbonyl}phenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-264 N-(3-aminopropyl)-4- { [9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H- pyrimido[5,4-<i] [2]benzazepin-2-yl]amino} -N-methylbenzamide

IV-265 N-(2-aminoethyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5 H-pyrimido[5,4- d] [2]benzazepin-2-yl]amino} -N-methylbenzamide

IV-266 4-(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ] [2]benzazepin-2- yl]amino}benzoyl)piperazine-2-carboxylic acid

IV-267 9-chloro-7-(2,6-difluorophenyl)-N- {4-[[3 -(dimethylamino)azetidin- 1 - yl](imino)methyl]phenyl}-5H-pyrimido[5,4-(3?][2]benzazepin-2 -amine rv-268 9-chloro-7-(2,6-difluorophenyl)-N-(4-{imino[3-(methylamino)p yrrolidin-l- yl]methyl}phenyl)-5H-pyrimido[5,4-(/][2]benzazepin-2-amine

IV-269 9-chloro-N-(4-chloro-3 - { [4-(dimethylamino)piperidin- 1 -yl] carbonyl} phenyl)-7- (2,6-difluorophenyl)-5H-pyrimido[5,4-£ ][2]benzazepin-2-amine

IV-270 9-chloro-7-(2,6-difluorophenyl)-N-[4-(5,5-dimethyl-4,5-dihyd ro-lH-imidazol-2- yl)phenyl]-5H-pyrimido[5,4-iii][2]benzazepin-2-amine

IV-271 N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-(5 ][2]benzazepin-2-yl]-N- pyrimidin-2-ylbenzene- 1 ,4-diamine

IV-272 4- { [9-(3 -aminoprop- 1 -yn- 1 -yl)-7-(2,6-difluorophenyl)-5H-pyrimido[5 ,4- i/][2]benzazepin-2-yl]amino}benzoic acid

IV-273 9-bromo-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimi do[5,4- d] [2]benzazepin-2-amine

IV-274 4- { [9-bromo-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-<fl [2]benzazepin-2- yl] amino} benzoic acid

IV-275 7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-9-(3 -pyrrolidin- 1 -ylprop- 1 -yn- 1 - yl)-5H-pyrimido[5,4-d][2]benzazepin-2 -amine

IV-276 9-(3 -aminoprop- 1 -yn- 1 -yl)-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H- pyrimido[5,4-<5T] [2]benzazepin-2 -amine

IV-277 4-({9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-i ][2]benzazepin-2- yl}amino)benzoic acid IV-278 N- {4-[(3-aminoazetidin- 1 -yl)carbonyl]phenyl} -9-chloro-7-(2,6-difluorophenyl)- 5H-pyrimido[5,4-i¾[2]benzazepin-2-amine

IV-279 4-[(9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-i ][2]benzazepin-2- yl)amino]benzoic acid

IV-280 N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i/][2 ]benzazepin-2- yl]amino}phenyl)-4-methylpiperazine-l-carboxamide

IV-281 9-chloro-N-(4-chloro-3 - { [3-(methy lamino)pyrrolidin- 1 -y 1] carbonyl } pheny l)-7- (2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-282 9-chloro-N-(4-chloro-3 - { [4-(methylamino)piperidin- 1 -yl]carbonyl} phenyl)-7- (2,6-difluorophenyl)-5H-pyrimido[5,4-i¾[2]benzazepin-2-amin e

IV-283 2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4 -<5?][2]benzazepin- 2-yl]amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide

IV-284 N-{4-[(3-aminopyrrolidin-l-yl)(imino)methyl]phenyl}-9-chloro -7-(2,6- difluorophenyl)-5H-pyrimido[5,4-iii][2]benzazepin-2 -amine

IV-285 2-(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ] [2]benzazepin-2- yl]amino}phenyl)-l,4,5,6-tetrahydropyrimidin-5-ol

IV-286 N- {4-[(3-aminoazetidin- 1 -yl)carbonyl]phenyl} -9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-i5i][2]benzazepin-2-amine

rv-287 N-{4-[(4-aminopiperidin-l-yl)carbonyl]phenyl}-9-chloro-7-[2- (trifluoromethyl)phenyl]-5H-pyrimido[5,4-i ][2]benzazepin-2 -amine

IV-288 9-chloro-N-(4- { [4-(methylamino)piperidin- 1 -yl]carbonyl}phenyl)-7-[2- (trifluoromethyl)pheny 1] -5H-pyrimido [5 ,A-d [2] benzazepin-2-amine

IV-289 N-{4-[(3-aminopyrrolidin-l-yl)carbonyl]phenyl}-9-chloro-7-[2 - (trifluoromethyl)phenyl] -5H-pyrimido [5 ,4-d] [2] benzazepin-2-amine

IV-290 9-chloro-N-(4- { [3 -(methylamino)pyrrolidin- 1 -yl]carbonyl} phenyl)-7-[2- (trifluoromethyl)phenyl] -5H-pyrimido [5 ,4-d] [2]benzazepin-2-amine

IV-291 9-chloro-N-(4-chloro-3 - { [3-(methylamino)azetidin- 1 -yl]carbonyl} phenyl )-7- (2,6-difluorophenyl)-5H-pyrimido[5,4-i/][2]benzazepin-2-amin e

IV-292 N-{3-[(4-aminopiperidin-l-yl)carbonyl]-4-chlorophenyl}-9-chl oro-7-(2,6- difluorophenyl)-5H-pyrimido[5,4-(5 ][2]benzazepin-2-amine

IV-293 9-chloro-7-(2,6-difluorophenyl)-N-(4- { [3-(dimethylamino)piperidin- 1 - yl]carbonyl}phenyl)-5H-pyrimido[5,4-i/] [2]benzazepin-2-amine

IV-294 methyl 4-amino-l-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5 ,4- </][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxyl ate IV-295 4-amino- 1 -(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4- d [2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxylic acid

IV-296 N-{4-[(3-aminoazetidin-l-yl)carbonyl]phenyl}-9-chloro-7-[2- (trifluoromethyl)phenyl]-5H-pyrimido[5,4-i ][2]benzazepin-2-amine

IV-297 9-chloro-N-(4- { [3 -(methylamino)azetidin- 1 -yljcarbonyl} phenyl)-7-[2- (trifluoromethyl)phenyl]-5H-pyrimido[5,4-t/][2]benzazepin-2- amine

IV-298 N-{4-[(4-aminopiperidin-l-yl)carbonyl]phenyl}-9-chloro-7-pyr idin-2-yl-5H- pyrimido[5,4-c ][2]benzazepin-2-amine

IV-299 N- {4- [(3 -aminopyrrolidin- 1 -yl)carbonyl]phenyl } -9-chloro-7-pyridin-2-yl-5H- pyrimido[5,4-( ][2]benzazepin-2-amine

IV-300 ethyl 2-amino-4-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[ 5,4- i ][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate

IV-301 4-{[9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-ii][2] benzazepin-2- yl] amino} benzoic acid

IV-302 9- { [3 -(dimethylamino)azetidin- 1 -yl] carbonyl } -7-(2-fluorophenyl)-N-(3 - methoxyphenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2 -amine

TV-303 7-(2-fluorophenyl)-2-[(3 -methoxyphenyl)amino] -N-methyl-N- [3 - (methylamino)propyl] -5H-pyrimido [5 ,4-d\ [2]benzazepine-9-carboxamide

IV-304 N- {4-[(4-aminopiperidin- 1 -yl)carbonyl]phenyl} -9-chloro-7-(3 -fluoropyridin-2- yl)-5H-pyrimido[5,4-c/] [2]benzazepin-2-amine

rv-305 N- {4- [(3 -aminopyrrolidin- 1 -yl)carbonyl]phenyl } -9-chloro-7-(3 -fluoropyridin-2- yl)-5H-pyrimido[5,4-if][2]benzazepin-2-amine

IV-306 2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } pheny l)-4,5 -dihydro- lH-imidazole-5 -carboxylic acid

IV-307 N-(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5 ,4-d [2]benzazepin-2- yl] amino } pheny l)-2-(dimethylamino)acetamide

IV-308 2-amino-N-(4- { [9-chloro-7-(2,6-difIuorophenyl)-5H-pyrimido [5,4- <f][2]benzazepin-2-yl]amino}phenyl)-2-methylpropanamide

IV-309 ethyl (2R)-4-amino-2-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyri mido[5,4- i ][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate

IV-310 4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-£/][ 2]benzazepin-2- yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide

rv-311 7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-(3-morpholin -4-ylpropyl)- 5H-pyrimido[5,4-ii][2]benzazepine-9-carboxamide IV-312 9-[(3,5-dimethylpiperazin-l-yl)carbonyl]-7-(2-fluorophenyl)- N-(3- methoxyphenyl)-5H-pyrimido[5,4-i/][2]benzazepin-2-amine

IV-313 9-chloro-N-(3-chloro-4-{[4-(dimethylamino)piperidin-l-yl]car bonyl}phenyl)-7- (2,6-difluorophenyl)-5H-pyrimido[5,4- ][2]benzazepin-2-amine

IV-314 ethyl 2-(4- { [9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i | [2]benzazepin- 2-yl]amino}phenyl)-4,5-dihydro-lH-imidazole-5-carboxylate

IV-315 9-chloro-N-(4- { [3 -(methylamino)pyrrolidin- 1 -yl]carbonyl} phenyl)-7-pyridin-2- yl-5H-pyrimido[5,4- ][2]benzazepin-2 -amine

IV-316 9-chloro-N-(4-{[4-(methylamino)piperidin-l-yl]carbonyl}pheny l)-7-pyridin-2- yl-5H-pyrimido [5 ,4-d] [2] benzazepin-2 -amine

IV-317 4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } benzoyl)piperazine-2-carboxamide

IV-318 N- { 4- [(3 -aminopyrrolidin- 1 -yl)carbonyl] -3 -chlorophenyl } -9-chloro-7-(2,6- difluorophenyl)-5H-pyrimido[5,4-if|[2]benzazepin-2-amine

IV-319 N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-i ][2]benzazepin-2- yl] amino } pheny l)piperidine-4-carboxamide

IV-320 4- { [9-chloro-7-(2-fluoro-6- {methyl[2-(methylamino)ethyl]amino}phenyl)-5H- pyrimido[5,4-ci][2]benzazepin-2-yl]amino}benzoic acid