method for the treatment of lung cancer, method for achieving a response evaluation criterion in sol

专利摘要:
  USE OF AN EFFECTIVE AMOUNT OF A KINASE TOR INHIBITOR, METHOD TO ACHIEVE A CRITERIA FOR EVALUATING RESPONSE IN SOLID TUMORS, METHOD FOR INCREASING SURVIVALMethods for treating or preventing advanced non-small cell lung cancer are provided herein, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of erlotinib or cytidine analogous to a patient containing non-cell lung cancer. small advanced.
公开号:BR112014020786A2
申请号:R112014020786-0
申请日:2013-02-22
公开日:2020-10-27
发明作者:Shuichan Xu；Kristen Mae Hege；Tam Minh Tran
申请人:Signal Pharmaceuticals, Llc；
IPC主号:

专利说明:

[0001] [0001] This application claims United States Provisional Application No. 61/603012, filed on February 24, 2012, states that US Provisional Application No. 61/716424, filed on October 19, 2012 and states that the US Provisional Application No. 61/725805 benefit, presented on November 13, 2012, contains the entire contents of each of which are incorporated herein by reference.
[0002] [0002] Methods for treating or preventing advanced non-small cell lung cancer are provided herein, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of erlotinib or a cytidine analog to a patient with advanced non-small cell lung cancer.
[0003] [0003] The link between abnormal protein phosphorylation and the cause or consequence of disease has been known for more than years. Thus, protein kinases have become a very important group of drug targets. See Cohen, Nature, 1: 309-315 (2002). Several protein kinase inhibitors have been used clinically to treat a wide variety of diseases, such as cancer and chronic inflammatory diseases, including stroke and diabetes. See Cohen, Eur. J. Biochem., 268: 5001-5010 (2001), Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005).
[0004] [0004] Protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a crucial role in cell signaling. Protein kinases can have positive or negative regulatory effects, depending on your target protein. Protein kinases are involved in specific signaling pathways that regulate cellular functions, such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Functional variations in cell signaling have been associated with many diseases, the best characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signaling molecules with proto-oncogenes and tumor suppressor genes has been well documented. Likewise, the link between diabetes and related conditions, and unregulated protein kinase levels, has been demonstrated. See, for example, Sridhar et al. Pharmaceutical Research, 17 (11): 1345-1353 (2000). Viral infections and related conditions have also been associated with the regulation of protein kinases. Park et al. Cell 101 (7): 777-787 (2000).
[0005] [0005] Since protein kinases regulate almost all cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell cycle control and angiogenesis, in which protein kinases play a crucial role are cellular processes associated with various disease states, such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases that tell you respect, atherosclerosis, macular degeneration, diabetes, obesity, and pain.
[0006] [0006] Protein kinases have become attractive targets for the treatment of cancer. Fabbro et al., Pharmacology & Therapeutics 93: 79-98 (2002). It has been proposed that the involvement of protein kinases in the development of human malignancies can occur by: (1) genomic rearrangements (eg, BCR-ABL in chronic myeloid leukemia), (2) mutations that lead to constitutively active kinase activity, such such as acute myeloid leukemia and gastrointestinal tumors, (3) the deregulation of kinase activity through the activation of oncogenes or loss of tumor suppressor functions, such as in cancers with oncogenic RAS, (4) the deregulation of kinase activity by overexpression , as is the case of EGFR and (5) ethopic expression of growth factors that can contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharmacology & Therapeutics 93: 79-98 (2002).
[0007] [0007] The elucidation of the complexity of protein kinase pathways and the complexity of the relationship and interaction between the various protein kinases and kinase pathways highlight the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have activity beneficial over multiple kinases or multiple kinase pathways. Consequently, there remains a need for new kinase modulators.
[0008] [0008] The protein called mTOR (rapamycin target in mammals), which is also called FRAP, RAFTI or RAPTI1), is an amino acid-2549 of protein Ser / Thr kinase, which has been shown to be one of the most critical proteins in mTOR / PI3K / Akt, which regulates cell growth and proliferation. Georgakis and Younes, Expert Rev. Anticancer Ther. 6 (1): 131-140 (2006). mTOR exists within two complexes, mMTORC1l and mTORC2. While mTORC1 is sensitive to rapamycin analogues (such as temsirolimus or everolimus), mTORC2 is mostly insensitive to rapamycin. Notably, rapamycin is not a TOR kinase inhibitor. Several mTOR inhibitors have been or are being evaluated in clinical trials for the treatment of cancer. Temsirolimus was approved for use in renal cell carcinoma in 2007 and sirolimus was approved in 1999 for the prophylaxis of kidney transplant rejection. Everolimus was approved in 2009 for patients with renal cell carcinoma who progressed to vascular endothelial growth factor receptor inhibitors in 2010 for subependimal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients requiring therapy , but are not candidates for surgical resection and, in 2011, for progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. There is still a need for RPT kinase inhibitors that inhibit both the mTORC1 and mTORC2 complexes.
[0009] [0009] Citation or identification of any reference in section 2 of this application should not be interpreted as an admission that the reference is art prior to this application.
[0010] [0010] Methods are provided here for treating or preventing non-small cell lung cancer, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of erlotinib or a cytidine analog to a cancer patient advanced non-small cell lung.
[0011] [0011] In certain embodiments, methods are provided here for obtaining a Response Response Criterion in solid tumors (for example, 1.1 RECIST) for a complete response, a partial response, or a stable disease in a lung cancer patient of advanced non-small cells, comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analog to said patient.
[0012] [0012] In certain embodiments, methods are provided herein to increase tumor progression-free survival of a patient with advanced non-small cell lung cancer, comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analog to said patient.
[0013] [0013] In certain embodiments, the TOR kinase inhibitor is a compound as described herein.
[0014] [0014] The present embodiments can be understood in more detail by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.
[0015] [0015] Figure 1 shows the viability and isobologram response curves for Compound 1 and 5-azacitidine for H1755 cells, and the synergy observed for the combination treatment, for two ratio combinations.
[0016] [0016] Figure 2 represents viability and isobologram response curves for Compound 1 and erlotinib for H1755 cells, and the synergy observed for the combination treatment, for two ratio combinations.
[0017] [0017] Figure 3 shows: A. Impact of the addition sequence and relation of CI values. The IC values of all combinations for each of the three addition sequences were compared by the t test. Yes: simultaneous addition of both compounds; SeqMl: Compound 1 first followed by addition of azacytidine; SeqM2: azacitidine first followed by the addition of Compound 1. B. Different ratios of azacitidine and Compound 1 do not significantly affect the IC values in SeqM2 thereof.
[0018] [0018] Figure 4 illustrates: A. Addition sequence has no impact on the CI values for the combination of Compound 1 and erlotinib. The IC values of all combinations for each of the three addition sequences were compared by the t test. Yes: simultaneous addition of both compounds; SeqMl: Compound 1 first followed by addition of azacytidine; SeqM2: azacitidine first followed by addition of Compound B. 1. Different proportions of Compound 1 and azacitidine significantly impact CI values.
[0019] [0019] Figures 5A-D illustrate combination rates of treatment with erlotinib, in combination with Compound 1 in various cell lines, in various concentrations. Figure 1A illustrates the combination indices in the AS549 cell line. Figure 1B shows the combination indices in the H1975 cell line. Figure 1C shows the combination indices in the HCC95 cell line. Figure 1E shows the combination indices in the H1650 cell line.
[0020] [0020] Figure 6 shows the analysis of the cell cycle in the A549 cell line treated with erlotinib, Compound 1, or the combination thereof.
[0021] [0021] Figures 7A and 7B show a biomarker using Western blot analysis. Cell lines were treated with erlotinib, Compound 1, or a combination of them for 1 to 3 days. Cell lysates were produced and 30 µg of proteins subjected to SDS-PAGE and Western blotting. Data for cell lines A549 and H1975 are shown in Figure 7A. Data for cell lines H1650 and HCC95 are shown in Figure 7B.
[0022] [0022] Figure 8 shows the antitumor activity of Compound 1 or erlotinib, when administered orally as isolated agents and in combination, in AS549 xenografts.
[0023] [0023] Figure 9 shows the antitumor activity of Compound 1 and erlotinib, when administered orally as isolated agents and in combination, in H1975 xenografts.
[0024] [0024] An "alkyl" group is a saturated, partially saturated or unsaturated straight-chain or branched acyclic hydrocarbon ring that has between 1 and 10 carbon atoms, usually with 1 to 8 carbon atoms or, in some embodiments, 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 alkis include -isopropyl, -sec-butyl, isobutyl, tert-butyl, -isopentyl, 2-methylpentyl, 3-
[0025] An "alkenyl" group is a straight or branched chain of acyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and including the bond of at least one carbon-carbon double bond. Representatives of straight and branched chain alkenyl (C2-Cgs) include -vinyl, -alyl, -l-butenyl, 2-butenyl, -isobutylenyl, -l-pentenyl, —-2-pentenyl, 3-methyl-l-butenyl , -2-methyl-2-butenyl, —-2,3-dimethyl-2-butenyl, 11-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, -2-heptenyl, -3-heptenyl, -l -octenyl, -2-octenyl, -3-octenyl and the like. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. An alkenyl group can be unsubstituted or substituted.
[0026] [0026] A "cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group of 3 to 10 carbon atoms, having a single cyclic ring or multiple hundred-quenched or bridged rings, which can be optionally substituted with 1 to 3 alkyl groups. In . in some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, the By way of example, only 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 unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, ”cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups refer, by way of example, cyclohexanone and the like.
[0027] [0027] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms, having a single ring (eg, phenyl) or multiple hundred-quenched rings (for example, naphthyl or anthryl). In some embodiments, the aryl groups contain 6-14 carbon atoms, and in others 6 to 12, or even 6 to carbon atoms in the ring portions of the groups. Particular aris include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aliphatic aromatic ring systems (for example, indanyl, tetrahydronaphthyl, and the like).
[0028] [0028] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, where the remainder of the atoms are carbon atoms. In some embodiments, the heteroaryl groups contain 5 to 6 ring atoms, and in others 6-9, or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiyl, benzothiyl for example, isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example, pyrrolopyridyl or lH-pyrrol [2,3-b] pyridyl), indazolyl, benzimidazolyl groups (for example, lH-benzo [d] imidazolyl) , imidazopyridyl (e.g., azabenzimidazolyl, 3H imidazo [4,5-b] pyridyl or 1H-imidazo [4,5-b] pyridyl), pyrazolpyridyl, triazolpyridyl, benzotriazolyl, benzoxazolil, benzothiazolyl, benzothiadiazolyl, isoxazolil, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.
[0029] [0029] A "heterocyclyl" is an aromatic group (also referred to as heteroaryl) or a non-aromatic cycloalkyl group, in which one to four of the ring carbon atoms are independently replaced with a hetero atom from the group consisting of O , S and N.
[0030] [0030] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined as above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, cycloalkyl moieties, or on both the alkyl and cycloalkyl moieties. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Substituted cycloalkylalkyl groups can be mono substituted or substituted more than once.
[0031] [0031] An "aralkyl" group is a radical of the formula: - alkyl-aryl, where aryl and alkyl are defined above. Substituted aralkyl groups can be substituted on the alkyl, aryl moieties, or on both portions of the alkyl and aryl groups. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl.
[0032] [0032] A "heterocycloalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, heterocyclyl moieties, or both "alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl-methyl, furan-3-yl-methyl, pyridine-3-yl-methyl, (tetrahydro-2H-pyran -4-yl) methyl, (tetrahydro-2H-pyran-4-yl) ethyl, tetrahydrofuran-2-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl propyl.
[0033] [0033] A "halogen" is fluorine, chlorine, bromine or iodine.
[0034] [0034] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.
[0035] [0035] An "alkoxy" group is -O- (alkyl), where alkyl is defined above.
[0036] [0036] An "alkoxyalkyl" group is - (alkyl) -O- (alkyl), where alkyl is defined above.
[0038] [0038] An "alkylamino" group is a radical group of the formula: -NH-alkyl or -N (alkyl) ,, where each alkyl is independently as defined above.
[0039] [0039] A "carboxy" group is a radical of the formula: -C (O0) OH.
[0040] [0040] An "aminocarbonyl" group represents a radical of the formula: -C (O) N (R) 2, -C (O) NH (RI) or -C (O) NHa, where each R * is, independently , a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl, as defined herein.
[0041] [0041] An "acylamino" group is a radical of the formula: -NHC (O) (R1) or -N (alkyl) C (O) (R *) where each alkyl and R * are independently defined above.
[0042] [0042] An "alkylsulfonylamino" group is a radical of the formula: NHSO (R *) or N (alkyl) SO- (R *), where each alkyl and R * are defined above.
[0043] [0043] A "urea" group is a radical of the formula: -N (alkyl) C (O) N (R *) to, -N (alkyl) C (O) NH (RI), -N (alkyl) C (O) NH3, —NHC (O) N (R *) 2, -NHC (O) NH (R *), or -NH (CO) NHR ', where each alkyl and R * are independently defined above.
[0044] [0044] When the groups described herein, with the exception of the alkyl group are referred to as "substituted", they can be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as a halogen group (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyan; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxiamine; aralkoxiamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; : isothiocyanate; cyanate; thiocyanate; oxygen (= O); B (OH)>, O (alkyl) aminocarbonyl; cycloalkyl, which can be monocyclic or fused or non-fused polycyclic (for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which can be monocyclic or fused or non-fused polycyclic (for example, pyrrolidyl, piperidyl , piperazinyl, morpholinyl, or thiazinyl); aryl or heteroaryl monocyclic or fused or non-fused polycyclic (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl , pyridazinyl, pyrimidinyl,
[0045] [0045] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or a base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base additions of TOR kinase inhibitors include, but are not limited to metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N, N ' - dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine Suitable nontoxic acids include, but are not limited to, inorganic and organic acids, such as acetic, alginic, anthranyl, benzenesulfonic, benzoic acid camphorsulfonic, citric, ethylene sulfifonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic onic, muscic, nitric, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric acid, tartaric acid and p-toluenesulfonic, hydrobromic, isethionic, pamoic, pantothenic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acid. Examples of specific salts therefore include hydrochloride and mesylate salts. Others are well known in the field, see, for example, Remington Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton
[0046] [0046] As used herein and unless otherwise indicated, the term "clathrate" means a TOR kinase inhibitor, or a salt thereof, in the form of a crystalline network containing spaces (for example, channels) that has a guest molecule (for example, a solvent or water) trapped inside or a crystal structure in which a TOR kinase is a guest molecule.
[0047] [0047] As used herein and unless otherwise indicated, the term "solvate" means a TOR kinase inhibitor, or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by intermolecular forces non-covalent. In one embodiment, the solvate is a hydrate.
[0048] [0048] As used herein and unless otherwise indicated, the term "hydrate" means a TOR kinase inhibitor, or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of water bound by intermolecular forces not covalent.
[0049] [0049] As used herein and unless otherwise indicated, the term "prodrug" means a TOR kinase inhibitor derivative that can hydrolyze, oxidize or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a TOR kinase inhibitor. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a TOR kinase inhibitor that include portions such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, “biohydrolyzable carbonates, biohydrides - hydrolysables, and biohydrolyzable phosphate analogs. In certain embodiments, prodrugs of compounds with functional carboxyl groups are the lower alkyl esters of carboxylic acid. carboxylate esters are conveniently formed by esterification of any of the carboxylic acid radicals present in the molecule. Prodrugs can generally be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6th edition. (Donald JU. Abraham ed., 2001, Wiley) and Design and Application of Prodrus (H. Bundgaard ed., 1985, Publishers Harwood Academic Gmfh).
[0050] [0050] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means a stereoisomer of a TOR kinase inhibitor that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound containing a 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 stereoisomerically pure compound typically comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of a stereoisomer of the compound and less than about 10%
[0051] [0051] It should be noted that TOR kinase inhibitors can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, TOR kinase inhibitors are isolated as either cis or trans. In other embodiments, the TOR kinase inhibitors are a mixture of the cis and trans isomers.
[0052] [0052] "Tautomers" refer to the isomeric forms of a compound that are in equilibrium with one another. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may be different, depending, for example, on whether the compound is a solid or is an organic or aqueous solution. For example, in aqueous solution, pyrazoles can have the following isomeric forms, which are referred to as tautomers with each other:
[0053] [0053] As is readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism and all tautomers of TOR kinase inhibitors are within the scope of the present invention.
[0054] [0054] It should also be noted that TOR kinase inhibitors may contain unnatural proportions of atomic isotopes in one or more atoms. For example, compounds can be radiolabeled with radioactive isotopes, such as, for example, tritium (* H), iodine-l25 (** I), sulfur (* S) 35 or carbon-14 (* C), or be isotopically enriched, such as with deuterium ( H), carbon-13 ("C), or nitrogen-15 (** N). As used herein, an "isotopologist" is an isotopically enriched compound. the term "isotopically enriched" refers to an atom that has an isotopic composition different from the natural isotopic composition of an atom. "Isotopically enriched" can also refer to a compound that contains at least one atom that has an isotopic composition different from the natural isotopic composition of an atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, for example, cancer and therapeutic inflammatory agents, research reagents, for example, reagents for the binding assay, or diagnostic agents, for example, in vivo imaging agents . All isotopic variations of the TOR kinase inhibitors as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologists of the TOR kinase inhibitors are provided, for example, they are TOR kinase inhibitors enriched by isotopologists such as deuterium, carbon-13, or nitrogen-15.
[0055] [0055] "Treatment" as used herein means a relief, in whole or in part, of advanced non-small cell lung cancer or a symptom associated with advanced non-small cell lung cancer, or reduction, or arrest of progression or worsening of these symptoms.
[0056] [0056] "Prevent", as used herein, means the prevention of the appearance, recurrence or spread, total or partial, of advanced non-small cell lung cancer, or a symptom thereof.
[0057] [0057] The term "effective amount" in relation to a TOR kinase inhibitor, erlotinib or a cytidine analog, means an amount alone or in combination capable of alleviating, totally or partially, a symptom associated with lung cancer advanced non-small cell lung cancer, or delay or halt the progression or worsening of these symptoms, or treatment or prevention of advanced non-small cell lung cancer in a subject with or at risk for advanced non-small cell lung cancer . The effective amount of the TOR kinase inhibitor, erlotinib or a cytidine analog, for example, in a pharmaceutical composition, may be at a level that will have the desired effect; for example, about 0.005 mg / kg body weight of the subject to about 100 mg / kg body weight of a patient, in unit dosage, for both oral and parenteral administration.
[0058] [0058] In one embodiment, erlotinib is TARCEVAG.
[0059] [0059] In certain embodiments, the cytidine analogue is 5-azacytidine (also known as 4-amino-1-BD-ribofuranosyl-1,3,5-triazine-2- (1H) on; National Service Center NSC- 102816; CAS registration number 320-67-2; azacitidine; Aza and AZA, and currently marketed as VIDAZAO). In certain embodiments, the cytidine analogue is 2'-deoxy-5-azacytidine (also - known as 5-aza-2'-deoxycytidine, decitabine, 5-aza-CdR, Dac, and DAC, and currently marketed as DACOGEN) . In certain embodiments, the cytidine analog is, for example: 1-B D-arabinofuranosylcytosine (cytarabine or Ara-C); pseudoiso-cytidine (psi ICR); 5-fluorine-2'-deoxycytidine (FCdR); 2 deoxy-2 ', 2'-difluorocytidine (gemcitabine); 5-aza-2'-deoxy-2 ', 2'-difluorocytidine; 5-aza-2'-deoxy-2'-fluorocytidine; 1- B-D-ribofuranosyl-2 (1H) pyrimidinone (Zebularine); 2 ', 3'-didesoxy-5-fluoro-3'-thiacitidine (Emtriva); 2'-cyclocytidine (Ancitabine); 11-B-D-arabinofuranosyl-5-azacytosine (Fazarabine or Ara-AC); 6-azacitidine (6-aza-CR); 5,6-dihydro-5-azacytidine (dH-aza-CR); Pentyloxy-carbonyl-5 '-deoxy-5-fluorocytidine (capecitabine); Ni-octadecyl-cytarabine; elaidic acid cytarabine; or a conjugate compound comprising a cytidine analogue and a fatty acid (e.g., a fatty acid-azacytidine conjugate, including, but not limited to, CP-4200 (Clavis Pharma ASA) or a compound disclosed in WO 2009 / 042767, such as aza-C-5'-petroselainic acid ester or C-5'-aza-petroselaidic acid ester).
[0060] [0060] In certain embodiments, the cytidine analogs provided herein include esterified derivatives of cytidine analogs, such as, for example, the esterified derivatives of S-azacitidine. In particular embodiments, the esterified derivatives are cytidine analogs that contain an ester unit (e.g., an acetyl group) at one or more positions in the cytidine analogue molecule. Esterified derivatives can be prepared by any method known in the art. In certain embodiments, the esterified derivatives of a cytidine analog serve as prodrugs of the cytidine analog, such that, for example, after administration of an esterified derivative, the derivative is deacetylated in vivo to provide the analog of cytidine. A particular embodiment here provides 2 ', 3', S'-triacetyl-5S-azacytidine (TAC), which has favorable physico-chemical and therapeutic properties. See, for example, International Publication No. WO 2008/092127 (International Application No. PCT / US2008 / 052124); Ziemba, A.J., et AL., * "Development of Oral Demetilating Agents for the Treatment of Myelodysplastic Syndrome" (Abstract No. 3369), In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; April 18-22, 2009; Denver, Co. Philadelphia (PA): AACR; 2009 (both of which are incorporated herein by reference in their entirety).
[0061] [0061] In certain embodiments, the cytidine analogs provided herein include any compound that is structurally related to cytidine or deoxycytidine and functionally mimics and / or antagonizes the action of cytidine or deoxycytidine. Certain embodiments herein provide salts, co-crystals, solvates (e.g., hydrates), complexes, prodrugs, precursors, metabolites and / or other derivatives of the cytidine analogs provided herein. For example, particular embodiments, co-crystals provide salts, solvates (for example, hydrates), complexes, precursors, metabolites and / or other 5-azacytidine derivatives. Certain embodiments provide cytidine analogs that are not salts, co-crystals, solvates (e.g., hydrates), or cytidine analogue complexes provided herein. For example, particular embodiments provide azacitidine
[0062] [0062] The cytidine analogs referred to herein can be prepared using synthetic methods and procedures referred to here or otherwise in the literature. For example, specific methods for the synthesis of 5-azacitidine are taught in, for example, United States Patent No.
[0063] [0063] As used herein, and unless otherwise specified, the term "in combination with" includes the administration of two or more therapeutic agents simultaneously, concurrently, sequentially or within any specific time limits, unless than otherwise indicated. In one embodiment, a TOR kinase inhibitor is administered in combination with erlotinib or a cytidine analog. In one embodiment, the agents are present in the subject's cell or body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same dosage form or composition unit. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent can be administered before (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or essentially following (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, one week, two weeks, three weeks, four weeks, five weeks, 6 weeks , 8 weeks, or 12 weeks after), the administration of a second therapeutic agent, or any combination thereof. For example, in one embodiment, the first agent can be administered before the second therapeutic agent, for example, in 1 week. In another, the first agent can be administered before (for example, 1 day before) and then at the same time with the second therapeutic agent.
[0064] [0064] The terms "patient" and "subject" as used herein include an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment of a mammal, in another embodiment of a human. In one embodiment, a "patient" or "subject" is a human with advanced non-small cell lung cancer. In one embodiment, a "patient" or "subject" is a human with Stage IIIB / IV advanced non-small cell lung cancer. In one embodiment, a "patient" or "subject" is a human with advanced non-small cell lung cancer. In one embodiment, a "patient" or "subject" is a human with Stage IIIB / IV advanced non-small cell lung cancer who has failed at least one standard therapy line. In one embodiment, a patient is a human being who has histologically advanced or non-small cell lung cancer | cytologically confirmed, including individuals who have progressed on (or have not been able to tolerate) standard anti-cancer and therapy or for whom no standard anti-cancer therapy exists. In one embodiment, the standard anti-cancer therapy is chemotherapy or EGFR inhibitor therapy.
[0065] [0065] In the context of advanced non-small cell lung cancer, inhibition can be assessed by inhibiting disease progression, inhibiting tumor growth, reducing primary tumor mass, relieving tumor-related symptoms, and inhibition of secreted tumor factors (including hormones secreted from the tumor, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, the slower development of primary or secondary tumors, decreases the occurrence of primary or secondary tumors, the severity of the side effects of the delayed or decreased disease, the growth of tumor weight and tumor regression, increased progression time (TTP), increased Progression-Free Survival (PFS), increased overall survival (OS), among others . OS as used here, the time from randomization to death from any cause, and is measured in the population with the intention to treat. TTP, as used here, means the time from randomization to objective tumor progression; the TTP does not include deaths. As used here, PFS is the time from randomization to objective tumor progression or death. In one embodiment, PFS rates will be calculated based on Kaplan-Meier estimates. In the extreme, a complete inhibition is referred to in this document as prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of clinically evident advanced non-small cell lung cancer or preventing the onset of a pre-clinically evident phase of advanced non-small cell lung cancer. In addition, this definition is intended to prevent the transformation of malignant cells or halt or reverse the progression of pre-malignant cells to malignant cells. This includes prophylactic treatment for people at risk of developing advanced non-small cell lung cancer. In certain embodiments, advanced non-small cell lung cancer can be Stage IIIB or Stage IV advanced non-small cell lung cancer.
[0066] [0066] In certain embodiments, the treatment of advanced non-small cell lung cancer can be evaluated by criteria for assessing response in solid tumors (RECIST
[0067] [0067] With regard to the assessment of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the sum of the largest diameter of target lesions, taking as a reference the sum of the largest diameter of the baseline, progressive disease (PD) is at least a 20% increase in the sum of the largest diameter of the target lesions, taking as reference the smallest sum of the largest diameter, verified from beginning of treatment or the appearance of one or more new lesions and stable disease (ED) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as
[0068] [0068] With regard to the assessment of non-target injuries, | a complete response (CR) is the disappearance of all non-target lesions and the normalization of the tumor marker level; incomplete response / stable disease (ED), is the persistence of one or more non-target lesions (s) and / or the maintenance of the tumor marker level, above normal limits, and progressive disease (PD) is the appearance of a or more of the new injuries and / or unequivocal progression of existing non-target injuries.
[0069] [0069] In certain embodiments, treatment of non-small cell lung cancer can be assessed by inhibiting phosphorylation of S6RP, 4E-BPl and / or AKT in circulating blood and / or tumor cells or tumor / aspirated biopsies, before, during and / or after treatment with a TOR kinase inhibitor. For example, the inhibition of phosphorylation of S6RP, 4E-BPl and / or AKT, evaluated in B cells, T cells and / or monocytes.
[0070] The compounds provided herein are generally referred to as "TOR kinase inhibitor (s)". In a specific embodiment, TOR kinase inhibitors do not include rapamycin or rapamycin analogs (rapalogs).
[0071] [0071] In one embodiment, TOR kinase inhibitors include compounds that have the following formula (1):
[0072] [0072] In one embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -CH72C (O) NH-.
[0073] [0073] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which -A-B-Q- taken together form -C (0O) CH, NH-.
[0074] [0074] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -C (O) NH-.
[0075] [0075] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -CH2C (0) O-.
[0076] [0076] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -C (0) CH20-.
[0077] [0077] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -C (0) O-.
[0078] [0078] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -A-B-Q- taken together form -C (O) NRº * -.
[0079] [0079] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which Y is CR.
[0080] [0080] In another embodiment, the TOR kinases of formula (1) are those in which X and Z are N and Y is CRº.
[0081] [0081] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which X and Z are N and Y is CH.
[0082] [0082] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which X and Z are CH and Y is N.
[0083] [0083] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which Y and Z are CH and X is N.
[0084] [0084] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which X and Y are CH and Z is N.
[0085] [0085] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which R 'is substituted aryl, such as substituted phenyl.
[0086] [0086] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which R 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[0087] [0087] In another embodiment, kinase inhibitors | TOR of formula (I) are those in which R '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 substituted.
[0088] [0088] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which R 'is H.
[0089] [0089] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which Rº is substituted Cisalkyl.
[0090] [0090] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which Rº is methyl or ethyl substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl substituted or unsubstituted heterocyclylalkyl .
[0091] [0091] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[0092] [0092] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[0093] [0093] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which D H.
[0094] [0094] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which L is a direct link.
[0095] [0095] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -ABQ- taken together form C (O) NH-, X and Z are N and Y is CH, R 'is substituted aryl or unsubstituted or substituted or unsubstituted heteroaryl, L is a direct bond and Rº is substituted or unsubstituted Ci-galquil.
[0096] [0096] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -ABQ- taken together form -C (O) NH-, X and Z are N and Y is CH, R 'is aryl substituted or unsubstituted, L is a direct bond and Rº is substituted or unsubstituted Ci-galquil.
[0097] [0097] In another embodiment, the TOR kinase inhibitors of formula (I) are those in which -ABQ- taken together form -C (O) NH-, X and Z are N and Y is CH, R 'is aryl substituted or unsubstituted, and Rº is Cigalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.
[0098] [0098] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which -ABQ- taken together form -C (O) NH-, X and Z are N and Y is CH, R 'is aryl substituted or unsubstituted, and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
[0099] [0099] In another embodiment, the TOR kinase inhibitors of formula (1) are those in which -ABQ- taken together form -C (O) NH-, X and Z are N and Y is CH, R1 is substituted phenyl , L is a direct bond, and Rº is substituted Ci-salquil.
[00100] [00100] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds in which X and Z are both N and Y is CH, -ABQ- is -C (O) NH-, L is a direct link , R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and Rº is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl Ci-galkyl.
[00101] [00101] In another embodiment, the TOR kinase inhibitors of formula (1) do not include compounds in which X and Z are both N and Y is CH, -ABQ- is -C (O) NH-, L is a direct link , Rº is phenyl, naphthyl, indanyl or biphenyl, each of which may optionally be “substituted with one or more substituents independently selected from the group consisting of substituted or unsubstituted Cigalkyl, substituted or unsubstituted salkenyl, substituted or unsubstituted aryl substituted, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00103] [00103] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds where X and Y are both N and Z is CH, -ABQ- is -C (O) NH-, L is a direct link , Rº is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and R is substituted or unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or an acetamide.
[00104] [00104] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds in which X and Y are both N and zZ is CH, -ABQ- is -C (O) NH-, L is a direct link , Rº is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, and Rº is an acetamide.
[00105] [00105] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds where X is N and Y and Z are both -CH, -ABQ- is -C (O) NH-, L is a bond direct, R 'is a (2,5'-bi-1H-benzimidazole) -5-carboxamide, and D HH.
[00106] [00106] In another embodiment, the TOR kinase inhibitors of formula (1) do not include compounds in which one of X and Z is CH and | the other is N, Y is CH, -A-B-Q- is -C (O) NH-, L is a direct bond, R 'is unsubstituted pyridine, and Rº is H, methyl or substituted ethyl.
[00107] [00107] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds where X and Z are both N and Y is -CH, -ABQ- is -C (O) NH-, Rº is H, C1--alkyl, C 7- -alkenyl, aryl or cycloalkyl, and L is NH.
[00108] [00108] In another embodiment, the TOR kinase inhibitors of formula (I) do not include compounds in which X and Z are both N and Y is CH, -ABQ- is -C (O) NR * -, Rº is H, Substituted or unsubstituted C 1 -alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclylalkyl and unsubstituted or substituted cycloalkyl or, and L is NH.
[00109] [00109] In another embodiment, the TOR kinase inhibitors of formula (1) do not include compounds in which R 'is a substituted or unsubstituted oxazolidinone.
[00110] [00110] In another embodiment, the TOR kinase inhibitors of formula (I) do not include one or more of the following compounds: 1,7-dihydro-2-phenyl-8H-purin-8-one, 1,2-dihydro- 3-phenyl-6H-
[00111] [00111] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (Ia): R2 tr N Á
[00112] [00112] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R 'is substituted aryl, such as phenyl.
[00113] [00113] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R 'is substituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl B.
[00114] [00114] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R '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.
[00115] [00115] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R 'is H.
[00116] [00116] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which D Ci-salquyl.
[00117] [00117] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or heterocycloalkyl replaced or not replaced.
[00118] [00118] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R ° is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00119] [00119] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00120] [00120] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which D H.
[00121] [00121] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which Y is CH.
[00122] [00122] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which L is a direct link.
[00123] [00123] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Cigalkyl.
[00124] [00124] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted Cigalkyl with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl , or heterocyclylalkyl.
[00125] [00125] In another embodiment, the TOR kinase inhibitors of formula (Ia) are those in which Rº is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00126] [00126] In another embodiment, the TOR kinase inhibitors of formula (Ia) do not include compounds in which Y is CH, L is a direct bond, R 'is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and Rº is Ci-salquil substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[00127] [00127] In another embodiment, TOR kinase inhibitors include compounds containing the following formula (Ib): R2 L /
[00128] [00128] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is substituted aryl, such as phenyl.
[00129] [00129] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is substituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[00130] [00130] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R '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.
[00131] [00131] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is H.
[00132] [00132] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which Rº is Ci-salquil.
[00133] [00133] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
[00134] [00134] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00135] [00135] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00136] [00136] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which Rº is H.
[00137] [00137] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which L is a direct link.
[00138] [00138] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Cigalkyl.
[00139] [00139] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is substituted or unsubstituted aryl and Rº is Ci-sgalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy , cycloalkyl, or heterocyclylalkyl.
[00140] [00140] In another embodiment, the TOR kinase inhibitors of formula (Ib) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00141] [00141] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (Ic): R2 —t N Á R 'Dx | O READ N
[00142] [00142] In one embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is substituted aryl, such as phenyl.
[00143] [00143] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[00144] [00144] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R '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.
[00145] [00145] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is H.
[00146] [00146] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which Rº is Cigalkyl.
[00147] [00147] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00148] [00148] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00149] [00149] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which Rº is substituted aryl, such as phenyl.
[00151] [00151] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which L is a direct link.
[00152] [00152] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Ci-salkyl.
[00153] [00153] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is substituted or unsubstituted aryl and Rº is Cigalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl , or heterocyclylalkyl.
[00154] [00154] In another embodiment, the TOR kinase inhibitors of formula (Ic) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00155] [00155] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (Id): R2 & í RO * N | O THE
[00156] [00156] In one embodiment, the TOR kinase inhibitors of formula (Id) are those in which R 'is substituted aryl, such as phenyl.
[00157] [00157] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which R 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[00158] [00158] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which R '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.
[00159] [00159] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which R 'is H.
[00160] [00160] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which Rº is Ci-salquil.
[00161] [00161] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which Rº is methyl or ethyl Ú substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00162] [00162] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00163] [00163] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00164] [00164] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which D H.
[00165] [00165] In another embodiment, the TOR kinase inhibitors | of formula (Id) are those where L is a direct link.
[00166] [00166] In another embodiment, TOR kinase inhibitors | of formula (Id) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Ci-salquil.
[00167] [00167] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted Cigsalkyl with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl , or heterocyclylalkyl.
[00168] [00168] In another embodiment, the TOR kinase inhibitors of formula (Id) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00169] [00169] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (Ie):
[00170] [00170] In one embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R 'is substituted aryl, such as phenyl.
[00171] [00171] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R 'is aryl substituted or not
[00172] [00172] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R '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.
[00173] [00173] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R is H.
[00174] [00174] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which Rº is Ci galquil.
[00175] [00175] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or heterocycloalkyl replaced or not replaced.
[00176] [00176] In another embodiment, the TOR kinase inhibitors of formula (Te) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00177] [00177] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00178] [00178] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which Rº is H.
[00179] [00179] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which L is a direct link.
[00180] [00180] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Ci-galkyl.
[00181] [00181] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R 'is substituted or unsubstituted aryl and Rº is Cisalkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy, cycloalkyl , or heterocyclylalkyl.
[00182] [00182] In another embodiment, the TOR kinase inhibitors of formula (Ie) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00183] [00183] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (If): R2
[00184] [00184] In one embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is substituted aryl, such as substituted phenyl.
[00185] [00185] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[00186] [00186] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R '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.
[00187] [00187] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is H.
[00188] [00188] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which Rº is substituted Cigalkyl.
[00189] [00189] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or heterocyclylalkyl replaced or not replaced.
[00190] [00190] In another embodiment, the TOR kinase inhibitors of the formula (If) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00191] [00191] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00192] [00192] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which D H.
[00193] [00193] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which L is a direct link.
[00194] [00194] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Cigalkyl.
[00195] [00195] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is substituted or unsubstituted aryl and Rº is Ci-galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy , cycloalkyl, or heterocyclylalkyl.
[00196] [00196] In another embodiment, the TOR kinase inhibitors of formula (If) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00197] [00197] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (Ig): R2 | -t N /
[00198] [00198] In one embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is substituted aryl, such as substituted phenyl.
[00199] [00199] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.
[00200] [00200] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R '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.
[00201] [00201] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is H.
[00202] [00202] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which Rº is substituted Cigalkyl.
[00203] [00203] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which Rº is methyl or ethyl substituted or unsubstituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or heterocycloalkyl replaced or not replaced.
[00204] [00204] In another embodiment, the TOR kinase inhibitors of the formula (Ig) are those in which Rº is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclylalkyl.
[00205] [00205] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00206] [00206] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which Rº is H.
[00207] [00207] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which L is a direct link.
[00208] [00208] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is substituted or unsubstituted aryl and Rº is unsubstituted Ci-galkyl.
[00209] [00209] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is substituted or unsubstituted aryl and Rº is Ci-galkyl substituted with one or more substituents selected from alkoxy, amino, hydroxy , cycloalkyl, or heterocyclylalkyl.
[00210] [00210] In another embodiment, the TOR kinase inhibitors of formula (Ig) are those in which R 'is substituted or unsubstituted aryl and Rº is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclylalkyl.
[00211] [00211] Representations of TOR kinase inhibitors of formula (1) include compounds from Table A.
[00212] [00212] Table A (S) -1- (1-hydroxy-3-methylbutan-2-yl) -6-phenyl-1H-imidazo ([4,5-b] pyrazin-2 (3H) -one; 1 - (((tetrahydro-2H-pyran-4-yl) methyl) -6- (3,4,5-trimethoxyphenyl) - 1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (R) -6- (naphthalen-1-1i1) -1- (1-phenylethyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; 1- (3-methoxybenzyl) -6- (4 - (methylsulfonyl) phenyl) -1H-imidazo [4,5-b] pyrazin-2 (3H) -one; (S) -1- (1-phenylethyl) -6- (quinolin-5-yl) -1H- imidazo [4,5- b] pyrazin-2 (3H) -one; 6- (4-hydroxyphenyl) -1l - ((tetrahydro-2H-pyran-4-yl) methyl) -lH- imidazo [4,5- b] pyrazin-2 (3H) -one; (S) -6- (naphthalen-1-yl) -1- (1-phenylethyl) -1H-imidazo [4,5- b] pyrazin-2 (3H) - ona;
[00213] [00213] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (II):
[00214] [00214] In one embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken together form -N (R ') CH2C (O) NH-.
[00215] [00215] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken together form -N (R2) C (O) CHANH-.
[00216] [00216] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken together form -N (Rº) C (O) NH-.
[00217] [00217] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken together form -N (R ) C = N-.
[00218] [00218] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken together form -C (R º) = cHNH-.
[00219] [00219] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which L is a direct link.
[00220] [00220] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which R 'is substituted aryl, such as substituted phenyl.
[00221] [00221] In another embodiment, the TOR kinase inhibitors | of formula (II) are those in which R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine
[00223] [00223] In another embodiment, the TOR kinase inhibitors | of formula (II) are those in which -X-A-B-Y- taken in | together form -N (R) C (O) NH- and Rº is substituted aryl, such as phenyl.
[00224] [00224] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH- and Rº is substituted or unsubstituted heteroaryl, such as Substituted and unsubstituted pyridine, substituted or unsubstituted indole or substituted and unsubstituted quinoline.
[00225] [00225] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH- and Rº is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
[00226] [00226] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which Rº is unsubstituted Ciresalkyl, such as -CH3CékHs.
[00227] [00227] In another embodiment, the TOR kinase inhibitors of formula (II) are those where RR is unsubstituted Ci-salquyl, such as unsubstituted methyl.
[00228] [00228] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00229] [00229] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which Rº is substituted aryl, such as halo, haloalkyl or substituted phenyl alkoxy.
[00230] [00230] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which R is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
[00231] [00231] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which Rº is substituted heterocyclylalkyl, such as substituted piperidine.
[00232] [00232] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which R 'and Rº are H.
[00233] [00233] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (R) C (O) NH- and Rº is unsubstituted aryl, such as phenyl not substituted.
[00234] [00234] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH-, R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine and Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00235] [00235] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -X-A-B-Y- taken in | together form -N (Rº) C (O) NH-, R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine and Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl and Rº and Rº are H.
[00236] [00236] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (R) C (O) NH-, L is a direct bond, Rº is substituted heteroaryl or unsubstituted, such as substituted or unsubstituted pyridine and Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl and R and Rº are H.
[00237] [00237] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH-, Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl and 8 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00238] [00238] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH-, Rº 'is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl and R is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and Rº and Rº are H.
[00239] [00239] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (R) C (O) NH-, L is a direct bond, R 'is aryl substituted or unsubstituted, such as substituted or unsubstituted phenyl and Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl, and R and Rº are H.
[00240] [00240] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (Rº) C (O) NH-, L is a direct bond, Rº is substituted heteroaryl or unsubstituted, Rº is substituted or unsubstituted Ci-galquil or substituted or unsubstituted cycloalkyl.
[00241] [00241] In another embodiment, the TOR kinase inhibitors of formula (II) are those in which -XABY- taken together form -N (R2) C (O) NH-, L is a direct bond, Rº is substituted aryl or not substituted, Rº is substituted or unsubstituted Cigalkyl or substituted or unsubstituted cycloalkyl.
[00242] [00242] In another embodiment, the TOR kinase inhibitors of formula (II) do not include 8,9-dihydro-8-oxo-9-phenyl-2- (3-pyridinyl) -7H-purine-6-carboxamide, 8 , 9-dihydro-8-oxo-9-phenyl- 2- (3-pyridinyl) -7H-purine-6-carboxamide, 8,9-dihydro-8-ox0-9-
[00243] [00243] In another embodiment, the TOR kinase inhibitors of formula (II) do not include compounds in which Rº is a substituted furanoside ring.
[00244] [00244] In another embodiment, the TOR kinase inhibitors of formula (II) do not include compounds in which Rº is a substituted or unsubstituted furanoside ring.
[00245] [00245] In another embodiment, the TOR kinase inhibitors of formula (II) do not include nucleosides (2'R) -2'-deoxy-2'-fluor-2'-C-methyl.
[00246] [00246] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (IIa): R2 R1 N É Dx | O
[00247] [00247] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which R 'is substituted aryl, substituted heteroaryl, such as substituted phenyl.
[00248] [00248] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline.
[00249] [00249] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which R 'is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
[00250] [00250] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Rº is substituted Ci-salkyl, such as -CH2CkHs.
[00251] [00251] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Rº is unsubstituted Ciesalkyl, such as unsubstituted methyl.
[00252] [00252] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Rº is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00253] [00253] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Rº is substituted aryl, such as halo, haloalkyl or substituted phenyl alkoxy.
[00254] [00254] In another embodiment, TOR kinase inhibitors of formula (IIa) are those in which Rº is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
[00255] [00255] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Rº is substituted heterocyclylalkyl, such as piperidine.
[00256] [00256] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which Re Rº are H.
[00257] [00257] In another embodiment, the TOR kinase inhibitors of formula (IIa) do not include 8,9-dihydro-8-oxo-9-phenyl-2- (3-pyridinyl) -7H-Purine-6-carboxy, 8 , 9-dihydro-8-oxo-9-phenyl- 2- (3-pyridinyl) -7H-Purine-6-carboximide, 8,9I-dihydro-8-ox0-9-phenyl-2- (3-pyridinyl) -7H-Purine-6-carboximide, 2- (4-cyanophenyl) -8-o0x0o-9-phenyl-8,9-dihydro-7H-purine-6-carboximide, 2- (4-nitrophenyl) -8-o0xo -9-phenyl-8,9-dihydro-7H-purine-6-carboximide, 9-benzyl-2- (4-methoxyphenyl) -8-0x0-8,9-dihydro-7H-purine-6-carboxy, 9 -phenylmethyl-9H-purine-2,6-dicarboximide, or 2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboximide.
[00258] [00258] In another embodiment, the TOR kinase inhibitors of formula (IIa) do not include compounds in which Rº is a substituted furanoside ring.
[00259] [00259] In another embodiment, the TOR kinase inhibitors of formula (IIa) do not include compounds in which R ° is a substituted or unsubstituted furanoside ring.
[00260] [00260] In another embodiment, the TOR kinase inhibitors of formula (IIa) do not include nucleosides (2'R) -2'-deoxy-2'-fluorine-2'-C-methyl.
[00261] [00261] In one embodiment, inhibitors include compounds containing the following formula (IIb): 1
[00262] [00262] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R 'is substituted aryl, such as substituted phenyl.
[00263] [00263] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline.
[00264] [00264] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R 'is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
[00265] [00265] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R º is substituted Cigalkyl, such as -CH2CkHs.
[00266] [00266] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R, is unsubstituted Cisgalkyl, such as unsubstituted methyl.
[00267] [00267] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R, is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00268] [00268] In another embodiment, the TOR kinase inhibitors of formula (IIa) are those in which R, is substituted aryl, such as halo, haloalkyl or substituted phenyl alkoxy.
[00269] [00269] In another embodiment, the TOR kinase inhibitors | of formula (IIb) are those in which R, is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
[00270] [00270] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R, is substituted heterocyclylalkyl, such as piperidine.
[00271] [00271] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R º and Rº are H.
[00272] [00272] In another embodiment, the TOR 2 XxFTTYO 2 kinase inhibitors of formula (IIb) are those in which it is -C (Rº) = CH- NH- and Rº is substituted aryl, such as phenyl.
[00273] [00273] In another embodiment, the TOR xFTTY— 2 kinase inhibitors of formula (IIb) are those in which it is -N (R) - CH = N- and Rº is substituted aryl, such as phenyl.
[00274] [00274] In another embodiment, the TOR kinase inhibitors of formula (IIb) are those in which R1 is substituted aryl, such as phenyl, and R2 is substituted aryl, such as phenyl.
[00275] [00275] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include 9-benzyl-9H-purine-2,6-
[00276] [00276] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds in which Rº is:: xFTTTTY— 2 cyclobutyl substituted when it is -N (Rº) -CH = N-.
[00277] [00277] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds where Rº is an as a => ATETMY— 2 E furanoside ring substituted when it is -N (Rº) -CH = N-.
[00278] [00278] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds in which Rº is ia; xTFTTY— 2 substituted pyrimidine when it is -C (R “) = CH-NH-.
[00279] [00279] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds where Rº is oxetane XxFTTY = 2 substituted when it is -N (Rº) -CH = N-.
[00280] [00280] In another embodiment, the TOR kinase inhibitors of formula (IIb) do not include compounds where Rº is xF Ty 2 cyclopentyl or heterocyclopentyl when it is "N (R ') = CH = N-.
[00281] [00281]
[00282] [00282] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (IIc): R2 R1 N N N Pá N o
[00283] [00283] In another embodiment, the TOR kinase inhibitors of formula (IIc) are those in which R 'is substituted aryl, such as substituted phenyl.
[00284] [00284] In another embodiment, the TOR kinase inhibitors of formula (IIc) are those in which R 'is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline.
[00285] [00285] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R 'is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
[00286] [00286] In another embodiment, the TOR kinase inhibitors of formula (IIc) are those in which Rº is substituted Ci-salkyl, such as -CH2CekHs.
[00287] [00287] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R, is unsubstituted Cisalkyl, such as unsubstituted methyl.
[00288] [00288] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R, is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00289] [00289] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R, is substituted aryl, such as halo, haloalkyl or substituted phenyl alkoxy.
[00290] [00290] In another embodiment, the TOR kinase inhibitors of formula (IICc) are those in which R, is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
[00291] [00291] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R, is substituted heterocyclylalkyl, such as piperidine.
[00292] [00292] In another embodiment, the TOR kinase inhibitors of formula (IIc) are those in which Rº and Rº are H.
[00293] [00293] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (IId): R2 R1 N N o
[00294] [00294] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R1 is substituted aryl, such as substituted phenyl.
[00295] [00295] In another embodiment, the TOR kinase inhibitors of formula (TTc) are those in which R1 is substituted or unsubstituted heteroaryl, such as substituted or unsubstituted pyridine, substituted or unsubstituted indole or substituted or unsubstituted quinoline.
[00296] [00296] In another embodiment, the TOR kinase inhibitors of formula (ITC) are those in which R11 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclopentyl.
[00297] [00297] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R2 is substituted Cl-8alkyl, such as -CH2C6H5.
[00298] [00298] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R2 is unsubstituted Cl-8alkyl, such as unsubstituted methyl.
[00299] [00299] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R2 is substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl.
[00300] [00300] In another embodiment, the TOR kinase inhibitors of formula (IIc) are those in which R2 is substituted aryl, such as halo, haloalkyl or substituted phenyl alkoxy.
[00301] [00301] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R2 is substituted or unsubstituted cycloalkyl, such as substituted or unsubstituted cyclohexyl or substituted or unsubstituted cycloheptyl.
[00302] [00302] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R2 is substituted heterocyclylalkyl, such as piperidine.
[00303] [00303] In another embodiment, the TOR kinase inhibitors of formula (IIC) are those in which R3 and R4 are H.
[00304] [00304] Representatives of TOR kinase inhibitors of formula (II) include compounds from Table B. Table B
[00305] [00305] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (III):
[00306] [00306] In some embodiments of compounds of formula (III), R ° is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In one embodiment, Rº is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, 1H-pyrrol [2,3-b] pyridyl, 1H-imidazo [4,5-b] pyridyl, 1H-imidazo [4,5- b] pyridin-2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 'is phenyl substituted with one or more substituents - “independently selected from a group consisting of C; 7-g substituted or unsubstituted alkyl (for example, methyl), substituted or unsubstituted heterocyclyl (for example, triazolyl or substituted or unsubstituted pyrazolyl), halogen (for example, fluorine), aminocarbonyl, cyano, hydroxyalkyl (for example, hydroxypropyl), and hydroxyl. In other embodiments, Rº is substituted pyridyl with one or more substituents independently selected from a group consisting of Cr; substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl (e.g. substituted or unsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and -NR ;, where each R is independently H, or Cr, substituted or unsubstituted alkyl. In other embodiments, D 1H-
[00307] [00307] In some embodiments of compounds of formula (III), Rº is N o * (Ss à (SS | NS Se 7 A VW (CR2), OR ECA SN oo 4 UI CRaOR RREO, CA RÇÕ,; R * O RN Sd NR O to LD NX Ux S o RN o (Fr Rm, Mo RR, 1º "% RN RNA Na N> RN ÁQANR y ir NA R: (CR N Xp, Í Rh E m RD m LZ m ja A o ". PA. '" A, or RNÁ NR [FR
[00308] [00308] In some embodiments of compounds of formula | (111), Rº is
[00309] [00309] In some embodiments of compounds of formula (111), R is H, C1-g substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, Cr, substituted or unsubstituted alkylheterocyclyl, C1 -, substituted or unsubstituted alkyl-aryl, or substituted or unsubstituted C1-a alkyl-cycloalkyl. For example, Rº is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C1-a alkyl ) -phenyl, (C1-a alkyl) -cyclopropyl, (C1-a4 alkyl) -cyclobutyl, (C1-a alkyl) -cyclopentyl, (C1-a alkyl) -cyclohexyl, (Ci-a alkyl) -pyrrolidyl, ( C1-a alkyl) -piperidyl, (C1-4 alkyl) -piperazinyl, (C1-4 alkyl) -morpholinyl, (C1-a alkyl) -tetrahydrofuranyl, or (C1-4 alkyl) - tetrahydropyranyl, each optionally substituted.
[00310] [00310] In other embodiments, Rº is H, Ci alkyl, (C1 aalkyl) (OR),
[00311] [00311] In some such embodiments, Rº is H, Cia alkyl, (Ci-aalkyl) (OR),
[00312] [00312] In some other embodiments of compounds of formula (III), R eunde Re R together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl. For example, in some embodiments, The compound of formula (III) is. Rº fo FR (RONN RONAN RONAN [o | | P Z Z NON TO NON TO N NO, H,
[00313] [00313] In some embodiments of compounds of formula | (III), Rº and Rº are both H. In others, one of RR and Ré He the other is other than H. Still in others, one of Rº and Rº is Ci, alkyl (for example, methyl) and the other is H. In still others, both Rº and Rº are C1-4 alkyl (for example, methyl).
[00314] [00314] In such embodiments described below, R 'is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, R 'is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, 1H-pyrrole [2,3-b] pyridyl, 1H-imidazo [4,5-b] pyridyl, 1H-imidazo [4,5- b] pyridin-2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 'is phenyl substituted with one or more substituents independently selected from a group consisting of Cir; substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl and hydroxyl. In others, Rº is pyridyl substituted with one or more substituents independently selected from a group consisting of cyano, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hydroxyalkyl, halogen, aminocarbonyl, -OR, and -NR ,, wherein each R is independently H, or a substituted or unsubstituted C1-, alkyl. In others, Rº is 1H-pyrrole [2,3-b] pyridyl or benzimidazolyl, optionally substituted with one or more substituents — independently selected from a group consisting of substituted or unsubstituted C1-g alkyl, and - NR, where R is independently H, or a C; 7, substituted or unsubstituted alkyl.
[00315] [00315] In certain embodiments, the compounds of formula (III) contain an R 'group established here and an Rº group established here.
[00316] [00316] In some embodiments of compounds of formula (III), the compound at a concentration of 10 µM inhibits mTOR, DNA-PK, or PI3K or a combination thereof, by at least about 50%. Compounds of formula (III) below can be kinase inhibitors in any suitable test system.
[00317] [00317] Representations of TOR kinase inhibitors of formula (III) include compounds from Table C.
[00318] [00318] Table C 6- (1H-pyrrole [2,3-b] pyridin-3-11) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazin [ 2,3-b] pyrazin-2 (1H) -one; 6- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-1yl) -4- i ((tetrahydro-2H-pyran-4-yl) methyl) -3 , 4-dihydropyrazin ([2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl ) -4 - ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazin [2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- ( 1H-1,2,4-triazol-3-yl) phenyl) -4 - ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazin (2,3-b] pyrazin-2 (1H) -one ;
[00319] [00319] In one embodiment, TOR kinase inhibitors include compounds containing the following formula (IV): R2 R N N o [CC
[00320] [00320] In some embodiments of compounds of formula (1V), R 'is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. For example, R 'is phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-pyrrole [2,3-b] pyridyl, indazolyl, indolyl, 1H-imidazo ([4,5-b] pyridyl, 1H-imidazo [4,5 - b] pyridin-2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each optionally substituted In some embodiments, R 'is phenyl substituted with one or more substituents selected independently of one group consisting of C1-g alkyl - substituted or unsubstituted (eg, methyl), substituted or unsubstituted heterocyclyl (eg, substituted or unsubstituted and substituted triazolyl or Dpirazolyl), aminocarbonyl, halogen (eg, fluorine), cyano, hydroxyalkyl and hydroxy.In other embodiments, Rº is pyridyl substituted with one or more substituents selected from substituted or unsubstituted Cirg alkyl (eg, methyl), substituted or unsubstituted heterocyclyl (eg, a substituted or unsubstituted triazolyl) , halogen, aminocarbonyl, cyano, hydroxyalkyl (e.g., hydroxypropyl), -OR, and -NR ,, wherein each R is independently H, or substituted or unsubstituted C1-a alkyl. In some embodiments, R ° is 1H-pyrrole [2,3-b] pyridyl or benzimidazolyl, optionally "substituted with one or more substituents selected independently of a group consisting of substituted or unsubstituted alkyl Cai-s, and -NR ,, in that R is independently H, or substituted or unsubstituted C1-a alkyl.
[00321] [00321] In some embodiments, Rº is N o * .. mm É * (Dery.oR Ch ES VD-eRa.oR a CARRO, ORA;
[00322] [00322] In some embodiments of formula (IV), Rº é = NA Eres o generates E "
[00323] [00323] In some confretizations of formula (IV), Rº is à, C1-substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, Cr, substituted or unsubstituted alkyl-heterocyclyl, C1-, substituted or unsubstituted alkyl-aryl, or C1-, substituted or unsubstituted alkyl-cycloalkyl. For example, Rº is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C1-a alkyl ) -phenyl, (C1-4 alkyl) -cyclopropyl, (C1-14 alkyl) -cyclobutyl, (C1-a alkyl) -cyclopentyl, (C1-a4 alkyl) -cyclohexyl, (C1-a alkyl) -pyrrolidyl, ( C1-a alkyl) -piperidyl, (C1-a alkyl) -piperazinyl, (C1-a alkyl) -morpholinyl, (C1-a4 alkyl) -tetrahydrofuranyl, or (C1-a alkyl) -tetrahydropyranyl, each optionally substituted.
[00324] [00324] In other embodiments, Rº is H, Cia alkyl, (CO. Aalkyl) (OR),
[00325] [00325] In other embodiments of formula (IV), Rº is H, Cia alkyl, (Ciaalkyl) (OR),
[00326] [00326] In other embodiments of formula (IV), Rº is H.
[00327] [00327] In some such embodiments, R 'is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, R 'is phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-pyrrole [2,3-b] pyridyl, indazolyl, indolyl, 1H-imidazo [4,5-b] pyridine, pyridyl, 1H-imidazo [4, 5-b] pyridin-2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each optionally substituted. In some embodiments, R 'phenyl substituted with one or more substituents selected independently of a group consisting of Cr; substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen (e.g., fluorine), cyano, hydroxyalkyl and hydroxy. In others, Rº is pyridyl substituted with one or more substituents - selected independently from a group consisting of substituted or unsubstituted C1i-g alkyl, substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and -NR% , wherein each R is independently H, or a substituted or unsubstituted C1-, alkyl. In still others, RO is 1H-pyrrole [2,3-b] pyridyl or benzimidazolyl, optionally substituted with one or more substituents selected independently of a group consisting of substituted or unsubstituted C 1 -alkyl, and -NR ,, in that R is: independently H, or a C174, substituted or unsubstituted alkyl.
[00328] [00328] In certain embodiments, the compounds of formula (IV) contain an R 'group established here and an Rº group established here.
[00329] [00329] In certain embodiments of compounds of formula (IV), the compound at a concentration of 10 µM inhibits mTOR, DNA-PK, PI3K, or a combination of them by at least about 50%. Compounds of formula (IV) shown below can be considered kinase inhibitors in any suitable test system.
[00330] [00330] Representative TOR kinase inhibitors of formula (IV) include the compounds of Table D. Table D
[00331] [00331] TOR kinase inhibitors can be obtained using standard, well-known synthetic methodology, see, for example, March, Jd. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992 The starting materials useful for the preparation of compounds of formula (III) and intermediates thereof, are therefore commercially available or can be prepared from commercially available materials using methods and known synthetic reagents.
[00332] [00332] Particular methods for the preparation of compounds of formula (I) are described in U.S. Patent No.
[00333] [00333] Methods are provided herein to treat or prevent advanced non-small cell lung cancer, comprising administering an effective amount of a TOR inhibitor kinase and an effective amount of erlotinib or a cytidine analog to a cancer patient advanced non-small cell lung. In certain embodiments, the cytidine analogue is oral azacytidine. In certain embodiments, advanced non-small cell lung cancer is non-small cell lung cancer, Phase IIIB non-small cell lung cancer, or Stage IV non-small cell lung cancer. In certain embodiments, the patient has failed at least one standard therapy line. In one embodiment, the standard is chemotherapy therapy or treatment with an EGFR inhibitor, for example, erlotinib. In one embodiment, non-small cell lung cancer is resistant to EGFR inhibitors, for example, resistant to erlotinib. In such an embodiment, non-small cell lung cancer is characterized by a mutation resistant to the EGFR inhibitor, for example, the EGFR T790M mutation. In another embodiment, non-small cell lung cancer has an EGFR-activating mutation, for example, the EGFR mutation L858R. In some embodiments, the methods further comprise screening the patient's non-small cell lung cancer for an EGFR inhibitor resistant mutation, for example, an erlotinib resistant mutation. Other methods include screening the patient's non-small cell lung cancer for a mutation that activates EGFR.
[00334] [00334] Methods are also provided to predict the therapeutic efficacy of treating a patient with non-small cell lung cancer with a TOR kinase inhibitor in combination with erlotinib or a cytidine analogue, which comprises obtaining a biological sample of the cancer of the patient and screening of said cancer of the patient to detect the presence of an EGFR mutation, in which the presence of a mutation is predictive of the therapeutic efficacy of treatment with the TOR kinase inhibitor in combination with erlotinib or a cytidine analog. In such an embodiment, the mutation is an activation mutation. In another, the mutation results in resistance to EGFR inhibitors. As is well known in the art, screening for an EGFR mutation can be performed by, for example, sequencing the EGFR gene.
[00335] [00335] In certain embodiments, methods are provided here for obtaining a response in Response Evaluation Criteria in Solid Tumors (for example, RECIST
[00337] [00337] In one embodiment, methods are provided here to prevent or delay some Evaluation Criteria for | Solid Tumor Response (eg, RECIST 1.1) of disease progression in a patient, which comprises administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analog to a cancer patient lung cancer of the patient. In certain embodiments, the cytidine analogue is oral azacytidine. In one embodiment, the prevention or delay of disease progression is characterized or achieved by a change in the total size of the target lesions, for example, between -30% and + 20% compared to pretreatment. In another embodiment, the change in the size of the target lesions is a reduction in the overall size of more than 30%, for example, a reduction of more than 50% in the size of the target lesion compared to pretreatment. In another, prevention is achieved or characterized by a reduction in size or a delay in the progression of non-target lesions compared to pretreatment. In one embodiment, prevention is achieved or characterized by a reduction in the number of target lesions compared to pretreatment. In another, prevention is achieved or characterized by a reduction in the number or quality of non-target lesions compared to pretreatment. In one embodiment, prevention is achieved or characterized by the absence or disappearance of the target lesions compared to pretreatment. In another, prevention is achieved or characterized by the absence or disappearance of non-target lesions compared to pre-treatment. In another embodiment, prevention is achieved or characterized by the prevention of new injuries, compared to pre-treatment. In yet another embodiment, prevention is achieved or characterized by the prevention of clinical signs and symptoms of disease progression compared to pretreatment, such as cancer-related cachexia or increased pain.
[00338] [00338] In certain embodiments, methods are provided here for decreasing the size of the target lesions in a patient, as compared to pretreatment, which comprises administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analog to a patient with advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00339] [00339] In certain embodiments, methods are provided here for decreasing the size of a non-target lesion in a patient in relation to pretreatment, which comprises administering an effective amount of a TOR kinase inhibitor in combination with a effective amount of erlotinib or a cytidine analog to a patient with advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00340] [00340] In certain embodiments, methods are provided here for obtaining a reduction in the number of target lesions in a patient, as compared to pretreatment, which comprises administering an effective amount of a TOR kinase inhibitor in combination with a effective amount of erlotinib or a cytidine analog to a patient with advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00341] [00341] In certain embodiments, methods are provided here for obtaining a reduction in the number of non-target lesions in a patient, as compared to pretreatment, which comprises administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analog for a patient containing advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00342] [00342] In certain embodiments, methods are provided herein for obtaining the absence of all target lesions in a patient, comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or an analogue of cytidine for a patient with advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00343] [00343] In certain embodiments, methods are provided here for obtaining an absence of all non-target lesions in a patient, comprising administration | of an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a | analogue of cytidine for a patient with advanced non-small cell lung cancer. In certain embodiments, the cytidine analogue is oral azacytidine.
[00344] [00344] In certain embodiments, methods for treating non-small cell lung cancer are provided herein, methods comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or an analogue of cytidine for a patient who has advanced non-small cell lung cancer, in which the treatment results in a complete response, partial response or stable disease are as determined by the Solid Tumor Response Assessment Criteria (for example, RECIST 1.1 ).
[00345] [00345] In certain embodiments, methods are provided herein for the treatment of non-small cell lung cancer, methods comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or an analogue of cytidine for a patient containing advanced non-small cell lung cancer, where treatment results in a reduction in the size of the target lesion, a reduction in the size of the non-target lesion and / or the absence of a new target and / or non-target lesions in relation to pre-treatment.
[00346] [00346] In certain embodiments, methods are provided herein for the treatment of advanced non-small cell lung cancer, methods comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or an analogue of cytidine for a patient who has advanced non-small cell lung cancer, where treatment results in the prevention or delay of clinical progression, such as cancer-related cachexia or increased pain.
[00347] [00347] In some embodiments, methods are provided here for the treatment of non-small cell lung cancer, methods comprising administering an effective amount of a TOR kinase inhibitor in combination: with an effective amount of erlotinib or an analogue of cytidine for a patient who has advanced non-small cell lung cancer, where treatment results in one or more of an inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor mass, relief of related symptoms with tumors, tumor inhibition (including hormones secreted by the tumor, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, delayed development of primary or secondary tumors, decreases the occurrence of primary or secondary tumors, delays Or it decreases the severity of the side effects of the disease, the growth of the stuck tumor and the regression of tumors, increased time to progression (TTP), increased progression-free survival (PFS), and / or increased overall survival (OS), among others.
[00348] [00348] In some embodiments, the TOR kinase inhibitor is a compound as described herein. In one embodiment, the TOR kinase inhibitor is compound 1 (a kinase & TOR inhibitor set forth herein with the molecular formula C21H2; Ns5O3). In one embodiment, Compound 1 is 7- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -1 - ((1r, 4r) -4-methoxycyclohexyl) -3,4- dihydropyrazine- [2 , 3-b] pyrazin-2 (1H) -one.
[00349] [00349] A TOR kinase inhibitor administered in combination with erlotinib or a cytidine analogue can further be combined with radiation therapy or surgery. In certain embodiments, a TOR kinase inhibitor is administered in combination with erlotinib or a cytidine analog to the patient who is undergoing radiation therapy, has previously been subjected to radiation therapy, or will be undergoing radiation therapy. In certain embodiments, a TOR kinase inhibitor is administered in combination with erlotinib or a cytidine analog to a patient who has undergone surgery, such as surgery to remove the tumor. In certain embodiments, the cytidine analogue is oral azacytidine.
[00350] [00350] Additionally, methods are provided here for the treatment of patients who have previously been treated for advanced non-small cell lung cancer, as well as those who have not been previously treated. In addition, methods are provided here for treating patients who have undergone surgery in an attempt to treat advanced non-small cell lung cancer, as well as those who do not. As patients with advanced non-small cell lung cancer have heterogeneous clinical manifestations and different clinical outcomes, the treatment given to a patient may vary, depending on his / her prognosis. The experienced physician will be able to readily determine without specific experimentation the specific secondary agents, the types of surgery, and the types of standard non-drug based therapy that can be effectively used to treat an individual patient with non-cell lung cancer. small advanced.
[00351] [00351] In certain embodiments, a TOR kinase inhibitor is administered in combination with a cytidine analog or erlotinib to a patient in cycles. Cycle therapy involves administering an active agent over a period of time, followed by resting for a period of time and repeating this sequential administration. Cycle therapy can reduce the development of resistance, prevent or reduce side effects, and / or improve treatment effectiveness.
[00352] [00352] In one embodiment, a TOR kinase inhibitor is administered in combination with a cytidine analogue or erlotinib daily in single or divided doses, for about 3 days, about 5 days, about a week, about two weeks, about three weeks, about four weeks (for example, 28 days), about five weeks, about six weeks, about seven weeks, about eight weeks, about 10 weeks, about 15 weeks, or about 20 weeks, followed by a rest period of about 1 day to about 10 weeks. In one embodiment, the methods provided herein contemplate treatments in cycles of about a week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, about 10 weeks, about weeks, or about 20 weeks. In some embodiments, a TOR kinase inhibitor is administered in combination with a cytidine or erlotinib analogue, in single or divided doses, for about 3 days, about 5 days, about a week, about two weeks, about three weeks, about four weeks (for example, 28 days), about five weeks, or about six weeks with a rest period of about 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days. In some embodiments, the rest period is 1 day. In some embodiments, the rest period is 3 days. In some embodiments, the rest period is 7 days. In some embodiments, the rest period is 14 days. In some embodiments, the rest period is 28 days. The frequency, number and length of the dosing cycles can be increased or decreased.
[00353] [00353] In one embodiment, the methods provided herein include: i) administering to a subject a first daily dose of a TOR kinase inhibitor in combination with a cytidine or erlotinib analog; ii) optionally, with a rest period of at least one day when a cytidine or erlotinib analogue is not administered to the individual; iii) administering a second dose of a TOR kinase inhibitor in combination with a cytidine or erlotinib analogue to the subject; and iv) repeating steps ii) through iii) a plurality of times.
[00354] [00354] In one embodiment, the methods provided herein comprise administering to the subject a dose of a cytidine or erlotinib analog on day 1, followed by administration of a TOR kinase inhibitor in combination with a cytidine or erlotinib analog to the subject in day 2 and subsequent days.
[00355] [00355] In certain embodiments, a TOR kinase inhibitor in combination with a cytidine analogue or erlotinib is administered continuously for about 1 to about 52 weeks. In certain embodiments, a TOR kinase inhibitor in combination with a cytidine analogue or erlotinib is administered continuously for about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In certain embodiments, a TOR kinase inhibitor in combination with a cytidine analogue or erlotinib is administered continuously for about 7, about 14, about 21, about 28, about 35, about 42, about 84, or about 112 days.
[00356] [00356] In certain embodiments, when a TOR kinase inhibitor is administered in combination with a cytidine analogue, the TOR kinase inhibitors are administered continuously for 28 days, while a cytidine analogue is administered continuously for 21 days, followed by 7 days without administration of a cytidine analog. In one embodiment, in a 28-day cycle, the cytidine analogue is administered alone on Day 1, the cytidine analogue and the kinase inhibitor TOR are administered in combination, on days 2-21l and the kinase inhibitor TOR is administered alone in days 22-28. In some such embodiments, starting from cycle 2, both the cytidine analogue and the TOR kinase inhibitor are administered on day 1, the cytidine analogue is continued until Day 21, while the TOR kinase inhibitor is maintained until per day
[00357] [00357] In certain embodiments, when a TOR kinase inhibitor, when administered in combination with a cytidine analog, in a 28-day cycle, the cytidine analog is administered alone on days 1-7 and the TOR kinase inhibitor is administered alone on days 8-28. Such 28-day cycles can be maintained as long as necessary, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or more.
[00358] [00358] In certain embodiments, when a TOR kinase inhibitor is administered in combination with a cytidine analog, the TOR kinase inhibitor is administered in an amount of about 5 mg to about 50 mg (e.g., about 10 mg , about 15 mg, about 30 mg, or about 45 mg) and a cytidine analog is administered in an amount of about 50 mg to about 350 mg (for example, about 100 mg, about 200 mg, or about 300 mg). In certain embodiments, an amount of about 10 mg of a TOR kinase inhibitor is administered in combination with about | 100 mg, about 200 mg, or about 300 mg of a cytidine analog. In certain embodiments, an amount of about mg of a TOR kinase inhibitor is administered in combination with about 100 mg, about 200 mg, or about 300 mg of a cytidine analog. In certain embodiments, an amount of about 30 mg of a TOR kinase inhibitor is administered in combination with about 100 mg, about 200 mg, or about 300 mg of a cytidine analog. In certain embodiments, an amount of about 45 mg of a TOR kinase inhibitor is administered in combination with about 100 mg, about 200 mg, or about 300 mg of a cytidine analog.
[00359] [00359] In certain embodiments, when a TOR kinase inhibitor is administered in combination with a cytidine analog, the ratio of TOR kinase inhibitor: cytidine analog is from about 1: 1 to approximately 1:10. In certain embodiments, when a TOR kinase inhibitor, when administered in combination with a cytidine analog, the ratio of the TOR kinase: cytidine analog is less than about 1: 1, less than 1: 3 or less than about 1:10. In certain embodiments, when a TOR kinase inhibitor is administered in combination with a cytidine analog, the ratio of TOR kinase: cytidine analogue is approximately 1: 1, approximately 1: 3, or approximately 1:10.
[00361] [00361] In certain embodiments, when a TOR kinase inhibitor is administered in combination with erlotinib, the ratio of TOR: erlotinib kinase inhibitor is from about 1: 1 to about 1:30. In certain embodiments, when a TOR kinase inhibitor is administered in combination with erlotinib, the ratio of TOR: erlotinib kinase inhibitor is less than about 1: 1, less than about 1:10 or less than about 1 : 30. In certain embodiments, when a TOR kinase inhibitor, when administered in combination with erlotinib, the ratio of TOR: erlotinib kinase inhibitor is about 1: 1, about 1:10 or about 1:30.
[00362] [00362] In some embodiments, when a TOR kinase inhibitor, when administered in combination with erlotinib, the TOR kinase inhibitor and erlotinib are taken on an empty stomach, for example, at least 1 hour before and 2 hours after ingestion .
[00363] [00363] Compositions are provided herein comprising an effective amount of a TOR kinase inhibitor and an effective amount of erlotinib or a cytidine analog and compositions, comprising an effective amount of a TOR and erlotinib kinase inhibitor or a cytidine analog and a pharmaceutically acceptable carrier or vehicle. In certain embodiments, the cytidine analogue is oral azacytidine.
[00364] [00364] In some embodiments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration.
[00365] [00365] The compositions can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate) , a binder (for example, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), a disintegrator (e.g. calcium or calcium citrate), a lubricant (eg magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulphate), a flavoring agent (eg citric acid, menthol, glycine or orange powder), a preservative (for example, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (for example, citric acid co, sodium citrate or acetic acid), a suspending agent (for example, methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (for example, hydroxypropylmethylcellulose), a diluent (for example, water), and base wax (for example, cocoa butter, white petroleum jelly or polyethylene glycol). The effective amount of the TOR kinase inhibitor at which the pharmaceutical composition can be at a level that will have the desired effect; for example, about 0.005 mg / kg of a patient's body weight to about 10 mg / kg of a patient's body weight, in unit dosage, for both oral and parenteral administration.
[00366] [00366] The dose of a TOR kinase inhibitor and the dose of erlotinib or a cytidine analogue to be administered to a patient is more widely variable and may be subject to the judgment of a healthcare professional. In general, TOR kinase inhibitors, erlotinib and a cytidine analog can be administered from one to four times a day at a dose of about 0.005 mg / kg of a patient's body weight to about 10 mg / kg of body weight of a patient, but the dosage above can be varied accordingly depending on the age, body weight and medical condition of the patient and the type of administration. In one embodiment, the dose is about 0.01 mg / kg of the patient's body weight to about 5 mg / kg of the patient's body weight, from about 0.05 mg / kg of the patient's body weight to about 1 mg / kg of a patient's body weight, from about 0.1 mg / kg of a patient's body weight to about 0.75 mg / kg of the patient's body weight or about 0.25 mg / kg of a patient's body weight up to about 0.5 mg / kg of a patient's body weight. In one embodiment, one dose is administered per day. In any case, the amount of TOR kinase inhibitor administered will depend on factors such as the solubility of the active component, the formulation used and the route of administration.
[00367] [00367] In another embodiment, methods are provided here for the treatment or prevention of advanced non-small cell lung cancer which comprise administration from about 0.375 mg / day to about 750 mg / day, from about 0.75 mg / day to about 375 mg / day, from about 3.75 mg / day to about 75 mg / day, from about 7.5 mg / day to about 55 mg / day, or about 18 mg / day up to about 37 mg / day of a TOR kinase inhibitor in combination with erlotinib or a cytidine analog to a patient in need thereof.
[00368] [00368] In another embodiment, methods are provided here for the treatment or prevention of advanced non-small cell lung cancer comprising the administration of about 1 mg / day to about 1200 mg / day, about 10 mg / day day to about 1200 mg / day, from about 100 mg / day to about 1200 mg / day, from about 400 mg / day to about 1200 mg / day, from about 600 mg / day to about 1200 mg / day, from about 400 mg / day to about 800 mg / day or from about 600 mg / day to about 800 mg / day of a TOR kinase inhibitor in combination with erlotinib or a cytidine analogue for a patient in need of them. In a particular embodiment, the methods disclosed herein comprise administration of 10 mg / day, 15 mg / day, 30 mg / day, 45 mg / day, 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 600 mg / day or 800 mg / day of a TOR kinase inhibitor in combination with erlotinib or a cytidine analog for a patient in need of them. In one embodiment, the methods disclosed herein comprise the administration of 10 mg / day, 15 mg / day, 30 mg / day, or 45 mg / day, of a TOR kinase inhibitor in combination with erlotinib or a cytidine analog to a patient in need of them.
[00369] [00369] In certain embodiments, the methods provided herein comprise administering between about 100 mg and about 400 mg, about 150 mg and about 350 mg or about 175 mg and about 325 mg of a cytidine analog alone or in combination with a TOR kinase inhibitor. In another embodiment, the methods provided herein comprise administration of about 100 mg, about 200 mg or about 300 mg of a cytidine analog alone or in combination with a TOR kinase inhibitor. In a particular embodiment, the cytidine analogue is oral azacytidine.
[00370] [00370] In another embodiment, the methods provided herein comprise administration of between about 1 mg and about 200 mg, about 10 mg and about 175 mg or about 25 mg and about 150 mg of erlotinib alone or in combination with a TOR kinase inhibitor. In another | embodiment, the methods provided herein comprise administration of about 25 mg, about 75 mg, about 100 mg or about 150 mg of erlotinib alone or in combination with a TOR kinase inhibitor.
[00371] [00371] In another embodiment, unit dosage formulations comprising between about 1 mg and about 2000 mg, about 1 mg and about 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, about 500 mg and about 1000 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg or about 2.5 mg to about 20 mg of a TOR kinase inhibitor alone or in combination with erlotinib or a cytidine analog. In another embodiment, unit dosage formulations comprising 1 mg, 2.5 mg, 5 mg, 10 mg, mg, 20 mg, 30 mg, 35 mg, 45 mg, 50 mg, 70 mg, 100 are provided here mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a TOR kinase inhibitor alone or in combination with erlotinib or cytidine analog. In another embodiment, unit dosage formulations which comprise between about
[00372] In another embodiment, unit dosage formulations comprising between about mg and about 200 mg, about 50 mg and about 150 mg or about 75 mg and about 150 mg of a cytidine analog are provided here , alone or in combination with a TOR kinase inhibitor. In another embodiment, unit dosage formulations comprising about 100 mg of a cytidine analog alone or in combination with a TOR kinase inhibitor are provided here.
[00373] [00373] In another embodiment, provided herein are unit dosage formulations comprising between about 1 mg and about 200 mg, about 10 mg and about 175 mg or about 25 mg and about 150 mg of erlotinib alone or in combination with a TOR kinase inhibitor. In another embodiment, unit dosage formulations comprising about 25 mg, about 100 mg or about 150 mg of erlotinib alone or in combination with a TOR kinase inhibitor are provided here.
[00374] [00374] In a particular embodiment, dosage unit formulations comprising about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 50 mg, about 75 mg, about 75 mg, about 100 mg or about
[00375] [00375] In certain embodiments, unit dosage formulations are provided here in which the TOR: kinase inhibitor ratio of the cytidine is from about 1: 1 to about 1:10. In certain embodiments, unit dosage formulations are provided here in which the TOR: kinase inhibitor ratio of the cytidine is less than about 1: 1, less than about 1: 3 or less than about 1:10. In certain embodiments, unit dosage formulations are provided herein in which the TOR: kinase inhibitor ratio of the cytidine is about 1: 1, about 1: 3, or about 1:10.
[00376] [00376] In certain embodiments, unit dosage formulations are provided here in which the TOR: erlotinib kinase inhibitor ratio is from about 1: 1 to about 1:30. In certain embodiments, unit dosage formulations are provided here in which the TOR: erlotinib inhibitor ratio is less than about 1: 1, less than about 1:10 or less than about 1:30. In certain embodiments, unit dosage formulations are provided here in which the TOR: erlotinib kinase inhibitor ratio is about 1: 1, about 1:10 or about 1:30.
[00377] [00377] A TOR kinase inhibitor can be administered in combination with erlotinib or a cytidine analog, once, twice, three, four or more times a day.
[00378] [00378] In certain embodiments, the methods provided herein comprise administering from about 5 mg to about 100 mg, from about 5 mg to about 50 mg, from about 10 mg to about 50 mg or about 15 mg to about 45 mg of a TOR kinase inhibitor in combination with about 50 mg to about 200 mg, from about 75 mg to about 175 mg or from about 100 mg to about 150 mg of erlotinib. In certain embodiments, the methods provided herein comprise administering about 10 mg, about 15 mg, about 30 mg or about 45 mg of a TOR kinase inhibitor in combination with about 75 mg, about 100 mg or about 150 mg of erlotinib.
[00379] [00379] In certain embodiments, the methods provided herein comprise administering from about 5 mg to about 100 mg, from about 5 mg to about 50 mg, from about 10 mg to about 50 mg or about 15 mg to about 45 mg of a TOR kinase inhibitor in combination with about 50 to about 350 mg, about 75 mg, and about 350 mg, from about 100 mg to about 350 mg, about from 150 mg to about 350 mg, from about 175 mg to about 325 mg or from about 200 mg to about 300 mg of a cytidine analog. In certain embodiments, the methods provided herein comprise administering about 10 mg, about 15 mg, about 30 mg or about 45 mg of a TOR kinase inhibitor in combination with about 100 mg, about 200 mg or about 300 mg of a cytidine analogue, such as oral azacytidine.
[00380] [00380] In certain embodiments, the methods provided herein comprise administration of about 10 mg, about
[00381] [00381] In certain embodiments, the methods provided herein comprise administration of about 10 mg, about mg, about 30 mg or about 45 mg of a: TOR kinase inhibitor in combination with about 100 mg, about 200 mg or about 300 mg of a cytidine analog.
[00382] [00382] A TOR kinase inhibitor can be administered in combination with erlotinib or a cytidine analog orally for reasons of convenience. In one embodiment, when administered orally, a TOR kinase inhibitor in combination with erlotinib or a cytidine analog is administered with a meal and water. In another embodiment, the TOR kinase inhibitor in combination with erlotinib or a cytidine analog is dispersed in water or juice (for example, apple juice or orange juice) and, administered orally as a suspension. In another embodiment, when administered orally, a TOR kinase inhibitor in combination with erlotinib or a cytidine analog is administered in a fasted state.
[00383] [00383] the TOR kinase inhibitor can also be administered in combination with a cytidine analog intravenously, such as intravenous infusion, or subcutaneously, such as subcutaneous injection. The mode of administration is left to the health professional, and may partially depend on the state of the medical condition.
[00384] [00384] In one embodiment, capsules containing a TOR kinase inhibitor in combination with erlotinib or a cytidine analog without an additional carrier, excipient or vehicle are provided here.
[00385] [00385] In another embodiment, compositions are provided herein which comprise an effective amount of a TOR kinase inhibitor, an effective amount of erlotinib or a cytidine analog, and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle it may comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.
[00386] [00386] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. The compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit that can be a single tablet or capsule or a convenient volume of a liquid. In one embodiment, solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules can be prepared by mixing a TOR kinase inhibitor with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different types, cellulose powder,
[00387] [00387] The tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Its formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. In one embodiment, the pharmaceutical composition is free of lactose. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methyl cellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethyl cellulose and waxes can also serve as binders. Illustrative tablet formulations comprising | Compound 1 are shown in Tables 2 and 3.
[00388] [00388] A lubricant may be needed in a tablet formulation to prevent the tablet and punctures from sticking to the mold. The lubricant can be chosen from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. tablet disintegrators are substances that swell when wet to break the tablet and release the compound. They include starches,
[00389] [00389] When it is intended to administer a TOR kinase inhibitor in combination with erlotinib or a cytidine analog as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by adding waxes to slightly increase its melting point. Water-miscible suppository bases comprising, in particular, polyethylene glycols of various molecular weights are in wide use.
[00390] [00390] The effect of the TOR kinase inhibitor in combination with erlotinib or a cytidine analog can be delayed or prolonged by the appropriate formulation. For example, a slowly soluble tablet of the TOR kinase inhibitor in combination with erlotinib or a cytidine analogue can be prepared and incorporated into a tablet or capsule, or as a slow-release implantable device. The technique also includes making tablets of several different dissolution rates and filling capsules with a mixture of the tablets. Tablets or capsules can be coated with a film that resists dissolution for a foreseeable period of time. Even parenteral preparations can be made with long action, by dissolving or suspending the kinase inhibitor TOR in combination with erlotinib or a cytidine analog in oily or emulsified vehicles that allow it to 'slowly disperse in the serum.
[00391] [00391] In certain embodiments, the TOR kinase inhibitor is administered in a formulation set out in United States Provisional Application No. 61/566109, filed on December 2, 2011, which is incorporated herein in its entirety (see in particular the page 22, paragraph [0067] to page 38, paragraph [00162] and page 55, paragraph [00216] to page 68, paragraph [00226]).
[00392] [00392] mTOR HTR-FRET assay. The following is an example of an assay that can be used to determine the TOR kinase inhibitory activity of a test compound. TOR kinase inhibitors were dissolved in DMSO and prepared as 10 mM stocks and diluted accordingly for the experiments. The reagents were prepared as follows:
[00393] [00393] "Simple TOR Buffer" (used to dilute the high glycerol TOR fraction): 10 mM Tris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen mTOR (Cat t PV4753) was diluted in buffer present at an assay concentration of 0.200 pg / ml.
[00394] [00394] ATP / substrate solution: 0.075 mM ATP, 12.5 mM MnCl2, 50 mM Hepes, pH 7.4, 50 mM B-GOP, 250 nM Microcystin LR, 0.25 mM EDTA , 5 mM DTT, and 3.5 pg / ml | GST-p70S6.
[00395] [00395] Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100, 0.01% BSA, 0.1 mM EDTA, 12.7 µg / ml Cy5-aGST Amersham (CatHPA92002V), 9 upg / mL a-phospho p70S6 (Thr389) (Monoclonal Mouse Signaling Cells * + À 9206L), 627 ng / mL a-mouse Lance Eu (Perkin Elmer CattADO0O077).
[00396] [00396] To 20 µl of simple mTOR buffer 0.5 µL of test compound in DMSO is added. To start the reaction 5 ÀupL of ATP solution / substrate was added to 20 pL of the TOR Simples buffer solution (control) and to the solution of the compound prepared above. The test was stopped after 60 minutes by adding 1 µl of a 60 mM EDTA solution; 10 µl of detection reagent solution was then added and the mixture was | left at rest for at least 2 hours before reading on a Perkin-Elmer Envision microplate reader set to detect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520 nm).
[00397] [00397] TOR kinase inhibitors were tested in the mTOR HTR-FRET assay and the activity was verified in it, with certain compounds with an IC of less than 10 pM in the assay, with some compounds that have an IC value, among 0.005 nM and 250 nM and, others with ICs, between 250 nM and 500 nM, others containing ICs, of 500 nM and 1 µM, and others containing ICsº of; 1 pM and 10 pv. |
[00398] [00398] Cell viability assay for cell lines. Compound 1 and the second agent (azacytidine or erlotinib) were added to a 384 well, flat bottom plate, black polystyrene, TC-treated (Cat * 3712, Corning, MA) via an acoustic distributor (EDC Biosystems) . Both Compound 1 and the second agent were serially diluted 3 times over the plate to ten concentrations in triplicate, in three different compound ratios. Both compounds were also added alone to determine their effects as individual agents. DMSO (without compound) were used as a control for 100% viability and background (without cells). Final test concentration of DMSO was 0.2% (v / v). Three different combinatorial sequences of additions were tested. In the first case, both Compound 1 and the second agent were added simultaneously (Yes) on an empty plate. The cells were then added directly to the top of the compounds in an optimized density to ensure that the cell growth was within the linear range of detection of the assay, after three days in culture. In the second case, Compound 1 was added to an empty plate immediately followed by the addition of cells. After 24 hours of cultivation, the second agent was then added to the previous plate and allowed to incubate for another 48 hours (SeqMl). Thus, the treatment time for Compound 1 and the second agent was 72 and 48 hours, respectively. In the third case, the second agent was added to an empty plate immediately followed by the addition of cells. After 24 hours of culture, compound 1 was then added to the previous plate and allowed to incubate for another 48 hours (SeqM2). Thus, the treatment time for Compound 1 and the second agent was 48 and 72 hours, respectively. After 72 hours of total incubation, cell viability was determined using the Promega CellTiter-Glo Luminescent Cell Viability Assay (CattHG7573, Promega, WI), using the usual procedures recommended by the manufacturer. Previous luminescence counts subtracted were converted into percentages of cell viability with respect to control cells treated with DMSO.
[00399] [00399] Dose response curves were generated using XLFit4 (IDBS, UK), adjusting the percentage of data control at each concentration, using a logistic model of parameter 4 / Sigmoidal Dose-Response Model [y = (A + ((BA) / (1 + ((C / x) 'D))))]. To evaluate the combinatorial effect of the two agents in a cell line, the data were analyzed by comparing their combinatorial response against the theoretical additive response of the two agents alone. The expected additive effect of the two agents (A and B) can be calculated using the fractionated product method (Webb 1961, Enzyme and Metabolic Inhibitors, New | York: Academic Press): (fu) A, B = (fu) A x (fu) B, where fu = | fraction not affected by treatment.
[00401] [00401] Results (CI values) are shown in Table 2-4 and Figures 1-4. Synergy is observed for many of the combinations of Compound 1 + azacytidine and Compound 1 + erlotinib. Table 2. Addition of simultaneous compound | Proportion Comp. | Proportion Comp. cell l: azacitidine l: erlotinib
[00402] [00402] As can be seen in the tables and figures, both S5-azacytidine and erlotinib showed synergy with Compound 1 in several NSCLC strains in vitro. The addition sequence affected the combinatorial effect for the combination of Compound 1 and 5-azacytidine. The best combinatorial effect was observed when 5-azacitidine was added before treatment with Compound 1. For the combination of Compound 1 and erlotinib, the ratio of two agents to the addition sequence affected the CI values. The best molar ratio was 1:30 for Compound 1: erlotinib.
[00403] [00403] Non-Small Cell Lung Cancer Primary Tumor Graft-DM179. DM179 is a graft model of | primary tumor derived from tumor tissues obtained from an NSCLC patient. Compound 1 and the second agent are tested as isolated agents and Compound 1 was tested in combination with the second agent (erlotinib or azacytidine) in the model. Naked mice are inoculated subcutaneously with fragments of the DM179 tumor of low passage in the lateral region. After the animals are inoculated, are the tumors allowed to grow to approximately 200 mm before randomization. The animals with DM179 tumors of about 200 mm º, are brought together and randomly divided into different treatment groups. Compound 1 was formulated in 0.5% CMC and 0.25% Tween 80 in water (as a suspension). The animals were administered orally with vehicle (CMC-Tween) or Compound 1 alone or in combination with the second agent, for example, once a day (QD), for 21 days. Treatment with Compound 1 and the second agents is simultaneous or staggered. Doses of compound 1 can vary between 1 and 10 mg / kg, and doses for the second agent or combination are determined based on experimental results from the single agent or in the literature. The positive control of paclitaxel (20 mg / kg, Q7Dx4) is administered intravenously (IV). Tumors are measured twice a week using calibrators and tumor volumes are measured using the formula of W x L / 2 (W = width, L = length).
[00404] [00404] Primary Tumor Graft from Non-Small Cell Lung Cancer BML-5. BML-5 is a primary tumor graft model derived from tissues obtained from tumors of NSCLC patients. Compound 1 and the second agent are tested as isolated agents and Compound 1 was tested in combination with the second agent (erlotinib or azacytidine) in the model. Naked mice are inoculated subcutaneously with low-pass tumor fragments BML-5 in the lateral region. After the animals are inoculated, are the tumors allowed to grow to approximately 200 mm before randomization. The animals with BML-5 tumors of about 200 mmº, are brought together and randomly divided into different treatment groups. Compound 1 was formulated in 0.5% CMC and 0.25% Tween 80 in water (as a suspension). The animals were administered orally with vehicle (CMC-Tween), Compound 1 alone or combined with the second agent, for example, once a day (QD), for 21 days. Treatment with Compound 1 and the second agents is simultaneous or staggered. Doses of compound 1 can vary between 1 and 10 mg / kg, and doses for the second agent or combination are determined on the basis of experimental single agent results or in the literature. The positive control of Docetaxel (20 mg / kg, Q7Dx3) is administered intravenously (IV). Tumors are measured twice a week using calibrators and tumor volumes are calculated using the formula of W x L / 2,
[00405] [00405] Non-Small Cell Lung Cancer Primary Tumor Graft-ST140. STl40 is a primary tumor graft model derived from tissues obtained from tumors of NSCLC patients. Compound 1 and the second agent are tested as isolated agents and Compound 1 was tested in combination with the second agent (erlotinib or azacytidine) in the model.
[00406] [00406] The selected TOR kinase inhibitors show, or are expected to show synergy in the models when used in combination with erlotinib or azacytidine.
[00407] [00407] Proliferation assays. NSCLC cell lines and their sensitivities expressed as 1IC values, for erlotinib and the TOR kinase inhibitor Compound 1 are shown in Table 5. Table 5 s 3/33 3/33) [3/3313 ã 2 [AS] EisIS / RIRDESE [SRS] S m RI8 gl o / o | m “lelal = lol =! lSZlololo s olm oojo ojo Soo oo o S | oo 819/94 SB 9/8/8/8/2 / [9/9/9/9. 9/8 | õ & s! [a S & 6 z = 1 = / S = = | 318] [He | ã R SF = / = / 2/2/2 / = / 3 2/2/8/2 / (á / 2/2/2 If 2 E to 3clalslálo s / s / 2/2) (e / 3 / 8 / ô | | aê I / O Rs 9 ss 2 2/9/8/90 [Y / 9/9/8 2 pi) “ie 2a 2a = | ella vila] | = | and is
[00408] [00408] Compound 1 and erlotinib demonstrated anti-proliferative activity in a panel of NSCLC cell lines with varying degrees of sensitivity so much that it reflected different IC values.
[00409] [00409] Combination indices. This study was carried out using cell lines resistant to erlotinib AS49, H1975, H1650 and HCC95. These cell lines showed different degrees of resistance to erlotinib and have different genetic states regarding the mutation situation in EGFR and KRAS. In combination with erlotinib, Compound 1 showed synergistic anti-proliferative effects in erlotinib-resistant NSCLC cell lines. The results are | shown in Figures 5A-5SD. Synergy was more pronounced at low concentrations, showing combination rates | less than 0.1-0.2, indicating a strong synergy (for interpretation of CI value, see Table 1). These results | indicate that Compound 1 is able to overcome drug resistance to erlotinib in NSCLC cells, revealing synergy effects with combined treatment.
[00410] [00410] Table 6 shows the synergy levels for the combination of erlotinib with Compound 1, in an NSCLC wild cell line (AS49), a cell line (H3255) with an active EGFR mutation (L858R), and a line cell (H1975) with an EGFR mutation (T790M), which is resistant to erlotinib. As can be seen, synergy, as defined by Table 1, was observed in all cell types, including the cell line resistant to erlotinib H1975 (ND = not determined).
[00411] [00411] Analysis of the Cell Cycle. In the analysis of the cell cycle, the use of propidium iodide showed an increase in the stop color of the cell cycle for the combination treatment using Compound 1 and erlotinib with a decrease in the S phase and an increase in the G0 / G1l phase. The results of these studies are shown in Figure 6. These results indicate that Compound 1 in combination with erlotinib caused the cell cycle to stop in NSCLC cells.
[00412] [00412] Analysis of Biomarkers Using Western Blotting. The data for precursor inhibition analyzes are shown in Figures 7A and 7B, in various cell types. The data indicate that the combination of Compound 1 and erlotinib, showed inhibition of a signaling component of the mTOR pathway, namely p4EBP1.
[00413] [00413] In vivo studies of Compound 1 alone or in combination with erlotinib in Xenografts A549 and H1975 in Nude Mice. A5S49 adenocarcinoma or H1975 cells in suspension of individual cells were implanted on the posterior sides of nude athymic mice. The control group was treated with a vehicle, the other groups were treated with erlotinib at 40 mg / kg 3x per week by oral tube, Compound 1 at 5 mg / kg / day orally by gavage, or a combination erlotinib at 40 mg / kg and Compound 1 at 5 mg / kg. For the A549 xenograft, treatments were started on day 26 after implantation and were stopped on day 53, while for H1975 xenograft, treatments were started on day 17 after implantation and were stopped on day 30.
[00414] [00414] As can be seen in Fig. 8, when compared to the untreated control group, the A549 xenograft was resistant to treatment with erlotinib at 40 mg / kg 3x per week. When Compound 1 was combined with erlotinib at 40 mg / kg 3x per week, tumor growth was effectively suppressed. Tumor growth increased when treatment with the combination of Compound 1 and erlotinib was stopped, but at a considerably slower rate compared to the individual treatment groups.
[00415] [00415] As can be seen in Fig. 9, when compared with the control group, the H1975 xenograft, moderately sensitive to treatment with erlotinib at 40 mg / kg 3x per week. When Compound 1 was combined with erlotinib at 40 mg / kg 3x per week, tumor growth was inhibited.
[00416] [00416] Conclusions. Compound 1 demonstrated an anti-proliferative activity from a panel of NSCLC cell lines. In NSCLC cells resistant to the erlotinib tyrosine kinase inhibitor EGFR, Compound 1 in combination with erlotinib demonstrated synergistic anti-proliferative effects. The synergistic effects of Compound 1 and erlotinib have also been shown to suppress tumor growth in AS49 xenografts. The synergistic effects of Compound 1 and erlotinib have also been demonstrated to inhibit the growth of H1975 xenografts. The mechanisms of synergistic effects have been found to involve changes in cell cycle arrest. Analysis of inhibition of the signaling pathway with drug combinations showed the inhibition of signaling components in the mTOR pathway.
[00417] [00417] Multicenter, Phase 1b Open Labeling Study of the Compound 1 mTOR 1 Kinase Inhibitor, in combination with erlotinib or Oral Azacitidine In Advanced Non-small Cell Lung Cancer. These will be a multicenter, open-label Phase 1b study of the TOR kinase inhibitor TOR Compound 1, in combination with erlotinib or oral azacytidine in advanced non-small cell lung cancer.
[00418] [00418] The main objectives of the study are to determine the safety and tolerability of Compound 1, when administered orally, in combination with erlotinib or oral azacytidine and to define the non-tolerated dose (DNT) and the maximum tolerated dose (DMT) each combination using NCI CTCAE v4; and characterize the pharmacokinetics (PK) of Compound 1 and azacytidine after oral administration of individual agents and after treatment in combination. The secondary objectives of the study are to assess the effect of the study drugs on | | biomarkers of the mTORC1 and mTORC2 pathways in the blood and in the tumor; provide information on the preliminary effectiveness of each; combination of drugs; and to characterize the PK of Compound 1 and metabolite M1 after oral administration of Compound 1 as a single agent or in combination with erlotinib or azacytidine | oral.
[00419] [00419] A clinical study of Compound 1 administered orally in combination with oral erlotinib or oral azacytidine was performed in subjects with NSCLC phase IIIB / IV who "failed at least one standard therapy line. It is a study evaluating the scaling or expansion of Phase lb of the increasing dose levels of Compound 1 in combination with two dose levels of erlotinib (Branch A) or two doses of oral azacitidine administered or simultaneously with Compound 1 (Branch B), or sequentially with Compound 1 (Branch C), followed by expansion of each combination group in one or more selected doses.
[00420] [00420] In Branch A, groups will receive escalating levels of continuous daily increasing doses (15 mg, 30 mg and
[00421] [00421] In Branch B, groups will receive escalating levels of continuous increasing daily doses of Compound 1 (15 mg, 30 mg and 45 mg), in parallel with one or more dosage levels of oral azacitidine (200 mg or 300 mg, as two or three 100 mg tablets) given on day 1 to 21 of each 28-day cycle, after a single initial dose of a compound seven days earlier, and a single dose of oral azacytidine on the first day of the first cycle .
[00422] [00422] On Branch C, groups will receive escalating levels of continuous increasing daily doses of Compound 1 (15 mg, 30 mg and 45 mg) administered on day 8-28 after one or more dosage levels of oral azacitidine (200 mg or 300 mg, as two or three 100 mg tablets) administered from day 1 to 7, of each 28-day cycle, after a single initial dose of Compound 1 seven days before the first cycle.
[00423] [00423] A standard dose escalation project "3 + 3" will be used to identify the initial toxicity of each combination. Participants will be assigned to study branches of treatment based on the investigator's choice and open slots. Groups of 3 individuals will have study drugs in defined dose increments and, in case of dose-limiting toxicity (TLD) on 1 of 3 evaluable subjects, groups will be expanded to 6 individuals.
[00424] [00424] An assessable subject for DLT is defined as one who received at least 20 of the 27 planned doses of Compound 1, and 21 of the 28 planned doses of erlotinib, during Cycle 1 on Branch A; and received at least 20 of the 27 planned doses of Compound 1, and 14 of the 21 planned doses of oral azacytidine, during Cycle 1 on Branch B; received at least: 14 out of 21 planned doses of Compound 1, and 6 out of 7 planned doses of oral azacytidine during Cycle 1 on Branch C; drug-related DLT study after receiving at least one dose.
[00425] [00425] The subjects that cannot be evaluated and are not due to the DLT will be replaced. Additional subjects within any dose group may be enrolled, at the discretion of the Safety Review Committee (CRS).
[00426] [00426] The dose will be considered DNT when two of the six | evaluable subjects in a drug-related group DLT experience in Cycle 1. DMT is defined as the last dose below NTD with 0 or 1 of 6 evaluable subjects experiencing DLT during Cycle 1. If 2 out of 6 DLT are observed in the first dose with any combination, a lower dose combination can be explored at the discretion of CRS. A dose of intermediate compound 1 (one between DNT and the last dose level before DNT) can be evaluated to accurately determine the DMT of the combination.
[00427] [00427] Upon completion of the dose increase, each treatment branch in combination will be expanded with about 10 additional evaluable subjects. Expansion can occur in the DMT established in the dose-increasing phase, or at one level | tolerable combination dose alternative, based on the analysis of safety data, PK and PD.
[00428] [00428] Tumor biopsy for analysis of genetic mutations and biomarkers of treatment activity is optional in the dose escalation phase, but mandatory during the dose expansion phase. Tumor biopsies paired to assess the activity of tumor biomarkers of Compound 1, erlotinib and / or oral azacytidine will be required in the expansion group.
[00429] [00429] The study population will consist of men and women, 18 years or older, with Phase IIIB / IV NSCLC, with disease progression after at least one standard first-line treatment regimen. First-line treatment may include chemotherapy or an EGFR inhibitor.
[00430] [00430] The registration should last about 15 months (9 months for the dose increase, six months for expansion). Completion of the next treatment and post-treatment asset is expected | to take an additional 6-12 months.
[00431] [00431] The dose levels to be explored in this Phase 1b study are shown below.
[00432] [00432] If unacceptable toxicity occurs at dose level 1, only a dose reduction for each drug is allowed: Compound 1 10 mg, erlotinib 75 mg, and oral azacitidine 100 mg.
[00433] [00433] Dosage levels 2a and 2b and dose levels 3a and 3b have comparable dose intensity and can be entered simultaneously.
[00434] [00434] The treatment is administered in cycles of 28 days. Compound 1 and erlotinib will be dosed daily in Branch A; oral azacitidine will be administered in parallel with Compound 1 on day 21, for the first of 28 days on Branch B; oral azacitidine will be administered only for 7 days before dosing the
[00435] [00435] After the first dose is administered on Day 1 in any group, subjects will be observed for at least 28 days before the next highest dose group | specified by the protocol can start. Increasing the intra-subject dose of study drugs is not permitted during Cycle 1, but may be authorized in cycles beyond Cycle 1, if approved by CRS. Dose reduction and interruption | temporary use of one or both drugs due to toxicity is allowed, but dose reduction during Cycle 1 will constitute DLT.
[00436] [00436] The study drugs are taken together at approximately the same time each morning. Due to a significant interaction of erlotinib with food, subjects on Branch A should take study drugs on an empty stomach at least 1 hour before and 2 hours after eating. There are no such dietary restrictions for subjects taking Compound 1 or oral azacitidine in Ramos B and C.
[00437] [00437] The study treatment can be interrupted if there is evidence of disease progression, unacceptable toxicity or decision of the subject / doctor to withdraw. Individuals can continue to receive study drugs in addition to disease progression, at the discretion of the investigator.
[00438] [00438] The estimated total number of subjects to be registered during the dose increase is 54 to 108, depending on the size of the group. About 30 additional subjects (10 per regimen) will be evaluated for safety, PK, PD and preliminary antitumor effects during the expansion phase.
[00439] [00439] The subjects will be evaluated as to their effectiveness every two cycles along Cycle 6 and every 3 cycles thereafter. All treated individuals will be included in the effectiveness analysis. The main efficacy variable is the tumor response rate and progression-free survival at the end of four treatment cycles. The tumor response will be determined by the investigator, based on criteria for evaluating response in solid tumors (RECIST 1.1; Eisenhauer EA, Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumors: Revised RECIST guideline ( version 1.1). European J. Cancer; 2009; (45) 228-247)).
[00440] [00440] Secondary and exploratory outcomes include evaluation of biomarkers of mTOR, EGFR, and oral blood and / or tumor azacitidine and exploration of PK, PD, toxicity and activity relationships.
[00441] [00441] The safety variables for this study are adverse events (AEs), clinical safety laboratory variables, 12-lead electrocardiograms (ECGS), left ventricular ejection fraction (LVEF) assessment, physical exams, vital signs, exposure to study treatment, parallel drug evaluation and pregnancy tests for women of potential childbearing age (FCBP).
[00442] [00442] During dose escalation, the decision whether to evaluate a higher dose or declare DMT will be determined by the CRS, based on its review of all clinical and laboratory safety data available for a given dose group.
[00443] [00443] CRS also selects the dose and schedule of Compound 1 in combination with erlotinib and oral azacitidine appropriate for group expansion. One or both of the Compound 1 and oral azacitidine schedules can be selected for group expansion. CRS will continue to review safety data "on a regular basis throughout the study and make recommendations on further study and dose modification, as appropriate.
[00444] [00444] The concentration time of Compound 1, Ml, erlotinib and oral azacytidine profiles will be determined from blood samples collected in series after administration of study drugs as individual agents and after treatment in combination. The pharmacokinetics (PK) of Compound 1 and azacitidine will be determined after oral administration of each drug as a single agent, and after the combination treatment (Compound 1 / oral azacitidine) with: (1) the maximum plasma concentration (Cnax ), (2) Area under the concentration-time curve (AUC), (3) time to maximum concentration (tmax), (4) terminal half-life (Ti / 2), (5) apparent total clearance (CL / F) and (6) the apparent volume of distribution (VZ / F).
[00445] [00445] The effects of erlotinib and oral azacitidine on Compound 1 and Ml PK will be evaluated, as well as the effect of Compound 1 on erlotinib and oral azacitidine PK. The systemic exposure of Compound 1 after administration of Compound 1 as a single agent or in combination with erlotinib or oral azacytidine will be correlated with safety, and the results of PD activity. The main metabolites of Compound 1, including M1, will be quantified in plasma. The PK of the Ml metabolite, after oral administration of | Compound 1 as a single agent or in combination with erlotinib or oral azacytidine will be characterized.
[00446] [00446] Assessment of biomarkers will include analysis of biomarkers from the mTOR pathway, and other signaling pathways where possible, in the blood and tumor after both single agent and combined treatment. In some cases, the changes of each biomarker will be determined by comparing the levels of markers in the pretreatment samples and on and, if possible, correlate with these PK results and tumor response over time.
[00447] [00447] Evaluation of gene DNA methylation and expression status in blood and tumor (where available) will be evaluated at the beginning and during treatment in combination drugs in Ramos B and C to explore potential predictors of sensitivity to Compound 1 in combination with oral azacitidine and the treatment effect combined with DNA methylation and expression.
[00448] [00448] Genetic sequencing of the tumor will be performed at the beginning of the study in biopsies of archival or screening tumors to test various genomic changes.
[00449] [00449] The inclusion criteria for the study are: (1) Men and women, over 18, with histological diagnosis or confirmed cytology, with Stage IIIB / IV Non-Small Cell Lung Cancer with tumor progression followed of at least one prior treatment regimen (chemotherapy or an Epidermal Growth Factor receptor inhibitor for advanced disease), (2) Eastern Cooperative Oncology Group Performance Score of 0 or 1, (3) the following laboratory values : absolute neutrophil count (CAN) 2 1.0 x 10º / L; hemoglobin (Hb) 29 g / dL; platelets (PLT) 2 100 x 10º / L; potassium within normal limits or correctable with supplements; AST / TGO and ALT / TGP <2.5 x Upper Limit of Normal (LSN) or It is 5.0 x LSN if the liver tumor is present; bilirubin IS 1.5 x ULN; estimation of serum creatinine clearance 2 60 mL / min / 1.73m using the Cockcroft-Gault equation; individuals who complete cycle 1 must meet the following hematological criteria at the beginning of each subsequent cycle: CAN> 1.0 x 10º / L; and platelets> 75 x 10º / L .; and if hematological criteria are not met, the onset of oral azacitidine in subsequent cycles may be delayed for up to 7 days to allow for recovery. If recovery does not occur after 7 days, this will be considered a DLT, (4) adequate contraception (if applicable), (5) Consent to recover archival tumor tissue, and (6) consent for repeated tumor biopsy ( expansion phase dose).
[00450] [00450] The exclusion criteria for the study are: (1) previous systemic cancer treatments or "investigative drugs within 4 weeks or five half-lives, whichever is shorter, (2) nervous system metastases symptomatic central, (3) known chronic or acute pancreatitis, (4) individuals with persistent diarrhea or | 2 NCI CTCAE grade 2 malabsorption despite medical treatment, (5) impaired cardiac function or heart disease, including any of the following: LVEF <45%, | as determined by MUGA or ECHO; complete left branch or bifascicular block; congenital long QT syndrome; persistent or clinically significant ventricular arrhythmias; QTcF> 460 ms on the Screening ECG (average of recordings in triplicate); unstable angina pectoris or myocardial infarction It is 3 months before starting the study drugs; uncontrolled hypertension (blood pressure 2 160/95 mmHg); (6) diabetes under active treatment with | u m from the following procedures: fasting blood glucose (FBG)> 126 mg / dL (7.0 mmol / L) or HbAlc 2 6.5% (7), infection known as Human Immunodeficiency Virus, active chronic hepatitis B or | virus infection (CC, (8) previous treatment with a | double investigation of TORC1 / TORC2, PI3K or AKT inhibitor, (9) major surgery It is 2 weeks before starting study drugs; no specific washing is required for Individuals must have recovered from any effects of recent therapy that may confuse the assessment of the safety of the study drug, (10) women who are pregnant or breastfeeding. Adults of! reproductive potential not employing two forms of control | birth, and (11) history of a second competing cancer that needs ongoing systemic treatment.
[00451] [00451] In some embodiments, patients undergoing the clinical protocol provided herein will show a positive tumor response, such as inhibition of tumor growth or a reduction in tumor size. In certain embodiments, patients undergoing the clinical protocol provided herein will achieve a Response Response Criteria in Solid Tumors (eg, RECIST 1.1) of complete response, partial response or stable disease after administration of an effective amount of a compound in combination with an efficient amount of erlotinib or oral azacytidine. In certain embodiments, patients undergoing the clinical protocol provided here will show increased survival without tumor progression. In some embodiments, patients undergoing the clinical protocol provided here show inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor mass, relief of tumor-related symptoms, and tumor inhibition (including secreted tumor hormones , such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, the slower development of “primary or secondary tumors, decreases the occurrence of primary or secondary tumors, delayed or lessened severity of the side effects of the disease, oTumor growth is tied to tumor regression, increased time to progression (TTP), increased progression-free survival (PFS), and / or increased overall survival (OS), among others.
[00452] [00452] Illustrative formulations Compound 1 useful in the methods provided herein are presented in Tables 7 and 8, below. Table 7 Moisture quantities mo a | Compound 1 15.38 Lactose monohydrate, NF (Fast | 63.98 49.22 Flo 316) Microcrystalline cellulose, NF 40.30 31.00 (Avicel pH 102) Sodium croscarmellose, NF (Ac- 3.90 3, 00 Di-Sol) | Stearic Aeido, ne - | 0,52 | o, ao] | Magnesium stearate, NF 130.0 4% by weight Yellow Opadry 03K12429 above
[00453] [00453] A number of references have been cited, and the findings that are incorporated here by reference in their entirety. The embodiments disclosed here are not limited in scope by specific embodiments disclosed in the examples that are proposed as illustrations of few aspects of the disclosed embodiments and any embodiments that are functionally equivalent are included in the present disclosure. Certainly, various modifications to the embodiments disclosed here are, in addition to those shown and described here, will become apparent to experts in the field and are expected to fall within the scope of the attached claims.

权利要求:
Claims (16)
[1]
1. Use of an effective amount of a TOR kinase inhibitor characterized by the fact that it is to prepare, in combination with an effective amount of erlotinib or a similar cytidine, a drug to treat a patient containing advanced non-small cell lung cancer, wherein the TOR kinase inhibitor has the following formula (IV): R Rº N N o [CC
A N N Rº
H (IV) or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer or prodrug thereof, where: Rº is substituted or unsubstituted alkyl Cris, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted heterocyclyl or unsubstituted, or substituted or unsubstituted heterocyclylalkyl; R is H, Cis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R is H, or Ci; substituted or unsubstituted alkyl.
[2]
2. Use according to claim 1, characterized in that it is to prepare, in combination with an effective amount of erlotinib, a drug to treat a patient containing advanced non-small cell lung cancer.
[3]
Use according to claim 1, characterized in that it is to prepare, in combination with an effective amount of a cytidine analog, a drug to treat a patient containing advanced non-small cell lung cancer.
[4]
4, Use according to claim 3, characterized in that the analogous cytidine is azacytidine.
[5]
5. Use according to claim 4, characterized in that azacitidine is oral azacitidine.
[6]
6. Method for achieving a Solid Tumor Response Assessment Criterion (RECIST 1.1) of complete response, partial response or stabilizing the disease in a patient with advanced non-small cell lung cancer, characterized by understanding the administration of a effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analogous to that patient, in which the TOR kinase inhibitor has the following formula (IV): R2 Rº NN o C>
AÚ N N Rº
H (IV)
or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer or prodrug thereof, wherein: R 'is Ci; substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R is H, Cis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R is H, or Ci; substituted or unsubstituted alkyl.
[7]
Method according to claim 6, characterized in that it comprises the administration of a TOR kinase inhibitor in combination with an effective amount of erlotinib to a patient containing advanced non-small cell lung cancer.
[8]
Method according to claim 6, characterized in that it comprises the administration of a TOR kinase inhibitor in combination with an effective amount of a cytidine analogous to a patient containing advanced non-small cell lung cancer.
[9]
Method according to claim 8, characterized in that the analogous cytidine is azacytidine.
[10]
Method according to claim 9, characterized in that the azacitidine is oral azacitidine.
[11]
11. Method for increasing survival without tumor progression in a patient with advanced non-small cell lung cancer, characterized by understanding the administration of an effective amount of a TOR kinase inhibitor in combination with an effective amount of erlotinib or a cytidine analogous to said patient, in which the TOR kinase inhibitor has the following formula (IV): R Rº N N o [CC
A N N Rº
H (IV) or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer or prodrug thereof, where: Rº is substituted or unsubstituted alkyl Cris, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted heterocyclyl or unsubstituted, or substituted or unsubstituted heterocyclylalkyl; R is H, Cis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R is H, or Ci; substituted or unsubstituted alkyl.
[12]
Method according to claim 11, characterized in that it comprises the administration of a TOR kinase inhibitor in combination with an effective amount of erlotinib to a patient containing advanced non-small cell lung cancer.
[13]
Method according to claim 11, characterized in that it comprises the administration of a TOR kinase inhibitor in combination with an effective amount of a cytidine analogous to a patient containing advanced non-small cell lung cancer.
[14]
14. Method according to claim 13, characterized in that the analogous cytidine is azacytidine.
[15]
15. Method according to claim 14, characterized in that azacitidine is oral azacitidine.
[16]
16. Method according to any one of claims 1 to 15, characterized in that the TOR kinase inhibitor is a compound of Table D.

类似技术:

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公开号 | 公开日 | 专利标题

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BR112014020786A2|2020-10-27|method for the treatment of lung cancer, method for achieving a response evaluation criterion in solid tumors, method for increasing survival

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JP6470822B2|2019-02-13|Treatment of cancer with a TOR kinase inhibitor

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同族专利:

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公开号 | 公开日

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KR20140123112A|2014-10-21|

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EA028462B1|2017-11-30|

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IL234169A|2020-06-30|

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ZA201406052B|2015-11-25|

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TW201338778A|2013-10-01|

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PH12017501500A1|2018-12-17|

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CN104271159B|2017-11-28|

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AU2013202305B2|2015-03-12|

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US9375443B2|2016-06-28|

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JP2015508103A|2015-03-16|

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JP6114317B2|2017-04-12|

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SG11201405064RA|2014-09-26|

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EP2817029B1|2019-07-10|

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US20130225518A1|2013-08-29|

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HK1199825A1|2015-07-24|

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NZ628410A|2016-03-31|

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NI201400095A|2016-12-02|

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EP2817029A1|2014-12-31|

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EA201491584A1|2014-12-30|

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TWI615143B|2018-02-21|

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PH12014501880B1|2014-11-24|

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WO2013126636A1|2013-08-29|

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MX2014010198A|2014-11-21|

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CN104271159A|2015-01-07|

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MY174308A|2020-04-06|

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CA2864905A1|2013-08-29|

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IL274647D0|2020-06-30|

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AU2013202305A1|2013-09-12|

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MX358303B|2018-08-14|

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PH12014501880A1|2014-11-24|

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KR102064626B1|2020-01-09|

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ES2742398T3|2020-02-14|

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法律状态:
2020-11-03| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 7A ANUIDADE. |

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2021-02-23| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2600 DE 03-11-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201261603012P| true| 2012-02-24|2012-02-24|

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US61/603,012|2012-02-24|

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US201261716424P| true| 2012-10-19|2012-10-19|

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US61/716,424|2012-10-19|

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US201261725805P| true| 2012-11-13|2012-11-13|

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US61/725,805|2012-11-13|

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PCT/US2013/027235|WO2013126636A1|2012-02-24|2013-02-22|Methods for treating non- small cell lung cancer using tor kinase inhibitor combination therapy|

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