Identification of gene expression profile as a predictive biomarker for LKB1 status

专利摘要:
Provided herein are methods for predicting the LKBl status of a patient or a biological sample, comprising the measurement of particular gene expression levels relative to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKBl gene or protein loss or mutation and the gene expression level of a reference sample with LKBl gene or protein loss or mutation. Further provided herein are methods for treating and/or preventing a cancer or a tumor syndrome in a patient, comprising administering an effective amount of a TOR kinase inhibitor to a patient having cancer or a tumor syndrome, characterized by particular gene expression levels.
公开号:AU2012290056A1
申请号:U2012290056
申请日:2012-08-02
公开日:2013-04-11
发明作者:Rajesh Chopra；Yuhong Ning；Peter WORLAND；Shuichan Xu；Weiming Xu
申请人:Signal Pharmaceuticals LLC；
IPC主号:C12Q1-68

专利说明:
WO 2013/019927 PCT/US2012/049281 IDENTIFICATION OF GENE EXPRESSION PROFILE AS A PREDICTIVE BIOMARKER FOR LKB1 STATUS [0001] This application claims the benefit of U.S. Provisional Application No. 61/514,798, filed August 32, 2011, the entire contents of which are incorporated herein by reference. 1. FIELD [0002] Provided herein are methods for predicting the LKB 1 status of a patient or a biological sample, comprising the measurement of particular gene expression levels relative to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene or protein loss or mutation and the gene expression level of a reference sample with LKB1 gene or protein loss or mutation. Further provided herein are methods for treating and/or preventing a cancer or a tumor syndrome in a patient, comprising administering an effective amount of a TOR kinase inhibitor to a patient having cancer or a tumor syndrome, characterized by particular gene expression levels. 2. BACKGROUND [0003] The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. See Cohen, Nat. Rev. Drug Disc., 1:309-315 (2002), Grimmiger et al. Nat. Rev. Drug Disc. 9(12):956-970 (2010). Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including diabetes and stroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001), Protein Kinase Inhibitors for the Treatment ofDisease: The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005).
WO 2013/019927 PCT/US2012/049281 [00041 The protein kinases belong to a large and diverse family of enzymes that catalyze protein phosphorylation and play a critical role in cellular signaling. Protein kinases may exert positive or negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with protooncogenes and tumor suppressor genes have been well documented. Similarly, the connection between diabetes and related conditions, and deregulated levels of protein kinases, has been demonstrated. See e.g., Sridhar et al. Pharm. Res. 17(11):1345-1353 (2000). Viral infections and the conditions related thereto have also been associated with the regulation of protein kinases. Park et al. Cell 10 1(7): 777-787 (2000). [00051 Protein kinases can be divided into broad groups based upon the identity of the amino acid(s) that they target (serine/threonine, tyrosine, lysine, and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs), such as growth factors and non receptor tyrosine kinases, such as the src kinase family. There are also dual-specific protein kinases that target both tyrosine and serine/threonine, such as cyclin dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs). [0006] Because protein kinases regulate nearly every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell-cycle control and angiogenesis, in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain. -2- WO 2013/019927 PCT/US2012/049281 [00071 Protein kinases have become attractive targets for the treatment of cancers. Fabbro et al. Pharm. Ther. 93:79-98 (2002). It has been proposed that the involvement of protein kinases in the development of human malignancies may occur by: (1) genomic rearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to constitutively active kinase activity, such as acute myelogenous leukemia and gastrointestinal tumors, (3) deregulation of kinase activity by activation of oncogenes or loss of tumor suppressor functions, such as in cancers with oncogenic RAS, (4) deregulation of kinase activity by over expression, as in the case of EGFR and (5) ectopic expression of growth factors that can contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharm. Ther. 93:79-98 (2002). [0008] The elucidation of the intricacy of protein kinase pathways and the complexity of the relationship and interaction among and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase pathways. Accordingly, there remains a need for new kinase modulators. [0009] The protein named mTOR (mammalian target of rapamycin), also called FRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr protein kinase, that has been shown to be one of the most critical proteins in the mTOR/PI3K/Akt pathway that regulates cell growth and proliferation. Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006). mTOR exists within two complexes, mTORCI and mTORC2. While mTORCI is sensitive to rapamycin analogs (such as temsirolimus or everolimus), mTORC2 is largely rapamycin insensitive. Notably, rapamycin is not a TOR kinase inhibitor. Several mTOR inhibitors have been or are being evaluated in clinical trials for the treatment of cancer. Temsirolimus was approved for use in renal cell carcinoma in 2007 and everolimus was approved in 2009 for renal cell carcinoma patients that have progressed on vascular endothelial growth factor receptor -3- WO 2013/019927 PCT/US2012/049281 inhibitors. In addition, sirolimus was approved in 1999 for the prophylaxis of renal transplant rejection. The interesting but limited clinical success of these mTORCI inhibitory compounds demonstrates the usefulness of mTOR inhibitors in the treatment of cancer and transplant rejection, and the increased potential for compounds with both mTORCI and mTORC2 inhibitory activity. [0010] Somatic mutations affect key pathways in lung cancer. Accordingly, identification of specific mutations associated with lung cancer may lead to improved therapeutic protocols. Recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in lung, cervical, breast, intestinal, testicular, pancreatic and skin cancer (Distribution of somatic mutations in STKi 1, Catalogue of Somatic Mutations in Cancer, Wellcome Trust Genome Campus, Hinxton, Cambridge). [0011] Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the reference is prior art to the present application. 3. SUMMARY [0012] Provided herein are methods for predicting the LKB1 status of a patient or a biological sample, comprising the measurement of a predictive gene expression level. Without being limited by theory, it is believed that certain gene expression levels are characteristic of LKB1 gene and/or protein mutation and/or loss. [0013] Further provided herein are methods for treating or preventing a cancer, for example non-small cell lung carcinoma or cervical cancer, or treating a tumor syndrome, for example Peutz-Jeghers Syndrome, comprising administering an effective amount of a TOR kinase inhibitor to a patient having a cancer or a tumor syndrome characterized by a particular gene expression level, relative to that of wild type. [0014] Further provided herein are methods for treating or preventing a cancer, for example non-small cell lung carcinoma or cervical cancer, comprising screening a patient's -4- WO 2013/019927 PCT/US2012/049281 cancer for the presence of a particular gene expression level relative to that of wild type and administering an effective amount of a TOR kinase inhibitor to the patient having a cancer characterized by a particular gene expression level. [00151 Further provided herein are methods for predicting LKB 1 gene and/or protein loss and/or mutation in a patient's ("test patient") cancer, for example non-small cell lung carcinoma or cervical cancer, comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of an LKB1 gene or protein loss or mutation in the patient's cancer. [0016] Further provided herein are methods for treating non-small cell lung carcinoma, cervical cancer or Peutz-Jeghers Syndrome, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma, cervical cancer or Peutz Jeghers Syndrome, wherein the gene expression level(s) of a biological test sample from said patient is characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level(s) of a wild type sample without LKB 1 gene and/or r protein loss and/or mutation, and wherein the genes are selected from Table 1. [00171 Further provided are methods for treating non-small cell lung carcinoma or cervical cancer, comprising screening a patient's carcinoma or cancer for the presence of LKB1 gene and/or protein loss and/or mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma or cervical -5- WO 2013/019927 PCT/US2012/049281 cancer characterized by a gene expression level characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level(s) of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [0018] Further provided herein are methods for predicting response to treatment with a TOR kinase inhibitor in a patient having cancer, for example non-small cell lung carcinoma or cervical cancer, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of response to TOR kinase inhibitor treatment of said patient's cancer. [0019] Further provided herein are methods for predicting therapeutic efficacy of TOR kinase inhibitor treatment of a patient having cancer, for example non-small cell lung carcinoma or cervical cancer, with a TOR kinase inhibitor, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein -6- WO 2013/019927 PCT/US2012/049281 loss and/or mutation, indicates an increased likelihood of therapeutic efficacy of said TOR kinase inhibitor treatment for said patient. [0020] Further provided herein are methods of screening a patient having cancer, for example non-small cell lung carcinoma or cervical cancer, for LKB1 gene and/or protein loss and/or mutation, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of LKB 1 gene and/or protein loss and/or mutation. [0021] Further provided herein are methods for treating a tumor syndrome, for example Peutz-Jeghers Syndrome, comprising comparing a patient's gene expression level(s) to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having a tumor syndrome characterized by a gene expression level(s) characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level(s) of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [0022] Further provided are methods for treating a tumor syndrome, for example Peutz Jeghers Syndrome, comprising screening a patient for the presence of LKB 1 gene and/or protein loss and/or mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having a tumor syndrome characterized by a gene expression level(s) characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level(s) of a wild -7- WO 2013/019927 PCT/US2012/049281 type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [0023] Further provided herein are methods for predicting LKB 1 gene and/or protein loss and/or mutation in a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of an LKB 1 gene and/or protein loss and/or mutation in the patient. [0024] Further provided herein are methods for predicting response to TOR kinase inhibitor therapy in a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB1 gene and/or protein loss and/or mutation, indicates an increased likelihood of response to TOR kinase inhibitor treatment of said patient's tumor syndrome. [00251 Further provided herein are methods for predicting therapeutic efficacy of treatment of a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, with a -8- WO 2013/019927 PCT/US2012/049281 TOR kinase inhibitor, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of therapeutic efficacy of said TOR kinase inhibitor treatment for said patient. [0026] Further provided herein are methods of screening a patient having a tumor syndrome, for example Peutz-Jeghers Syndrome, for LKB1 gene and/or protein loss and/or mutation, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation and the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood for LKB 1 gene and/or protein loss and/or mutation. [00271 In certain embodiments provided herein, the gene expression level of the biological test sample is obtained using gene mRNA measurement. In certain of the methods and embodiments provided herein, the gene expression level of the biological test sample is obtained using RT-PCR or Affymetrix HGUl33plus2. In some embodiments, comparison of gene expression levels is performed using Prediction Analysis of Microarrays for R ("PAMR") (http://cran.r-project.org/web/packages/pamr/pamr.pdf). -9- WO 2013/019927 PCT/US2012/049281 [00281 Further provided herein are kits comprising one or more containers filled with a TOR kinase inhibitor or a pharmaceutical composition thereof, reagents for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome and instructions for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome. [0029] In some embodiments, the TOR kinase inhibitor is a compound as described herein. [0030] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. 4. BRIEF DESCRIPTION OF THE DRAWINGS [0031] FIG 1. Figure 1 provides a heatmap of the gene expression level of certain LKB1 positive (wild type) and negative (LKB 1 gene and/or protein loss and/or mutation) non-small cell lung cancer cell types obtained using prediction analysis of microarrays (PAM) extraction. [0032] FIG 2. Figure 2 provides a list of enriched GeneOntology groups. [0033] FIG. 3. Figure 3 lists the LKB1 mutation status of non small cell lung cancer (NSCLC) cell lines, based on reported DNA sequences, the reported mutation, the presence (positive) or absence (negative) of intact LKB 1 protein (as determined by Western immunoblotting). [0034] FIG 4. Figure 4 provides a list of enriched pathway groups. 5. DETAILED DESCRIPTION 5.1 DEFINITIONS [00351 An "alkyl" group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from I to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative - 10 - WO 2013/019927 PCT/US2012/049281 alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH 3 ), -CH=C(CH 3
)
2 , -C(CH 3
)=CH
2 ,
-C(CH
3
)=CH(CH
3 ), -C(CH 2
CH
3
)=CH
2 , -C--CH, -C--C(CH 3 ), -C--C(CH 2
CH
3 ), -CH 2 C--CH,
-CH
2
C--C(CH
3 ) and -CH 2
C-C(CH
7
CH
3 ), among others. An alkyl group can be substituted or unsubstituted. Unless otherwise indicated, when the alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); B(OH)2, or 0(alkyl)aminocarbonyl. [00361 An "alkenyl" group is a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8 carbon atoms, and including at least one carbon carbon double bond. Representative straight chain and branched (C 2 -Cs)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl and the like. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. An alkenyl group can be unsubstituted or substituted. [00371 A "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. In some embodiments, - 11 - WO 2013/019927 PCT/US2012/049281 the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as adamantyl and the like. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanone and the like. [00381 An "aryl" group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). [0039] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl (for example, isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example, pyrrolopyridyl or 1H pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example, azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or 1H-imidazo[4,5 - 12 - WO 2013/019927 PCT/US2012/049281 b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. [0040] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of 0, S and N. In some embodiments, heterocyclyl groups include 3 tol0 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclylalkyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example, tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, - 13 - WO 2013/019927 PCT/US2012/049281 imidazopyridyl (azabenzimidazolyl; for example, 1H-imidazo[4,5-b]pyridyl, or 1H-imidazo[4,5 b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below. [0041] An "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Representative substituted cycloalkylalkyl groups may be mono- substituted or substituted more than once. [0042] An "aralkyl" group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl indanyl. [00431 A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, - 14 - WO 2013/019927 PCT/US2012/049281 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyrdine-3-yl methyl, (tetrahydro-2H pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl, tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. [0044] A "halogen" is fluorine, chlorine, bromine or iodine. [00451 A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups. [0046] An "alkoxy" group is -O-(alkyl), wherein alkyl is defined above. [00471 An "alkoxyalkyl" group is -(alkyl)-O-(alkyl), wherein alkyl is defined above. [0048] An "amino" group is a radical of the formula: -NH 2 . [0049] An "alkylamino" group is a radical of the formula: -NH-alkyl or -N(alkyl) 2 , wherein each alkyl is independently as defined above. [00501 A "carboxy" group is a radical of the formula: -C(O)OH. [00511 An "aminocarbonyl" group is a radical of the formula: -C(O)N(R#) 2 , -C(O)NH(R) or -C(O)NH 2 , wherein each R# is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein. [0052] An "acylamino" group is a radical of the formula: -NHC(O)(R#) or -N(alkyl)C(O)( R#), wherein each alkyl and R4 are independently as defined above. [0053] An "alkylsulfonylamino" group is a radical of the formula: -NHSO 2 (R#) or -N(alkyl)SO 2 (R4), wherein each alkyl and R# are defined above. [0054] A "urea" group is a radical of the formula: -N(alkyl)C(O)N(R) 2 , -N(alkyl)C(O)NH(R), -N(alkyl)C(O)NH 2 , -NHC(O)N(R) 2 , -NHC(O)NH(R), or -NH(CO)NHR#, wherein each alkyl and R# are independently as defined above. [00551 When the groups described herein, with the exception of alkyl group, are said to be "substituted," they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; - 15 - WO 2013/019927 PCT/US2012/049281 hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); B(OH) 2 , 0(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. [00561 As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the TOR kinase inhibitors include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and - 16 - WO 2013/019927 PCT/US2012/049281 methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, Remington's Pharmaceutical Sciences, 1 8 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice ofPharmacy, 19 th eds., Mack Publishing, Easton PA (1995). [0057] As used herein and unless otherwise indicated, the term "clathrate" means a TOR kinase inhibitor, or a salt thereof, in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within or a crystal lattice wherein a TOR kinase inhibitor is a guest molecule. [00581 As used herein and unless otherwise indicated, the term "solvate" means a TOR kinase inhibitor, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In one embodiment, the solvate is a hydrate. [0059] As used herein and unless otherwise indicated, the term "hydrate" means a TOR kinase inhibitor, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. [00601 As used herein and unless otherwise indicated, the term "prodrug" means a TOR kinase inhibitor derivative that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a TOR kinase inhibitor. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a TOR kinase inhibitor that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In certain embodiments, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery - 17 - WO 2013/019927 PCT/US2012/049281 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application ofProdrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh). [0061] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a TOR kinase inhibitor that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The TOR kinase inhibitors can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof. The use of stereomerically pure forms of such TOR kinase inhibitors, as well as the use of mixtures of those forms are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amountsv of the enantiomers of a particular TOR kinase inhibitor may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., - 18 - WO 2013/019927 PCT/US2012/049281 Tables ofResolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). [0062] It should also be noted the TOR kinase inhibitors can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the TOR kinase inhibitors are isolated as either the cis or trans isomer. In other embodiments, the TOR kinase inhibitors are a mixture of the cis and trans isomers. [00631 "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: H HN N [0064] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of the TOR kinase inhibitors are within the scope of the present invention. [00651 It should also be noted the TOR kinase inhibitors can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (121) sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched - 19 - WO 2013/019927 PCT/US2012/049281 compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the TOR kinase inhibitors as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the TOR kinase inhibitors, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched TOR kinase inhibitors. [0066] "Treating" as used herein, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease (e.g., cancer or a tumor syndrome), or slowing, or halting of further progression or worsening of those symptoms. [00671 "Preventing" as used herein, means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or disorder (e.g., cancer), or a symptom thereof. [0068] The term "effective amount" in connection with an TOR kinase inhibitor means an amount capable of alleviating, in whole or in part, symptoms associated with cancer, for example non-small cell lung carcinoma or cervical cancer, or a tumor syndrome, for example Peutz-Jeghers Syndrome, or slowing or halting further progression or worsening of those symptoms, or preventing or providing prophylaxis for cancer, for example non-small cell lung carcinoma or cervical cancer, or a tumor syndrome, for example Peutz-Jeghers Syndrome in a subject at risk for cancer, for example non-small cell lung carcinoma or cervical cancer, or a tumor syndrome, for example Peutz-Jeghers Syndrome. The effective amount of the TOR kinase inhibitor, for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration. As will be apparent to those skilled in the art, it is to be expected that the effective amount of a TOR kinase inhibitor disclosed herein may vary depending on the severity of the indication being treated. - 20 - WO 2013/019927 PCT/US2012/049281 [00691 As used herein "wild type" refers to the typical or most common form of a characteristic (for example, gene sequence or presence, or protein sequence, presence, level or activity), as it occurs in nature, and the reference against which all others are compared. As will be understood by one skilled in the art, when used herein, wild type refers to the typical gene expression levels as they most commonly occur in nature. Similarly, a "control patient", as used herein, is a patient who exhibits the wild type gene expression levels. In certain embodiments, the gene expression level is comprised of the gene expression level of one or more of the genes set forth in Table 1. [00701 As used herein "LKB 1 gene or protein mutation" refers to, for example, a LKB 1 gene mutation resulting in a decrease in LKB 1 mRNA expression, a decrease in LKB 1 protein production or a non-functional LKB 1 protein, as compared to wild type. As used herein "LKB 1 gene or protein loss" refers to a reduced level of LKB 1 protein or the absence of LKB 1 protein, as compared to wild type levels. The phrase "LKB1 gene and/or protein loss and/or mutation" includes each of the following, alone or in combination with one or more of the others: (1) LKB1 gene loss; (2) LKB1 gene mutation; (3) LKB1 protein loss; and (4) LKB1 protein mutation. [00711 As used herein "reduced level" or "loss" means a reduction in level relative to levels observed in wild type. In one embodiment the reduction is 10% - 50% or 50%-100%. In some embodiments, the reduction is 20%, 30%, 40%, 50%, 60%, 70%, 80%. 90% or 100% (complete loss) relative to wild type. [0072] As used herein in connection with the comparison of gene expression level(s) of a biological test sample with wild-type samples and/or reference samples, "similarity" is determined using the Nearest Shrunken Centroid Method (see Tibsharani et al., PNAS 99: 6567-6572 (2002). The Nearest Shrunken Centroid Method computes a standardized centroid for each class of samples, for example, wild type samples and reference samples. This centroid is the average gene expression level for each gene in each class divided by the within-class standard deviation for that gene. Nearest centroid classification then takes the gene expression - 21 - WO 2013/019927 PCT/US2012/049281 profile of a new sample (e.g., biological test sample) and compares it to each of these class centroids. The class (e.g., the reference sample or the wild-type sample) whose centroid that the gene expression profile of the new sample is closest to, in squared distance, is the predicted class or the class the new sample has the higher similarity to. As used herein, "higher similarity" of the biological test sample means that the gene expression level(s) of the biological sample is determined to be more similar to either the reference levels that represent the gene expression level(s) of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation (LKB 1 positive, or wild type) or the gene expression level(s) of a reference sample with LKB 1 gene and/or protein loss and/or mutation (LKB1 negative).. [0073] The terms "patient" and "subject" as used herein include an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. [0074] In one embodiment, a "patient" or "subject" is a human whose cancer DNA comprises a LKB 1 gene mutation, relative to that of a control patient or wild type. In another embodiment, a "patient" or "subject" is a human whose cancer DNA contains a LKB1 gene mutation, relative to that of a control patient or wild type. In another embodiment, a "patient" or "subject" is a human having a cancer, for example non-small cell lung carcinoma or cervical cancer, characterized by LKB 1 gene and/or protein loss and/or mutation, relative to that of a control patient or wild type. In particular embodiments, the LKB 1 gene and/or protein loss and/or mutation is identified by certain gene expression levels, measured using RT-PCR or the Affymetrix HGUl33plus2 platform, and compared to wild type using the statistical package PAMR. In certain embodiments, the gene expression level is comprised of the gene expression levels of one or more of the genes set forth in Table 1. [00751 In another embodiment, a "patient" or "subject" is a human whose DNA comprises a LKB 1 gene mutation, relative to that of a control patient or wild type. In another - 22 - WO 2013/019927 PCT/US2012/049281 embodiment, a "patient" or "subject" is a human whose DNA contains a LKB 1 gene mutation, relative to that of a control patient or wild type. In another embodiment, a "patient" or "subject" is a human having LKB 1 gene and/or protein loss and/or mutation, relative to that of a control patient or wild type. In another embodiment, a "patient" or "subject" is a human having LKB 1 gene and/or protein loss and/or mutation, relative to that of a control patient or wild type, and also having a tumor syndrome, for example Peutz-Jeghers Syndrome. In particular embodiments, the LKB 1 gene and/or protein loss and/or mutation is identified by certain gene expression levels measured using RT-PCR or the Affymetrix HGUl33plus2 platform and compared to wild type using the statistical package PAMR. In certain embodiments, the gene expression level is comprised of the gene expression levels of one or more of the genes set forth in Table 1. [0076] The term "expression" as used herein refers to the transcription from a gene to give an RNA nucleic acid molecule at least complementary in part to a region of one of the two nucleic acid strands of the gene. The term "expression" as used herein also refers to the translation from the RNA molecule to give a protein, a polypeptide or a portion thereof. [00771 The expression of a gene that is "upregulated" is generally "increased" relative to wild type. The expression of a gene that is "downregulated" is generally "decreased" relative to wild type. In certain embodiments, a gene from a patient sample can be "upregulated," i.e., gene expression can be increased, for example, by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 1,000%, 5,000% or more of a comparative control, such as wild type. In other embodiments, a gene from a patient sample can be "downregulated," i.e., gene expression can be decreased, for example, by about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 1% or less of a comparative control, such as wild type. [0078] The term "likelihood" generally refers to an increase in the probability of an event. The term "likelihood" when used in reference to the effectiveness of a patient response - 23 - WO 2013/019927 PCT/US2012/049281 generally contemplates an increased probability that a cancer or tumor syndrome, or symptom thereof, will be lessened or decreased. [00791 The term "predict" generally means to determine or tell in advance. When used to "predict" the effectiveness of a cancer or tumor syndrome treatment, for example, the term "predict" can mean that the likelihood of the outcome of the treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially. [00801 The terms "determining", "measuring", "evaluating", "assessing" and "assaying" as used herein generally refer to any form of measurement, and include determining if an element is present or not. These terms include both quantitative and/or qualitative determinations. [0081] In the context of cancer, for example non-small cell lung carcinoma or cervical cancer, or a tumor syndrome, for example Peutz-Jeghers Syndrome, inhibition may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of clinically evident cancer, carcinoma or tumor altogether or preventing the onset of a preclinically evident stage of cancer, carcinoma or tumor in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the cancer, carcinoma or tumor. - 24 - WO 2013/019927 PCT/US2012/049281 5.2 GENE EXPRESSION PROFILE [0082] Table 1 sets forth the genes for which the gene expression compared to wild type, indicate a higher likelihood of LKB 1 gene and/or protein loss and/or mutation. Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 229839_at SCARA5 scavenger receptor class A, member 5 -120.683 (putative) 219612 s at FGG fibrinogen gamma chain -67.798 235849_at SCARA5 scavenger receptor class A, member 5 -35.633 (putative) 205649 s at FGA fibrinogen alpha chain -30.292 206549 at INSL4 insulin-like 4 (placenta) -24.589 230830 at OSTbeta organic solute transporter beta -24.265 205650 s at FGA fibrinogen alpha chain -22.98 231213_at PDE1A phosphodiesterase 1A, calmodulin- -20.621 dependent 217564_s_at CPS1 carbamoyl-phosphate synthetase 1, -19.299 mitochondrial 241535 at NA NA -17.5 219764 at FZD1O frizzled homolog 10 (Drosophila) -16.83 214303 x at MUC5AC mucin 5AC, oligomeric mucus/gel-forming -16.35 204920_at CPS1 carbamoyl-phosphate synthetase 1, -15.906 mitochondrial 244567 at NA NA -15.493 205009 at TFFI trefoil factor 1 -15.383 206528_at TRPC6 transient receptor potential cation channel, -14.276 subfamily C, member 6 205403 at IL1R2 interleukin 1 receptor, type II -12.759 216238 s at FGB fibrinogen beta chain -12.071 229778 at C12orf39 chromosome 12 open reading frame 39 -11.705 1569378 at FLJ33297 hypothetical gene supported by AK090616 -10.97 228186 s at RSPO3 R-spondin 3 homolog (Xenopus laevis) -10.185 204988 at FGB fibrinogen beta chain -10.144 211372 s at IL1R2 interleukin 1 receptor, type II -10.037 213432 at MUC5B mucin 5B, oligomeric mucus/gel-forming -9.855 - 25 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 222712 s at MUC13 mucin 13, cell surface associated -9.374 214385 s at MUC5AC mucin 5AC, oligomeric mucus/gel-forming -9.346 206153_at CYP4F1 1 cytochrome P450, family 4, subfamily F, -8.054 polypeptide 11 228969_at AGR2 anterior gradient homolog 2 (Xenopus -8.022 laevis) 207052 at HAVCRI hepatitis A virus cellular receptor 1 -7.623 205305 at FGL1 fibrinogen-like 1 -7.594 232687 at NA NA -7.471 212224_at ALDH1A1 aldehyde dehydrogenase 1 family, member -7.208 Al 230251 at C6orfl76 chromosome 6 open reading frame 176 -7.171 212935_at MCF2L MCF.2 cell line derived transforming -6.718 sequence-like 226992 at NOSTRIN nitric oxide synthase trafficker -6.706 215189 at KRT86 keratin 86 -6.706 228507 at NA NA -6.645 220479 at LOC29034 hypothetical LOC29034 -6.621 232267 at GPR133| G protein-coupled receptor 133 -6.25 205137_x_at USHIC Usher syndrome IC (autosomal recessive, -6.104 severe) 206515_at CYP4F3 cytochrome P450, family 4, subfamily F, -5.965 polypeptide 3 205221_at HGD homogentisate 1,2-dioxygenase -5.952 (homogentisate oxidase) 233413 at NA NA -5.911 229655_at FAM19A5 family with sequence similarity 19 -5.616 (chemokine (C-C motif)-like), member A5 239650 at NCKAP5 NCK-associated protein 5 -5.516 236300 at NA NA -5.51 209616_s_at CES 1 carboxylesterase 1 (monocyte/macrophage -5.483 serine esterase 1) 226248 s at KIAA1324 KIAA1324 -5.47 218541 s at C8orf4 chromosome 8 open reading frame 4 -5.395 242426 at NRG4 neuregulin 4 -5.273 - 26 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 209959_at NR4A3 nuclear receptor subfamily 4, group A, -5.267 member 3 232608_x_at CARD14 caspase recruitment domain family, member -5.249 14 228057 at DDIT4L DNA-damage-inducible transcript 4-like -5.175 206155_at ABCC2 ATP-binding cassette, sub-family C -5.122 (CFTR/MRP), member 2 201884_at CEACAM5 carcinoembryonic antigen-related cell -5.04 adhesion molecule 5 228962_at PDE4D phosphodiesterase 4D, cAMP-specific -4.976 (phosphodiesterase E3 dunce homolog, Drosophila) 237471 at tcag7.1307 hypothetical LOC154822 -4.847 206389 s at PDE3A phosphodiesterase 3A, cGMP-inhibited -4.798 233076_at JAKMIP3 Janus kinase and microtubule interacting -4.794 protein 3 206645_s_at NROB1 nuclear receptor subfamily 0, group B, -4.779 member 1 210663 s at KYNU kynureninase (L-kynurenine hydrolase) -4.746 210662 at KYNU kynureninase (L-kynurenine hydrolase) -4.689 202023 at EFNA1 ephrin-Al -4.639 238755 at NA NA -4.622 234563 at NA NA -4.521 238029_s_at SLC16A14 solute carrier family 16, member 14 -4.489 (monocarboxylic acid transporter 14) 1556331 a at NA NA -4.391 205234_at SLC16A4 solute carrier family 16, member 4 -4.378 (monocarboxylic acid transporter 5) 236741 at WDR72 WD repeat domain 72 -4.351 214308_s_at HGD homogentisate 1,2-dioxygenase -4.346 (homogentisate oxidase) 219049_at CSGALNACT1 chondroitin sulfate N- -4.339 acetylgalactosaminyltransferase 1 204385 at KYNU kynureninase (L-kynurenine hydrolase) -4.325 - 27 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 220393_at LGSN lengsin, lens protein with glutamine -4.273 synthetase domain 206644_at NROB1 nuclear receptor subfamily 0, group B, -4.259 member 1 204491_at PDE4D phosphodiesterase 4D, cAMP-specific -4.236 (phosphodiesterase E3 dunce homolog, Drosophila) 219508_at GCNT3 glucosaminyl (N-acetyl) transferase 3, -4.17 mucin type 211184_s_at USHIC Usher syndrome IC (autosomal recessive, -4.135 severe) 204014 at DUSP4 dual specificity phosphatase 4 -4.114 229280 s at FLJ22536 hypothetical locus LOC401237 -4.077 219300 s at CNTNAP2 contactin associated protein-like 2 -3.97 203963 at CA12 carbonic anhydrase XII -3.96 204351 at SlooP S100 calcium binding protein P -3.95 203238 s at NOTCH3 Notch homolog 3 (Drosophila) -3.945 214307_at HGD homogentisate 1,2-dioxygenase -3.942 (homogentisate oxidase) 206561_s_at AKR1B1O aldo-keto reductase family 1, member B10 -3.937 (aldose reductase) 226034 at NA NA -3.935 205477 s at AMBP alpha-1-microglobulin/bikunin precursor -3.897 1555854 at NA NA -3.893 217626 at NA NA -3.871 205501 at PDE1OA phosphodiesterase IA -3.741 217388 s at KYNU kynureninase (L-kynurenine hydrolase) -3.734 220540 at KCNK15 potassium channel, subfamily K, member 15 -3.669 209173_at AGR2 anterior gradient homolog 2 (Xenopus -3.657 laevis) 211840_s_at PDE4D phosphodiesterase 4D, cAMP-specific -3.646 (phosphodiesterase E3 dunce homolog, Drosophila) 219429 at FA2H fatty acid 2-hydroxylase -3.627 227614 at HKDC1 hexokinase domain containing 1 -3.615 -28- WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 206643 at HAL histidine ammonia-lyase -3.593 204105 s at NRCAM neuronal cell adhesion molecule -3.567 205460 at NPAS2 neuronal PAS domain protein 2 -3.548 39248 at AQP3 aquaporin 3 (Gill blood group) -3.544 216248_s_at NR4A2 nuclear receptor subfamily 4, group A, -3.519 member 2 212906 at GRAMD1B GRAM domain containing 1B -3.514 227202 at CNTN1 contactin 1 -3.498 221577 x at GDF15 growth differentiation factor 15 -3.484 240173 at NA NA -3.466 242871_at PAQR5 progestin and adipoQ receptor family -3.432 member V 242626 at SAMD5 sterile alpha motif domain containing 5 -3.379 222784 at SMOCi SPARC related modular calcium binding 1 -3.34 1562102_at AKR1C1 aldo-keto reductase family 1, member C1 -3.314 (dihydrodiol dehydrogenase 1; 20-alpha (3 alpha)-hydroxysteroid dehydrogenase) 204622_x_at NR4A2 nuclear receptor subfamily 4, group A, -3.313 member 2 202388 at RGS2 regulator of G-protein signaling 2, 24kDa -3.312 226192 at NA NA -3.283 202889 x at MAP7 microtubule-associated protein 7 -3.26 227209 at CNTN1 contactin 1 -3.244 204621_s_at NR4A2 nuclear receptor subfamily 4, group A, -3.233 member 2 227174 at WDR72 WD repeat domain 72 -3.199 1556698 a at GPRIN3 GPRIN family member 3 -3.199 233177 s at PNKD paroxysmal nonkinesigenic dyskinesia -3.193 210837_s_at PDE4D phosphodiesterase 4D, cAMP-specific -3.117 (phosphodiesterase E3 dunce homolog, Drosophila) 243438 at PDE7B phosphodiesterase 7B -3.081 205698 s at MAP2K6 mitogen-activated protein kinase kinase 6 -3.077 - 29 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 203708_at PDE4B phosphodiesterase 4B, cAMP-specific -3.069 (phosphodiesterase E4 dunce homolog, Drosophila) 241726 at NA NA -3.047 202986_at ARNT2 aryl-hydrocarbon receptor nuclear -3.045 translocator 2 222783 s at SMOCI SPARC related modular calcium binding 1 -3.026 1554717_a_at PDE4D phosphodiesterase 4D, cAMP-specific -2.97 (phosphodiesterase E3 dunce homolog, Drosophila) 244387 at NA NA -2.964 218631 at AVPIl arginine vasopressin-induced 1 -2.938 228653 at SAMD5 sterile alpha motif domain containing 5 -2.92 1569433 at SAMD5 sterile alpha motif domain containing 5 -2.903 221667 s at HSPB8 heat shock 22kDa protein 8 -2.886 214240 at GAL galanin prepropeptide -2.886 237029_at HGD homogentisate 1,2-dioxygenase -2.868 (homogentisate oxidase) 225516_at SLC7A2 solute carrier family 7 (cationic amino acid -2.845 transporter, y+ system), member 2 230563 at RASGEFlA RasGEF domain family, member 1A -2.843 222073_at COL4A3 collagen, type IV, alpha 3 (Goodpasture -2.83 antigen) 236610 at NA NA -2.819 205311_at DDC dopa decarboxylase (aromatic L-amino acid -2.809 decarboxylase) 206017 at KIAA0319 KIAA0319 -2.801 221067 s at C12orf39 chromosome 12 open reading frame 39 -2.765 238498 at NA NA -2.762 204015 s at DUSP4 dual specificity phosphatase 4 -2.757 215471 s at MAP7 microtubule-associated protein 7 -2.736 237031 at NA NA -2.719 203747 at AQP3 aquaporin 3 (Gill blood group) -2.718 - 30 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 210836_x_at PDE4D phosphodiesterase 4D, cAMP-specific -2.711 (phosphodiesterase E3 dunce homolog, Drosophila) 240180 at NA NA -2.703 208078 s at NA NA -2.691 202890 at MAP7 microtubule-associated protein 7 -2.687 214602 at COL4A4 collagen, type IV, alpha 4 -2.655 223721_s_at DNAJC12 DnaJ (Hsp40) homolog, subfamily C, -2.652 member 12 209772 s at CD24 CD24 molecule -2.62 228825 at PTGRI prostaglandin reductase 1 -2.616 214234 s at NA NA -2.597 219194_at SEMA4G sema domain, immunoglobulin domain (Ig), -2.581 transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4G 238441_at PRKAA2 protein kinase, AMP-activated, alpha 2 -2.579 catalytic subunit 218326_s_at LGR4 leucine-rich repeat-containing G protein- -2.574 coupled receptor 4 208284 x at GGT1 gamma-glutamyltransferase 1 -2.549 239067 s at PANX2 pannexin 2 -2.546 240349_at PRKAA2 protein kinase, AMP-activated, alpha 2 -2.534 catalytic subunit 204567_s_at ABCG1 ATP-binding cassette, sub-family G -2.525 (WHITE), member 1 235924 at NA NA -2.504 227210 at NA NA -2.501 211653_x_at AKR1C2 aldo-keto reductase family 1, member C2 -2.497 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III) 225330 at IGF1R insulin-like growth factor 1 receptor -2.497 1557147 a at NA NA -2.496 -31 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 209160_at AKR1C3 aldo-keto reductase family 1, member C3 -2.49 (3-alpha hydroxysteroid dehydrogenase, type II) 209699_x_at AKR1C2 aldo-keto reductase family 1, member C2 -2.477 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III) 211417 x at GGT1 gamma-glutamyltransferase 1 -2.459 241764 at NA NA -2.458 214235 at NA NA -2.451 39249 at AQP3 aquaporin 3 (Gill blood group) -2.444 232921 at KIAA1549 KIAA1549 -2.44 203192_at ABCB6 ATP-binding cassette, sub-family B -2.428 (MDR/TAP), member 6 212327 at LIMCH1 LIM and calponin homology domains 1 -2.423 212328 at LIMCH1 LIM and calponin homology domains 1 -2.42 242794 at MAML3 mastermind-like 3 (Drosophila) -2.416 227892_at PRKAA2 protein kinase, AMP-activated, alpha 2 -2.401 catalytic subunit 200731_s_at PTP4A1 protein tyrosine phosphatase type IVA, -2.393 member 1 214434 at HSPA12A heat shock 70kDa protein 12A -2.384 39549 at NPAS2 neuronal PAS domain protein 2 -2.374 213462 at NPAS2 neuronal PAS domain protein 2 -2.348 213155 at WSCD1 WSC domain containing 1 -2.341 218416_s_at SLC48A1 solute carrier family 48 (heme transporter), -2.33 member 1 242917 at RASGEFlA RasGEF domain family, member 1A -2.31 224937 at PTGFRN prostaglandin F2 receptor negative regulator -2.308 205850_s_at GABRB3 gamma-aminobutyric acid (GABA) A -2.307 receptor, beta 3 210263_at KCNF1 potassium voltage-gated channel, subfamily -2.29 F, member 1 226448_at FAM89A family with sequence similarity 89, member -2.288 A - 32 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 225056_at SIPA1L2 signal-induced proliferation-associated 1 -2.278 like 2 210964 s at GYG2 glycogenin 2 -2.262 238537 at NA NA -2.26 208322_s_at ST3GAL1 ST3 beta-galactoside alpha-2,3- -2.256 sialyltransferase 1 218417_s_at SLC48A1 solute carrier family 48 (heme transporter), -2.255 member 1 204151_x_at AKR1C1 aldo-keto reductase family 1, member C1 -2.251 (dihydrodiol dehydrogenase 1; 20-alpha (3 alpha)-hydroxysteroid dehydrogenase) 243586 at NA NA -2.239 208650 s at CD24 CD24 molecule -2.229 223575 at KIAA1549 KIAA1549 -2.229 210558_at AKR1C4 aldo-keto reductase family 1, member C4 -2.228 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4) 216594_x_at AKR1C1 aldo-keto reductase family 1, member C1 -2.224 (dihydrodiol dehydrogenase 1; 20-alpha (3 alpha)-hydroxysteroid dehydrogenase) 219475 at OSGINI oxidative stress induced growth inhibitor 1 -2.219 203615_x_at SULTIA1 sulfotransferase family, cytosolic, 1A, -2.209 phenol-preferring, member 1 217590_s_at TRPA1 transient receptor potential cation channel, -2.202 subfamily A, member 1 223633 s at BCAN brevican -2.199 200965 s at ABLIMI actin binding LIM protein 1 -2.194 221802 s at KIAA1598 KIAA1598 -2.184 215695 s at GYG2 glycogenin 2 -2.178 65517_at APIM2 adaptor-related protein complex 1, mu 2 -2.176 subunit 208651 x at CD24 CD24 molecule -2.175 242037 at ASPH aspartate beta-hydroxylase -2.168 224950 at PTGFRN prostaglandin F2 receptor negative regulator -2.166 - 33 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 215299_x_at SULTIA1 sulfotransferase family, cytosolic, 1A, -2.161 phenol-preferring, member 1 226039_at MGAT4A mannosyl (alpha-1,3-)-glycoprotein beta- -2.145 1,4-N-acetylglucosaminyltransferase, isozyme A 212651 at RHOBTBI Rho-related BTB domain containing 1 -2.131 200732_s_at PTP4A1 protein tyrosine phosphatase type IVA, -2.099 member 1 209276 s at GLRX glutaredoxin (thioltransferase) -2.097 211302_s_at PDE4B phosphodiesterase 4B, cAMP-specific -2.095 (phosphodiesterase E4 dunce homolog, Drosophila) 223058_at FAM107B family with sequence similarity 107, -2.095 member B 215635 at NA NA -2.078 204505_s_at EPB49 erythrocyte membrane protein band 4.9 -2.062 (dematin) 222496 s at RBM47 RNA binding motif protein 47 -2.059 48106_at SLC48A1 solute carrier family 48 (heme transporter), -2.056 member 1 211382_s_at TACC2 transforming, acidic coiled-coil containing -2.054 protein 2 218681 s at SDF2L1 stromal cell-derived factor 2-like 1 -2.04 216548 x at HMGB3L1 high-mobility group box 3-like 1 -2.031 234986 at NA NA -2.02 223059_s_at FAM107B family with sequence similarity 107, -2.017 member B 202421 at IGSF3 immunoglobulin superfamily, member 3 -2.009 225033_at ST3GAL1 ST3 beta-galactoside alpha-2,3- -2.006 sialyltransferase 1 207709_at PRKAA2 protein kinase, AMP-activated, alpha 2 -1.999 catalytic subunit 238489_at PRKAA2 protein kinase, AMP-activated, alpha 2 -1.996 catalytic subunit 236140 at GCLM glutamate-cysteine ligase, modifier subunit -1.994 - 34 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 218035 s at RBM47 RNA binding motif protein 47 -1.99 200730_s_at PTP4A1 protein tyrosine phosphatase type IVA, -1.986 member 1 266 s at CD24 CD24 molecule -1.985 204058_at MEl malic enzyme 1, NADP(+)-dependent, -1.968 cytosolic 1557689 at NA NA -1.96 226886_at GFPT1 glutamine-fructose-6-phosphate -1.959 transaminase 1 216379 x at CD24 CD24 molecule -1.925 209771 x at CD24 CD24 molecule -1.916 241459 at LIMCH1 LIM and calponin homology domains 1 -1.916 39548 at NPAS2 neuronal PAS domain protein 2 -1.911 206662 at GLRX glutaredoxin (thioltransferase) -1.904 221245 s at FZD5 frizzled homolog 5 (Drosophila) -1.893 207178 s at FRK fyn-related kinase -1.89 203343 at UGDH UDP-glucose dehydrogenase -1.861 209607 x at NA NA -1.856 212325 at LIMCH1 LIM and calponin homology domains 1 -1.845 226055 at ARRDC2 arrestin domain containing 2 -1.838 226653_at MARKI MAP/microtubule affinity-regulating kinase -1.809 1 205459 s at NPAS2 neuronal PAS domain protein 2 -1.799 226003 at KIF21A kinesin family member 21A -1.756 229002_at FAM69B family with sequence similarity 69, member -1.732 B 202206 at ARL4C ADP-ribosylation factor-like 4C 1.504 231017 at STK 11 serine/threonine kinase 11 1.514 1554769 at ZNF785 zinc finger protein 785 1.594 201105 at LGALS1 lectin, galactoside-binding, soluble, 1 1.603 218154 at GSDMD gasdermin D 1.604 211799 x at HLA-C major histocompatibility complex, class I, C 1.633 1553193 at ZNF441 zinc finger protein 441 1.669 201109 s at THBS1 thrombospondin 1 1.672 221903 s at CYLD cylindromatosis (turban tumor syndrome) 1.682 - 35 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 242028 at NA NA 1.689 201110 s at THBS1 thrombospondin 1 1.703 211962 s at ZFP36L1 zinc finger protein 36, C3H type-like 1 1.707 225328 at NA NA 1.719 238940 at KLF12 Kruppel-like factor 12 1.739 231215 at NA NA 1.753 221534 at C1 1orf68 chromosome 11 open reading frame 68 1.766 228213 at H2AFJ H2A histone family, member J 1.779 235171 at NA NA 1.81 214860_at SLC9A7 solute carrier family 9 (sodium/hydrogen 1.836 exchanger), member 7 216526 x at HLA-C major histocompatibility complex, class I, C 1.839 201466 s at JUN jun oncogene 1.848 228394 at STKI serine/threonine kinase 10 1.851 1555675_at BLID BH3-like motif containing, cell death 1.886 inducer 239426_at SLC2A8 solute carrier family 2 (facilitated glucose 1.888 transporter), member 8 208812 x at HLA-C major histocompatibility complex, class I, C 1.899 242458_at RALGPS2 Ral GEF with PH domain and SH3 binding 1.902 motif 2 229224 x at LOC643085 hypothetical LOC643085 1.906 230536 at PBX4 pre-B-cell leukemia homeobox 4 1.913 1553247 a at ZNF709 zinc finger protein 709 1.918 1552671_a_at SLC9A7 solute carrier family 9 (sodium/hydrogen 1.918 exchanger), member 7 226550 at NA NA 1.939 230112 at 4-Mar membrane-associated ring finger (C3HC4) 4 1.955 228121 at TGFB2 transforming growth factor, beta 2 1.956 211165 x at EPHB2 EPH receptor B2 1.985 209651_at TGFB1Il transforming growth factor beta 1 induced 1.989 transcript 1 219427_at FAT4 FAT tumor suppressor homolog 4 1.99 (Drosophila) 208025 s at HMGA2 high mobility group AT-hook 2 1.996 - 36 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 214459 x at HLA-C major histocompatibility complex, class I, C 1.996 203047 at STKI serine/threonine kinase 10 1.996 203988_s_at FUT8 fucosyltransferase 8 (alpha (1,6) 1.997 fucosyltransferase) 227503 at NA NA 2.005 211529 x at HLA-G major histocompatibility complex, class I, G 2.012 209304_x_at GADD45B growth arrest and DNA-damage-inducible, 2.014 beta 211528 x at HLA-G major histocompatibility complex, class I, G 2.031 1558626 at NA NA 2.037 1558105 a at NA NA 2.044 201462 at SCRN1 secernin 1 2.047 208729 x at HLA-B major histocompatibility complex, class I, B 2.062 207574_s_at GADD45B growth arrest and DNA-damage-inducible, 2.064 beta 37547 at BBS9 Bardet-Biedl syndrome 9 2.069 225388 at TSPAN5 tetraspanin 5 2.072 210875 s at ZEBI zinc finger E-box binding homeobox 1 2.077 232247 at ZNF502 zinc finger protein 502 2.077 209140 x at HLA-B major histocompatibility complex, class I, B 2.08 227088 at PDE5A phosphodiesterase 5A, cGMP-specific 2.083 229014 at FLJ42709 hypothetical LOC441094 2.096 227489 at SMURF2 SMAD specific E3 ubiquitin protein ligase 2 2.102 244180 at ZNF793 zinc finger protein 793 2.114 239105 at NA NA 2.116 210655 s at NA NA 2.119 232774_x_at ZIKI zinc finger protein interacting with K 2.123 protein 1 homolog (mouse) 211911 x at HLA-B major histocompatibility complex, class I, B 2.125 212607_at AKT3 v-akt murine thymoma viral oncogene 2.136 homolog 3 (protein kinase B, gamma) 244241 x at NA NA 2.137 209305_s_at GADD45B growth arrest and DNA-damage-inducible, 2.14 beta 1558391 s at ZNF599 zinc finger protein 599 2.164 - 37 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 217624 at PDAP1 PDGFA associated protein 1 2.182 202084 s at SEC14L1 SEC14-like 1 (S. cerevisiae) 2.187 225524 at ANTXR2 anthrax toxin receptor 2 2.2 231879 at COL12A1 collagen, type XII, alpha 1 2.204 236044_at PPAPDC1A phosphatidic acid phosphatase type 2 2.224 domain containing 1A 219765 at ZNF329 zinc finger protein 329 2.238 1558683 a at HMGA2 high mobility group AT-hook 2 2.247 218718 at PDGFC platelet derived growth factor C 2.249 214995 s at NA NA 2.254 241826 x at ZNF738 zinc finger protein 738 2.257 219523 s at ODZ3 odz, odd Oz/ten-m homolog 3 (Drosophila) 2.262 205596 s at SMURF2 SMAD specific E3 ubiquitin protein ligase 2 2.327 218986_s_at DDX60 DEAD (Asp-Glu-Ala-Asp) box polypeptide 2.336 60 204292 x at STK 11 serine/threonine kinase 11 2.348 230820 at NA NA 2.354 212985_at APBB2 amyloid beta (A4) precursor protein- 2.356 binding, family B, member 2 202082 s at SEC14L1 SEC14-like 1 (S. cerevisiae) 2.363 210001 s at SOCS1 suppressor of cytokine signaling 1 2.371 206659 at NA NA 2.374 235027 at NA NA 2.38 228208 x at ZNF354C zinc finger protein 354C 2.391 208790 s at PTRF polymerase I and transcript release factor 2.406 239761_at GCNT1 glucosaminyl (N-acetyl) transferase 1, core 2.414 2 (beta-1,6-N acetylglucosaminyltransferase) 218273_s_at PDP1 pyruvate dehyrogenase phosphatase 2.415 catalytic subunit 1 1562386 s at ZNF501 zinc finger protein 501 2.416 204897 at PTGER4 prostaglandin E receptor 4 (subtype EP4) 2.435 213325 at PVRL3 poliovirus receptor-related 3 2.437 222572_at PDP1 pyruvate dehyrogenase phosphatase 2.441 catalytic subunit 1 - 38 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 205505_at GCNT1 glucosaminyl (N-acetyl) transferase 1, core 2.461 2 (beta-1,6-N acetylglucosaminyltransferase) 222880_at AKT3 v-akt murine thymoma viral oncogene 2.463 homolog 3 (protein kinase B, gamma) 239669 at NA NA 2.468 229533 x at ZNF680 zinc finger protein 680 2.479 238149 at ZNF818P zinc finger protein 818 pseudogene 2.481 201649 at UBE2L6 ubiquitin-conjugating enzyme E2L 6 2.49 239204 at ZNF75A zinc finger protein 75a 2.495 233002 at PPP4R4 protein phosphatase 4, regulatory subunit 4 2.529 238944 at ZNF404 zinc finger protein 404 2.546 203989 x at F2R coagulation factor II (thrombin) receptor 2.552 1567224 at HMGA2 high mobility group AT-hook 2 2.558 1562415 a at SPOCD1 SPOC domain containing 1 2.566 232020 at SMURF2 SMAD specific E3 ubiquitin protein ligase 2 2.584 200665_s_at SPARC secreted protein, acidic, cysteine-rich 2.6 (osteonectin) 218656 s at LHFP lipoma HMGIC fusion partner 2.606 230345_at SEMA7A semaphorin 7A, GPI membrane anchor 2.613 (John Milton Hagen blood group) 1561633 at HMGA2 high mobility group AT-hook 2 2.631 228054 at TMEM44 transmembrane protein 44 2.631 205514 at ZNF415 zinc finger protein 415 2.633 209505_at NR2F1 nuclear receptor subfamily 2, group F, 2.657 member 1 228843 at NA NA 2.665 201325 s at EMPI epithelial membrane protein 1 2.681 202686 s at AXL AXL receptor tyrosine kinase 2.691 201324 at EMPI epithelial membrane protein 1 2.724 206557 at ZNF702P zinc finger protein 702 pseudogene 2.738 231930 at ELMODI ELMO/CED-12 domain containing 1 2.745 228278_at NFIX nuclear factor I/X (CCAAT-binding 2.765 transcription factor) - 39 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 227828_s_at FAM176A family with sequence similarity 176, 2.783 member A 220738_s_at RPS6KA6 ribosomal protein S6 kinase, 90kDa, 2.788 polypeptide 6 207156 at HIST1H2AG histone cluster 1, H2ag 2.821 224833_at ETSI v-ets erythroblastosis virus E26 oncogene 2.838 homolog 1 (avian) 1569470 a at FRMD5 FERM domain containing 5 2.841 235417 at SPOCD1 SPOC domain containing 1 2.844 202083 s at SEC14L1 SEC14-like 1 (S. cerevisiae) 2.852 222571_at ST6GALNAC6 ST6 (alpha-N-acetyl-neuraminyl-2,3 -beta- 2.859 galactosyl- 1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6 244551 at NA NA 2.893 224822 at DLC1 deleted in liver cancer 1 2.895 207068 at ZFP37 zinc finger protein 37 homolog (mouse) 2.901 236847 at C19orfl8 chromosome 19 open reading frame 18 2.911 217999_s_at PHLDA1 pleckstrin homology-like domain, family A, 2.921 member 1 222719 s at PDGFC platelet derived growth factor C 2.948 209890 at TSPAN5 tetraspanin 5 2.996 238050 at ANTXR2 anthrax toxin receptor 2 3.015 225387 at TSPAN5 tetraspanin 5 3.021 208081 s at ZNF442 zinc finger protein 442 3.046 230831 at FRMD5 FERM domain containing 5 3.057 209156 s at COL6A2 collagen, type VI, alpha 2 3.088 240407 at LOC100126784 hypothetical LOC100126784 3.09 228950 s at GPR177 G protein-coupled receptor 177 3.109 221958 s at GPR177 G protein-coupled receptor 177 3.125 228368 at ARHGAP20 Rho GTPase activating protein 20 3.236 221087 s at APOL3 apolipoprotein L, 3 3.27 232231 at RUNX2 runt-related transcription factor 2 3.292 204823 at NAV3 neuron navigator 3 3.293 218691 s at PDLIM4 PDZ and LIM domain 4 3.35 229059 at NA NA 3.352 -40 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 1557636 a at C7orf57 chromosome 7 open reading frame 57 3.352 231766 s at COL12A1 collagen, type XII, alpha 1 3.362 1552658 a at NAV3 neuron navigator 3 3.378 229430 at NA NA 3.44 235944 at HMCN1 hemicentin 1 3.44 228949 at GPR177 G protein-coupled receptor 177 3.444 204415 at IF16 interferon, alpha-inducible protein 6 3.521 206170 at ADRB2 adrenergic, beta-2-, receptor, surface 3.533 1552309 a at NEXN nexilin (F actin binding protein) 3.534 218312 s at ZSCAN18 zinc finger and SCAN domain containing 18 3.547 223794 at ARMC4 armadillo repeat containing 4 3.565 230968 at NA NA 3.696 206230 at LHX1 LIM homeobox 1 3.852 239043 at ZNF404 zinc finger protein 404 3.869 202411 at IF127 interferon, alpha-inducible protein 27 3.906 231470 at NA NA 3.994 226103 at NEXN nexilin (F actin binding protein) 4.055 226218 at IL7R interleukin 7 receptor 4.061 213338 at TMEM158 transmembrane protein 158 4.302 231728 at CAPS calcyphosine 4.309 205798 at IL7R interleukin 7 receptor 4.332 214175 x at PDLIM4 PDZ and LIM domain 4 4.526 211564 s at PDLIM4 PDZ and LIM domain 4 4.593 239250 at ZNF542 zinc finger protein 542 4.607 233504 at C9orf84 chromosome 9 open reading frame 84 4.71 243818 at SFTA1P surfactant associated 1 (pseudogene) 4.772 219885 at SLFN12 schlafen family member 12 5.084 215446 s at LOX lysyl oxidase 5.089 213139 at SNAI2 snail homolog 2 (Drosophila) 5.214 204298 s at LOX lysyl oxidase 5.555 203153_at IFITI interferon-induced protein with 5.74 tetratricopeptide repeats 1 206421_s_at SERPINB7 serpin peptidase inhibitor, clade B 5.838 (ovalbumin), member 7 - 41 - WO 2013/019927 PCT/US2012/049281 Probe Symbol Gene Name Fold Change (LKB1 Pos/ LKB1 Neg) 204205_at APOBEC3G apolipoprotein B mRNA editing enzyme, 6.054 catalytic polypeptide-like 3G 206157_at PTX3 pentraxin-related gene, rapidly induced by 6.193 IL-I beta 1569039 s at ZNF677 zinc finger protein 677 6.8 244552 at ZNF788 zinc finger family member 788 7.004 228974 at NA NA 7.033 228617 at XAFl XIAP associated factor 1 7.056 231098 at NA NA 7.498 203435 s at MME membrane metallo-endopeptidase 7.574 202202 s at LAMA4 laminin, alpha 4 7.834 1560562 a at ZNF677 zinc finger protein 677 8.104 203434 s at MME membrane metallo-endopeptidase 8.713 1555759 a at CCL5 chemokine (C-C motif) ligand 5 9.405 227655 at SNORD123 small nucleolar RNA, C/D box 123 9.436 209619_at CD74 CD74 molecule, major histocompatibility 10.572 complex, class II invariant chain 235236 at LOC100131897 Uncharacterized protein LOC100131897 13.196 231729 s at CAPS calcyphosine 15.222 211518 s at BMP4 bone morphogenetic protein 4 17.634 1555673 at NA NA 20.578 1405 i at CCL5 chemokine (C-C motif) ligand 5 23.398 231867 at ODZ2 odz, odd Oz/ten-m homolog 2 (Drosophila) 29.634 209396 s at CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39) 42.124 209395 at CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39) 48.846 242206 at NA NA 70.713 [0083] Fold Change values were computed by dividing the average gene expression for LKB1 positive cell lines (wild type) with the average gene expression of LKB1 negative cell lines (see FIG. 3 for positive and negative LKB1 cell lines). When the fold change is < 1, the negative reciprocal of the original value is taken as the final fold change. A negative Fold - 42 - WO 2013/019927 PCT/US2012/049281 Change value therefore means that LKB 1 positive cell lines have a lower expression than LKB 1 negative cell lines. 5.3 TOR KINASE INHIBITORS [0084] The compounds provided herein are generally referred to as TOR kinase inhibitors or "TORKi." In a specific embodiment, the TORKi do not include rapamycin or rapamycin analogs (rapalogs). In certain embodiments, compounds provided herein are also DNA-PK inhibitors or "DNA-PKi." [0085] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (I): R 2 L1 X N A R1 Y B Z Q (I) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: 33 X, Y and Z are at each occurrence independently N or CR , wherein at least one of X, Y and Z is N and at least one of X, Y and Z is CR3; -A-B-Q- taken together form -CHR 4 C(O)NH-, -C(O)CHR 4 NH-, -C(O)NH-,
-CH
2 C(O)O-, -C(O)CH 2 0-, -C(O)O- or C(O)NR 3 ; L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; - 43 - WO 2013/019927 PCT/US2012/049281 R2 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R3 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclylalkyl, -NHR 4 or -N(R 4
)
2 ; and
R
4 is at each occurrence independently substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00861 In one embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -CH 2 C(O)NH-. [0087] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)CH 2 NH-. [00881 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-. [00891 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -CH 2 C(O)O-. [0090] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)CH 2 0-. [0091] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)O-. [0092] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NR 3 -. [00931 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein Y is CR 3 . - 44 - WO 2013/019927 PCT/US2012/049281 [00941 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein X and Z are N and Y is CR'. [0095] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein X and Z are N and Y is CH. [00961 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein X and Z are CH and Y is N. [0097] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein Y and Z are CH and X is N. [00981 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein X and Y are CH and Z is N. [0099] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R 1 is substituted aryl, such as substituted phenyl. [00100] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [00101] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [00102] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R 1 is H. [001031 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R 2 is substituted C 1 _salkyl. [00104] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or - 45 - WO 2013/019927 PCT/US2012/049281 unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [001051 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [001061 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is Ci 4 alkyl substituted with substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00107] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [001081 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00109] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein R2 is H. [00110] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein L is a direct bond. [00111] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-, X and Z are N and Y is CH, R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, L is a direct bond, and R 2 is substituted or unsubstituted C1_salkyl. [00112] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-, X and Z are N and Y is CH, R 1 is substituted or unsubstituted aryl, L is a direct bond, and R 2 is substituted or unsubstituted CIsalkyl. [001131 In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-, X and Z are N and Y is CH, R 1 is substituted or - 46 - WO 2013/019927 PCT/US2012/049281 unsubstituted aryl, and R 2 is CIsalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [00114] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-, X and Z are N and Y is CH, R 1 is substituted or unsubstituted aryl, and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00115] In another embodiment, the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(O)NH-, X and Z are N and Y is CH, R 1 is substituted phenyl, L is a direct bond, and R 2 is substituted CIsalkyl. [001161 In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Z are both N and Y is CH, -A-B-Q- is -C(O)NH-, L is a direct bond,
R
1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R 2 is C 1 _ salkyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [00117] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Z are both N and Y is CH, -A-B-Q- is -C(O)NH-, L is a direct bond,
R
1 is phenyl, naphthyl, indanyl or biphenyl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 _salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [001181 In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Z are both N and Y is CH, -A-B-Q- is -C(O)NH-, L is a direct bond,
R
1 is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of C 1
_
4 alkyl, amino, aminoC 1 _ 1 2 alkyl, halogen, hydroxy, hydroxyC 1 _4alkyl, C 1 _4alkyloxyC 1 _4alkyl, -CF 3 , C1-12alkoxy, aryloxy, arylCI1 2 alkoxy, -CN, -OCF 3 , -CORg, -COORg, -CONRgRh, -NRgCORh, -SO2Rg, -SO3Rg or SO2NRgRh, wherein each Rg and Rh are independently selected from the group consisting of - 47 - WO 2013/019927 PCT/US2012/049281 hydrogen, CI 4 alkyl, C 3
-
6 cycloalkyl, aryl, arylCi- 6 alkyl, heteroaryl or heteroarylCi- 6 alkyl; or A is a 5- to 6-membered monocyclic heteroaromatic ring having from one, two, three or four heteroatoms independently selected from the group consisting of N, 0 and S, that monocyclic heteroaromatic ring may be optionally substituted with one or more substituents each independently selected from the group consisting of Ci- 6 alkyl, amino, aminoCi-12alkyl, halogen, hydroxy, hydroxyC 1
_
4 alkyl, C 1
_
4 alkyloxyC 1
_
4 alkyl, Ci- 1 2 alkoxy, aryloxy, aryl Ci- 1 2 alkoxy, -CN, CF 3 , -OCF 3 , -CORi, -COORi, -CONRiRj, -NRiCORj, -NRiS0 2 Rj, -S0 2 Ri, -S0 3 Ri or -S0 2 NRiRj, wherein each Ri and Rj are independently selected from the group consisting of hydrogen, C1_ alkyl, C 3
-
6 cycloalkyl, aryl, arylCi- 6 alkyl, heteroaryl or heteroarylCi- 6 alkyl; or A is a 8- to 10 membered bicyclic heteroaromatic ring from one, two, three or four heteroatoms selected from the group consisting of N, 0 and S, and may be optionally substituted with one, two or three substituents each independently selected from the group consisting of Ci- 6 alkyl, amino, aminoC 1 _ 1 2 alkyl, halogen, hydroxy, hydroxyC 1 _4alkyl, C 1 _4alkyloxyC 1 _4alkyl, Ci-1 2 alkoxy, aryloxy, aryl C 1 _ 1 2 alkoxy, -CN, -CF 3 , -OCF 3 , -CORk, -COORk, -CONRkR1, -NRkCOR1, -NRkSO 2 R1, -SO 2 Rk, SO 3 Rk or -SO 2 NRkR1, wherein each Rk and Ri are independently selected from the group consisting of hydrogen, C1_ alkyl, C 3
-
6 cycloalkyl, aryl, arylCi- 6 alkyl, heteroaryl or heteroarylC1_ 6 alkyl, and R 2 is C1_salkyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [00119] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Y are both N and Z is CH, -A-B-Q- is -C(O)NH-, L is a direct bond, R1 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R2 is substituted or unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or an acetamide. [00120] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Y are both N and Z is CH, -A-B-Q- is -C(O)NH-, L is a direct bond, R1 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R2 is an acetamide. -48- WO 2013/019927 PCT/US2012/049281 [001211 In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X is N and Y and Z are both CH, -A-B-Q- is -C(O)NH-, L is a direct bond, R1 is a (2,5'-Bi-1H-benzimidazole)-5-carboxamide, and R2 is H. [00122] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein one of X and Z is CH and the other is N, Y is CH, -A-B-Q- is -C(O)NH-, L is a direct bond, R 1 is unsubstituted pyridine, and R 2 is H, methyl or substituted ethyl. [00123] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Z are both N and Y is CH, -A-B-Q- is -C(O)NH-, R 1 is H, CIsalkyl,
C
2 _salkenyl, aryl or cycloalkyl, and L is NH. [00124] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein X and Z are both N and Y is CH, -A-B-Q- is -C(O)NR-, R 2 is H, substituted or unsubstituted C1_salkyl, substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl, and L is NH. [00125] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds wherein R 1 is a substituted or unsubstituted oxazolidinone. [001261 In another embodiment, the TOR kinase inhibitors of formula (I) do not include one or more of the following compounds: 1,7-dihydro-2-phenyl-8H-Purin-8-one, 1,2-dihydro-3 phenyl-6H-Imidazo[4,5-e]-1,2,4-triazin-6-one, 1,3-dihydro-6-(4-pyridinyl)-2H-Imidazo[4,5 b]pyridin-2-one, 6-(1,3-benzodioxol-5-yl)-1,3-dihydro-1-[(1S)-1-phenylethyl]- 2H-Imidazo[4,5 b]pyrazin-2-one, 3-[2,3-dihydro-2-oxo-3-(4-pyridinylmethyl)-1H-imidazo[4,5-b]pyrazin-5-yl] Benzamide, 1-[2-(dimethylamino)ethyl]-1,3-dihydro-6-(3,4,5-trimethoxyphenyl)-2H Imidazo[4,5-b]pyrazin-2-one, N-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-N'-[4-(1,2,3,4 tetrahydro-2-oxopyrido[2,3-b]pyrazin-7-yl)-1-naphthalenyl]-Urea, N-[4-(2,3-dihydro-2-oxo-1H imidazo[4,5-b]pyridin-6-yl)-1-naphthalenyl]-N'-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-Urea, 1,3-dihydro-5-phenyl-2H-Imidazo[4,5-b]pyrazin-2-one, 1,3-dihydro-5-phenoxy-2H-Imidazo[4,5 b]pyridin-2-one, 1,3-dihydro-1-methyl-6-phenyl-2H-Imidazo[4,5-b]pyridin-2-one, 1,3-dihydro - 49 - WO 2013/019927 PCT/US2012/049281 5-(1H-imidazol-1-yl) 2H-Imidazo[4,5-b]pyridin-2-one, 6-(2,3-dihydro-2-oxo-1H-imidazo[4,5 b]pyridin-6-yl)-8-methyl-2(1H)-Quinolinone and 7,8-dihydro-8-oxo-2-phenyl-9H-purine-9 acetic acid. [001271 In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Ia): R 2 R1 L NN' R1- N N H (Ia) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: L is a direct bond, NH or 0; Y is N or CR 3 ;
R
1 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; R2 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R3 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclylalkyl, -NHR 4 or -N(R 4
)
2 ; and - 50 - WO 2013/019927 PCT/US2012/049281 R4 is at each occurrence independently substituted or unsubstituted C1_salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [001281 In one embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [00129] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [001301 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [001311 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R 1 is H. [00132] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R2 is substituted C1_salkyl. [001331 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00134] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00135] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. -51 - WO 2013/019927 PCT/US2012/049281 [001361 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R2 is H. [00137] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein Y is CH. [001381 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein L is a direct bond. [001391 In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [00140] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [00141] In another embodiment, the TOR kinase inhibitors of formula (Ta) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00142] In another embodiment, the TOR kinase inhibitors of formula (Ta) do not include compounds wherein Y is CH, L is a direct bond, R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R 2 is CIsalkyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [001431 In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Tb): R 2 L R1/ N 0 N H (Ib) - 52 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00144] In one embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [001451 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [001461 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [001471 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R 1 is H. [001481 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R2 is substituted C1_salkyl. [00149] In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 53 - WO 2013/019927 PCT/US2012/049281 [001501 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00151] In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00152] In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R2 is H. [001531 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein L is a direct bond. [00154] In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [00155] In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [001561 In another embodiment, the TOR kinase inhibitors of formula (Tb) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00157] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Tc): R 2 R1 L N N H (Ic) - 54 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [001581 In one embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [00159] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [001601 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [001611 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is H. [00162] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is substituted C1_salkyl. [001631 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 55 - WO 2013/019927 PCT/US2012/049281 [001641 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00165] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [001661 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is H. [00167] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein L is a direct bond. [001681 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [001691 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [00170] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00171] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Id): R 2 L R1f N N N H (Id) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: - 56 - WO 2013/019927 PCT/US2012/049281 L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00172] In one embodiment, the TOR kinase inhibitors of formula (Id) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [001731 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [00174] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [00175] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R 1 is H. [001761 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is substituted C1_salkyl. [00177] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 57 - WO 2013/019927 PCT/US2012/049281 [001781 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00179] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [001801 In another embodiment, the Heteroaryl Compounds of formula (Id) are those wherein R2 is H. [001811 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein L is a direct bond. [00182] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [001831 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R1 is substituted or unsubstituted aryl and R 2 is Cisalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [00184] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00185] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (le): R 2 R1L N N H (1e) - 58 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [001861 In one embodiment, the TOR kinase inhibitors of formula (Je) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [00187] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [001881 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [001891 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R 1 is H. [00190] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R2 is substituted C1_salkyl. [00191] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 59 - WO 2013/019927 PCT/US2012/049281 [001921 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [001931 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00194] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R2 is H. [00195] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein L is a direct bond. [001961 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [00197] In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [001981 In another embodiment, the TOR kinase inhibitors of formula (Je) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00199] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (If): R2 L N N R1X (I N N 0 H (If) - 60 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00200] In one embodiment, the TOR kinase inhibitors of formula (If) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [00201] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [00202] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [002031 In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R 1 is H. [00204] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R2 is substituted C1_salkyl. [00205] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 61 - WO 2013/019927 PCT/US2012/049281 [002061 In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00207] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [002081 In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R2 is H. [00209] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein L is a direct bond. [00210] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [00211] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [00212] In another embodiment, the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [002131 In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Ig): R 2 L N R1/ N N (Ig) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: - 62 - WO 2013/019927 PCT/US2012/049281 L is a direct bond, NH or 0;
R
1 is H, substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted C 2 salkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R2 is H, substituted or unsubstituted Cisalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [00214] In one embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [00215] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. [002161 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted quinoline, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted indole, or substituted or unsubstituted thiophene. [002171 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is H. [002181 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R2 is substituted C1_salkyl. [00219] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. - 63 - WO 2013/019927 PCT/US2012/049281 [002201 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl. [00221] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00222] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R2 is H. [002231 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein L is a direct bond. [00224] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted C1_salkyl. [002251 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R1 is substituted or unsubstituted aryl and R 2 is C1_salkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl. [002261 In another embodiment, the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl. [002271 Representative TOR kinase inhibitors of formula (I) include: (S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-((tetrahydro-2H-pyran-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; (R)-6-(naphthalen-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(3-methoxybenzyl)-6-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-hydroxyphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H) one; - 64 - WO 2013/019927 PCT/US2012/049281 (S)-6-(naphthalen- 1-yl)-1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -(1 -hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; (R)- 1 -(1 -hydroxy-3-methylbutan-2-yl)-6-phenyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -phenylethyl)-6-(quinolin-5 -yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -(1 -hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 1 -benzyl-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(4-methoxybenzyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -isopropyl-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -cyclohexyl-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 5-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -isobutyl-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(2-hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(5-isopropyl-2-methoxyphenyl)- 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; (R)- 1 -(1 -phenylethyl)-6-(quinolin-5 -yl)-1 H-imidazo[4,5-c]pyridin-2(3H)-one; (S)- 1 -(1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-c]pyridin-2(3H)-one; 3-(1 -phenylethyl)-5-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; (R)-3-(1 -phenylethyl)-5-(quinolin-5 -yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; (R)-6-(5-isopropyl-2-methoxyphenyl)- 1 -(3-methylbutan-2-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; - 65 - WO 2013/019927 PCT/US2012/049281 (S)-6-(5-isopropyl-2-methoxyphenyl)- 1 -(tetrahydrofuran-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H) one; (S)-6-(5-isopropyl-2-methoxyphenyl)- 1 -(3-methylbutan-2-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 1 -cyclopentyl-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)-6-(5-isopropyl-2-methoxyphenyl)- 1 -(tetrahydrofuran-3-yl)-1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 1 -(cyclopropylmethyl)-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(cyclopentylmethyl)-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(cyclohexylmethyl)-6-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(5-isopropyl-2-methoxyphenyl)- 1 -neopentyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -isopropyl-6-(3-isopropylphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -isopropyl-6-(2-methoxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)-3-(1 -hydroxy-3-methylbutan-2-yl)-5-(5-isopropyl-2-methoxyphenyl)- 1 H-imidazo[4,5 b]pyridin-2(3H)-one; (R)- 1 -(2-hydroxy- 1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -(2-hydroxy- 1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -benzhydryl-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -(1 -phenylpropyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -phenylpropyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(5-isopropyl-2-methoxyphenyl)- 1 -(tetrahydro-2H-pyran-3-yl)-1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 1-(3-methoxybenzyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -methyl-3-(1 -phenylethyl)-5-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)- 1 -methyl-3-(1 -phenylethyl)-5-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; - 66 - WO 2013/019927 PCT/US2012/049281 1 -(cyclopentylmethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(2-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(4-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -cyclopentyl-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(3-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(3-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(4-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(quinolin-5-yl)-1 -(tetrahydro-2H-pyran-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(quinolin-5-yl)-1 -(tetrahydro-2H-pyran-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -((1 s,4s)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -((1r,4r)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(isoquinolin-5-yl)-1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (R)- 1 -(1 -phenylethyl)-6-(quinolin-5 -yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; 1 -(1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; 1 -isopropyl-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(4-chlorophenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-(1 -(4-(methylsulfonyl)phenyl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -(pyridin-4-yl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 5-methyl-i -((S)- 1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 5-methyl-i -((R)- 1 -phenylethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -phenylethyl)-6-(quinolin-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(3-fluorophenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(2-fluorophenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -phenylethyl)-6-(quinolin-6-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(piperidin-4-ylmethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -(pyridin-2-yl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; - 67 - WO 2013/019927 PCT/US2012/049281 1 -(1 -(pyridin-3-yl)ethyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -((1 s,4s)-4-(hydroxymethyl)cyclohexyl)-6-(quinolin-5-yl)-1 H-imidazo[4,5 -b]pyrazin-2(3H) one; N-(4-(2-oxo-3-(1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5 yl)phenyl)methanesulfonamide; 6-(3-(methylsulfonyl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(3-aminophenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(3-(dimethylamino)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -phenyl-6-(quinolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(1 -phenylethyl)-6-(4-(trifluoromethyl)phenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; N-(3-(2-oxo-3-(1 -phenylethyl)-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5 yl)phenyl)methanesulfonamide; 6-(4-(methylsulfonyl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 3-(1 -phenylethyl)-5-(quinolin-5-yl)oxazolo[5,4-b]pyrazin-2(3H)-one; 1 -(cyclopentylmethyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one 6-(4-hydroxyphenyl)- 1 -isopropyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-hydroxyphenyl)- 1 -isobutyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-hydroxyphenyl)- 1 -((tetrahydro-2H-pyran-3-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 1 -(cyclohexylmethyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 5-(3-Hydroxyphenyl)-3-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one; 4-(3-(3-Methoxybenzyl)-2-oxo-2,3-dihydrooxazolo[5,4-b]pyrazin-5-yl)-N-methyl benzamide; 1-Cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-Cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide; Methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate; - 68 - WO 2013/019927 PCT/US2012/049281 1 -(Cyclohexylmethyl)-6-(pyridin-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N methylbenzamide; 1 -(Cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(pyridin-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile; 1 -(Cyclohexylmethyl)-6-(1 H-indol-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N isopropylbenzamide; 1-(2-Hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(1 H-indol-6-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 3-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5-yl)benzamide; 6-(4-(Aminomethyl)phenyl)- 1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)- 1 -((1 -methylpiperidin-4-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one;; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile; 1 -((1 s,4s)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(pyridin-2-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide; 1 -(Cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 1 -(Cyclohexylmethyl)-6-(4-hydroxy-2-methylphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid; 6-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 69 - WO 2013/019927 PCT/US2012/049281 6-(4-Hydroxyphenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 6-(4-Hydroxyphenyl)- 1 -phenethyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -((1r,4r)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1 H-1,2,4-Triazol-3-yl)phenyl)- 1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 1 -(Cyclohexylmethyl)-6-phenyl- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(1 H-pyrazol-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(1 H-pyrazol-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(1 -oxoisoindolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(3-(1 H-Tetrazol-5-yl)phenyl)- 1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(2-oxoindolin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(1 H-indazol-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(6-methoxypyridin-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)- 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)- 1 -(piperidin-4-ylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 1 -(Cyclohexylmethyl)-6-(6-hydroxypyridin-3-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(2-methoxypyridin-4-yl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 4-(3-((1r,4r)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin-5 yl)benzamide; 2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl) acetic acid; 2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl) acetamide; - 70 - WO 2013/019927 PCT/US2012/049281 1 -(Cyclohexylmethyl)-6-(2-oxoindolin-6-yl)- 1 H-imidazo [4,5 -b]pyrazin-2(3H)-one; 4-(3 -(Cyclohexylmethyl)-2-oxo-2,3 -dihydro-l1H-imidazo [4,5 -b]pyrazin-5 -yl)-3 -methyl benzoic acid; N-Methyl-4-(2-oxo-3 -((tetrahydro-2H-pyran-4-yl)methyl)-2,3 -dihydro- 1H-imidazo [4,5 b]pyrazin-5 -yl)benzamide; 4-(2-oxo-3 -((Tetrahydro-2H-pyran-4-yl)methyl)-2,3 -dihydro- 1H-imidazo [4,5 -b]pyrazin-5 yl)benzamide; 7-(4-Hydroxyphenyl)- 1-(3 -methoxybenzyl)-3 ,4-dihydropyrazino [2,3-b]pyrazin-2( 1H)-one; 6-(4-(2-Hydroxypropan-2-yl)phenyl)- 1-((tetrahydro-2H-pyran-4-yl)methyl)- 1H-imidazo [4,5 b]pyrazin-2(3H)-one; 6-( 1H-Indol-5 -yl)-l -((tetrahydro-2H-pyran-4-yl)methyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; 6-(4-(4H- 1,2,4-Triazol-3 -yl)phenyl)- 1-((tetrahydro-2H-pyran-4-yl)methyl)- 1H-imidazo [4,5 b]pyrazin-2(3H)-one; 6-( 1H-Benzo [d]imidazol-5 -yl)-l -(cyclohexylmethyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; 4-(2-oxo-3 -(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-2,3 -dihydro- 1H-imidazo [4,5 -b]pyrazin-5 yl)benzamide; 6-(3 -(2H- 1,2,3 -Triazol-4-yl)phenyl)- 1-(cyclohexylmethyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H) one; 6-(4-( 1H-Imidazol- 1-yl)phenyl)- 1-(cyclohexylmethyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; 6-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)- 1-((1 r,4r)-4-hydroxycyclohexyl)- 1H-imidazo [4,5 -b]pyrazin 2(3H)-one; 6-(4-(2H-tetrazol-5 -yl)phenyl)- 1-(cyclohexylmethyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(2-hydroxypyridin-4-yl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; 6-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)- 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1H-imidazo [4,5 b]pyrazin-2(3H)-one; 6-(4-( 1H-Imidazol-2-yl)phenyl)- 1-(cyclohexylmethyl)- 1H-imidazo [4,5 -b]pyrazin-2(3H)-one; - 71 - WO 2013/019927 PCT/US2012/049281 6-(4-(1 H- 1,2,3-Triazol- 1 -yl)phenyl)- 1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; 6-(4-(2-Hydroxypropan-2-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(4-(5-methyl-i H-1,2,4-triazol-3-yl)phenyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(1 H-Pyrazol-3-yl)phenyl)- I -(cyclohexylmethyl)- I H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1 H-Pyrazol-4-yl)phenyl)- I -(cyclohexylmethyl)- I H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(5-(Aminomethyl)- I H-1,2,4-triazol-3-yl)phenyl)- I -(cyclohexylmethyl)- I H-imidazo[4,5 b]pyrazin-2(3H)-one hydrochloride; 1-(Cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-iH-1,2,4-triazol-3-yl)phenyl)-iH-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-i-((ir,4r)-4-methoxycyclohexyl)-iH-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-i-((tetrahydrofuran-2-yl)methyl)-iH-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(3-(iH-1,2,4-Triazol-3-yl)phenyl)-i-(cyclohexylmethyl)-iH-imidazo[4,5-b]pyrazin-2(3H) one; 1-((ir,4r)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-iH-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-Hydroxyphenyl)-i-((is,4s)-4-methoxycyclohexyl)-iH-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-i-((ir,4r)-4-(methoxymethyl)cyclohexyl)-iH-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(i-Methyl-iH-pyrazol-4-yl)-i-((tetrahydro-2H-pyran-4-yl)methyl)-iH-imidazo[4,5-b]pyrazin 2(3H)-one; 1-(((ir,4r)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-iH-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-Hydroxyphenyl)-i-((tetrahydrofuran-3-yl)methyl)-iH-imidazo[4,5-b]pyrazin-2(3H)-one; - 72 - WO 2013/019927 PCT/US2012/049281 1 -(((1 s,4s)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(1 H-Benzo[d]imidazol-5-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one hydrochloride; 6-(4-(5-(Morpholinomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4 yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride; 1-(Cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(2-Methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one hydrocholoride; 6-(4-(5-(Methoxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl) 1H-imidazo[4,5-b]pyrazin-2(3H)-one; 1-((1s,4s)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(3-Methyl-iH-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(1H-Pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H) one; 6-(2-Amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one di hydrochloride; 6-(4-(5-(2-Hydroxypropan-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4 yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(5-Isopropyl-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H imidazo[4,5-b]pyrazin-2(3H)-one; - 73 - WO 2013/019927 PCT/US2012/049281 4-(2-Methoxy-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide hydrochloride; 4-(1-((1s,4s)-4-Hydroxycyclohexyl)-2-methoxy-1H-imidazo[4,5-b]pyrazin-6-yl) benzamide; 6-(4-Hydroxyphenyl)-1-((1s,4s)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(3H-imidazo[4,5-b]pyridin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one; 1-(2-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(1H-Pyrazol-1-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H) one; 6-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(1H-Imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one hydrochloride; 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl) 1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1H-Imidazol-5-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5 b]pyrazin-2(3H)-one hydrochloride; 6-(4-Hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(4,5-Dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1H-1,2,4-Triazol-5-yl)phenyl)-1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-imidazo [4,5 b]pyrazin-2(3H)-one; - 74 - WO 2013/019927 PCT/US2012/049281 6-(4-(1 H-1,2,4-Triazol-5-yl)phenyl)- 1 -(((1r,4r)-4-methoxycyclohexyl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(6-(1 H-1,2,4-Triazol-3-yl)pyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1 H-1,2,4-Triazol-3-yl)phenyl)- 1 -(2-(2-oxopyrrolidin- 1 -yl)ethyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(5-((dimethylamino)methyl)- 1 H-1,2,4-triazol-3-yl)phenyl)- 1 -((tetrahydro-2H-pyran-4 yl)methyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)- 1 -(pyrrolidin-2-ylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride; 6-(2-Aminobenzimidazol-5-yl)-1-(cyclohexylmethyl)-4-imidazolino[4,5-b]pyrazin-2-one di hydrochloride; 6-(2-(Dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl) methyl)-1H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)-1-(piperidin-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H) one hydrochloride; 1-(Cyclohexylmethyl)-6-(2-(methylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H) one; 6-(3-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H imidazo[4,5-b]pyrazin-2(3H)-one; 1-(Cyclohexylmethyl)-6-(2-(2-methoxyethylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(5-((methylamino)methyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4 yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one; - 75 - WO 2013/019927 PCT/US2012/049281 6-(4-(5-Oxopyrrolidin-2-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(5-methyl-i H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(1 H-imidazol-2-yl)phenyl)- I -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- I H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(4H- 1,2,4-triazol-3-yl)phenyl)- I -(2-methyl-2-morpholinopropyl)- I H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(4H- 1,2,4-Triazol-3-yl)phenyl)- I -(1 -morpholinopropan-2-yl)- I H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(Pyrrolidin-2-yl)phenyl)- I -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- I H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(5-(aminomethyl)- I H-1,2,4-triazol-3-yl)phenyl)- I -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- I H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(5-(Hydroxymethyl)thiophen-2-yl)- I -((tetrahydro-2H-pyran-4-yl)methyl)- I H-imidazo[4,5 b]pyrazin-2(3H)-one; (ir,4r)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro- I H-imidazo[4,5-b]pyrazin- I -yl)cyclo hexanecarboxamide; (I s,4s)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro- I H-imidazo[4,5-b]pyrazin- I yl)cyclohexanecarboxamide; 6-(4-(5-methyl-i H-1,2,4-triazol-3-yl)phenyl)- I -(2-morpholinoethyl)- I H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(5-Oxopyrrolidin-3-yl)phenyl)- I -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- I H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(Pyrrolidin-3-yl)phenyl)- I -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- I H-imidazo[4,5-b]pyrazin 2(3H)-one; - 76 - WO 2013/019927 PCT/US2012/049281 6-(1 H-benzo[d]imidazol-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(3-(Hydroxymethyl)thiophen-2-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(5-(2-Hydroxyethyl)thiophen-2-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(pyrimidin-5-yl)-1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(6-Fluoropyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(6-Aminopyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(5-methyl-i H-imidazol-2-yl)phenyl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(5-Methyl-i H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-(2-oxopyrrolidin- 1 -yl)ethyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(6-(Methylamino)pyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(2-aminopyrimidin-5-yl)-1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(2-hydroxypropan-2-yl)phenyl)- 1 -(((1r,4r)-4-methoxycyclohexyl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-hydroxyphenyl)- 1 -((1 -methylpiperidin-3-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 1 -(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 H-imidazo[4,5-b]pyrazin 2(3H)-one; - 77 - WO 2013/019927 PCT/US2012/049281 6-(4-(hydroxymethyl)thiophen-2-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(1 H-benzo[d]imidazol-6-yl)- 1 -(((1r,4r)-4-methoxycyclohexyl)methyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(4,5-dimethyl- 1 H-imidazol-2-yl)phenyl)- 1-(2-morpholinoethyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1 -(2-morpholino-2-oxoethyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 6-(4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5 b]pyridin-2(3H)-one; (R)-6-(4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (S)-6-(4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; (1r,4r)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin- 1 yl)cyclohexanecarboxamide; 6-(3-Methyl-4-(1 H-1,2,4-Triazol-3-yl)phenyl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-B]pyrazin-2(3H)-one; 6-(4-(1 H-imidazol-2-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5 b]pyrazin-2(3H)-one; 6-(4-(5-(Aminomethyl)- 1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; - 78 - WO 2013/019927 PCT/US2012/049281 6-(1 H-benzo[d]imidazol-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(2-Aminopyrimidin-5-yl)-1 -(cyclohexylmethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-Hydroxyphenyl)- 1 -((1 -methylpiperidin-2-yl)methyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride; 6-(3-Methyl-4-(1 H-1,2,4-Triazol-3-yl)phenyl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-B]pyrazin-2(3H)-one; 1 -(Cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 H-imidazo[4,5-b]pyrazin 2(3H)-one; 6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1 -((tetrahydro-2H-pyran-4-yl)methyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)- 1 H imidazo[4,5-b]pyrazin-2(3H)-one; 6-(4-(4H- 1,2,4-Triazol-3-yl)phenyl)- 1 -(2-morpholino-2-oxoethyl)- 1 H-imidazo[4,5-b]pyrazin 2(3H)-one; (R)-6-(4-(4H- 1,2,4-Triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; (R)-6-(4-(1 H-1,2,4-Triazol-3-yl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-B]pyrazin-2(3H) one; (S)-6-(4-(4H- 1,2,4-Triazol-3-yl)phenyl)- 1 -(1 -phenylethyl)- 1 H-imidazo[4,5-b]pyrazin-2(3H) one; (1r,4r)-4-(6-(4-(2-Hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyrazin- 1 yl)cyclohexanecarboxamide; and 6-(4-(5-Methyl-iH-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H imidazo[4,5-b]pyrazin-2(3H)-one, - 79 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof. [00228] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (II): L N X R1~ YY N Y*"B o NR 3
R
4 (II) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein:
R
1 is substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; -X-A-B-Y- taken together form -N(R 2
)CH
2 C(O)NH-, -N(R 2
)C(O)CH
2 NH-,
-N(R
2 )C(O)NH-, -N(R 2 )C=N-, or -C(R 2 )=CHNH-; L is a direct bond, NH or 0; R2 is substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; and R3 and R 4 are independently H or C1_salkyl. [00229] In one embodiment, the TOR kinase inhibitors of formula (II) are those wherein X-A-B-Y- taken together form -N(R2)CH 2 C(O)NH-. - 80 - WO 2013/019927 PCT/US2012/049281 [002301 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)CH 2 NH-. [002311 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-. [00232] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C=N-. [002331 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -C(R 2)=CHNH-. [00234] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein L is a direct bond. [00235] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R 1 is substituted aryl, such as substituted phenyl. [002361 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. [00237] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. [002381 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH- and R 1 is substituted aryl, such as phenyl. [002391 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH- and R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. - 81 - WO 2013/019927 PCT/US2012/049281 [002401 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH- and R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. [00241] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is substituted C1_salkyl, such as -CH 2
C
6
H
5 . [00242] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is unsubstituted CIsalkyl, such as unsubstituted methyl. [002431 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00244] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl. [002451 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl. [002461 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R2 is substituted heterocyclylalkyl, such as substituted piperidine. [002471 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein R3 and R4 are H. [002481 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH- and R 2 is unsubstituted aryl, such as unsubstituted phenyl. [00249] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, and R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. - 82 - WO 2013/019927 PCT/US2012/049281 [002501 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R3 and R4 are H. [00251] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, L is a direct bond, R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R3 and R4 are H. [00252] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [002531 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R 3 and R 4 are H. [00254] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, L is a direct bond, R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R 3 and R4 are H. [00255] In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted heteroaryl, L is a direct bond and R 2 is substituted or unsubstituted C 1 _salkyl or substituted or unsubstituted cycloalkyl. [002561 In another embodiment, the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R2)C(O)NH-, R 1 is substituted or unsubstituted aryl, - 83 - WO 2013/019927 PCT/US2012/049281 L is a direct bond and R 2 is substituted or unsubstituted CIsalkyl or substituted or unsubstituted cycloalkyl. [002571 In another embodiment, the TOR kinase inhibitors of formula (II) do not include 8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide, 8,9-dihydro-8-oxo-9 phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide, 8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl) 7H-purine-6-carboxamide, 2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6 carboxamide, 2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide, 9 benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide, 2-methyl-8-oxo-9 phenyl-8,9-dihydro-7H-purine-6-carboxamide, 9-benzyl-9H-purine-2,6-dicarboxamide, 9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl-9H-Purine-6-carboxamide, 9-benzyl-2 methyl-9H-purine-6-carboxamide, 9-(2-hydroxyethyl)-2-methyl-9H-purine-6-carboxamide, 9-(2 hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide, 9-(2-hydroxyethyl)-2-(prop-1 enyl)-9H-purine-6-carboxamide, 9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide, 9-(3 hydroxypropyl)-2-methyl-9H-purine-6-carboxamide, 9-(3-hydroxypropyl)-2-(trifluoromethyl) 9H-purine-6-carboxamide, 2-methyl-9-phenylmethyl-9H-purine-6-carboxamide or 2-methyl-9-p D-ribofuranosyl-9H-purine-6-carboxamide. [00258] In another embodiment, the TOR kinase inhibitors of formula (II) do not include compounds wherein R2 is a substituted furanoside. [002591 In another embodiment, the TOR kinase inhibitors of formula (II) do not include compounds wherein R2 is a substituted or unsubstituted furanoside. [002601 In another embodiment, the TOR kinase inhibitors of formula (II) do not include (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides. [002611 In one embodiment, the TOR kinase inhibitors include compounds having the following formula (IIa): - 84 - WO 2013/019927 PCT/US2012/049281 R 2 R N N N N H 0 NR 3
R
4 (Ila) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein:
R
1 is substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R2 is substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; and R3 and R 4 are independently H or C1_salkyl. [00262] In one embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein
R
1 is substituted aryl, substituted or unsubstituted heteroaryl, such as substituted phenyl. [002631 In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. [00264] In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. - 85 - WO 2013/019927 PCT/US2012/049281 [002651 In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R2 is substituted C 1 _salkyl, such as -CH 2
C
6
H
5 . [002661 In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R2 is unsubstituted CIsalkyl, such as unsubstituted methyl. [00267] In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [002681 In another embodiment, the TOR kinase inhibitors of formula (IIa) are those wherein R2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl. [002691 In another embodiment, the TOR kinase inhibitors of formula (IIa) are those wherein R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl. [00270] In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R2 is substituted heterocyclylalkyl, such as substituted piperidine. [00271] In another embodiment, the TOR kinase inhibitors of formula (Ila) are those wherein R3 and R4 are H. [00272] In another embodiment, the TOR kinase inhibitors of formula (Ila) do not include 8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide, 8,9-dihydro-8-oxo-9 phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide, 8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl) 7H-Purine-6-carboxamide, 2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6 carboxamide, 2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide, 9 benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide, 9-phenylmethyl-9H purine-2,6-dicarboxamide, or 2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide. [002731 In another embodiment, the TOR kinase inhibitors of formula (Ila) do not include compounds wherein R2 is a substituted furanoside. [00274] In another embodiment, the TOR kinase inhibitors of formula (Ila) do not include compounds wherein R2 is a substituted or unsubstituted furanoside. - 86 - WO 2013/019927 PCT/US2012/049281 [002751 In another embodiment, the TOR kinase inhibitors of formula (Ila) do not include (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides. [00276] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Ilb): R1 N N o NR 3
R
4 (I1b) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: - x is -C(R 2 )=CH-NH- or -N(R 2 )-CH=N-;
R
1 is substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R2 is substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; and
R
3 and R 4 are independently H or C1_salkyl. [002771 In one embodiment, the TOR kinase inhibitors of formula (Ilb) are those wherein
R
1 is substituted aryl, such as substituted phenyl. - 87 - WO 2013/019927 PCT/US2012/049281 [002781 In another embodiment, the TOR kinase inhibitors of formula (Ib) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. [002791 In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. [002801 In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R2 is substituted C1_salkyl, such as -CH 2
C
6
H
5 . [002811 In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R2 is unsubstituted C 1 _salkyl, such as unsubstituted methyl. [00282] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [002831 In another embodiment, the TOR kinase inhibitors of formula (IIb) are those wherein R2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl. [00284] In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl. [00285] In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R2 is substituted heterocyclylalkyl, such as substituted piperidine. [002861 In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R 3 and R 4 are H. [00287] In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein ' Y is -C(R 2 )=CH-NH- and R 2 is substituted aryl, such as substituted phenyl. - 88 - WO 2013/019927 PCT/US2012/049281 [002881 In another embodiment, the TOR kinase inhibitors of formula (Ib) are those wherein ' is -N(R 2)-CH=N- and R 2 is substituted aryl, such as substituted phenyl. [002891 In another embodiment, the TOR kinase inhibitors of formula (1Ib) are those wherein R 1 is substituted aryl, such as phenyl, and R 2 is substituted aryl, such as substituted phenyl. [00290] In another embodiment, the TOR kinase inhibitors of formula (1Ib) do not include 9-benzyl-9H-purine-2,6-dicarboxamide, 9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl 9H-Purine-6-carboxamide, 9-benzyl-2-methyl-9H-purine-6-carboxamide, 9-(2-hydroxyethyl)-2 methyl-9H-purine-6-carboxamide, 9-(2-hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6 carboxamide, 9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide, 9-(2 hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide, 9-(3-hydroxypropyl)-2-methyl-9H-purine-6 carboxamide, 9-(3-hydroxypropyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide, 9-phenylmethyl-9H-purine-2,6-dicarboxamide, 2-methyl-9-phenylmethyl-9H-purine-6 carboxamide or 2-methyl-9-p-D-ribofuranosyl-9H-purine-6-carboxamide. [00291] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds wherein R 2 is substituted cyclobutyl when xY is -N(R 2 )-CH=N-. [00292] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds wherein R 2 is a substituted furanoside when XY is -N(R 2 )-CH=N-. [002931 In another embodiment, the TOR kinase inhibitors of formula (1Ib) do not include compounds wherein R 2 is substituted pyrimidine when XY is -C(R 2 )=CH-NH-. [00294] In another embodiment, the TOR kinase inhibitors of formula (1Ib) do not include compounds wherein R2 is substituted oxetane when ' ' is -N(R 2 )-CH=N-. - 89 - WO 2013/019927 PCT/US2012/049281 [002951 In another embodiment, the TOR kinase inhibitors of formula (1Ib) do not include compounds wherein R2 is substituted cyclopentyl or a heterocyclopentyl when 'Y is -N(R 2)-CH=N-. [00296] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (I1c): R 2 Ri N N N 0 H 0 NR 3
R
4 (Ic) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein:
R
1 is substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R2 is substituted or unsubstituted CIsalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; and
R
3 and R 4 are independently H or C1_salkyl. [002971 In one embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein
R
1 is substituted aryl, such as substituted phenyl. - 90 - WO 2013/019927 PCT/US2012/049281 [002981 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. [00299] In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. [003001 In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R2 is substituted C1_salkyl, such as -CH 2
C
6
H
5 . [003011 In another embodiment, the TOR kinase inhibitors of formula (Ic) are those wherein R2 is unsubstituted C 1 _salkyl, such as unsubstituted methyl. [00302] In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [003031 In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl. [00304] In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl. [00305] In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R2 is substituted heterocyclylalkyl, such as substituted piperidine. [003061 In another embodiment, the TOR kinase inhibitors of formula (I1c) are those wherein R 3 and R 4 are H. [00307] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (Id): - 91 - WO 2013/019927 PCT/US2012/049281 R 2 R N N 0 N N N H 0 NR 3
R
4 (I1d) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein:
R
1 is substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; R2 is substituted or unsubstituted C 1 _salkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl; and R3 and R 4 are independently H or C1_salkyl. [003081 In one embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein
R
1 is substituted aryl, such as substituted phenyl. [003091 In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline. [003101 In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl. - 92 - WO 2013/019927 PCT/US2012/049281 [003111 In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R2 is substituted C 1 _salkyl, such as -CH 2
C
6
H
5 . [00312] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is unsubstituted CIsalkyl, such as unsubstituted methyl. [003131 In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl. [00314] In another embodiment, the TOR kinase inhibitors of formula (Id) are those wherein R2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl. [00315] In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl. [003161 In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R2 is substituted heterocyclylalkyl, such as substituted piperidine. [00317] In another embodiment, the TOR kinase inhibitors of formula (I1d) are those wherein R3 and R4 are H. [003181 Representative TOR kinase inhibitors of formula (II) include: 9-benzyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; N-methyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; 8-oxo-9-phenyl-2-(pyridin-2-yl)-8,9-dihydro-7H-purine-6-carboxamide; 2-(2-chloropyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide; 2-(2-methoxypyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide; N,N-dimethyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; 9-methyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; 2-(4-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(3-hydroxyphenyl)-8-oxo-9-o-tolyl-8,9-dihydro-7H-purine-6-carboxamide; 2-(1H-indol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; - 93 - WO 2013/019927 PCT/US2012/049281 2-( 1H-indol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -hydroxyphenyl)-9-(4-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(2-hydroxypyridin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-chlorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-fluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2,6-difluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-cycloheptyl-8-oxo-2-(pyridin-3 -yl)-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-methoxyphenyl)-8-oxo-2-(quinolin-5 -yl)-8 ,9-dihydro-7H-purine-6-carboxamide; 2-cyclopentyl-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-methoxyphenyl)-8-oxo-2-(3 -(trifluoromethyl)phenyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-methoxyphenyl)-2-(6-methoxypyridin-3 -yl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -hydroxyphenyl)-8-oxo-9-(4-(trifluoromethyl)phenyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 9-benzyl-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -hydroxyphenyl)-8-oxo-9-(2-(trifluoromethoxy)phenyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2,4-dichlorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-methoxyphenyl)-2-(3 -nitrophenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -cyanophenyl)-8-oxo-9-phenyl-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(3 -fluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)phenyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(5 -fluoropyridin-3 -yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(l1 -benzylpiperidin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; benzyl 4-(6-carbamoyl-8-oxo-2-(pyridin-3 -yl)-7H-purin-9(8H)-yl)piperidine-l1-carboxylate; - 94 - WO 2013/019927 PCT/US2012/049281 9-cyclohexyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 9-(2-methoxyphenyl)-8-oxo-2-(3-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; 9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamide; 6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide; 6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide; 2-(3-aminophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(3-hydroxyphenyl)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide; 9-Cyclopentyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 9-tert-Butyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydo-7H-purine-6-carboxamide; [2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N-methylcarbox-amide; 2-phenyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; [2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N,N-dimethyl carboxamide; 2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(4-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; 9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide; 2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide; 9-Isopropyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydo-7H-purine-6-carboxamide; Methyl 4-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl) benzoate; 2-(2-Chloro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox amide; - 95 - WO 2013/019927 PCT/US2012/049281 2-(3-Cyanophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(2-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(3-Hydroxyphenyl)-9-(4-methoxy-2-methylphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 2-(3-Hydroxyphenyl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; 2-(4-Cyano-phenyl)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 4-[6-Carbamoyl-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl]-benzoic acid; Methyl 3-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate; 3-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoic acid; 2-(3-Hydroxyphenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(1H-Indazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(4-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 9-(2-Ethylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 9-(2,5-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(3-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carbox amide; 9-(2,6-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(2-Hydroxyphenyl)-9-(2-methoxyphenyl)purine-6-carboxamide; 2-(1H-Indazol-5-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2,3-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-[4-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide; 2-[3-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide; 9-(2-Methoxyphenyl)-8-oxo-2-(pyridin-4-yl)-8,9-dihydro-7H-purine-6-carboxamide; 2-(4-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide; 2-(2-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide; 2-[4-(1-Hydroxy-isopropyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; - 96 - WO 2013/019927 PCT/US2012/049281 2-[3 -(1 -Hydroxy-isopropyl)phenyl] -9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Methoxyphenyl)-2-(4-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2,4-Difluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Methoxyphenyl)-2- {3 -[(methylsulfonyl)amino]phenyl} -8-oxo-7-hydropurine-6 carboxamide; 9-(4-Chloro-2-fluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Chlorophenyl)-8-oxo-2-(3 -pyridyl)-7-hydropurine-6-carboxamide; 8-Oxo-2-(3 -pyridyl)-9- [2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide; 9-(3 -Chloro-2-fluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(2-Fluoro-3 -trifluoromethylphenyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6 carboxamide; 9-(2, 3, 4-Trifluorophenyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-( 1H-Benzo [d]imidazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2- [3-(Acetylamino)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(3 -hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5 ,6,7,8-tetrahydropteridine-4-carbox-amide; 9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-4-yl-7-hydropurine-6-carboxamide; 9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-3 -yl-7-hydropurine-6-carboxamide; 9-(4-Aminocyclohexyl)-2-(3 -hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2- [3-(Difluoromethyl)phenyl] -9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide; 2- [5-(Difluoromethyl)-2-fluorophenyl] -9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6 carboxamide; 2-( 1H-benzo [d]imidazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; - 97 - WO 2013/019927 PCT/US2012/049281 2-(6-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; 2-(1H-benzo[d]imidazol-6-yl)-9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-Benzimidazol-6-yl-8-oxo-9-[2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide; 2-(5-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; trans-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino) cyclohexyl carbamate; (R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6 carboxamide; (S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6 carboxamide; (cis)-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino) cyclohexyl carbamate; 2-(trans-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 2-(4-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; 2-(cis-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 2-(4-((1H-Imidazol-1-yl)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H purine-6-carboxamide; 2-(4-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6 carboxamide; (R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6 carboxamide; - 98 - WO 2013/019927 PCT/US2012/049281 (S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(2-Hydroxyethylamino)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide ; 9-(2-Methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)- 1H-benzo [d]imidazol-6-yl)-8 ,9-dihydro-7H purine-6-carboxamide; 2-(3 -(1H-i ,2,4-Triazol-3 -yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide; 9-(Biphenyl-2-yl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)-9-(2-fluorophenyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-Methoxyphenyl)-2-(2-methyl- 1H-benzo [d]imidazol-6-yl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(3 -(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(2-(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-tert-Butylphenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -Hydroxyphenyl)-8-oxo-9-(2-phenoxyphenyl)-8 ,9-dihydro-7H-purine-6-carboxamide; 2-( 1H-Benzo [d]imidazol-6-yl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-( 1H-Indazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(2-Hydroxypyridin-3 -yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 2-( 1H-Imidazo [4,5 -b]pyridin-6-yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; - 99 - WO 2013/019927 PCT/US2012/049281 2-(4-(l1 H-Imidazol- 1 -yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-Cyclohexylphenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(4-( 1H-Imidazol-2-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(l1 H-Benzo [d]imidazol- 1 -yl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-( 1H-Imidazo [4,5 -b]pyridin-6-yl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-Isopropylphenyl)-8-oxo-2-( 1H-pyrrolo [2,3 -b]pyridin-5 -yl)-8 ,9-dihydro-7H-purine-6 carboxamide; 2-( 1H-Imidazo [4,5 -b]pyridin-6-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8 ,9-dihydro-7H-purine 6-c arboxamide; 9-(2-Methoxyphenyl)-2-(2-(methylthio)- 1 H-benzo [d]imidazol-5 -yl)-8-oxo-8 ,9-dihydro-7H purine-6-carboxamide; 2-( 1H-Indol-5 -yl)-9-(2-isopropylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(Cyclohexylmethyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2,3 -Dihydro- 1 H-inden- Il-yl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(3 -Hydroxyphenyl)-9-isobutyl-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(trans-4-Methoxycyclohexyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(cis-4-Methoxycyclohexyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(3 -Hydroxyphenyl)-8-oxo-9-(5 ,6,7,8-tetrahydronaphthalen- Il-yl)-8 ,9-dihydro-7H-purine-6 carboxamide; - 100 - WO 2013/019927 PCT/US2012/049281 2-(4-( 1H-i ,2,4-Triazol-3 -yl)phenyl)-9-cyclohexyl-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -Hydroxyphenyl)-9-( 1H-indol-4-yl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-Fluoro-3 -methoxyphenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-Fluoro-5 -methoxyphenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-Cyclohexyl-2-( 1H-imidazo [4,5 -b]pyridin-6-yl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -Hydroxyphenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(3 -Hydroxyphenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(2-Cyclopentylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -Hydroxyphenyl)-8-oxo-9-(piperidin-4-yl)-8 ,9-dihydro-7H-purine-6-carboxamide; 9-(2-Fluoro-4-methoxyphenyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-( 1H-benzo [d]imidazol-6-yl)-9-cyclohexyl-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-Benzimidazol-6-yl-9-(trans-4-methoxycyclohexyl)-8-oxo-7-hydropurine-6-carboxamide; 2-(4-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; 2-(3 -Hydroxyphenyl)-9-(cis-4-(methoxymethyl)cyclohexyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 9-(trans-4-Aminocyclohexyl)-2-(3 -hydroxyphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6 carboxamide; 2-(3 -Hydroxyphenyl)-9-(2-isobutylphenyl)-8-oxo-8 ,9-dihydro-7H-purine-6-carboxamide; (R)-2-(3 -Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3 -yl)-8 ,9-dihydro-7H-purine-6 carboxamide; (S)-2-(3 -Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3 -yl)-8 ,9-dihydro-7H-purine-6-carboxamide; - 101 - WO 2013/019927 PCT/US2012/049281 2-(3-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; 2-(4-(1H-1,2,3-Triazol-5-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine 6-carboxamide; 2-(1H-Benzo[d]imidazol-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; 2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine 6-carboxamide; 2-(3-Hydroxyphenyl)-9-((1r,4r)-4-(methoxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6 carboxamide; and 9-(2-Isopropylphenyl)-2-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-oxo-8,9-dihydro-7H purine-6-carboxamide, and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof. [00319] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (III): R 2 1 R3 R1 N N R4 N N 0 H (III) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein: - 102 - WO 2013/019927 PCT/US2012/049281 R' is substituted or unsubstituted C1-s alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R2 is H, substituted or unsubstituted C 1 _s alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R3 and R 4 are each independently H, substituted or unsubstituted C 1
_
8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkylalkyl, or R3 and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; or R 2 and one of R3 and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl, wherein in certain embodiments, the TOR kinase inhibitors do not include the compounds depicted below, namely: HO ,, N N N 1N:LO H 6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 103 - WO 2013/019927 PCT/US2012/049281 N-NH N H N N H 6-(4-(1 H-1,2,4-triazol-5-yl)phenyl)-3 -(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; or, N-NH N H N N N N ]O H (R)-6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one. [00320] In some embodiments of compounds of formula (III), R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In one embodiment, R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C1-s alkyl (for example, methyl), substituted or unsubstituted heterocyclyl (for example, substituted or unsubstituted triazolyl or pyrazolyl), halogen (for example, fluorine), aminocarbonyl, cyano, hydroxyalkyl (for example, hydroxypropyl), and hydroxy. In other embodiments, R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1 _s alkyl, substituted or unsubstituted heterocyclyl (for example, substituted or unsubstituted triazolyl), halogen, aminocarbonyl, - 104 - WO 2013/019927 PCT/US2012/049281 cyano, hydroxyalkyl, -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted C 1 _4 alkyl. In yet other embodiments, R 1 is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1 _s alkyl, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted C1_ alkyl. [00321] In some embodiments of compounds of formula (III), R 1 is R (CR2)nO0R -d (CR2)OR
R
2 ~0 ~ Rm N'N RmNR2 R N > 0 N'RN N~> NN N R2 R'm RNN NR R N -R' N-R NIN. R mR m m ,o r RN-R NR | R'm wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1
_
4 alkyl (for example, methyl); R' is at each occurrence independently a substituted or unsubstituted C1_4 alkyl, halogen (for example, fluorine), cyano, -OR, or -NR 2 ; m is 0-3; and n is 0-3. It will be understood by those skilled in the art that any of the subsitutuents R' may be attached to any suitable atom of any of the rings in the fused ring systems. It will also be - 105 - WO 2013/019927 PCT/US2012/049281 understood by those skilled in the art that the connecting bond of R 1 (designated by the bisecting wavy line) may be attached to any of the atoms in any of the rings in the fused ring systems. [00322] In some embodiments of compounds of formula (III), R 1 is (C 2)O RN -=== N = N
(CR
2 )nOR N.NR (CR 2 )nOR NNR Rm m R R R R R'm ,Rm,'m ,or R'm wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1
_
4 alkyl; R' is at each occurrence independently a substituted or unsubstituted C 1 4 alkyl, halogen, cyano, -OR, or -NR 2 ; m is 0-3; and n is 0-3. [003231 In some embodiments of compounds of formula (III), R 2 is H, substituted or unsubstituted C1-s alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 1 4 alkyl-heterocyclyl, substituted or unsubstituted C 1 _ 4 alkyl-aryl, or substituted or unsubstituted C 1 4 alkyl-cycloalkyl. For example, R 2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C 1
_
4 alkyl)-phenyl, (C 1
_
4 alkyl) cyclopropyl, (C1-4 alkyl)-cyclobutyl, (C1-4 alkyl)-cyclopentyl, (C 1-4 alkyl)-cyclohexyl, (C1-4 alkyl)-pyrrolidyl, (C 1-4 alkyl)-piperidyl, (C1-4 alkyl)-piperazinyl, (C1-4 alkyl)-morpholinyl, (CI alkyl)-tetrahydrofuranyl, or (CI alkyl)-tetrahydropyranyl, each optionally substituted. - 106 - WO 2013/019927 PCT/US2012/049281 [003241 In other embodiments, R 2 is H, C 1
_
4 alkyl, (C1_ 4 alkyl)(OR), R' R X R _/R R o o , N R R' ,or O R wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1 4 alkyl (for example, methyl); R' is at each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C 1
_
4 alkyl (for example, methyl); and p is 0-3. [003251 In some such embodiments, R2 is H, C 1 4 alkyl, (C 1 _4alkyl)(OR), 0 rK0N0 R' ,or wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1
_
2 alkyl; R' is at each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C 1-2 alkyl; and p is 0-1. - 107 - WO 2013/019927 PCT/US2012/049281 [003261 In some other embodiments of compounds of formula (III), R 2 and one of R3 and R4 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl. For example, in some embodiments, the compound of formula (III) is R" R"r0 p R" / R( N N
R
1 N N R 1 N N N N O N NO, NN 0, H H H R NR N O
R
1 N NNR N N N N 0 ,or N N 0 H H wherein R is at each occurrence independently H, or a substituted or unsubstituted C1_ alkyl; R" is H, OR, or a substituted or unsubstituted C 1 4 alkyl; and R 1 is as defined herein. [00327] In some embodiments of compounds of formula (III), R3 and R4 are both H. In others, one of R3 and R 4 is H and the other is other than H. In still others, one of R3 and R4 is C 1 _ 4 alkyl (for example, methyl) and the other is H. In still others, both of R3 and R4 are C1_ alkyl (for example, methyl). [003281 In some such embodiments described above, R 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl, 1H imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1
_
8 alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl and hydroxy. In others, R 1 is pyridyl substituted with one or more substituents independently - 108 - WO 2013/019927 PCT/US2012/049281 selected from the group consisting of cyano, substituted or unsubstituted C 1 _s alkyl, substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen, aminocarbonyl, -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted C1_ alkyl. In others, R 1 is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1 _s alkyl, and NR 2 , wherein R is independently H, or a substituted or unsubstituted C 1 4 alkyl. [00329] In certain embodiments, the compounds of formula (III) have an R 1 group set forth herein and an R 2 group set forth herein. [003301 In some embodiments of compounds of formula (III), the compound at a concentration of 10 iM inhibits motor, DNA-PK, or P13K or a combination thereof, by at least about 50%. Compounds of formula (III) may be shown to be inhibitors of the kinases above in any suitable assay system. [003311 Representative TOR kinase inhibitors of formula (III) include: 6-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-methoxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-hydroxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 109 - WO 2013/019927 PCT/US2012/049281 6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino [2,3 b]pyrazin-2(1H)-one; 6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(trans-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3 b]pyrazin-2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; 6-(6-(1 H-1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-isopropyl-3,4-dihydropyrazino [2,3 -b]pyrazin-2(1 H) one; 6-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; -110- WO 2013/019927 PCT/US2012/049281 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-(2-methoxyethyl)-6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 6-(3-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 5-(8-(2-methoxyethyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4 methylpicolinamide; - 111 - WO 2013/019927 PCT/US2012/049281 3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)benzamide; 3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)benzonitrile; 5-(8-(trans-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4 methylpicolinamide; 6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(1 H-indazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; 4-((1 R,3 S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-((1 S,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-((1R,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-((1S,3 S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-ethyl-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 6-(1 H-pyrrolo [2,3 -b]pyridin-5 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(1 H-indol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; 6-(1 H-indol-5 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; -112- WO 2013/019927 PCT/US2012/049281 4-(((l1 R,3 S)-3 -methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 4-(((l1 S,3R)-3 -methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(3 -fluoro-2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(3 -fluoro-2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)-4-(2-methoxyethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 3,3 -dimethyl-6-(4-methyl-6-(4H- 1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-((tetrahydro-2H-pyran-4 yl)methyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((l R,3 S)-3 -methoxycyclopentyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((l S,3R)-3 -methoxycyclopentyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(((l S ,3S)-3 -methoxycyclopentyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(((l R,3R)-3 -methoxycyclopentyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((l S,3 S)-3 -methoxycyclopentyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((l R,3R)-3 -methoxycyclopentyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(((l R,3 S)-3 -methoxycyclopentyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(((l S ,3R)-3 -methoxycyclopentyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; -113- WO 2013/019927 PCT/US2012/049281 6-(3-fluoro-4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 6-(3-fluoro-4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7'-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1'-((tetrahydro-2H-pyran-4-yl)methyl)- 'H spiro [cyclopentane- 1,2'-pyrazino [2,3 -b]pyrazin] -3'(4'H)-one; 7'-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1'-((tetrahydro-2H-pyran-4-yl)methyl)- 'H spiro [cyclobutane- 1,2'-pyrazino [2,3 -b]pyrazin]-3'(4'H)-one; 4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7'-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1'H-spiro[cyclopentane- 1,2'-pyrazino[2,3 b]pyrazin]-3'(4'H)-one; 7'-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1'H-spiro[cyclobutane- 1,2'-pyrazino[2,3 b]pyrazin]-3'(4'H)-one; 7'-(2-methyl-4-(4H- 1,2,4-triazol-3-yl)phenyl)- 1'H-spiro[cyclopropane- 1,2'-pyrazino[2,3 b]pyrazin]-3'(4'H)-one; (R)-6-(4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; (S)-6-(4-(4H- 1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(1 H-indazol-5 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; 4-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)benzamide; 4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; -114- WO 2013/019927 PCT/US2012/049281 4-ethyl-3 ,3 -dimethyl-6-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 3,3 -dimethyl-6-(2-methyl-6-(4H- 1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-((tetrahydro-2H-pyran-4 yl)methyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; (R)-6-(6-( 1 -hydroxyethyl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 3,3 -dimethyl-6-(2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)-4-((tetrahydro-2H-pyran-4 yl)methyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3 -yl)-4-(trans-4-methoxycyclohexyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3 -yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 3,3 -dimethyl-6-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin 2(1 H)-one; 3,3 -dimethyl-6-(2-methyl-6-(4H- 1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-4 yl)ethyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3 -yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3 -yl)-4-(trans-4-methoxycyclohexyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; (S)-6-(6-( 1 -hydroxyethyl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 3,3 -dimethyl-6-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4 yl)ethyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; -115- WO 2013/019927 PCT/US2012/049281 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-(cis-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-(trans-4-methoxycyclohexyl)-6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 9-(6-(4H- 1,2,4-triazol-3 -yl)-3 -pyridyl)-6,11,4a-trihydromorpholino [4,3 -e]pyrazino [2,3 b]pyrazin-5-one; 6-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 5-(8-(cis-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-6 methylpicolinonitrile; 6-(6-(4H- 1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 9-(4-(4H- 1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4a trihydropiperazino[1,2-e]pyrazino [2,3 -b]pyrazin-5 -one; 9-(4-(4H- 1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3 b]pyrazin-5-one; -116- WO 2013/019927 PCT/US2012/049281 9-(4-(4H- 1,2,4-triazol-3 -yl)-2-methylphenyl)-3 -(2-methoxyethyl)-6, 11 ,4a trihydropiperazino[ [1,2-e]pyrazino [2,3 -b]pyrazin-5 -one; 4-(cyclopentylmethyl)-6-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 9-(6-(4H- 1 ,2,4-triazol-3 -yl)-2-methyl-3 -pyridyl)-6, 11 ,4a-trihydromorpholino [4,3 -e]pyrazino [2,3 b]pyrazin-5 -one; 4-(trans-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 4-(cis-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((tetrahydrofuran-3 -yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-neopentyl-3 ,4-dihydropyrazino [2,3 -b]pyrazin 2(1 H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-isobutyl-3 ,4-dihydropyrazino[2,3 -b]pyrazin-2( 1H) one; 3 -methyl-6-(2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(piperidin-4-yl)-3 ,4-dihydropyrazino[2,3 -b]pyrazin 2(1 H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-3 -yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 8-(4-(4H- 1,2,4-triazol-3 -yl)-2-methylphenyl)(3 aS ,2R)-2-methoxy-5,10,3 a-trihydropyrazino [2,3 b]pyrrolidino [ 1 ,2-e]pyrazin-4-one; -117- WO 2013/019927 PCT/US2012/049281 8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3 b]pyrrolidino[ 1,2-e]pyrazin-4-one; 8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3 b]pyrrolidino[ 1,2-e]pyrazin-4-one; 8-(4-(4H- 1,2,4-triazol-3 -yl)-2-methylphenyl)(2S,3 aS)-2-methoxy-5,10,3 a-trihydropyrazino [2,3 b]pyrrolidino[ 1,2-e]pyrazin-4-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(2-methyl-6-(4H- 1,2,4-triazol-3 -yl)pyridin-3 -yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 9-(4-(4H- 1,2,4-triazol-3-yl)-2-methylphenyl)-3-methyl-6,11,4a-trihydropiperazino[1,2 e]pyrazino [2,3 -b]pyrazin-5 -one; 9-(4-(4H- 1,2,4-triazol-3 -yl)phenyl)-6,11,4a-trihydromorpholino [4,3 -e]pyrazino [2,3 -b]pyrazin-5 one; 9-(4-(4H- 1,2,4-triazol-3 -yl)-2-methylphenyl)-6,11,4a-trihydropiperidino [1,2-e]pyrazino [2,3 b]pyrazin-5-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; -118- WO 2013/019927 PCT/US2012/049281 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-phenethyl-3 ,4-dihydropyrazino [2,3 -b]pyrazin 2(1 H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(tetrahydro-2H-pyran-4-yl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 4-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((trans-4-methoxycyclohexyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((cis-4-methoxycyclohexyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(tetrahydrofuran-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(tetrahydrofuran-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-phenyl-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H) one; (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 -methyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 9- [6-(l1 -hydroxy-isopropyl)-3 -pyridyl] -6,11 ,4a-trihydromorpholino [4,3 -e]pyrazino [2,3 b]pyrazin-5 -one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-4-(2-methoxyethyl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 6-(2-amino-7-methyl- 1 H-benzo [d]imidazol-5 -yl)-4-(3 -(trifluoromethyl)benzyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; -119- WO 2013/019927 PCT/US2012/049281 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3 b]pyrazin-5-one; 6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 8-(4-(4H- 1,2,4-triazol-3-yl)-2-methylphenyl)-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2 e]pyrazin-4-one; 6-(4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-ethyl-3,4-dihydropyrazino [2,3 -b]pyrazin-2(1 H)-one; 6-(4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino [2,3 -b]pyrazin 2(1H)-one; 6-(4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-(3 -(trifluoromethyl)benzyl)-3,4-dihydropyrazino [2,3 b]pyrazin-2(1H)-one; 6-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-methyl- 1 H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and 6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one, - 120 - WO 2013/019927 PCT/US2012/049281 and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof. [00332] In one embodiment, the TOR kinase inhibitors include compounds having the following formula (IV): R 2 R1 N N 0 N N H (IV) and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof, wherein:
R
1 is substituted or unsubstituted C1-s alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R2 is H, substituted or unsubstituted C 1 _s alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R3 is H, or a substituted or unsubstituted C 1 _s alkyl, - 121 - WO 2013/019927 PCT/US2012/049281 wherein in certain embodiments, the TOR kinase inhibitors do not include 7-(4 hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, depicted below: O HO N N O N N H [003331 In some embodiments of compounds of formula (IV), R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. For example, R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5 b]pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted
C
1 _s alkyl (for example, methyl), substituted or unsubstituted heterocyclyl (for example, a substituted or unsubstituted triazolyl or pyrazolyl), aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl and hydroxy. In other embodiments, R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C1-s alkyl (for example, methyl), substituted or unsubstituted heterocyclyl (for example, a substituted or unsubstituted triazolyl), halogen, aminocarbonyl , cyano, hydroxyalkyl (for example, hydroxypropyl), -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted C 1
_
4 alkyl. In some embodiments, R 1 is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1
_
8 alkyl, and -NR 2 , wherein R is independently H, or a substituted or unsubstituted C1_ alkyl. - 122 - WO 2013/019927 PCT/US2012/049281 [003341 In some embodiments, R 1 is R -(CR2)nOR NR -(CR 2 )nOR R 0 N R2 Rm RN N- RN N N- R' ~R m m - m o r
R-
RN N NR R N-RR m R'm NR R'm wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1
_
4 alkyl (for example, methyl); R' is at each occurrence independently a substituted or unsubstituted C 1 _4 alkyl (for example, methyl), halogen (for example, fluoro), cyano, -OR, or NR 2 ; m is 0-3; and n is 0-3. It will be understood by those skilled in the art that any of the subsitutuents R' may be attached to any suitable atom of any of the rings in the fused ring systems. - 123 - WO 2013/019927 PCT/US2012/049281 [003351 In some embodiments of compounds of formula (IV), R 1 is N-= NR (CR2)OR .NR N2O.NR 2nN N (CRjAOR N N' R CR R R ~N N ,- N - N~ N R'mR'm m or R'm wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
14 alkyl; R' is at each occurrence independently a substituted or unsubstituted C 1 _4 alkyl, halogen, cyano, -OR or -NR 2 ; m is 0-3; and n is 0-3. [00336] In some embodiments of compounds of formula (IV), R 2 is H, substituted or unsubstituted C1-s alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 1 4 alkyl-heterocyclyl, substituted or unsubstituted C 1 _ 4 alkyl-aryl, or substituted or unsubstituted C 1 4 alkyl-cycloalkyl. For example, R 2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C 1 4 alkyl)-phenyl, (C 1
_
4 alkyl) cyclopropyl, (C1-4 alkyl)-cyclobutyl, (C1-4 alkyl)-cyclopentyl, (C1-4 alkyl)-cyclohexyl, (C1-4 alkyl)-pyrrolidyl, (C 14 alkyl)-piperidyl, (C 14 alkyl)-piperazinyl, (C1-4 alkyl)-morpholinyl, (CI alkyl)-tetrahydrofuranyl, or (CI alkyl)-tetrahydropyranyl, each optionally substituted. - 124 - WO 2013/019927 PCT/US2012/049281 [003371 In other embodiments, R 2 is H, C 1
_
4 alkyl, (C1_ 4 alkyl)(OR), R' R'R R' R ,or wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1 4 alkyl (for example, methyl); R' is at each occurrence independently H, -OR, cyano,or a substituted or unsubstituted C 1
_
4 alkyl (for example, methyl); and p is 0-3. - 125 - WO 2013/019927 PCT/US2012/049281 [003381 In other embodiments of compounds of formula (IV), R 2 is H, C1_ alkyl, (C1_ 4 alkyl)(OR), R' R R , R RR or R wherein R is at each occurrence independently H, or a substituted or unsubstituted
C
1 2 alkyl; R' is at each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C1-2 alkyl; and p is 0-1. [003391 In other embodiments of compounds of formula (IV), R3 is H. [00340] In some such embodiments described herein, R 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine, pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted
C
1 _s alkyl, substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen, cyano, hydroxyalkyl and hydroxy. In others, R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of C 1 _s alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted C1_ alkyl. In still others, R 1 is - 126 - WO 2013/019927 PCT/US2012/049281 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted C 1 _s alkyl, and NR 2 , wherein R is independently H, or a substituted or unsubstituted CIA alkyl. [00341] In certain embodiments, the compounds of formula (IV) have an R 1 group set forth herein and an R 2 group set forth herein. [00342] In some embodiments of compounds of formula (IV), the compound at a concentration of 10 iM inhibits motor, DNA-PK, P13K, or a combination thereof by at least about 50%. Compounds of formula (IV) may be shown to be inhibitors of the kinases above in any suitable assay system. [00343] Representative TOR kinase inhibitors of formula (IV) include: 7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 127 - WO 2013/019927 PCT/US2012/049281 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -((trans-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -((trans-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(cis-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -((cis-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(tetrahydro-2H-pyran-4-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(1 H-indol-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -((trans-4-hydroxycyclohexyl)methyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -((cis-4-hydroxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(trans-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 128 - WO 2013/019927 PCT/US2012/049281 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-1 -isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H) one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(trans-4-methoxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(trans-4-hydroxycyclohexyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-methoxyethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -isopropyl-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 1 -ethyl-7-(5-fluoro-2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(2-hydroxypyridin-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 1 -isopropyl-7-(4-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide; 7-(1 H-indazol-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(2-aminopyrimidin-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(2-aminopyridin-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; - 129 - WO 2013/019927 PCT/US2012/049281 7-(6-(methylamino)pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-hydroxypyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(4-(1 H-pyrazol-3-yl)phenyl)- 1 -(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H) one; 7-(pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(1 H-indazol-4-yl)- 1 -(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H)-one; 7-(1 H-indazol-6-yl)- 1 -(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H)-one; 7-(pyrimidin-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(6-methoxypyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 1 -ethyl-7-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H)-one; 1 -ethyl-7-(1 H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1 H)-one; 7-(pyridin-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(6-aminopyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 1 -methyl-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8 tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine 1-oxide; - 130 - WO 2013/019927 PCT/US2012/049281 4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3 b]pyrazin-2-yl)picolinamide; 5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl) 4-methylpicolinamide; 7-(1 H-pyrazol-4-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 1 -(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 3-((7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin 1(2H)-yl)methyl)benzonitrile; 1 -((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)benzamide; 5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)-4-methylpicolinamide; 3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin- 1 (2H) yl)methyl)benzonitrile; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((1 R,3R)-3-methoxycyclopentyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((1 S,3R)-3-methoxycyclopentyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((1 S,3 S)-3-methoxycyclopentyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((1 R,3 S)-3-methoxycyclopentyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 131 - WO 2013/019927 PCT/US2012/049281 7-(1 H-indazol-6-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(2-morpholinoethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -(2-morpholinoethyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 1 -isopropyl-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(1 H-imidazo[4,5-b]pyridin-6-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2 yl)benzamide; 7-(1 H-indazol-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 132 - WO 2013/019927 PCT/US2012/049281 7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(tetrahydro-2H-pyran-4-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((IS,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((1 R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((1 R,3 S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((IS,3 S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(1 H-indol-5-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 1 -ethyl-7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(1 H-indol-6-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin 2(1H)-one; 7-(4-(2-hydroxypropan-2-yl)phenyl)- 1 -(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -(tetrahydro-2H-pyran-4-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -((cis-4-methoxycyclohexyl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)- 1 H-benzo[d]imidazol-6-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; - 133 - WO 2013/019927 PCT/US2012/049281 7-(7-methyl-2-oxo-2,3 -dihydro- 1 H-benzo [d]imidazol-5 -yl)-lI -((tetrahydro-2H-pyran-4 yl)methyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(2-methyl-4-(4H- 1,2,4-triazol-3 -yl)phenyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 1 -(2-methoxyethyl)-7-(4-methyl-6-( 1 H-i ,2,4-triazol-3 -yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 1 -benzyl-7-(2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin 2(1 H)-one; 7-(3 -fluoro-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -(2-methoxyethyl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 7-(3 -fluoro-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(3 -fluoro-2-methyl-4-( 1 H-i ,2,4-triazol-3 -yl)phenyl)- 1 -(2-methoxyethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 1 -(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-lI -(trans-4-methoxycyclohexyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(5 -fluoro-2-methyl-4-(4H- 1 ,2,4-triazol-3 -yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(3 -fluoro-2-methyl-4-( 1 H-i ,2,4-triazol-3 -yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 1 -(2-methoxyethyl)-7-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-lI -((trans-4-methoxycyclohexyl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; - 134 - WO 2013/019927 PCT/US2012/049281 1 -(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 7-(4-(2-hydroxypropan-2-yl)phenyl)- 1 -(2-methoxyethyl)-3 ,4-dihydropyrazino [2,3 -b]pyrazin 2(1 H)-one; (S)-7-(6-( 1 -hydroxyethyl)pyridin-3 -yl)-l -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; (R)-7-(6-( 1 -hydroxyethyl)pyridin-3 -yl)-lI -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(2-methyl-6-(4H- 1 ,2,4-triazol-3 -yl)pyridin-3 -yl)-lI -((tetrahydro-2H-pyran-4-yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(4-(2-hydroxypropan-2-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-lI -(4-(trifluoromethyl)benzyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-l1 -(3 -(trifluoromethyl)benzyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-l1 -(3 -methoxypropyl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 7-(4-methyl-6-( 1 H-i ,2,4-triazol-3 -yl)pyridin-3 -yl)-lI -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-lI -(2-methoxyethyl)-3 ,4-dihydropyrazino [2,3 b]pyrazin-2( 1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3 -yl)-lI -((tetrahydro-2H-pyran-4-yl)methyl)-3 ,4 dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; 7-(4-methyl-2-(methylamino)- 1 H-benzo [d]imidazol-6-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl) 3 ,4-dihydropyrazino [2,3 -b]pyrazin-2( 1H)-one; - 135 - WO 2013/019927 PCT/US2012/049281 7-(2-amino-4-methyl- 1 H-benzo[d]imidazol-6-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(2-methyl-6-(4H- 1,2,4-triazol-3-yl)pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; (R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-i -(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; (S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-i -(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl) 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(2-amino-4-methyl- 1 H-benzo[d]imidazol-6-yl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(2-methyl-4-(1 H-1,2,4-triazol-3-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(4-(1 H-1,2,4-triazol-5-yl)phenyl)- 1 -(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 1 -(1 -hydroxypropan-2-yl)-7-(2-methyl-6-(1 H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4 dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and 1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3 b]pyrazin-2(1H)-one, and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof. - 136 - WO 2013/019927 PCT/US2012/049281 [003441 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: 0 0 HO OH OH N NN N 00 or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [003451 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: 0
N..--
N HN N N 0 NO H or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. - 137 - WO 2013/019927 PCT/US2012/049281 [003461 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: 0 0 N N N N H NN or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [003471 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: N NNN H 0~ N N ON - 138 - WO 2013/019927 PCT/US2012/049281 or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [00348] In one embodiment, the TOR kinase inhibitor is a compound having the following formula: 0 N H N I 0 o/ or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [00349] In one embodiment, the TOR kinase inhibitor is a compound having the following formula: ou NH2 N N N H HON HO 00 or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. - 139 - WO 2013/019927 PCT/US2012/049281 [003501 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: N NH N NH 0 or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [003511 In one embodiment, the TOR kinase inhibitor is a compound having the following formula: N0 N N4 or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer, or prodrug thereof. [00352] In one embodiment, the TOR kinase inhibitor is a compound disclosed in WO 2008/023161 (see, e.g., page 5, line 5 to page 11, line 15), WO 2009/007751 (see, e.g., page 9, - 140 - WO 2013/019927 PCT/US2012/049281 line 8 to page 26, line 8), WO 2009/007749 (see, e.g., page 9, line 21 to page 29, line 23), WO 2009/007750 (see, e.g., page 9, line 21 to page 32, line 22), WO 2009/007748 (see, e.g., page 9, line 6 to page 42, line 28), WO 2008/032028 (see, e.g., page 11, line 13 to page 21, line 13), WO 2008/032086 (see, e.g., page 10 line 21 to page 15, line 22), WO 2008/032072 (see, e.g., page 11, line 11 to page 16, line 13), WO 2008/032033 (see, e.g., page 11, line 3 to page 16, line 5), WO 2008/032089 (see, e.g., page 11, line 11 to page 16, line 13), WO 2008/032060 (see, e.g., page 11, line 3 to page page 16, line 6), WO 2008/032091 (see, e.g., page 11, line 11 to page 16, line 13), WO 2008/032036 (see, e.g., page 11, line 13 to page 21, line 13), WO 2008/032077 (see, e.g., page 10, line 21 to page 15, line 22), WO 2008/032064 (see, e.g., page 11, line 3 to page 16, line 5), WO 2008/032027 (see, e.g., page 10, line 21 to page 15, line 22), WO 2007/135398 (see, e.g., page 11, line 28 to page 16, line 6), WO 2007/129052 (see, e.g., page 10, line 8 to page 13, line 5), WO 2007/129044 (see, e.g., page 10, line 22 to page 13, line 20), WO 2007/080382 (see, e.g., page 9, line 20 to page 32, line 32), WO 2007/066102 (see, e.g., page 9, line 22 to page 14, line 17), WO 2007/066099 (see, e.g., page 9, line 22 to page 14, line 14), WO 2007/066103 (see, e.g., page 9, line 22 to page 14, line 16), WO 2007/060404 (see, e.g., 5, line 4 to page 7, line 25), WO 2006/090169 (see, e.g., page 4, lines 1-25), WO 2006/090167 (see, e.g., page 3, line 33 to page 6, line 23), WO 2008/115974 (see, e.g., page 4, paragraph [0012] to page 127, paragraph [0257]), WO 2009/052145 (see, e.g., page 5, paragraph [0015] to page 81, paragraph [0082]), WO 2010/006072 (see, e.g., page 28, line I to page 34, line 1), WO 2007/044698 (see, e.g., page 3, paragraph [0010] to the bottom of page 7), WO 2007/044813 (see, e.g., page 3, paragraph [0010] to the middle of page 7), WO 2007/044729 (see, e.g., page 3, paragraph [0010] to the bottom of page 10), WO 2007/129161 (see, e.g., page 2, line 10 to page 9, line 19), WO 2006/046031 (see, e.g., page 2, line 15 to page 4, line 12), WO 2003/072557 (see, e.g., page 1, line 4 to page 2, line 27), WO 2004/048365 (see, e.g., page 1, line 4 to page 4, line 17), WO 2004/078754 (see, e.g., page 1, line 4 to page 2, line 21), WO 2004/096797 (see, e.g., page 1, line 4 to page 2, line 34), WO - 141 - WO 2013/019927 PCT/US2012/049281 2005/021519 (see, e.g., page 1, line 4 to page 4, line 17) or US 2007/112005 (see, e.g., page 2, paragraph [0012] to page 22, paragraph [0065]), each of which is incorporated by reference herein in its entirety. 5.4 METHODS FOR MAKING TOR KINASE INHIBITORS [00353] The TOR kinase inhibitors can be obtained via standard, well-known synthetic methodology, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. Starting materials useful for preparing compounds of formula (III) and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents. [00354] Particular methods for preparing compounds of formula (I) are disclosed in U.S. Application No. 11/975,652, filed October 18, 2007, incorporated by reference herein in its entirety. Particular methods for preparing compounds of formula (II) are disclosed in U.S. Application No. 11/975,657, filed October 18, 2007, incorporated by reference herein in its entirety. Particular methods for preparing compounds of formula (III) and (IV) are disclosed in U.S. Application No. 12/605,791, filed October 26, 2009, incorporated by reference herein in its entirety. 5.5 METHODS OF USE [003551 Without being limited by theory, it is believed that LKB1 plays an important role in the nutrient sensing arm of the mTOR pathway. In particular, it is believed that LKB 1 is a negative regulator of the mTOR pathway under stress conditions, such as hypoxia and low glucose. LKB1 suppresses mTOR activity via its downsteam kinase, AMP-activated protein kinase (AMPK). In response to energy stress, LKB1 phosphorylates the AMPK catalytic subunit at T172 and this phosphorylation is essential for activation of AMPK. Activated AMPK phosphorylates TSC2 and raptor, and suppresses mTOR activity (Shackelford DB and Shaw JS, Nat. Rev Cancer 9:563 (2009)). Therefore, phosphorylation or activity of AMPK can be used as a marker for LKB1 status. In basal conditions, it is believed that loss of LKB1 and/or AMPK - 142 - WO 2013/019927 PCT/US2012/049281 can result in activation of the mTOR pathway. In cancer cells, under stress conditions, it is believed that the LKB1/AMPK pathway may actually play a protective role by causing cells to slow down their proliferation and thus evade apoptosis induced by the stress condition. However, it is believed that in LKB 1 mutant cancer cells (e.g., cells harboring a LKB 1 gene mutation resulting in a decrease in LKB 1 mRNA expression, a decrease in LKB 1 protein production or a non-functional LKB1 protein), in the absence of the negative signal to motor, the cancer cells continue to proliferate and undergo metabolic catastrophe. Accordingly, without being limited by theory, it is believed that TOR kinase inhibitors by their effects on cell metabolism cause a stress response in cancer cells and in LKB1 mutant cancer cells, and in the absence of a negative signal to slow the growth of the cells, result in cell death. Also without being limited by theory, it is believed that the expression levels of certain genes are characteristic of LKB1 gene or protein mutation or loss, such that measurement of the gene expression levels of a biological sample can be used to predict LKB1 status of the biological sample. [00356] Provided herein are methods for predicting the LKB 1 status of a patient or a biological sample, comprising the measurement of a predictive gene expression level. Without being limited by theory, it is believed that certain gene expression levels are characteristic of LKB1 gene and/or protein mutation and/or loss. [003571 Further provided herein are methods for treating or preventing a cancer, for example non-small cell lung carcinoma or cervical cancer, or treating a tumor syndrome, for example Peutz-Jeghers Syndrome, comprising administering an effective amount of a TOR kinase inhibitor to a patient having a cancer or a tumor syndrome characterized by a particular gene expression level, relative to that of wild type. [00358] Further provided herein are methods for treating or preventing a cancer, for example non-small cell lung carcinoma or cervical cancer, comprising screening a patient's cancer for the presence of a particular gene expression level relative to that of wild type and - 143 - WO 2013/019927 PCT/US2012/049281 administering an effective amount of a TOR kinase inhibitor to the patient having a cancer characterized by a particular gene expression level. Further provided herein are methods for predicting LKB 1 gene and/or protein loss and/or mutation in a patient's ("test patient") cancer, for example non-small cell lung carcinoma or cervical cancer, comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/ or protein loss and/or mutation, indicates an increased likelihood of an LKB 1 gene and/or protein loss and/or mutation in the patient's cancer. [003591 Further provided herein are methods for treating non-small cell lung carcinoma, cervical cancer or Peutz-Jeghers Syndrome, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma, cervical cancer or Peutz Jeghers Syndrome, wherein the gene expression level(s) of a biological test sample from said patient is characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [00360] Further provided are methods for treating non-small cell lung carcinoma or cervical cancer, comprising screening a patient's carcinoma or cancer for the presence of LKB1 gene and/or protein loss and/or mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma or cervical cancer characterized by a gene expression level(s) characterized by higher similarity to the gene - 144 - WO 2013/019927 PCT/US2012/049281 expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation than the gene expression level of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [00361] Further provided herein are methods for predicting response to treatment with a TOR kinase inhibitor in a patient, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of response to TOR kinase inhibitor treatment of said patient's cancer. [00362] Further provided herein are methods for predicting therapeutic efficacy of TOR kinase inhibitor treatment of a patient having cancer, for example non-small cell lung carcinoma or cervical cancer, with a TOR kinase inhibitor, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of therapeutic efficacy of said TOR kinase inhibitor treatment for said patient. - 145 - WO 2013/019927 PCT/US2012/049281 [003631 Further provided herein are methods screening a patient having cancer, for example non-small cell lung carcinoma or cervical cancer, for LKB1 gene and/or protein loss and/or mutation, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of LKB 1 gene and/or protein loss and/or mutation. [00364] Further provided herein are methods for treating a tumor syndrome, for example Peutz-Jeghers Syndrome, comprising comparing a patient's gene expression level(s) to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having Peutz-Jeghers Syndrome characterized by a gene expression level characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, than the gene expression level of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. [003651 Further provided are methods for treating a tumor syndrome, for example Peutz Jeghers Syndrome, comprising screening a patient for the presence of LKB 1 gene and/or protein loss and/or mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having a tumor syndrome characterized by a gene expression level characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, than the gene expression level of a wild type sample without LKB 1 gene and/or protein loss and/or mutation, and wherein the genes are selected from Table 1. - 146 - WO 2013/019927 PCT/US2012/049281 [003661 Further provided herein are methods for predicting LKB 1 gene and/or protein loss and/or mutation in a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of an LKB 1 gene and/or protein loss and/or mutation in the patient. [003671 Further provided herein are methods for predicting response to TOR kinase inhibitor therapy in a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of response to TOR kinase inhibitor treatment of said patient's tumor syndrome. [00368] Further provided herein are methods for predicting therapeutic efficacy of treatment of a patient having a tumor syndrome, for example, Peutz-Jeghers Syndrome, with a TOR kinase inhibitor, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said - 147 - WO 2013/019927 PCT/US2012/049281 biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood of therapeutic efficacy of said TOR kinase inhibitor treatment for said patient. [00369] Further provided herein are methods screening a patient having a tumor syndrome, for example Peutz-Jeghers Syndrome, for LKB1 gene and/or protein loss and/or mutation, comprising: a) obtaining a biological test sample from the patient; b) obtaining the gene expression level(s) of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level(s) to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation; wherein the gene expression level(s) of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation, indicates an increased likelihood for LKB 1 gene and/or protein loss and/or mutation. [003701 In certain embodiments provided herein, the gene expression level of the biological test sample is obtained using gene mRNA measurement. In certain of the methods and embodiments provided herein, the gene expression level of the biological test sample is obtained using RT-PCR or Affymetrix HGUl33plus2. In some embodiments, comparison of gene expression levels is performed using Prediction Analysis of Microarrays for R ("PAMR") (http://cran.r-project.org/web/packages/parnr/pamr.pdf). In some embodiments, similarity between gene expression level(s) of a biological test sample with wild-type samples and/or reference samples is determined using PAMR. - 148 - WO 2013/019927 PCT/US2012/049281 [003711 Further provided herein are kits comprising one or more containers filled with a TOR kinase inhibitor or a pharmaceutical composition thereof, reagents for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome and instructions for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome. In one embodiment, the measurement comprises measurement of the expression level(s) of one or more genes from Table 1. In one embodiment, the gene expression measurement instructions are RT-PCT or Affymetrix HGUl33plus2 instructions. In one embodiment, the kit further comprises instructions for comparing the expression levels to a set of reference levels that represent the gene expression levels of a biological wild-type sample without LKB 1 gene and/or protein loss and/or mutation, and the gene expression level of a reference sample with LKB 1 gene and/or protein loss and/or mutation. In one embodiment, the instructions for the comparison of expression levels are instructions for using PAMR. [00372] In one embodiment, the LKB1 gene mutation or loss results in a decrease in LKB1 mRNA expression (e.g., relative to wild type). In another embodiment, the LKB1 gene mutation or loss results in a change in LKB 1 mRNA structure (e.g., relative to wild type). In another embodiment, the LKB 1 gene mutation or loss results in a decrease in LKB 1 protein production (e.g., relative to wild type). In another embodiment, the LKB1 gene mutation or loss results in a change in LKB 1 protein structure (e.g., relative to wild type). Types of gene mutations contemplated include mutations of the LKB 1 DNA sequence in which the number of bases is altered, categorized as insertion or deletion mutations (frameshift mutations), and mutations of the DNA that change one base into another, categorized as missense mutations, which are subdivided into the classes of transitions (one purine to another purine, or one pyrimidine to another pyrimidine) and transversions (a purine to a pyrimidine, or a pyrimidine to a purine) and nonsense mutations, wherein a codon encoding an amino acid is changed to a stop codon, thus resulting in truncated protein. - 149 - WO 2013/019927 PCT/US2012/049281 [003731 In certain embodiments, the gene expression level(s), for example, in a biological test sample, as referenced herein is comprised of the expression level(s) of one or more of the genes set forth in Table 1. In a further embodiment, the gene expression level(s) does not include the expression level of IGF1R. [00374] In certain embodiments, the gene expression levels associated with LKB 1 gene and/or protein mutation and/or loss, for example in a biological test sample, are characterized by an upregulation of one or more genes indicated in Table 1 as having a negative Fold Change value and/or a downregulation of one or more genes in Table 1 as having a positive Fold Change value. [003751 In a particular embodiment, the gene expression levels associated with LKB1 gene and/or protein mutation and/or loss, for example, in a biological test sample, is characterized by upregulation of one or more of the following genes: scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin-like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 open reading frame 39; hypothetical gene supported by AK090616; R-spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II. [00376] In a particular embodiment, the gene expression levels associated with LKB1 gene and/or protein mutation and/or loss, for example, in a biological test sample, are characterized by downregulation of one or more of the following genes: chitinase 3-like 1 (cartilage glycoprotein-39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain. - 150 - WO 2013/019927 PCT/US2012/049281 [003771 In a particular embodiment, the gene expression levels associated with LKB1 gene and/or protein mutation and/or loss, for example in a biological test sample, are characterized by upregulation of one or more of the following genes: scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin-like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 open reading frame 39; hypothetical gene supported by AK090616; R-spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II, and further characterized by downregulation of one or more of the following genes: chitinase 3-like 1 (cartilage glycoprotein 39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC 100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain. [00378] In one embodiment, the gene expression levels associated with LKB1 gene and/or protein mutation and/or loss, for example in a biological test sample, are characterized by upregulation of one or more of the following genes: homogentisate 1,2-dioxygenase (homogentisate oxidase); ATP-binding cassette, sub-family C (CFTR/MRP), member 2; chromosome 12 open reading frame 39; fibrinogen beta chain; fibrinogen gamma chain; R spondin 3 homolog (Xenopus laevis); kynureninase (L-kynurenine hydrolase); carbamoyl phosphate synthetase 1, mitochondrial; SPARC related modular calcium binding 1; interleukin 1 receptor, type II; chromosome 6 open reading frame 176; neuronal PAS domain protein 2; chondroitin sulfate N-acetylgalactosaminyltransferase 1; insulin-like 4 (placenta); nitric oxide synthase trafficker; and phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila). In some embodiments, the gene expression levels associated with LKB 1 gene and/or protein mutation and/or loss, for example in a biological test sample, are - 151 - WO 2013/019927 PCT/US2012/049281 characterized by downregulation of one or more of the following genes: bone morphogenetic protein 4; and pentraxin-related gene, rapidly induced by IL-I beta. [003791 In certain embodiments, gene expression is upregulated by a factor of about 2, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120 or more relative to wild type. In certain embodiments, gene expression is downregulated by a factor of about 2, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120 or more relative to wild type. [00380] In certain embodiments, the cancer, for example non-small cell lung carcinoma or cervical cancer, or the tumor syndrome, for example Peutz-Jeghers Syndrome, results directly or indirectly from LKB 1 gene and/or protein loss and/or mutation, relative to that of wild type. [00381] In one embodiment, the LKB1 gene mutation is a somatic mutation. [00382] In one embodiment, a patient or a patient's cancer is screened for LKB1 gene and/or protein loss and/or mutation by obtaining a biological sample from said patient or said patient's cancer, and measuring the gene expression level(s) of said sample ex vivo. In certain embodiments, the ex vivo analysis is performed using microarray analysis or sequence based techniques, such as serial analysis of gene expression (SAGE or SuperSAGE). [00383] In certain of the methods and embodiments provided herein, the gene expression levels are measured using RT-PCR or Affymetrix HGUl33plus2. In some embodiments, the gene expression levels are compared to wild type gene expression levels using the statistical package Prediction Analysis of Microarrays for R ("PAMR"). In some embodiments, similarity between gene expression level(s) of a biological test sample with wild-type samples and/or reference samples is determined using PAMR. In certain embodiments, the gene expression level is comprised of the gene expression levels of one or more of the genes set forth in Table 1. - 152 - WO 2013/019927 PCT/US2012/049281 [003841 In certain of the methods and embodiments provided herein, the gene expression level(s) (such as those of Table 1) is correlated with increased likelihood of LKB1 gene and/or protein loss and/or mutation. [003851 A TOR kinase inhibitor can be combined with other pharmacologically active compounds ("second active agents") in methods and compositions described herein. It is believed that certain combinations may work in the treatment of particular types of diseases or disorders, and conditions and symptoms associated with such diseases or disorders. A TOR kinase inhibitor can also work to alleviate adverse effects associated with certain second active agents, and vice versa. [003861 One or more second active ingredients or agents can be used in the methods and compositions described herein. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). [003871 Examples of second active agents include, but are not limited to, agents that modulate AMP levels (e.g., an AMP activator), glucose uptake, metabolism or a stress response. In one embodiment, the second active agent is 2-deoxyglucose. In one embodiment, the second active agent is metformin. In one embodiment, the second active agent is phenformin. In another embodiment, the second active agent is pemetrexed (e.g., ALIMTA@). [003881 Administration of a TOR kinase inhibitor and one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A preferred route of administration for a TOR kinase inhibitor is oral. Preferred routes of administration for the second active agents or ingredients of the invention are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56th ed., 2002). - 153 - WO 2013/019927 PCT/US2012/049281 [003891 In one embodiment, a second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of a TOR kinase inhibitor and any optional additional active agents concurrently administered to the patient. [00390] Further provided herein are methods of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. TOR kinase inhibitors and other active ingredients can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy. 5.6 PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION [00391] Provided herein are compositions comprising an effective amount of a TOR kinase inhibitor and compositions comprising an effective amount of a TOR kinase inhibitor and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical composition described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration. [00392] The TOR kinase inhibitors can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, - 154 - WO 2013/019927 PCT/US2012/049281 gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the TOR kinase inhibitor in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration. [00393] The dose of a TOR kinase inhibitor to be administered to a patient is rather widely variable and can be patient to the judgment of a health-care practitioner. In general, the TOR kinase inhibitors can be administered one to four times a day in a dose of about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration. In one embodiment, the dose is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient's body weight, about 0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's body weight. In one embodiment, one dose is given per day. In any given case, the amount of the TOR kinase inhibitor administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration. - 155 - WO 2013/019927 PCT/US2012/049281 [003941 In another embodiment, provided herein are methods for the treatment or prevention of a disase or disorder comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of a TOR kinase inhibitor to a patient in need thereof. [003951 In another embodiment, provided herein are methods for the treatment or prevention of a disase or disorder comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of a TOR kinase inhibitor to a patient in need thereof. In a particular embodiment, the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of a TOR kinase inhibitor to a patient in need thereof. [00396] In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and about 2000 mg, about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a TOR kinase inhibitor. [003971 In a particular embodiment, provided herein are unit dosage formulation comprising about 100 mg or 400 mg of a TOR kinase inhibitor. [00398] In another embodiment, provided herein are unit dosage formulations that comprise 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a TOR kinase inhibitor. [00399] A TOR kinase inhibitor can be administered once, twice, three, four or more times daily. - 156 - WO 2013/019927 PCT/US2012/049281 [004001 A TOR kinase inhibitor can be administered orally for reasons of convenience. In one embodiment, when administered orally, a TOR kinase inhibitor is administered with a meal and water. In another embodiment, the TOR kinase inhibitor is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension. In another embodiment, when administered orally, a TOR kinase inhibitor is administered in a fasted state. [00401] The TOR kinase inhibitor can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition. [00402] In one embodiment, provided herein are capsules containing a TOR kinase inhibitor without an additional carrier, excipient or vehicle. [004031 In another embodiment, provided herein are compositions comprising an effective amount of a TOR kinase inhibitor and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In a further embodiment, provided herein are compositions comprising an effective amount of a TOR kinase inhibitor, and a pharmaceutically acceptable carrier or vehicle, and one or more agents that modulate AMP levels, glucose uptake, metabolism or a stress response. In one embodiment, the composition is a pharmaceutical composition. [00404] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in - 157 - WO 2013/019927 PCT/US2012/049281 pharmaceutical chemistry. Capsules can be prepared by mixing a TOR kinase inhibitor with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. [004051 Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. In one embodiment, the pharmaceutical composition is lactose-free. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders. [00406] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation. - 158 - WO 2013/019927 PCT/US2012/049281 [004071 When it is desired to administer a TOR kinase inhibitor as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use. [00408] The effect of the TOR kinase inhibitor can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the TOR kinase inhibitor can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the TOR kinase inhibitor in oily or emulsified vehicles that allow it to disperse slowly in the serum. 6. EXAMPLES 6.1 GENE EXPRESSION [00409] Gene expression analysis. 40 NSCLC cell lines were grouped into two groups, namely LKB 1 positive and LKB 1 negative cell lines based on quantified western measurements, wherein cell lines with LKB 1/Act protein ratio larger than 25 were classified as LKB1 positive, and cell lines with LKB 1/Act protein ratio less than 25 were classified as LKB1 negative. [00410] The free software R package PAMR was used, which implements "nearest shrunken centroids" (see: PNAS 99 (10): 6567-6572 (2002)) to identify subsets of genes that distinguish LKB1 positive from LKB1 negative NSCLC cell lines. PAMR selected 463 probes with 10-fold cross validation error at 22% (78% accuracy). After removing probes that had a small fold difference between the two groups (<1.5 fold), a 458-probe signature was obtained. Results are set forth in Table 1 and FIGS. 1-2. [00411] This experiment demonstrates that a particular gene expression level is associated with the loss of LKBl. - 159 - WO 2013/019927 PCT/US2012/049281 [004121 A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety. - 160 -

权利要求:
Claims (38)
[1] 1. A method for predicting LKB 1 gene or protein loss or mutation in a patient's cancer, comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level of one or more genes selected from Table 1 in said biological sample; c) comparing said gene expression level to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene or protein loss or mutation, and the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation; wherein the gene expression level of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation, indicates an increased likelihood of an LKB 1 gene or protein loss or mutation in the patient's cancer.
[2] 2. The method of claim 1, wherein the gene expression level of the biological test sample is obtained using gene mRNA measurement.
[3] 3. The method of claim 1, wherein the gene expression level of the biological test sample is obtained using RT-PCR or Affymetrix HGUl33plus2.
[4] 4. The method of claim 1, wherein the comparison of gene expression levels is performed using PAMR.
[5] 5. The method of claim 1, wherein the cancer is non-small cell lung carcinoma or cervical cancer. - 161 - WO 2013/019927 PCT/US2012/049281
[6] 6. The method of claim 1, wherein the gene expression level of the biological test sample is characterized by an upregulation of one or more genes in Table 1 as having a negative Fold Change value.
[7] 7. The method of claim 1, wherein the gene expression level of the biological test sample is characterized by a downregulation of one or more genes in Table 1 as having a positive Fold Change value.
[8] 8. The method of claim 1, wherein the gene expression level of the biological test sample is characterized by upregulation of one or more of the following genes: scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl-phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 open reading frame 39; hypothetical gene supported by AK090616; R-spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II.
[9] 9. The method of claim 1, wherein the gene expression level is characterized by downregulation of one or more of the following genes: chitinase 3-like 1 (cartilage glycoprotein 39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC 100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain.
[10] 10. A method for treating non-small cell lung carcinoma, cervical cancer or Peutz Jeghers Syndrome, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma, cervical cancer or Peutz-Jeghers Syndrome, wherein the gene expression level of a biological test sample from said patient is characterized - 162 - WO 2013/019927 PCT/US2012/049281 by higher similarity to the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation than the gene expression level of a wild type sample without LKB 1 gene or protein loss or mutation, and wherein the genes are selected from Table 1.
[11] 11. The method of claim 10, wherein the gene expression level of the biological test sample is obtained using gene mRNA measurement.
[12] 12. The method of claim 10, wherein the gene expression level of the biological test sample is obtained using RT-PCR or Affymetrix HGUl33plus2.
[13] 13. The method of claim 10, wherein the comparison of expression levels is performed using PAMR.
[14] 14. The method of claim 10, wherein the gene expression level of the biological test sample is characterized by an upregulation of one or more genes indicated in Table 1 as having a negative Fold Change value.
[15] 15. The method of claim 10, wherein the gene expression level of the biological test sample is characterized by a downregulation of one or more genes in Table 1 as having a positive Fold Change value.
[16] 16. The method of claim 10, wherein the gene expression level of the biological test sample is characterized by upregulation of one or more of the following genes: scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl-phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 - 163 - WO 2013/019927 PCT/US2012/049281 open reading frame 39; hypothetical gene supported by AK090616; R-spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II.
[17] 17. The method of claim 10, wherein the gene expression level of the biological test sample is characterized by downregulation of one or more of the following genes: chitinase 3 like 1 (cartilage glycoprotein-39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC 100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain.
[18] 18. A method for treating non-small cell lung carcinoma or cervical cancer, comprising screening a patient's carcinoma or cancer for the presence of LKB1 gene or protein loss or mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma or cervical cancer characterized by a gene expression level characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation than the gene expression level of a wild type sample without LKB 1 gene or protein loss or mutation, and wherein the genes are selected from Table 1.
[19] 19. The method of claim 18, wherein the gene expression level is obtained using gene mRNA measurement.
[20] 20. The method of claim 18, wherein the gene expression level is obtained using RT-PCR or Affymetrix HGU133plus2.
[21] 21. The method of claim 18, wherein the comparison of expression levels is performed using PAMR.
[22] 22. The method of claim 18, wherein the gene expression level of the patient's carcinoma or cancer is characterized by upregulation of one or more of the following genes: - 164 - WO 2013/019927 PCT/US2012/049281 scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin-like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl-phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 open reading frame 39; hypothetical gene supported by AK090616; R spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II.
[23] 23. The method of claim 18, wherein the gene expression level of the patient's carcinoma or cancer is characterized by downregulation of one or more of the following genes: chitinase 3-like 1 (cartilage glycoprotein-39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC 100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain.
[24] 24. A method for treating Peutz-Jeghers Syndrome, comprising comparing a patient's gene expression level to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having Peutz-Jeghers Syndrome characterized by a gene expression level characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation than the gene expression level of a wild type sample without LKB 1 gene or protein loss or mutation, and wherein the genes are selected from Table 1.
[25] 25. The method of claim 24, wherein the gene expression level is obtained using gene mRNA measurement.
[26] 26. The method of claim 24, wherein the gene expression level is obtained using RT-PCR or Affymetrix HGU133plus2. - 165 - WO 2013/019927 PCT/US2012/049281
[27] 27. The method of claim 24, wherein the comparison of gene expression levels is performed using PAMR.
[28] 28. The method of claim 24, wherein the patient's gene expression level is characterized by upregulation of one or more of the following genes: scavenger receptor class A, member 5 (putative); fibrinogen gamma chain; fibrinogen alpha chain; insulin-like 4 (placenta); organic solute transporter beta; phosphodiesterase 1A, calmodulin-dependent; carbamoyl phosphate synthetase 1, mitochondrial; frizzled homolog 10 (Drosophila); mucin 5AC, oligomeric mucus/gel-forming; trefoil factor 1; transient receptor potential cation channel, subfamily C, member 6; interleukin 1 receptor, type II; fibrinogen beta chain; chromosome 12 open reading frame 39; hypothetical gene supported by AK090616; R-spondin 3 homolog (Xenopus laevis); and interleukin 1 receptor, type II.
[29] 29. The method of claim 24, wherein the patient's gene expression level is characterized by downregulation of one or more of the following genes: chitinase 3-like 1 (cartilage glycoprotein-39); odz, odd Oz/ten-m homolog 2 (Drosophila); chemokine (C-C motif) ligand 5; bone morphogenetic protein 4; calcyphosine; Uncharacterized protein LOC100131897; and CD74 molecule, major histocompatibility complex, class II invariant chain.
[30] 30. A method of predicting response to treatment with a TOR kinase inhibitor in a patient having cancer, the method comprising: a) obtaining a biological test sample from the patient's cancer; b) obtaining the gene expression level of one or more genes selected from Table 1 in said biological test sample; c) comparing said gene expression level to a set of reference levels that represent the gene expression level of a biological wild-type sample without LKB 1 gene or protein loss or - 166 - WO 2013/019927 PCT/US2012/049281 mutation and the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation; wherein the gene expression level of the biological test sample characterized by higher similarity to the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation, indicates an increased likelihood of response to TOR kinase inhibitor treatment of said patient's cancer.
[31] 31. The method of claim 30, wherein the gene expression level of the biological test sample is obtained using gene mRNA measurement.
[32] 32. The method of claim 30, wherein the gene expression level of the biological test sample is obtained using RT-PCR or Affymetrix HGUl33plus2.
[33] 33. The method of claim 30, wherein the comparison of gene expression levels is performed using PAMR.
[34] 34. A kit comprising one or more containers filled with a TOR kinase inhibitor or a pharmaceutical composition thereof, reagents for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome and instructions for measuring gene expression levels of a patient's cancer or of a patient having a tumor syndrome.
[35] 35. The kit of of claim 34, wherein the measurement comprises measurement of the expression level one or more genes from Table 1.
[36] 36. The kit of claim 34, wherein the gene expression measurement instructions are RT-PCT or Affymetrix HGUl33plus2 instructions.
[37] 37. The kit of claim 35, further comprising instructions for comparing the expression levels to a set of reference levels that represent the gene expression levels of a biological wild - 167 - WO 2013/019927 PCT/US2012/049281 type sample without LKB 1 gene or protein loss or mutation and the gene expression level of a reference sample with LKB 1 gene or protein loss or mutation.
[38] 38. The kit of claim 37, wherein the instructions for the comparison of expression levels are instructions for using PAMR. - 168 -

类似技术:

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AU2012290056B2|2015-03-19|Identification of gene expression profile as a predictive biomarker for LKB1 status

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同族专利:

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CA2843887A1|2013-02-07|

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法律状态:
2015-07-16| FGA| Letters patent sealed or granted (standard patent)|

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2019-02-28| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US201161514798P| true| 2011-08-03|2011-08-03||

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US61/514,798||2011-08-03||

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PCT/US2012/049281|WO2013019927A1|2011-08-03|2012-08-02|Identification of gene expression profile as a predictive biomarker for lkb1 status|

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