WO2011097333A1 - Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors - Google Patents
Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors Download PDFInfo
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- WO2011097333A1 WO2011097333A1 PCT/US2011/023524 US2011023524W WO2011097333A1 WO 2011097333 A1 WO2011097333 A1 WO 2011097333A1 US 2011023524 W US2011023524 W US 2011023524W WO 2011097333 A1 WO2011097333 A1 WO 2011097333A1
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- 0 *N(c1nc(II)cnc1O1)C1=O Chemical compound *N(c1nc(II)cnc1O1)C1=O 0.000 description 1
- FPEIJQLXFHKLJV-UHFFFAOYSA-N C(c1cnccc1)N(CC1)CCC1[n]1ncc2c(N3CCOCC3)nc(-c(cc3)cc4c3[nH]cc4)nc12 Chemical compound C(c1cnccc1)N(CC1)CCC1[n]1ncc2c(N3CCOCC3)nc(-c(cc3)cc4c3[nH]cc4)nc12 FPEIJQLXFHKLJV-UHFFFAOYSA-N 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N CC(C)(c(cc1)ccc1N(c(c(cc(cc1)-c2cc(cccc3)c3nc2)c1nc1)c1N1C)C1=O)C#N Chemical compound CC(C)(c(cc1)ccc1N(c(c(cc(cc1)-c2cc(cccc3)c3nc2)c1nc1)c1N1C)C1=O)C#N JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57411—Specifically defined cancers of cervix
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- TOR kinase inhibitor 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 a LKBl and/or AMPK gene or protein loss or mutation.
- 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
- 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).
- tyrosine kinases include receptor tyrosine kinases (RTKs), such as growth factors and nonreceptor tyrosine kinases, such as the src kinase family.
- RTKs receptor tyrosine kinases
- CDKs cyclin dependent kinases
- MAPKs mitogen-activated protein kinases
- 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.
- 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.
- Protein kinases have become attractive targets for the treatment of cancers.
- genomic rearrangements ⁇ e.g., BCR-ABL in chronic myelogenous leukemia
- mutations leading to constitutively active kinase activity such as acute myelogenous
- mTOR mammalian target of rapamycin
- FRAP FRAP
- RAFTI or RAPTl is a 2549-amino acid Ser/Thr protein kinase, that has been shown to be one of the most critical proteins in the mTOR/PBK/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, mTORCl and mTORC2. While mTORCl is sensitive to rapamycin analogs (such as temsirolimus or everolimus), mTORC2 is largely rapamycin- insensitive. Notably, rapamycin is not a TOR kinase inhibitor.
- 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 inhibitors. In addition, sirolimus was approved in 1999 for the prophylaxis of renal transplant rejection.
- the interesting but limited clinical success of these mTORCl inhibitory compounds demonstrates the usefulness of mTOR inhibitors in the treatment of cancer and transplant rejection, and the increased potential for compounds with both mTORCl and mTORC2 inhibitory activity.
- a cancer for example non- small cell lung carcinoma or cervical cancer
- a tumor syndrome for example Koz- Jeghers Syndrome
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for treating or preventing a cancer comprising screening a patient's cancer for the presence of LKB 1 gene or protein loss or mutation relative to that of a control patient or wild type and administering an effective amount of a TOR kinase inhibitor to the patient having a cancer characterized by the LKB1 gene or protein loss or mutation.
- test patient for example non-small cell lung carcinoma or cervical cancer
- methods for detecting LKB1 gene or protein loss or mutation in a patient's (“test patient”) cancer comprising: obtaining a biological sample from the test patient's cancer;
- measuring one or more of the level of LKB 1 mRNA expression, the level of LKB 1 protein expression, determining the methylation status of the LKB1 gene or otherwise identifying the presence of gene or protein loss or mutation e.g., by direct cDNA or exon DNA sequencing or SNP analysis or multiple ligation probe amplification (MLPA) to identify copy number loss, or immunohistochemistry (IHC), immunofluorescence (IF) or Western Blot to determine loss of protein); and comparing said measurement with a control measurement from a patient's ("control patient") cancer which is not characterized by a LKB l gene or protein loss or mutation (wild type); wherein a change in LKB l mRNA expression, LKBl protein expression, LKBl mRNA structure, LKBl gene methylation status and/or LKBl protein structure in the biological sample from the test patient, relative to that of the control patient or wild-type, indicates the presence of LKBl gene or protein loss or mutation in the test patient's cancer.
- control patient a patient'
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for predicting the likelihood of a patient having a cancer comprising screening said patient's cancer for the presence of a LKBl gene or protein loss or mutation relative to that of a control patient or wild type, wherein the presence of LKBl gene or protein loss or mutation predicts an increased likelihood that TOR kinase inhibitor therapy will treat said cancer.
- a patient having cancer for example non-small cell lung carcinoma or cervical cancer
- a TOR kinase inhibitor comprising screening said patient's cancer for the presence of LKBl gene or protein loss or mutation relative to that of a control patient or wild type, wherein the presence of LKBl gene or protein loss or mutation in the patient's cancer is predictive of therapeutic efficacy of treatment with a TOR kinase inhibitor.
- a TOR kinase inhibitor comprising screening the patient for the presence of a LKBl gene or protein loss or mutation relative to that of a control patient or wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having the LKB 1 gene or protein loss or mutation.
- Syndrome comprising: obtaining a biological sample from the test patient; measuring one or more of the level of LKBl mRNA expression, the level of LKBl protein expression, determining the methylation status of the LKBl gene or otherwise identifying the presence of gene or protein loss or mutation (e.g. , by direct cDNA or exon DNA sequencing or SNP analysis or multiple ligation probe amplification (MLPA) to identify copy number loss, or immunohistochemistry
- IHC immunofluorescence
- IF immunofluorescence
- Western Blot to determine loss of protein
- LKBl gene or protein loss or mutation wild type
- a change in LKBl mRNA expression, LKBl protein expression, LKBl mRNA structure, LKBl gene methylation status and/or LKBl protein structure in the biological sample from the test patient, relative to that of the control patient or wild-type indicates the presence of LKBl gene or protein loss or mutation in the test patient.
- a tumor syndrome for example Koz-Jeghers Syndrome
- methods for predicting the likelihood of a patient having a tumor syndrome comprising screening said patient for the presence of LKBl gene or protein loss or mutation relative to that of a control patient or wild type, wherein the presence of LKBl gene or protein loss or mutation predicts an increased likelihood that TOR kinase inhibitor therapy will treat said tumor syndrome.
- a tumor syndrome for example Koz-Jeghers Syndrome
- a TOR kinase inhibitor comprising screening said patient for the presence of LKBl gene or protein loss or mutation relative to that of a control patient or wild type, wherein the presence of LKBl gene or protein loss or mutation in the patient is predictive of therapeutic efficacy of treatment with a TOR kinase inhibitor.
- a cancer for example non- small cell lung carcinoma or cervical cancer
- a tumor syndrome for example Kozapos syndrome
- a cancer for example non- small cell lung carcinoma or cervical cancer
- a tumor syndrome for example Koz- Jeghers Syndrome
- pAMPK phospho-AMPK
- the pAMPK is pAMPK T172.
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for treating or preventing a cancer comprising screening a patient's cancer for the presence of AMPK gene or protein loss or mutation relative to that of a control patient or wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having a cancer characterized by the AMPK gene or protein loss or mutation.
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for treating or preventing a cancer comprising screening a patient's cancer for the presence of a reduced level of pAMPK protein and/or AMPK activity relative to that of a control patient or wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having a cancer characterized by a reduced level of pAMPK protein and/or AMPK activity.
- the pAMPK is pAMPK T172.
- test patient for example non-small cell lung carcinoma or cervical cancer
- methods for detecting AMPK gene or protein loss or mutation in a patient's (“test patient”) cancer comprising: obtaining a biological sample from the test patient's cancer;
- AMPK mRNA expression e.g., by direct cDNA or exon DNA sequencing or SNP analysis or multiple ligation probe amplification (MLPA) to identify copy number loss, or immunohistochemistry (IHC), immunofluorescence (IF), or Western Blot to determine loss of protein); and comparing said measurement with a control measurement from a patient's ("control patient") cancer which is not characterized by a AMPK gene or protein or mutation (wild type); wherein a change in AMPK mRNA expression, AMPK protein expression, AMPK mRNA structure, AMPK gene methylation, and/or AMPK protein structure in the biological sample from the test patient, relative to that of a control patient or wild type, indicates the presence of AMPK gene or protein loss or mutation in the test patient's cancer.
- control patient a patient's
- test patient a patient's (“test patient") cancer
- test patient for example non-small cell lung carcinoma or cervical cancer
- obtaining a biological sample from the test patient's cancer comprising: obtaining a biological sample from the test patient's cancer; measuring one or more of the level of, pAMPK protein expression, the level of
- AMPK activity or otherwise measuring the level of pAMPK protein (e.g.,
- IHC immunohistochemistry
- IF immunofluorescence
- Western Blot to determine the amount of pAMPK protein or the amount of phosphorylation of AMPK at specific sites, for example at the T172 site), and/or the level of AMPK activity (e.g. AMPK kinase assay, see Sanders et al. Biochem.J.
- control patient a patient's
- AMPK activity wild type
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for predicting the likelihood of a patient having a cancer comprising screening said patient's cancer for the presence of a AMPK gene or protein loss or mutation, relative to that of a control patient or wild type, wherein the presence of AMPK gene or protein loss or mutation predicts an increased likelihood that TOR kinase inhibitor therapy will treat said cancer.
- a cancer for example non-small cell lung carcinoma or cervical cancer
- methods for predicting the likelihood of a patient having a cancer comprising screening said patient's cancer for the presence of a reduced level of pAMPK protein and/or AMPK activity relative to that of a control patient or wild type, wherein the presence of a reduced level of pAMPK protein and/or AMPK activity predicts an increased likelihood that TOR kinase inhibitor therapy will treat said cancer.
- a patient having cancer for example non-small cell lung carcinoma or cervical cancer
- a TOR kinase inhibitor comprising screening said patient's cancer for the presence of AMPK gene or protein loss or mutation relative to that of a control patient or wild type, wherein the presence of AMPK gene or protein loss in the patient's cancer is predictive of therapeutic efficacy of treatment with a TOR kinase inhibitor.
- a patient having cancer for example non-small cell lung carcinoma or cervical cancer
- a TOR kinase inhibitor comprising screening said patient's cancer for the presence of a reduced level of pAMPK protein and/or AMPK activity relative to that of a control patient or wild type, wherein the presence a reduced level of pAMPK protein and/or AMPK activity in the patient's cancer is predictive of therapeutic efficacy of treatment with a TOR kinase inhibitor.
- cancer for example non-small cell lung carcinoma or cervical cancer
- a tumor syndrome for example Koz-Jeghers Syndrome
- administering an effective amount of a TOR kinase inhibitor and an effective amount of one or more agents that modulate AMP levels, glucose uptake, metabolism or a stress response to a patient having cancer or a tumor syndrome.
- compositions comprising one or more
- TOR kinase inhibitors and one or more agents that modulate AMP levels, glucose uptake, metabolism or a stress response and a pharmaceutically acceptable carrier, excipient or diluent.
- kits comprising one or more containers filled with a
- TOR kinase inhibitor or a pharmaceutical composition thereof reagents for detecting LKBl gene or protein loss or mutation, or AMPK gene or protein loss or mutation, or both, in a patient's cancer or in a patient having a tumor syndrome and instructions for detecting LKBl gene or protein loss or mutation, or AMPK gene or protein loss or mutation, or both, in a patient's cancer or in a patient having a tumor syndrome.
- kits comprising one or more containers filled with a
- TOR kinase inhibitor or a pharmaceutical composition thereof reagents for detecting a reduced level of pAMPK protein and/or AMPK activity in a patient's cancer or in a patient having a tumor syndrome, and instructions for detecting a reduced level of pAMPK protein and/or AMPK activity in a patient's cancer or in a patient having a tumor syndrome.
- the TOR kinase inhibitor is a compound as described herein.
- FIG 1A Figure 1 lists the LKBl mutation status of non small cell lung cancer
- NSCLC NSCLC cell lines
- FIG IB Figure IB illustrates a LI-COR Western blot showing LKBl protein levels across the panel of NSCLC cell lines from Fig. 1 A. The experiment confirms lack of LKBl protein for lines reported as LKBl gene mutants.
- FIG 2C Figure 2C illustrates the application of the Fisher test and Wilcoxon test to analyze the correlation between Compound 1 sensitivity (defined as IC 50 ⁇ 5 ⁇ ) and the presence or absence of intact LKBl protein (as determined by Western immunoblotting). The resulting p-values indicate that cell lines without intact LKB 1 protein are more sensitive to Compound 1.
- FIG 3A Figure 3A illustrates a LI-COR Western blot showing phospho- AMPK
- T172, AMPK, LKBl, and actin levels from selected NSCLC cell lines are correlated to p AMPK T 172 levels except for HI 437.
- FIG 3B Figure 3B illustrates the result of the application of the Wilcoxon test to analyze the correlation between LKBl status and pAMPK/actin ratio in forty-two NSCLC cell lines.
- LKBl status was defined as either negative or positive based on Western immunoblotting.
- the y-axis is Logio of pAMPK/actin ratio.
- alkyl group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 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 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.
- An alkyl group can be substituted or unsubstituted.
- alkyl groups described herein when they 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;
- 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 -Cg)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-l-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
- 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.
- 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.
- substituted cycloalkyl groups include, by way of example, cyclohexanone and the like.
- 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).
- 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.
- 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.
- 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-l,3-diimine), indolyl, azaindolyl (for example, pyrrolopyridyl or 1H- pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (for example, lH-benzo[d]imidazolyl), imidazopyridyl (for example, azabenzimidazolyl, 3H-imidazo[4,5-b
- 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 O, S and N.
- heterocyclyl groups include 3 to 10 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.
- heterocyclyl includes fused ring species, including those comprising fused aromatic and non- aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl.
- the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
- heterocyclyl group examples 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
- 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.
- cycloalkylalkyl 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.
- 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.
- heterocyclylalkyl 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,
- halogen is fluorine, chlorine, bromine or iodine.
- a "hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
- alkoxy is -O-(alkyl), wherein alkyl is defined above.
- alkoxyalkyl is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
- amino group is a radical of the formula: -NH 2 .
- alkylamino is a radical of the formula: -NH-alkyl or -N(alkyl) 2 , wherein each alkyl is independently as defined above.
- a "carboxy” group is a radical of the formula: -C(0)OH.
- aminocarbonyl is a radical of the formula: -C(0)N(R ) 2 ,
- each R is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.
- acylamino is a radical of the formula: -NHC(0)(R ) or
- alkylsulfonylamino is a radical of the formula: -NHS0 2 (R ) or
- a "urea” group is a radical of the formula: -N(alkyl)C(0)N(R ) 2 ,
- substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl;
- 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,
- 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.
- 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, ⁇ , ⁇ '-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
- methanesulfonic acids examples include hydrochloride and mesylate salts.
- Others are well-known in the art, see for example, Remington 's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).
- 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.
- 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.
- 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.
- 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.
- 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,
- 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 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.
- stereomerically pure means one stereoisomer of a TOR kinase inhibitor that is substantially free of other stereoisomers of that compound.
- 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.
- 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.
- the TOR kinase inhibitors can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
- 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.
- 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: [0073] 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.
- the TOR kinase inhibitors can contain unnatural proportions of atomic isotopes at one or more of the atoms.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon- 13 ( 13 C), or nitrogen- 15 ( 15 N).
- an "isotopologue" is an isotopically enriched compound.
- 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.
- isotopic composition refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched 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.
- 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.
- isotopologues of the TOR kinase inhibitors for example, the isotopologues are deuterium, carbon- 13, or nitrogen- 15 enriched TOR kinase inhibitors.
- Treating 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.
- a disorder or disease e.g., cancer or a tumor syndrome
- Preventing 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.
- an TOR kinase inhibitor 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
- 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.
- 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.
- 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.
- 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.
- wild type refers to the typical sequence of LKB1 gene or protein or AMPK gene or protein, or the typical level of LKB1 gene or protein, AMPK gene or protein, pAMPK protein, or AMPK activity, as it most commonly occurs in nature.
- a "control patient”, as used herein, is a patient who possesses the wild type characteristics (presence, sequence, level, activity) for LKBl and/or AMPK.
- LKBl gene or protein mutation refers to, for example, a LKBl gene mutation resulting in a decrease in LKBl mRNA expression, a decrease in LKBl protein production or a non- functional LKBl protein, as compared to wild type.
- LKBl gene or protein loss refers to a reduced level of LKBl protein or the absence of LKBl protein, as compared to wild type levels.
- AMPK activity refers to the activity of AMP-activated protein kinase. As understood by one skilled in the art, AMPK requires activation by phosphorylation to exert its kinase activity. In the context of AMPK activity, it is understood that AMPK activity and pAMPK activity can be used interchangeably.
- 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.
- a "patient” or “subject” is a human whose cancer DNA comprises a LKBl and/or an AMPK gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human whose cancer DNA contains a
- a "patient” or “subject” is a human whose cancer DNA comprises a LKBl and/or an AMPK gene mutation and a KRAS gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human having a cancer, for example non-small cell lung carcinoma or cervical cancer, characterized by LKBl and/or AMPK gene or protein loss or mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human having a cancer, for example non-small cell lung carcinoma or cervical cancer, characterized by LKBl and/or AMPK gene or protein loss or mutation and a KRAS gene mutation, relative to that of a control patient or wild type.
- a cancer for example non-small cell lung carcinoma or cervical cancer, characterized by LKBl and/or AMPK gene or protein loss or mutation and a KRAS gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human whose DNA comprises a LKBl and/or an AMPK gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human whose DNA contains a LKBl and/or an AMPK gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human whose DNA comprises a LKBl and/or an AMPK gene mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human whose DNA comprises a LKBl and/or an
- AMPK gene mutation and a KRAS gene mutation relative to that of a control patient or wild type.
- a "patient” or “subject” is a human having LKBl and/or AMPK gene or protein loss or mutation, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human having LKBl and/or AMPK gene or protein loss or mutation, relative to that of a control patient or wild type, and also having a tumor syndrome, for example 22, Zaz-Jeghers Syndrome.
- a "patient” or “subject” is a human having LKB1 and/or AMPK gene or protein loss or mutation and a KRAS gene mutation, relative to that of a control patient or wild type, wherein said human also has a tumor syndrome, for example Koz-Jeghers Syndrome.
- a "patient” or “subject” is a human having a cancer, for example non-small cell lung carcinoma or cervical cancer, characterized by a reduced level of pAMPK protein and/or AMPK activity, relative to that of a control patient or wild type.
- a "patient” or “subject” is a human having a cancer, for example non-small cell lung carcinoma or cervical cancer, characterized by a reduced level of pAMPK protein and/or AMPK activity and a KRAS gene mutation, relative to that of a control patient or wild type.
- the pAMPK is pAMPK T172.
- a "patient” or “subject” is a human having a reduced level of pAMPK protein and/or AMPK activity, relative to that of a control patient or wild type, and also having a tumor syndrome, for example Koz-Jeghers Syndrome.
- a "patient” or “subject” is a reduced level of pAMPK protein and/or AMPK activity and a KRAS gene mutation, relative to that of a control patient or wild type , wherein said human also has a tumor syndrome, for example Koz-Jeghers Syndrome.
- the pAMPK is pAMPK T172.
- 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
- 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. 6.2 TOR KINASE INHIBITORS
- TOR kinase inhibitors are generally referred to as TOR kinase inhibitors or "TORKi.”
- the TORKi do not include rapamycin or rapamycin analogs (rapalogs).
- compounds provided herein are also DNA-PK inhbitors or "DNA-PKi.”
- the TOR kinase inhibitors include compounds having the following formula (I):
- X, Y and Z are at each occurrence independently N or CR 3 , wherein at least one of X, Y and Z is N and at least one of X, Y and Z is CR 3 ;
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl;
- R 2 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 is H, substituted or unsubstituted Ci.galkyl, 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 Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (I) are those wherein -
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -C(0)CH 2 NH-.
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -C(0)NH-.
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -CH 2 C(0)0-.
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -C(0)CH 2 0-.
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -C(0)0-.
- the TOR kinase inhibitors of formula are those wherein -A-B-Q- taken together form -C(0)NR 3 -.
- the TOR kinase inhibitors of formula are those wherein Y is CR 3 .
- the TOR kinase inhibitors of formula are those wherein X and Z are N and Y is CR 3 .
- the TOR kinase inhibitors of formula are those wherein X and Z are N and Y is CH.
- the TOR kinase inhibitors of formula are those wherein X and Z are CH and Y is N.
- the TOR kinase inhibitors of formula are those wherein Y and Z are CH and X is N.
- the TOR kinase inhibitors of formula are those wherein X and Y are CH and Z is N.
- the TOR kinase inhibitors of formula (I) are those wherein R 1 is substituted aryl, such as substituted phenyl.
- 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.
- 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.
- 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.
- the TOR kinase inhibitors of formula (I) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is Ci_ 4 alkyl substituted with substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (I) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (I) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(0)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 Ci_galkyl.
- the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(0)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 Ci_galkyl.
- the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(0)NH-, X and Z are N and Y is CH, R 1 is substituted or unsubstituted aryl, and R 2 is Ci_ 8 alkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(0)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
- the TOR kinase inhibitors of formula (I) are those wherein -A-B-Q- taken together form -C(0)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 Ci_galkyl.
- 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(0)NH-, L is a direct bond,
- R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
- R 2 is Ci_
- 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(0)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 Ci_ 8 alkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
- 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(0)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 Ci_ 4 alkyl, amino, aminoCi_ i 2 alkyl, halogen, hydroxy, hydroxyCi_ 4 alkyl, Ci_ 4 alkyloxyCi_ 4 alkyl, -CF 3 , Ci_i 2 alkoxy, aryloxy, arylCi_i 2 alkoxy, -CN, -OCF 3 , -COR g , -COOR g , -CONR g R h , -NR g COR h , -S0 2 R g , -S0
- Ci_ 6 alkyl independently selected from the group consisting of Ci_ 6 alkyl, amino, aminoCi_i 2 alkyl, halogen, hydroxy, hydroxyCi_ 4 alkyl, Ci_ 4 alkyloxyCi_ 4 alkyl, Ci_i 2 alkoxy, aryloxy, aryl Ci_i 2 alkoxy, -CN, - CF 3 , -OCF 3 , -CORi, -COORi, -CONRiR j , -NRiCOR j , -NRiS0 2 R j , -S0 2 Ri, -S0 3 Ri Or -S0 2 NRiR j , wherein each Ri and R j are independently selected from the group consisting of hydrogen, Ci_ 4 alkyl, C 3 _ 6 cycloalkyl, aryl, arylCi_ 6 alkyl, heteroaryl or heteroarylCi_ 6 alkyl; or A is a 8- to
- 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(0)NH-, L is a direct bond, R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R 2 is substituted or unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or an acetamide.
- 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(0)NH-, L is a direct bond, R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R 2 is an acetamide.
- 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(0)NH-, L is a direct bond, R 1 is a (2,5'-Bi-lH-benzimidazole)-5-carboxamide, and R 2 is H.
- 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(0)NH-, L is a direct bond, R 1 is unsubstituted pyridine, and R 2 is H, methyl or substituted ethyl.
- 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(0)NH-, R 1 is H, Ci_ 8 alkyl, C 2 - 8 alkenyl, aryl or cycloalkyl, and L is NH.
- 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(0)NR 3 -, R 2 is H, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl, and L is NH.
- the TOR kinase inhibitors of formula (I) do not include compounds wherein R 1 is a substituted or unsubstituted oxazolidinone.
- the TOR kinase inhibitors of formula (I) do not include one or more of the following compounds: l,7-dihydro-2-phenyl-8H-Purin-8-one, l,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-(l,3-benzodioxol-5-yl)-l,3-dihydro-l-[(lS)-l-phenylethyl]- 2H-Imidazo[4,5- b]pyrazin-2-one, 3-[2,3-dihydro-2-oxo-3-(4-pyridinylmethyl)-lH-imidazo[4,5-b]pyrazin-5-yl]-
- the TOR kinase inhibitors include compounds having the following formula (la):
- L is a direct bond, NH or O
- Y is N or CR 3 ;
- R 1 is H, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl;
- R 2 is H, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 is H, substituted or unsubstituted Ci_galkyl, 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 Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (la) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
- the TOR kinase inhibitors of formula (la) 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.
- 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.
- the TOR kinase inhibitors of formula (la) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (la) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (la) are those wherein Y is CH. [00141] In another embodiment, the TOR kinase inhibitors of formula (la) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (la) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci.galkyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci_ 8 alkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- the TOR kinase inhibitors of formula (la) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (la) 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 Ci.galkyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
- the TOR kinase inhibitors include compounds having the following formula (lb):
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and R 2 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (lb) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
- the TOR kinase inhibitors of formula (lb) 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.
- 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.
- the TOR kinase inhibitors of formula (lb) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (lb) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (lb) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (lb) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (lb) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci_galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- the TOR kinase inhibitors of formula (lb) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors include compounds having the following formula (Ic):
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and
- R 2 is H, substituted or unsubstituted Ci_galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- 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.
- 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.
- 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.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (Ic) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci.galkyl.
- the TOR kinase inhibitors of formula (Ic) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci.galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- 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.
- the TOR kinase inhibitors include compounds having the following formula (Id):
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and
- R 2 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Id) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- 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.
- 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.
- 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.
- the TOR kinase inhibitors of formula (Id) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (Id) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (Id) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Id) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (Id) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the Heteroaryl Compounds of formula (Id) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (Id) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (Id) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci.galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- 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.
- the TOR kinase inhibitors include compounds having the following formula (Ie):
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and
- R 2 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 1 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
- the TOR kinase inhibitors of formula (Ie) 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.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (Ie) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (Ie) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci.galkyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci.galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ie) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors include compounds having the following formula (If):
- L is a direct bond, NH or O
- R 1 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl; and
- R 2 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (If) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- 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.
- 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.
- the TOR kinase inhibitors of formula (If) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (If) are those wherein R 2 is substituted Ci.galkyl.
- the TOR kinase inhibitors of formula (If) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (If) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (If) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (If) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (If) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci.galkyl.
- the TOR kinase inhibitors of formula (If) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci.galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- 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.
- the TOR kinase inhibitors include compounds having the following formula (Ig):
- L is a direct bond, NH or O;
- R 1 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted C 2 _ 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl;
- R 2 is H, substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ig) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- 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.
- 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.
- 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.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is H.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 2 is substituted Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 2 is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 2 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted
- the TOR kinase inhibitors of formula (Ig) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 2 is H.
- the TOR kinase inhibitors of formula (Ig) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is unsubstituted Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (Ig) are those wherein R 1 is substituted or unsubstituted aryl and R 2 is Ci.galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
- 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.
- Representative TOR kinase inhibitors of formula (I) include:
- the TOR kinase inhibitors include compounds having the following formula (II):
- substituted or unsubstituted heteroaryl substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- L is a direct bond, NH or O
- R 2 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 and R 4 are independently H or Ci_galkyl.
- the TOR kinase inhibitors of formula (II) are those wherein -
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)CH 2 NH-.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH-.
- the TOR kinase inhibitors of formula (II) are those wherein L is a direct bond.
- the TOR kinase inhibitors of formula (II) are those wherein R 1 is substituted aryl, such as substituted phenyl.
- 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.
- the TOR kinase inhibitors of formula (II) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH- and R 1 is substituted aryl, such as phenyl.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH- and R 1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH- and R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is substituted Ci.galkyl, such as -CH 2 C 6 H 5 .
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is unsubstituted Ci.galkyl, such as unsubstituted methyl.
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl.
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
- the TOR kinase inhibitors of formula (II) are those wherein R 2 is substituted heterocyclylalkyl, such as substituted piperidine.
- the TOR kinase inhibitors of formula (II) are those wherein R 3 and R 4 are H.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH- and R 2 is unsubstituted aryl, such as unsubstituted phenyl.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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 R 3 and R 4 are H.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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 R 3 and R 4 are H.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)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 R 4 are H.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH-, R 1 is substituted or unsubstituted heteroaryl, L is a direct bond and R 2 is substituted or unsubstituted Ci_ 8 alkyl or substituted or unsubstituted cycloalkyl.
- the TOR kinase inhibitors of formula (II) are those wherein -X-A-B-Y- taken together form -N(R 2 )C(0)NH-, R 1 is substituted or unsubstituted aryl, L is a direct bond and R 2 is substituted or unsubstituted Ci_ 8 alkyl or substituted or unsubstituted cycloalkyl.
- the TOR kinase inhibitors of formula (II) do not include
- the TOR kinase inhibitors of formula (II) do not include compounds wherein R 2 is a substituted furanoside.
- the TOR kinase inhibitors of formula (II) do not include compounds wherein R 2 is a substituted or unsubstituted furanoside.
- the TOR kinase inhibitors of formula (II) do not include
- the TOR kinase inhibitors include compounds having the following formula (II a):
- R 1 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 2 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 and R 4 are independently H or Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein
- R 1 is substituted aryl, substituted or unsubstituted heteroaryl, such as substituted phenyl.
- 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.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is substituted Ci.galkyl, such as -CH 2 C 6 H 5 .
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is unsubstituted Ci_ 8 alkyl, such as unsubstituted methyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 2 is substituted heterocyclylalkyl, such as substituted piperidine.
- the TOR kinase inhibitors of formula (Ila) are those wherein R 3 and R 4 are H.
- the TOR kinase inhibitors of formula (Ila) do not include
- the TOR kinase inhibitors of formula (Ila) do not include compounds wherein R 2 is a substituted furanoside.
- the TOR kinase inhibitors of formula (Ila) do not include compounds wherein R 2 is a substituted or unsubstituted furanoside.
- the TOR kinase inhibitors of formula (Ila) do not include
- the TOR kinase inhibitors include compounds having the following formula (lib):
- R 1 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 2 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 and R 4 are independently H or Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (lib) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (lib) 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.
- the TOR kinase inhibitors of formula (lib) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is substituted Ci.galkyl, such as -CH 2 C 6 H 5 .
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is unsubstituted Ci_ 8 alkyl, such as unsubstituted methyl.
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl.
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
- the TOR kinase inhibitors of formula (lib) are those wherein R 2 is substituted heterocyclylalkyl, such as substituted piperidine.
- the TOR kinase inhibitors of formula (lib) are those wherein R 3 and R 4 are H.
- the TOR kinase inhibitors of formula (lib) are those wherein R 1 is substituted aryl, such as phenyl, and R 2 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (lib) do not include
- the TOR kinase inhibitors of formula (lib) do not include compounds wherein R 2 is substituted cyclopentyl or a heterocyclopentyl when
- the TOR kinase inhibitors include compounds having the following formula (He):
- R 1 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 2 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 and R 4 are independently H or Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (lie) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (lie) 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.
- the TOR kinase inhibitors of formula (lie) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is substituted Ci.galkyl, such as -CH 2 C 6 H 5 .
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is unsubstituted Ci_ 8 alkyl, such as unsubstituted methyl.
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl.
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
- the TOR kinase inhibitors of formula (lie) are those wherein R 2 is substituted heterocyclylalkyl, such as substituted piperidine.
- the TOR kinase inhibitors of formula (lie) are those wherein R 3 and R 4 are H.
- the TOR kinase inhibitors include compounds having the following formula (II d):
- R 1 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 2 is substituted or unsubstituted Ci.galkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl;
- R 3 and R 4 are independently H or Ci_ 8 alkyl.
- the TOR kinase inhibitors of formula (II d) are those wherein
- R 1 is substituted aryl, such as substituted phenyl.
- the TOR kinase inhibitors of formula (lid) 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.
- the TOR kinase inhibitors of formula (lid) are those wherein R 1 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is substituted Ci_galkyl, such as -CH 2 C 6 H 5 .
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is unsubstituted Ci_ 8 alkyl, such as unsubstituted methyl.
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is substituted aryl, such as halo, haloalkyl or alkoxy substituted phenyl.
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
- the TOR kinase inhibitors of formula (lid) are those wherein R 2 is substituted heterocyclylalkyl, such as substituted piperidine.
- the TOR kinase inhibitors of formula (lid) are those wherein R 3 and R 4 are H.
- Representative TOR kinase inhibitors of formula (II) include:
- the TOR kinase inhibitors include compounds having the following formula (III):
- R 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
- R 2 is H, substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted
- heterocyclylalkyl substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;
- R 3 and R 4 are each independently H, substituted or unsubstituted Ci_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 R 3 and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;
- the TOR kinase inhibitors do not include the compounds depicted below, namel :
- R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
- R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, lH-pyrrolo[2,3-b]pyridyl, 1H- imidazo[4,5-b]pyridyl, lH-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, or pyrazolyl, each optionally substituted.
- R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted Ci_ 8 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.
- substituents independently selected from the group consisting of substituted or unsubstituted Ci_ 8 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.
- R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted heterocyclyl (for example, substituted or unsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted Ci_ 4 alkyl.
- R 1 is lH-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 Ci_ 8 alkyl, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted Ci_ 4 alkyl.
- R 1 is lH-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 Ci_ 8 alkyl, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted Ci_ 4 alkyl.
- R is at each occurrence independently H, or a substituted or unsubstituted Ci_4 alkyl (for example, methyl); R' is at each occurrence independently a substituted or unsubstituted Ci_ 4 alkyl, halogen (for example, fluorine), cyano, -OR, or -NR 2 ; m is 0-3; and n is 0-3.
- any of the subsitutuents R' may be attached to any suitable atom of any of the rings in the fused ring systems.
- 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.
- R is at each occurrence independently H, or a substituted or unsubstituted Ci_4 alkyl; R' is at each occurrence independently a substituted or unsubstituted Ci_ 4 alkyl, halogen, cyano, -OR, or -NR 2 ; m is 0-3; and n is 0-3.
- R 2 is H, substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Ci_ 4 alkyl-heterocyclyl, substituted or unsubstituted Ci_ 4 alkyl-aryl, or substituted or unsubstituted Ci_ 4 alkyl-cycloalkyl.
- 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, (C 1-4 alkyl)-cyclobutyl, (C 1-4 alkyl)-cyclopentyl, (C 1-4 alkyl)-cyclohexyl, (C 1-4 alkyl)-pyrrolidyl, (C 1-4 alkyl)-piperidyl, (C 1-4 alkyl)-piperazinyl, (C 1-4 alkyl)-morpholinyl, (Ci_4 alkyl)-tetrahydro
- R 2 is H, Ci_ 4 alkyl, (Ci_ 4 alkyl)(OR),
- R is at each occurrence independently H, or a substituted or unsubstituted Ci_ 4 alkyl (for example, methyl); R' is at each occurrence independently H, -OR, cyano, or a substituted or unsubstituted Ci_ 4 alkyl (for example, methyl); and p is 0-3.
- R 2 is H, Ci_ 4 alkyl, (Ci_ 4 alkyl)(OR),
- R is at each occurrence independently H, or a substituted or unsubstituted Ci_2 alkyl; R' is at each occurrence independently H, -OR, cyano, or a substituted or
- R 4 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl.
- the compound of formula (III) is
- R is at each occurrence independently H, or a substituted or unsubstituted Ci_ 4 alkyl; R" is H, OR, or a substituted or unsubstituted Ci_ 4 alkyl; and R 1 is as defined herein.
- R 3 and R 4 are both H. In others, one of R 3 and R 4 is H and the other is other than H. In still others, one of R 3 and R 4 is Ci_ 4 alkyl (for example, methyl) and the other is H. In still others, both of R 3 and R 4 are Ci_ 4 alkyl (for example, methyl).
- R 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
- R 1 is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, lH-pyrrolo[2,3-b]pyridyl, lH-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.
- R 1 is phenyl substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl and hydroxy.
- R 1 is pyridyl substituted with one or more substituents independently selected from the group consisting of cyano, substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen, aminocarbonyl, -OR, and -NR 2 , wherein each R is independently H, or a substituted or unsubstituted Ci_ 4 alkyl.
- R 1 is
- lH-pyrrolo[2,3-b]pyridyl or benzimidazolyl optionally substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted Ci_g alkyl, and - NR 2 , wherein R is independently H, or a substituted or unsubstituted Ci_ 4 alkyl.
- the compounds of formula (III) have an R 1 group set forth herein and an R 2 group set forth herein.
- the compound at a concentration of 10 ⁇ inhibits mTOR, DNA-PK, or PI3K 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.
- Representative TOR kinase inhibitors of formula (III) include:
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Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
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JP2012552068A JP6114554B2 (en) | 2010-02-03 | 2011-02-03 | Identification of LKB1 mutations as predictive biomarkers for susceptibility to TOR kinase inhibitors |
KR1020177027392A KR101942212B1 (en) | 2010-02-03 | 2011-02-03 | IDENTIFICATION OF LKBl MUTATION AS A PREDICTIVE BIOMARKER FOR SENSITIVITY TO TOR KINASE INHIBITORS |
NZ601581A NZ601581A (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
CA2788678A CA2788678C (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
MX2012009030A MX2012009030A (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors. |
RU2012137279/15A RU2565034C2 (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as prognostic biomarker of sensitivity to tor-kinase inhibitors |
KR1020127022877A KR20120123513A (en) | 2010-02-03 | 2011-02-03 | IDENTIFICATION OF LKBl MUTATION AS A PREDICTIVE BIOMARKER FOR SENSITIVITY TO TOR KINASE INHIBITORS |
CN201180017277XA CN102821767A (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as predictive biomarker for sensitivity to tor kinase inhibitors |
ES11740321.2T ES2670659T3 (en) | 2010-02-03 | 2011-02-03 | Identification of mutation in LKB1 as a predictive biomarker for sensitivity to TOR kinase inhibitors |
SG2012057568A SG183155A1 (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
UAA201210290A UA110697C2 (en) | 2010-02-03 | 2011-02-03 | The use of inhibitors tor-kinase for the treatment of tumors in patients with reduced protein pampk and / or activity ampk |
BR112012019459A BR112012019459A2 (en) | 2010-02-03 | 2011-02-03 | identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors. |
EP11740321.2A EP2531194B1 (en) | 2010-02-03 | 2011-02-03 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
AU2011212927A AU2011212927B2 (en) | 2010-02-03 | 2011-02-03 | Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors |
IL221282A IL221282A (en) | 2010-02-03 | 2012-08-02 | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
PH12020500203A PH12020500203A1 (en) | 2010-02-03 | 2020-01-27 | Identification of lkb1 mutation as a predictive boimarker for sensitivity to tor kinase inhibitors |
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AR (1) | AR080643A1 (en) |
AU (1) | AU2011212927B2 (en) |
BR (1) | BR112012019459A2 (en) |
CA (1) | CA2788678C (en) |
CR (1) | CR20120406A (en) |
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NZ (1) | NZ601581A (en) |
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