TW201444551A - Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or AHI1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives - Google Patents

Abstract

Methods and compositions suitable for the treatment of malignancies in subjects with a germline deletion polymorphism that blocks the activity of thymidine kinase inhibitors in triggering apoptosis in tumor cells or in subjects having a mutation in or a dysregulation of the AHI1 gene are disclosed. These methods employ an alkylating hexitol derivative such as dianhydrogalactitol, a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol, a derivative or analog of diacetyldianhydrogalactitol, dibromodulcitol, and a derivative or analog of dibromodulcitol. The compositions can include such alkylating hexitol derivatives. The methods can further include administration of a BH3 mimetic, and the compositions can further include a BH3 mimetic. In subjects having a dysregulation of the AHI1 gene, the methods can further include the administration of an agent modulating the expression or activity of the AHI1 gene or AHI1 protein, and the compositions can further include such an agent.

Description

Treatment of malignant tumors with anti-tyrosine kinase inhibitors in patients with gene polymorphism or AHI1 dysregulation or mutation in patients with phytol polymorphism, dihydrodehydrated cyclohexyl alcohol, dibromodusol or analogs or derivatives thereof method

The present invention relates to the use of dianhydrogalactitol, diacetyldian hydrogalactitol, dibromodulcitol or the like or derivatives thereof for the treatment of genetic polymorphisms A method for treating a malignant tumor of a tyrosine-kinase-inhibitor resistant patient, a method for treating a malignant tumor resistant to the expression of an AHI1 (abelson-helper integration site-1) gene, or a therapeutic third A method of triple-negative breast cancer, and a malignant tumor of an anti-tyrosine kinase inhibitor for treating a malignant tumor or a triple-negative breast cancer patient having gene polymorphism, resistance regulation of the AHI1 gene expression Pharmaceutical composition.

The use of Tyrosine Kinase Inhibitors (TKIs) is reliable for effective therapeutic response in patients with malignancies thought to be driven by the activity of oncogene kinases (PAJänne et al., "For small molecules Potential sensitivity of cancer factor inhibitors by cancer kinases, Nat. Rev. Drug Discov. 8:709-723 (2009), and is incorporated by reference). However, before the use of TKIs, such malignant tumors are generally considered to be highly chemically resistant, such as breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor Tyrosine kinase (ABL1) kinase-driven chronic myeloid leukemia (CML) and EGFR non-small-cell lung carcinoma (NSCLC) (AM Carella et al., "In the case of chronic myelogenous leukemia New biology in current biology and current treatment options, Haematologica 82: 478-495 (1997) and JHSchiller et al., "Comparison of four chemotherapy regimens for advanced non-small cell lung cancer", New Engl. J. Med. 346: 92-98 (2002), both of which are included by reference). After the emergence and clinical application of TKIs, the response to treatment in these two malignancies is usually close to 80% (VLKeedy et al., "The Interim Clinical Opinion of the American Society of Clinical Oncology: About the First Line of Epidermal Growth Factor Receptor (Epidermal Growth Factor) Receptor, EGFR) anti-tyrosine kinase therapy, EGFR mutation test in patients with advanced non-small cell lung cancer, J. Clin. Oncol. 29: 2121-2127 (2011) and M. Baccarani et al., "chronic bone marrow Sexual Leukemia: An Update on the Concept and Management Recommendations of the European Leukemia Network, J. Clin. Oncol. 27: 6041-6051 (2009), both of which are included by reference.

However, TKIs have been shown to be as effective in treating many types of malignancies (previously considered incurable by chemotherapy), and a significant proportion of patients are resistant to TKI chemotherapy. Many of these patients are of East Asian origin, indicating the presence of genetic variants that may cause resistance to TKI chemotherapy.

Therefore, there is an urgent need for therapeutic methods and pharmaceutical compositions that can treat malignant tumors in patients with TKI chemotherapy resistance.

In addition, there are other malignant tumors, particularly including, but not limited to, chronic lymphocytic leukemia (CLL), which is associated with the AHI1 gene, particularly with mutations or disorders of the AHI1 gene. The AHI1 gene is a gene encoding a mold protein having a WD40 repeat sequence and an SH3 region. The insertion of the provirus at the gene cluster of this gene is associated with the development of malignant tumors and may be a manifestation of the truncated form of the gene (X. Jiang et al., "Ahi-1, a novel coding with WD40 repeats The gene of the sequence and the model protein of the SH3 region is a targeted target for Ahi-1 and Miss-2 proviral insertion", J. Virol. 76: 9046-9059 (2002), and is incorporated by reference. Philadelphia chromosome-positive (Ph+) human leukemia has also been shown to modulate the abnormality of the AHI1 gene (X. Jiang et al., "The abnormal regulation of Ph+ in human leukemia of AHI-1, by insertion in a mouse model of leukemia] Genes for sexual mutation activation", Blood 103: 3897-3904 (2004), and are incorporated by reference.

Therefore, there is an urgent need to improve methods for the treatment of malignancies, particularly leukemia, associated with mutations or abnormal regulation of the AHI1 gene.

In addition, triple-negative breast cancer is a form of breast cancer characterized by a tumor that does not exhibit an estrogen receptor (ER), a progesterone receptor (PR) or a HER-2 gene. Because these cancers do not respond to endocrine therapy or many targeted drugs, this form of breast cancer represents an important clinical challenge. Current treatment strategies for triple-negative breast cancer include many chemotherapeutic agents, such as anthracyclines, taxanes, ixabepilone, and platinum, as well as selected biologics, and may contain anti-EGFR drugs.

However, there is an urgent need for improved methods to treat triple-negative breast cancer.

The present invention relates to methods and pharmaceutical compositions for providing a selective therapeutic route for the treatment of malignant tumors in patients with TKI chemotherapy resistance.

One aspect of the present invention provides a method of treating a malignant tumor, wherein the malignant tumor is characterized by resistance to at least one tyrosine kinase inhibitor (TKI), wherein: (1) at least one mutation in a gene And encoding a protein which is a target of at least one TKI; or (2) the presence of at least one additional gene in a native or mutant state encoding an anti-therapeutic effect of at least one TKI A product of sex comprising: administering a therapeutically effective amount of a monoalkylated hexitol derivative. In an alternative, at least one additional gene in the native or mutant state of the product encoding a resistance to a therapeutic effect of at least one TKI is AHI-1 . In another alternative, the resistance to at least one TKI is due to a mutation in the kinase region of the ABL1 protein, which is part of a BCR-ABL fusion protein that is a target of a TKI. The method can further comprise the step of administering a therapeutically effective amount of a BH3 analog to the target subject. In one alternative, the method can further comprise the step of administering a therapeutically effective amount of a STAT5 inhibitor, a JAK2 inhibitor, a Src inhibitor, or a combination of two or more kinase inhibitors.

Another aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor having a polymorphism of a germ cell which confers resistance to TKIs, comprising: administering a therapeutically effective amount of a therapeutic agent To the target subject to treat the malignant tumor The therapeutic agent is selected from the group consisting of a derivative or analog of Weikangol, Weikangol, a dihydroquinone, a derivative or analog of dihydroquinone, and a dibromo A group of dulcitol, and a derivative or analog of dibromodusol.

The malignant tumor may be chronic myelogenous leukemia (CML) or non-small cell lung carcinoma (NSCLC). In another alternative, the malignancy can be triple negative breast cancer.

Another aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene, comprising: administering a therapeutically effective amount of a therapeutic agent to a target subject a step of treating the malignant tumor, the therapeutic agent being selected from the group consisting of a derivative or analog of Weikangol, Weikangol, dihydroquinone dihydrated cyclohexanol, a derivative of dihydroquinone dihydrated dulcitol or A group of analogs, dibromodusol, and derivatives or analogs of dibromodusol. In this alternative, the malignancy can be chronic myeloid leukemia. The method can further comprise: administering a therapeutically effective amount of an agent that modulates the performance or activity of the AHI1 gene or the AHI1 protein.

Another aspect of the present invention is to provide a method of combined screening and treatment, which combines: screening for germ cell deletion polymorphism, and TKIs resistance in a target subject if the germ cell deletion polymorphism is found to be present Treatment of malignant tumors.

Generally, the method comprises the steps of: (1) screening for a germ cell deletion polymorphism in a target subject having a malignant tumor; and (2) if the germ cell deletion polymorphism is found in the malignant tumor In the target object, a therapeutically effective amount of a therapeutic agent is administered to the target subject to treat the malignant tumor, and the therapeutic agent is selected from the group consisting of a derivative or the like of Weikangol, Weikangol, and diethyl hydrazine. A group consisting of a derivative or analog of piranol, diethylene quinone dihydrated cyclohexanol, dibromodusol, and a derivative or analog of dibromodusol.

The method may further comprise: administering (1) a BH3 analog; or (2) a BH3 analog and an anti-tyrosine kinase therapeutic agent to a target subject having a malignant tumor in which a germ cell is deficient in polymorphism; The step of treating the effective amount of both.

Suitable BH3 analogs include, but are not limited to: (1) a peptide; (2) modified peptides; (3) triazinyl-based peptipeptides; (4) p-benzoguanamine-based p-peptides; (5) benzamidine-based p-peptides; (6) Ouba Obatoclax; (7) TW37; (8) an analog or derivative of TW37; (9) (-) gossypol; (10) gossypol derivatives; (11) isoxazoline derived (12) A-385358; (13) an analog or derivative of A-385358; (14) ABT-737; (15) an analog or derivative of ABT-737; (16) ABT-263 (17) an analog or derivative of ABT-263; (18) TM-1206; and (19) an analog or derivative of TM-1206.

A particularly good BH3 analog is ABT-737.

The tyrosine kinase inhibitor can be, but is not limited to, imatinib, bosutinib, nilotinib or dasatinib. A particularly good tyrosine kinase inhibitor is imatinib. In another alternative, the tyrosine kinase inhibitor can be, but is not limited to, erlotinib, afatinib or dacomitinib.

Another aspect of the present invention is to provide a method for increasing the efficacy and/or reducing side effects of administration of an alkylated hexitol derivative for treating a primary anti-TKI tumor, the method comprising the steps of: (1) confirming At least one factor or parameter associated with the efficacy and/or side effects of the administration of the alkylated hexitol derivative, the alkylated hexitol derivative being used to treat a primary anti-TKI tumor; And (2) modifying the factor or parameter for increasing the efficacy and/or side effects of administration of the alkylated hexitol derivative for treating the anti-TKI tumor .

Typically, in the method, the factor or parameter is selected from the group consisting of: (1) dose adjustment; (2) route of administration; (3) schedule of administration; (4) indication of use (5) choice of stage of disease; (6) other indications; (7) selection of patients; (8) patient/disease phenotype; (9) patient/disease genotype; (10) pre/post treatment Preparation; (11) Toxicity management; (12) Pharmacokinetic/pharmacodynamic monitoring; (13) Concomitant administration; (14) Chemical sensitization; (15) Chemical synergism; (16) Post-treatment patient management (17) Selective medical/therapeutic support; (18) Improvement of API products; (19) Diluent system; (20) Solvent system; (21) Excipients; (22) Dosage form; (23) Dose kit And packaging; (24) drug delivery system; (25) drug conjugated form; (26) compound analog; (27) precursor; (28) multiple drug system; (29) biotherapeutic potentiation; (30) antibiotic therapy (31) radiotherapy enhancement; (32) novel mechanism of action; (33) selective target cell population therapy; and (34) use of an agent that increases its activity.

Another aspect of the present compositions is to provide a composition for increasing the efficacy and/or side effects of an undesired administration therapy using a monoalkylated hexitol derivative for treatment In a primary anti-TKI tumor, the composition comprises a selection scheme selected from the group consisting of: (i) a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modification A therapeutically effective amount of a derivative, analog or precursor of an alkylated hexitol derivative, wherein the modified alkylated hexitol derivative or the same is compared to an unmodified alkylated hexitol derivative A derivative, analog or precursor of a modified alkylated hexitol derivative has an increased therapeutic effect or a reduced side effect for treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene; (ii) a combination And comprising: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative a therapeutically effective amount of an analog, or precursor; and b) at least one additional therapeutic agent, a chemically sensitizing therapeutic agent, a chemically potentiating therapeutic agent, a diluent, an excipient, a solvent system or a drug delivery system, wherein an unmodified alkylation is compared a hexitol derivative having a therapeutic increase in a malignant tumor associated with a primary or secondary mutation or abnormal regulation of the AHI1 gene Adding efficacy or reducing side effects; (iii) monoalkylated hexitol derivatives, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modification incorporated into a dosage form A therapeutically effective amount of a derivative, analog or precursor of an alkylated hexitol derivative, wherein the monoalkylation incorporated into the dosage form is compared to an unmodified alkylated hexitol derivative a derivative, analog or precursor of a hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative having a primary antibody Treatment of TKI tumors or malignant tumors associated with mutation or abnormal regulation of the AHI1 gene increases efficacy or reduces side effects; (iv) monoalkylated hexitol derivatives, a modification incorporated into a dose kit and package A therapeutically effective amount of an alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative, analog or precursor thereof, wherein one is unmodified An alkylated hexitol derivative incorporated into the dosage kit and package a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor The treatment has an effect of reducing or reducing side effects on the treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene; and (v) a monoalkylated hexitol derivative modified by a drug substance product, A therapeutically effective amount of a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor thereof, wherein Modified alkylated hexitol derivative, modified alkylated hexitol derivative, modified alkylated hexitol derivative or monoalkylated hexitol derivative or modified by the drug substance product Derivatives, analogs or precursors of alkylated hexitol derivatives have therapeutic effects or reduced side effects for the treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene.

The composition may, for example, comprise: a combination of drugs (including, among other options): a BH3 analog, a therapeutic agent that is chemically sensitized, a chemically potentiated therapeutic agent, and a drug substance product improvement. , a diluent, a solvent system, an excipient, a dosage form, a dose set and packaging, a drug delivery system, a modification of a therapeutic agent, a precursor system or a multi-drug system.

Figure 1 is a graph showing the effect of the growth of miconol on MDA-MB-231 cancer cells (the concentration of Weikangol 0.1-100 μM, 3000 cells/cells, 72 hours (two replicates)).

Fig. 2 is a graph showing the effect of growth of Weikangol on HC C1143 cancer cells (the concentration of Weikangol 0.1 to 100 μM, 3000 cells/well, 72 hours (two repetitions)).

Figure 3 is a graph showing the effect of the growth of Utilol on K562 cancer cells (the concentration of Weikang alcohol 0.1 to 100 μM, 2000 cells/well, 72 hours (two repetitions)).

Figure 4 is a graph showing the effect of the growth of K562-Ahi-1 cancer cells on the defense of Stefanol (the concentration of Weikangol 0.1 to 100 μM, 2000 cells/well, 72 hours (two repetitions)).

The present invention provides a plurality of methods and pharmaceutical compositions for treating malignant tumors in patients resistant to TKI chemotherapy, particularly where the resistance is due to genetic polymorphism. The invention further provides a plurality of methods and pharmaceutical compositions for treating malignancies (particularly leukemias) associated with mutation or abnormal regulation of the AHI1 gene. The invention further provides a plurality of methods and pharmaceutical compositions for treating triple negative breast cancer.

Recent studies have demonstrated that TKI chemotherapy resistance is at least in part due to gene polymorphism that affects apoptosis responses to TKI cells.

In particular, these polymorphisms include, but are not necessarily limited to, polymorphism (also known as BIM ) in the gene BCL2L11 , which encodes a single BH3 segment protein of a BCL-2 family member. The single BH3 segment protein activates cell death by resisting the BCL2 family (BCL2, BCL2-like 1 (BCL-XL, also known as BCL2L1), myeloid cell leukemia sequence-1 (MCL1) and An activating member of BCL2-related protein A1 (BCL2A1), or by ligating to a pro-apoptotic BCL2 family member (BCL2-associated X protein, BAX) and BCL2-antagonism / killing factor (BCL2-antagonist/killer 1, BAK1)), and directly activate its pro-apoptotic function; activation of pro-apoptotic function will lead to cell death (RJ Youle and A. Strasser, "BCL-2 protein Family: Resistance to Activation Mediates Cell Death", Nat. Rev. Mol. Cell. Biol. 9: 47-59 (2008), and is incorporated by reference).

It has also previously been shown that several kinase-driven cancers, such as CML and EGFR NSCLC, can inhibit BIM transcription by mitogen-activated protein kinase 1 (MAPK-1)-dependent phosphorylation, or by targeting proteases. The body-degraded BIM protein maintains a survival advantage. In all of these malignancies, TKIs require BIM regulation to induce apoptosis in cancer cells, and inhibition of BIM expression is sufficient to confer resistance to TKIs in vitro (J. Kuroda et al., "Bim and Bad mediated Bcr" /Abl ⁺ Imatinib-induced killing of leukemia cells, and overcomes resistance due to their loss by a BH3 analog", Proc. Natl. Acad. Sci. USA 103: 14907-14912 (2006); KJAichberger Et al., "Low-level performance of mediators of pro-apoptotic Bcl-2 interactions in leukemia cells with chronic myelogenous leukemia: the role of BCR/ABL, the nature of potential message delivery pathways, and the use of novel drugs "Re-expression of compounds", Cancer Res. 65: 9436-9444 (2005); R. Kuribara et al., "The role of Bim in normal and Bcl-Abr-expression of hematopoietic cells in apoptosis", Mol. Cell .Biol. 24: 6172-6183 (2004); MSCragg et al., "Gefitinib-induced killing of mutant NSCLC cell lines exhibiting BIM, and may be enhanced by BH3 analogs", PLoS Med. 4:1681-1689 (2007); Y.Gong et al., "EGFR dependence in mutations Induction of BIM in adenocarcinoma is critical for apoptosis triggered by EGFR kinase inhibitors," PLoS Med. 4: e294 (2007); DB Costa et al., "BIM mediators in lung cancer with oncogene EGFR mutations EGFR tyrosine kinase inhibitors induce apoptosis", PLoS Med. 4: 1669-1679 (2007), all of which are incorporated by reference.

Among the BIM genes that cause the growth of alternative splicing isoforms of BIM, a recent finding has revealed a deletion polymorphism, which is an important BH3 region lacking the promotion phase involved in apoptosis. This polymorphism has profound effects on the TKI sensitivity of CML and EGFR NSCLC cells, and a set of such deleted dual genes is sufficient to render the cells inherently TKI resistant. Thus, this polymorphism acts on a dominant effect to render such cells resistant to TKI chemotherapy. The findings also include results: individuals with polymorphism have significantly worse TKI responses than individuals with no polymorphism. In particular, the presence of polymorphism is associated with lesser degree of response to imatinib and TKI in TKI, and a shorter, non-deteriorating survival with EGFR TKI therapy in EGFR NSCLC (progression-free survival) , PFS) (KPNg et al., "A common BIM deficiency in cancer, polymorphism and innate resistance and poor response to tyrosine kinase inhibitors", Nature Med.doi 10.138/nm.2713 (March 18, 2012) and include it by reference).

To identify these new TKI drug resistance mechanisms in CML, perform a large number of parallel DNA sequencing of double-end double tags to examine the genomes of five CML samples derived from the target subject, which are sensitive to treatment with TKIs. Sex or resistance. BCR-ABL1 translocation was found in all CML samples, but was not found in control samples derived from patients with complete remission.

Although various structural variations that are common to all anti-TKI samples have been discovered, a particular variation is considered to be particularly significant. This mutation occurs in intron 2 of the BIM gene and is contained in an identical 2903-bp deletion, which is common for all three samples from resistant patients; in fact, This variation is the same in all three patients who are indicated to be germline and polymorphic. The screening revealed a significant frequency of this polymorphism in patients of East Asian descent (but is absent in individuals of African or European descent).

Examination of the structure of the BIM gene revealed that splicing of the exon 3 and splicing of exon 4 occurred in the stop codon and the presence of a polyadenylation signal in the exon 3 Mutually exclusive ways. The sequencing of all recognizable BIM transcripts in CML cells has confirmed that exon 3 and exon 4 are never present in the same transcript. Since at the 5' end of exon 3, it is close (107 bp) to the intron exon boundary, it is concluded that the deletion polymorphism as described above will result in preferential splicing of exon 3 above exon 4. . When a minigene is constructed to assess the presence of a deletion, it will result in the selected inclusion of exon 3 above exon 4; in this model system, for exons above exon 4 There is at least a five-fold preference for inclusions within 3. The results in this model system were confirmed by studies of primary CML cells; the same preference was shown for polymorphic CML-containing cells, whereas general BIM transcription was not affected by polymorphism. Similar results were obtained in lymphoblastic cells obtained from individuals with normal healthy HapMap, indicating that this polymorphism has a cell line-independent response. Thus, these results indicate that the 2.9-kb deletion region is a cis-element comprising a splicing that inhibits BIM exon 3, which results in preferential splicing of exon 3 over exon 4 in the cell in which the deletion is occluded.

The pro-apoptotic BH3 region is encoded entirely by exon 4 of BIM (M. Adachi et al., "Dynamic protein light chain-linked single BH3 segment protein Bim isomer nomenclature", Cell Death Different. 12:192-193 (2005) and include it by reference). This region is required for the apoptotic function of BIM (EH Cheng et al., "BCL-2, BCL-X (L) isolated BH3 region molecules that prevent BAX-mediated apoptosis and BAK-mediated apoptosis," Mol. Cell. 8: 705-711 (2001); DCHuang and A. Strasser, "Single BH3 Segment Protein: Basic Priming of Cell Death in Apoptosis", Cell 103: 839-842 (2000), all of these Both are included by reference). These observations illustrate a previously unknown mechanism for TKI resistance. In this mechanism, after exposure to TKI, polymorphic CML cells are included, and it is conceivable that other malignant cells carrying this polymorphism or other polymorphism that alters BIM splicing will be beneficial for exons - The BIM transcript of 3 is expressed above the BIM transcript containing exon-4, resulting in decreased expression of BH3-containing BIM isoforms and thus impairing BH3-region-dependent apoptosis. To confirm this, a Japanese cell line, KCL22 (I. Kubonishi and I. Miyoshi, "Establishment of a Ph1-chromosome-positive cell line from chronic myelogenous leukemia in the acute transformation phase", Int. J. Cell Cloning 1:105 -117 (1983) and included by reference) which contains a test for a 2.9-kb deletion; it is demonstrated that exon 3 to exon 4 transcripts are expressed from that line compared to cells that do not have the deletion The increase in the ratio. Upon exposure to TKI, these KCL22 cells also showed reduced induction of transcripts containing exon 4, while exhibiting a decreased concentration of BIMEL protein and a major BH3-containing BIM isoform (M. Adachi et al. 2005)).

Consistent with these findings, exposure to imatinib (although effective BCR-ABL1 inhibition), KCL22 cells are resistant to imatinib-induced apoptosis and show signs of impaired apoptosis, as in BCR-ABL1-dependent The reduction in sexual messaging is confirmed. After increasing the exon-containing BIM BH3 4-isomers and the encoded (but not containing exon 3) exhibits BIM isomer, KCL22 cells also have high sensitivity to induce apoptosis. In turn, this suggests that impaired imatinib-induced apoptosis in KCL22 cells can be restored by an increase in a class of BH3 drugs that functionally mimic a single by binding and inhibiting the BCL2 family members. BH3 segment protein (MSCragg et al., "The ability to release inhibitors of oncogene kinases by BH3 analogs", Nat. Rev. Cancer 9:321-326 (2009), and is incorporated by reference).

One of these BH3 analogs is ABT-737. ABT-737 is 4[4-[(4'-Chloro[1,1'-biphenyl]-2-yl)methyl]1-piperazinyl]-N-[[4-[[(1R)-3-dimethyl Amino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]benzamide. The structural formula of ABT-737 is as shown in the following formula (I). The activity of ATB-737 is described in MF van Delft et al., "If neutralizing Mcl-1, the BH3 analog ABT-737 targets the selective Bcl-2 protein via Bak/Bax and effectively induces apoptosis", Cancer Cell 10: 398-399 (2006) and described in MF Bruncko et al., "Study on Dual Inhibitors of Effective Bcl-2 and Bcl-xL", J. Med. Chem. 50: 641-662 (2007) Both are included by reference.

Additional BH3 analogs include, but are not limited to, analogs or derivatives of ABT-737, including the following: (1) an analog of ABT-737 in which chlorine bonded to the phenyl ring is replaced by fluorine, bromine or iodine; An analog of ABT-737, wherein one or more hydrogens of the benzene ring are substituted with a lower alkyl group; (3) an analog of ABT-737, wherein one or more hydrogens of the piperazinyl moiety are substituted with a lower alkyl group; And (4) an analog of ABT-737 wherein the dimethylamino moiety is substituted with another moiety comprising one or two lower alkyl groups, the lower alkyl group being an amine group attached to the diethylamino moiety.

Other BH3 analogs are known in the art and are further described below.

The use of a BH3 analog in KCL22 did revert to imatinib-induced apoptosis. The results also confirmed that the siRNA-mediated gene expression of the transcript containing exon 3 did not sensitize KCL22 cells to imatinib, indicating that exons were contained in TKI resistance. The isomer of 3 may not play an important role.

Among the BIM genes of the original imatinib-sensitive K562 CML cells, gene targeting by zinc finger nuclease (ZFN) was used to accurately reconstruct the deletion polymorphism. Prior to this targeting, these K562 cells lacked this deletion polymorphism and were sensitive to imatinib; the cells responded to imatinib by initiating apoptosis. After gene targeting by ZFN, the cells were analyzed for BIM splicing and expression, and then for changes and TKI-induced apoptosis. Generating a secondary manifestation strain (subclone) is a deletion of the polymorphic hetero zygote (K562- BIM ^{i2 +/-)} or homozygous ^{(K562- BIM i2 - / -)} . In the BIM-γ protein expression of cells from two sub-expression strains in polymorphic dose-dependent behavior, an increase in the ratio of exon 3 to exon 4 transcripts, as well as a small but reproducible increase Observed. Even in the absence of polymorphic cell homozygotes, the low performance of BIM-γ protein is due to the relatively short half-life (<1 hr) of the BIM-γ protein. After exposure to imatinib, cells containing deletion polymorphism also showed reduced induction of transcripts containing exon 4, while showing increased up-regulation of BIMEL protein, attenuating apoptosis signals, and reducing apoptosis. Death was measured by DNA fragmentation in an ELISA based assay. As in KCL22 cells, the combination of the BH3 analog ABT-737 with imatinib as described above increases the ability of the thymidine kinase inhibitor imatinib to activate apoptosis in cell-containing polymorphism.

In the treatment of cell-containing polymorphism with or without imatinib, The most abundant BIM isomer, BIMEL, is now available. Similar to the results seen with ABT-737, in the deficient K562 cells, the forced expression of BIMEL also enhanced the ability of imatinib to activate apoptosis. Similarly, primary CML cells obtained from target subjects with deletion polymorphism are less sensitive to imatinib-induced death and have cell-deficient polymorphism compared to cells without deletion. The relative TKI resistance can be overcome by an increase in the BH3 analog ABT-737.

These results have confirmed that the BIM lacks polymorphism by being far from containing BH3 The offset splicing of the construct damages the apoptotic response to imatinib and this bias is sufficient to render the CML cells essentially resistant to imatinib. These results have also been demonstrated that the apoptosis response to imatinib can be restored by treatment of cell-containing polymorphism with a BH3 analog, such as ABT-737, but the invention is not limited this.

As mentioned above, TKI therapy resistance is a particularly popular target in East Asian descent. of. Therefore, a retrospective analysis has been performed on the impact of the polymorphism of the TKI response in the East Asian target with CML. This analysis involved a group of newly diagnosed patients with chronic CML from a similar person in Singapore, Malaysia or Japan. In these patients, the clinical response was compared to a first-line therapy with a standard dose of imatinib (400 mg/day) in individuals with and without deletion polymorphism. The clinical response was classified according to the European Leukemia Net (ELN) guidelines; according to the ELN criteria (which included a target that never achieved a complete cellular response or 3-log reduction at the BCR-ABL1 transcript level) Resistant individuals are defined as "unsatisfactory reactions" or "failures", while sensitive individuals are "best reactants" that meet the definition of ELN. Among the two geographical peers, the target with missing polymorphism is more likely to have impedance disease than the sensitive disease; the impedance disease between patients with polymorphism Compared with those that are not available, the overall odds ratio is 2.94, showing a significant result. In contrast, there was no significant difference between the two groups regarding other potential prognostic or confounding factors, including the mean time from diagnosis to initiation of imatinib treatment, the diagnostic Sokal score, or pre-treatment with interferon. It should also be noted that most resistant target subjects with deletion polymorphism did not respond to second-generation TKI therapy with bosutinib, nilotinib or dasatinib, one with the cell line The findings of congenital drug resistance observed in the same, and a finding that the resistance conferred by polymorphism is not limited to imatinib, but extended to other TKI therapeutic agents.

In the TKI resistance of CML and the BCR-ABL1 kinase region, the acquisition of somatic mutations is the most commonly associated, and up to 50% of resistant individuals can be found in the chronic phase of the disease (P. La Rosée and A. Hochhaus, "Resistance of Imatinib in Chronic Myelogenous Leukemia: Mechanism and Clinical Significance", Curr. Hematol. Malig. Rep. 3: 72-79 (2008), and is incorporated by reference). However, the deletion polymorphism described above is a germ cell line and is sufficient to cause innate TKI resistance in vitro , even in the absence of kinase-regional mutations, individuals with predicted germ cell deletion polymorphism are predicted TKI therapy is resistant. In a study to validate this hypothesis, the target audience was divided into three clinical groups: (1) drug resistance without a BCR-ABL1 mutation; (2) drug resistance with a BCR-ABL1 mutation; 3) Sensitivity. Individuals with deletion polymorphism are more likely to be in group (1) than those in groups (2) and (3). This is a strong and powerful evidence for the in vivo effects of polymorphism in the development of resistance to TKI therapy.

BIM biomarker in another kinase-driven cancer (ie EGFR NSCLC) The role of the stimuli has also been validated, in which patients with EGFR inhibitors, sensitive mutations in EGFR predict high response rates (JGPaez et al., "EGFR mutations in lung cancer: gefitinib Correlation of the clinical response of Gefitinib Therapy, Science 304: 1497-1500 (2004); TJ Lynch et al., "Activating in the potential response to epidermal growth factor receptors in gefitinib for non-small cell lung cancer Mutation", N. Engl. J. Med. 350: 2129-2139 (2004), both of which are incorporated by reference, and wherein BIM performance is necessary for TKI sensitivity. EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, and vandetanib. An additional and related aspect of non-small cell lung cancer is that it is particularly common in East Asian countries where activated EGFR mutations can be as high as 50% of NSCLCs (15% in Western countries) and are abundant among female East Asian non-smokers. of.

Therefore, NSCLC cell lines harboring TKI-sensitized EGFR mutations were searched but searched for inexplicable TKI resistance (defined as the absence of any known mutations conferring secondary resistance). One such cell line, HCC2279, was identified, which significantly did not activate apoptosis (although it was effective EGFR inhibition). In HCC2279 cells, the presence of this polymorphism was confirmed; the role of polymorphism in BIM function was also determined. This deletion results in a greater performance of the exon-3 containing BIM isomer compared to the BIM isoform containing exon 4 (and therefore BH3) compared to cells without polymorphism. In particular, the major peripheral blood mononuclear cells are derived from a target subject with EGFR NSCLC, with or without the polymorphism of the deletion, which also shows the same result (increased inclusion in the cells with polymorphism) The performance of the BIM isomer of sub3). Upon exposure to TKI, HCC2279 cells also reduced the induction of transcripts containing exon 4 and BIMEL protein, while impairing the activation of apoptotic signals as measured by poly ADP ribose polymerase (PARP) cleavage. Consistent with this concept, TKI resistance is a result of a decrease in the concentration of a BH3-containing BIM protein, and the increase in the BH3 drug ABT-737 as described above enhances the TKI-induced apoptosis signal and cell death. To confirm that this deletion polymorphism in EGFR NSCLC is sufficient to cause TKI resistance, this deletion polymorphism was introduced into TKI-sensitive PC9 cells. Similar to the discovery of K562- BIM ^i2-/- cells, it was found that PC9- BIM ^i2-/- cells have exon-4 and BH3-containing BIM transcription, respectively, compared to PC9- BIM ^i2+/+ cells. The reduced performance of the body and protein, the TKI resistance in nature, and the desensitization of the TKIs by the BH3 analog ABT-737.

In the target of NSCLC with activated EGFR mutation, one study also A determination was made to determine the presence or absence of polymorphism associated with the timing of response to EGFR TKIs. Regarding known prognostic factors, there was no difference in individuals with or without polymorphism, including stages (more than 85% of target subjects were stage IV). However, in individuals with deletion polymorphism, the presence of polymorphism predicted a significantly shorter progression-free survival with a median PFS of 6.6 months (compared to those without 11.9 months) (PFS). ). In the multivariate analysis using the Cox regression model, only the deletion polymorphism and the presence of the TKI drug-resistant exon 20 mutation were present (J. Wu et al., "Lung cancer with epidermal growth factor exon 20 mutation and no Good gefitinib treatment response is relevant", Clin. Cancer Res. 14: 4877-4882 (2008); H. Sasaki et al., "EGFR exon 20 insertion mutation in Japanese lung cancer", Lung Cancer 58 :324-328 (2007), both of which are included by reference) to become an independent prognostic factor for shorter PFS.

These results indicate the nature of the following, although cancer should be based on its somatic cells Classified by driving mutations, germ cell polymorphism can directly modulate the response of such cancers to target treatments and can strongly influence clinical outcomes. In particular, these results indicate that a common BIM deletion polymorphism contributes to the heterogeneity of the response seen by the molecule defining the patient with a particular type of cancer treated with targeted therapy. In different cancers, these results also highlight how single germ cell polymorphism can strongly influence clinical outcomes, and the cancer shares a common or largely common biology in these malignant tumors that mediate TKI sensitivity and may Reacts to the core role of BIM. This is likely to include other malignancies that also depend on TKI-sensitive BIM (PMGordon and DEFisher, "In mediating imatinib-induced apoptosis in c-KIT-dependent gastrointestinal stromal tumor cell lines "The role of the pro-apoptotic factor BIM", J. Biol. Chem. 285: 14109-14114 (2010); B. Will et al., "The cell induced by Bim-mediated JAK2 inhibition in JAK2 mutant human red blood cells. Death and apoptosis induced by JAK2 inhibition by the BH3 analog ABT-737, Bloom 115: 2901-2909 (2010), both of which are incorporated by reference).

This BIM deficiency polymorphism was found only in individuals of East Asian descent. therefore, Interestingly, in CML, a higher proportion of unresolved cytogenetic responses to imatinib among individuals in East Asia (~50%) has been compared to individuals in Europe and North America (26%). Report. It is estimated that in ~21% of East Asian patients, the polymorphism of the deletion constitutes resistance; this may explain, to some extent, the difference in the rate of complete cell formation between the two world populations. Observed.

For example, the biomarkers of the germline used for TKI resistance are included in the day after tomorrow (also Above the biomarkers of somatic cells, the BIM deletion polymorphism also offers several advantages. First, the timing of this BIM deficiency polymorphism can be used to predict the individual's risk of developing TKI resistance. Second, because the deletion polymorphism is a germ cell polymorphism that is not related to the DNA or tumor type of any particular tumor, the assessment of the polymorphic state of the individual does not require analysis of tumor-specific DNA. The ability to use this polymorphic screening in the initial presentation time of a patient provides the potential to prevent the emergence of TKI resistance by therapeutic means, such as at initial performance time or in the treatment of one or more TKI drugs BH3-like drugs are given on the first signs of resistance. In fact, in a solid tumor condition (eg, EGFR NSCLC), the deletion polymorphism is a germ cell polymorphism that is not associated with the DNA of any particular tumor; or the germ cell polymorphism The type of tumor in sex is particularly advantageous, where a second biopsy for tumor-specific tissue usually requires an invasive procedure, and the risks that such a procedure may bring, including infection. Before the treatment predicts TKI reactivity, these diagnostic measurements can be performed in conjunction with measurements of BIM RNA levels in tumors (A. Faber et al., "BIM performance in untreated cancers predicts reactivity to kinase inhibitors", Cancer Discov .1:352-365 (2011)); however, after exposure to TKI, the discovery of this polymorphism as described above emphasizes the importance of biomarkers that can also predict functional heterogeneity of BIM Induction of the body.

Results As described above, in the role of BIM function to explain the deletion polymorphism, a novel splicing mechanism is described in CML and EGFR-driven NSCLC, and the polymorphism contributes to drug resistance by such a splicing mechanism. . This suggests that pharmacological recovery of BIM function can overcome this particular form of TKI resistance in both cancers. These results also support the progressive recognition of changes in the splicing pattern of genes within human disease (L.Cartegni et al., "Listening to Silence and Understanding Nonsense: Exon Mutations Affect Splicing", Nat. Rev. Genet. 3: 285-298 (2002); N. López-Bigas et al., “Splicing mutations are the most common cause of hereditary diseases?”, FEBS Lett. 579: 1900-1903 (2005), both of which are cited by reference. Including) and providing a new paradigm that inherits germ cell mutations that contribute to resistance to targeted cancer treatment. Although the presence of this polymorphism is closely related to clinical TKI resistance and shorter PFS, other genetic factors, acquired and inherited, may determine the final response of TKI therapy in any individual patient. Several other mechanisms of EGFR-independent drug resistance have been described, including up-regulation of hepatocyte growth factor-dependent signaling (S. Yano et al., "Hepatocyte growth factor-induced lung glands with epidermal growth factor receptor activating mutations" Gefitinib resistance in cancer, Cancer Res. 68: 9479-9487 (2008), and by reference), activation of B-kappaB (NF-κB)-dependent nuclear factor-kappaB Light chain enhancer (TGBivona et al., "FAS and NF-κB signal regulation dependence in lung cancer on mutant EGFR", Nature 471: 523-526 (2011), and by reference) and v -Ki-ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS) mutation (M. Takeda et al., "Inhibition of epidermal growth factor receptor tyrosine kinase in EGFR-mutant positive patients with non-small cell lung cancer" Once again ( De Novo ) resistance, J. Thorac. Oncol. 5: 399-400 (2010), and is included by reference).

Clinical TKIs resistance is usually classified as primary or secondary, with the latter It occurs in individuals who experience a preliminary response to TKI therapy and then develops resistance. It is generally believed that secondary resistance is mediated by acquired somatic mutations that occur under selective pressure of TKI therapy, whereas the innate mechanism of drug resistance, including germ cell polymorphism, is more May be resistant to primary infection and lack any prior response. This method of reasoning is based on the hypothesis that the germ cell polymorphism conferring resistance causes absolute rather than relative TKIs resistance. However, the results indicate that by creating both CML and EGFR NSCLC cells with this deletion polymorphism, the results indicate that this BIM polymorphism causes relative TKI resistance. In the BIM protein concentration, this is consistent with cancer cells that are sensitive to small changes (Kuroda et al. (2006); A Egle et al., "Bim is a Myc-induced mouse B cell leukemia inhibitory gene", Proc. USA 101:6164-6169 (2004) and includes it by reference). This means that cells carrying the deletion polymorphism are not completely resistant to TKIs, and in some cases Underneath, there may be some reactions.

These results also indicate that other polymorphisms can explain other cancer biology The heterogeneity between the aspects. It is also possible that these polymorphisms may or may occur at a higher frequency in a particular population, especially those known to be innately mated. Many of these populations are known and, in some cases, have been shown to have an increased risk of developing certain types of cancer. In particular, the therapy with alkylated hexitol derivatives described herein is useful in patients with germ cell mutations or somatic mutations, as described below.

In a family called two with pro-apoptotic activity and anti-apoptotic activity In the BCL-2 family, this BH3 region is a region shared between many proteins. These proteins contain BAK, BAX, BIK, BID and HRK in addition to BIM. This BH3 region is retained in both the pro-apoptotic BCL-2 family protein and the anti-apoptotic BCL-2 family protein. The BH3 region of the pro-apoptotic protein provides a dual function. It is essential for its cell death activity and regulation of heterologous dimerization with anti-apoptotic proteins.

The sequence of the natural human BIMEL, the main form of BIM, is as follows: MAKQPSDVSSECDREGRQLQPAERPPQLRPGAPTSLQTEPQGNPEGNHGGEGDSCPHGSPQGPLAPPASPGPFATRSPLFIFMRRSSLLSRSSSGYFSFDTDRSPAPMSCDKSTQTPSPPCQAFNHYLSAMASMRQAEPADMRPEIWIAQELRRIGDEFNAYYARRVFLNNYQAAEDHPRMVILRLLRYIVRLVWRMH (SEQ ID NO: 1).

The BH3 region in this protein is residues 148-162 (15 amino acids) having the sequence IAQELRRIGDEFNAY (SEQ ID NO: 2). Sequences similar to the BH3 portion in BIMEL were found in other proteins, including: LACIGDEMD (SEQ ID NO: 3) in BIK, LKALGDELD (SEQ ID NO: 4) in HRK, LAIIGDDIN in BAK ( SEQ ID NO: 5), LAQVGDSMD (SEQ ID NO: 6) in BID, LKRIGDELD (SEQ ID NO: 7) in BAX, LKKNSDWIW (SEQ ID NO: 8) in BNIP3, in BAD LRRMSDEFE (SEQ ID NO: 9) , in the BCL-2 LRQAGDDFS (SEQ ID NO: 10) , and in LREAGDEFE of BCL-X _L (SEQ ID NO: 11). In general, these sequences have a plurality of amino acids, including a primary leucine (L), corresponding to the fifth amino acid of the BH3 region in BIMEL; and one-day aspartic acid (D), corresponding to BIMEL The tenth amino acid of the BH3 region. Other identical or suitably substituted amino acids occur in these sequences. These homology are described in M. Yasuda et al., "Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 comprises a BH3 region and a mitochondrial targeting sequence", J. Biol. Chem. 273: 12415-12421 (1998) and is included by reference.

As mentioned above, many BH3 analogs have been discovered, including ABT-737. BH3 analogs are described in G. Lessene et al., "BCL-2 Family Antagonists for Cancer Therapy," Nature Rev. Drug Discovery 7: 989-1000 (2007), and are incorporated by reference.

In mammalian cells, the occurrence or non-occurrence of apoptosis is controlled by the interaction between pro- and pro-apoptotic proteins, particularly members of the BCL-2 family of proteins. In mammalian cells, five activating proteins, BCL-2, BCL-X _L , BCL-w, MCL1 and A1, counteract the pro-apoptotic function of BAK and BAX. The killing activity of BAK and BAX is localized on the outer membrane of the mitochondria, which becomes permeable in response to death signals. As a result, cytochrome c is released from the granulosa to the cytosol, leading to activation of the apoptosis protease chain reaction and induction of apoptosis.

The five activating proteins share all four sequence homology with BAK and BAX The region (called BCL-2 homology 1, BH1, BH2, BH3, and BH4) is the same. They also have a carboxy terminal membrane anchoring sequence and a similar tertiary structure. However, there are other proteins that organize apoptosis. These additional pro-apoptotic proteins are BH-3 only proteins, indicated that they lack the BH1, BH2 and BH4 regions. In mammals, eight single BH3 segment proteins are known, namely BIM, BID, PUMA, NOXA, BAD, BMF, HRK and BIK; in response to stress signals, these proteins are transcribed or After the translation processing and up.

The BH3 region of the pro-apoptotic protein is the major mediator of interactions with members of the anti-apoptotic (promoting) family. For example, it has been proposed that a pro-protein, BCL-X _L , counteracts BAK or BAX, both BAK and BAX promote apoptosis by binding to their BH3 region and a single BH3 segment protein The continuation mitigates this opposition by similarly binding to the BCL-X _L ; this will prevent this opposition by competition. It is also possible that there is a direct interaction between certain single BH3 segment proteins and BAX. However, either mode strongly suggests that a BH3 analog that binds to activating proteins will induce or promote apoptosis.

There is a selective interaction between a single BH3 segment protein and activating protein. When BAD and NOXA have complementary binding profiles, BIM and PUMA are linked to all five activating proteins. Mutant BH3 sequences with altered selectivity patterns have been discovered, as discussed further below.

Potential BH3 analogs include: (1) a peptide; (2) a modified peptide; (3) a triazinyl-based peptide; (4) a p-benzoguanamine-based peptide; (5) a benzophenone Urinary urea-based peptides; (6) erbatomin; (7) TW37; (8) (-) gossypol; (9) gossypol derivatives; (10) isoxazoline derivatives; (11) A-385358; (12) ABT-737; (13) ABT-263; and (14) TM-1206.

The general principles applicable to the design of BH3 analogs include the following: (1) binding occurs between a hydrophobic groove located on Bcl-X _L and the BH3 region (eg, BAD); (2) the single BH3 The segment protein BAD adopts a helical structure attached to the hydrophobic groove located on the Bcl-XL; and (3) four positions in the BH3 region at positions i, i+3, i+7 and i+11 The hydrophobic amino acid is necessary for the binding of Bad to Bcl-XL and interaction in the four hydrophobic pockets located in the Bcl-XL binding groove; the hydrophobic residue in the BH3 region is highly conserved.

These BH3 analogs are described in detail below.

The modified peptide contains a pinned BID BH3 helix, which is described in L.D. Walensky et al. "Stapled BID BH3 helix directly binds and activates BAX", Mol. Cell 24:199-210 (2006) and LD Walensky et al., "BH3 helix activation by a hydrocarbon-stuffed Apoptosis in vivo, Science 305: 1466-1470 (2004), both of which are incorporated by reference. These pinned helices are the substitutions of S-pentenyl alanine derivatives into the BH3 helix at two positions, and the positive leucine for methionine at an adjacent position. The replacement is produced. Then, a hydrocarbon crosslink is formed by ruthenium-catalyzed olefin substitution, leaving a bridging structure having a double bond.

Another alternative for modifying peptide PH3 analogs comprises a helix-based peptide folding, described in JDSadowsky et al., "BH3 region/Bcl-x _L recognized ( α / β + α ) peptide Antagonists: Promising general strategies for protein-protein interaction based on inhibition of folding bodies, J. Am. Chem. Soc. 129: 139-154 (2007), and are incorporated by reference.

Soft piperidinyl quasi three classes peptides are described in JMDavis et al., "A- helix analogs as 2,3 ';6',3" - Synthesis "Three Soft piperidine scaffold, Org.Letters 7: 5404-5408 (2005) and include it by reference.

Phenylamino-based pseudopeptides are described in H.Yin & A.D. Hamilton, "Bak peptide targets the para-phenylamine derivative as an analog of the helical region of the Bcl-xL protein", Bioorg. Med. Chem. Lett. 14: 1375-1379 (2004), and by reference included.

The benzammonium-based BH3 analog is described in US Patent Application Publication No. 2008/0153802 by Lessene et al., which is incorporated herein by reference.

Obattopra is 2-(2-((3,5-dimethyl-1 H -pyrrol-2-yl)methenyl)-3-methoxy-2 H -pyrrole-5-yl)- 1 H -吲哚, and has a structure shown by the following formula (II).

TW37 is N -[(2-tert-butyl-benzenesulfonyl)-phenyl]-2,3,4-trihydroxy-5-(2-isopropyl-benzyl)-benzamide. And having the structure shown in the following formula (III), and described in GP Wang et al., "Structure-based design of an effective small molecule inhibitor of anti-apoptotic Bcl-2 protein", J. Med. Chem. 50: 3163-3166 (2006) and described in MA Verhaegen et al., "A novel BH3 analog reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species", Cancer Res. 66:11348-11359 (2006), both of which are included by reference.

Additional BH3 analogs include, but are not limited to, analogs and derivatives of TW37, including the following: (1) analogs of TW37, wherein one or more hydrogens of the phenyl ring are substituted with a lower alkyl group; and (2) similar to TW37 A substance in which one or more hydrogens in a hydroxyl group of a trihydroxyphenyl moiety are substituted with a lower alkyl group.

ABT-263 is (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]- 2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholinyl-1-(phenylthio)butan-2-yl)amino)-3-(( Trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide, and has a structure shown by the following formula (IV). The activity of ABT-263 is described in C. Tse et al., "ABT-263: An Effective and Oral Bioavailable Bcl-2 Family Inhibitor", Cancer Res. 68:3421-3428 (2008) and described In ARShoemaker et al., "in a group of small cell lung cancer xenograft models Activity of the Bcl-2 family inhibitor ABT-263", Clin. Cancer Res. 14: 3268-3277 (2008).

Additional BH3 analogs include, but are not limited to, analogs or derivatives of ABT-263 And comprising: (1) an analog of ABT-263 in which a chlorine bonded to a benzene ring is replaced by fluorine, bromine or iodine; (2) an analog of ABT-263 in which one or more are substituted with a lower alkyl group a benzene ring hydrogen; (3) an analog of ABT-263, wherein one or more piperazinyl moieties are substituted with a lower alkyl group; and (4) an analog of ABT-263, wherein one or two are included Another portion of the lower alkyl group is substituted for the dimethylamino moiety, which is an amine group attached to the diethylamino moiety.

a compound having partial structural homology (with ABT-737) is A-385358. A-385358 is [(R)-4-(3-dimethylamino-1-phenylsulfonylmethyl-propylamino)-N-[4-(4,4-dimethyl-peline) Pyridin-1-yl)-benzylindolyl]-3-nitro-benzenesulfonamide, and has a structure represented by the following formula (V). The activity of A-385358 is described in ARShoemaker et al., "A small molecule inhibitor of Bcl-XL enhances the activity of cytotoxic drugs in vitro and in vivo", Cancer Res. 66: 8731-8739 (2006), and by reference It is included.

Additional BH3 analogs include, but are not limited to, analogs or derivatives of A-385358 And comprising: (1) an analog of A-385358, wherein one or more hydrogens of the benzene ring are substituted with a lower alkyl group; and (2) an analog of A-385358, wherein one or two lower alkyl groups are included Another portion of the group replaces the dimethylamino moiety, which is an amine group attached to the diethylamine moiety.

The (-) enantiomer of gossypol has been shown to have similar activity to BH3; this The similar activity of the enantiomers of BH3 is described in JPQiu et al., "Different pathways for cell killing by the antifungal of the genus Gossypol," Exp. Biol. Med. 227:398- 401 (2002) and include it by reference.

In terms of the similar activity of BH3, the activity of gossypol derivatives and analogues was Described in GZTang et al., "Acylpyrogallols as an inhibitor of anti-apoptotic Bcl-2 protein", J. Med. Chem. 51: 717-720 (2008), and by reference It is included. A particularly pronounced gossypol phenol derivative is apogossypolone; the similar activity of Aper gourd BH3 is described in AAArnold et al., "Pre-clinical study of apogophenol: small in vesicles A new non-peptide Pan small molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in the fissure cell lymphoma model, Mol. Cancer 7: 20-30 (2008), and by reference included.

TM-1206 has a structure shown by the following formula (VI). TM-1206 BH3 Similar activities are described in G. Z. Tang et al. (2007).

Additional BH3 analogs include, but are not limited to, analogs or derivatives of TM-1206 And comprising: (1) an analog of TM-1206, wherein one or more hydrogens of the benzene ring are substituted with a lower alkyl group; and (2) an analog of TM-1206, wherein one or more are substituted with a lower alkyl group Hydrogen in the hydroxyl group of the trihydroxyphenyl moiety.

Other BH3 analogs are known in the art.

In a patient with the above-mentioned germ cell deletion polymorphism, a series of selection options An alternative treatment and an agent as an alkylating agent can treat anti-TKI malignancies. The ability of these selective agents to treat drug-resistant malignancies is significant when the severity of the problem is considered. As described above, in people of East Asian descent (about 15% of cases), the above-mentioned germ cell deletion polymorphism is considered to be caused by TKIs resistance, such as Gleevec. This means that in this category, approximately 552,000 patients develop at least 78,000 lung cancer cases each year in patients with germ cell deletion polymorphism, thereby developing resistance to TKIs such as Gleevec. In addition, it is estimated that there is at least one drug-resistant chronic myeloid leukemia (CML) per 100,000 population, or approximately 2,500 per year; this is a very conservative estimate in populations bearing germ cell depletion polymorphism The number of cases of drug-resistant CML is likely to be higher.

These agents are further described below, which can also be used in other anti-TKI Treatment of malignant tumors, in which one or more mutations, germ cell mutations, or somatic mutations affecting a particular cell or tissue form, prevent the BIM protein or another protein (in which phosphorylation is initiated for TKI initiation of apoptosis) Required) phosphorylation.

Can be successfully used in a class of patients with germ cell deletion polymorphism The therapeutic agents are galactitol, substituted galacitols, dulcitol and substituted dulcitol, including Wei Kang alcohol, diacetyl dianol, dibromodusol and its derivatives. analog.

These galactitol, substituted galactitol, dulcitol and substituted dulcitol are precursors to alkylating agents or alkylating agents, as discussed further below.

The structure of Weikangol is as shown in the following formula (VII).

Further, it is within the scope of the present invention to have a derivative of Weikangol, for example, hydrogen having one or two hydroxyl groups of Weikang alcohol substituted with a lower alkyl group, which has one or more lower alkane a group substituted with hydrogen attached to two epoxy rings, or having a methyl group present in the twecomol, the methyl group being attached to the same carbon having a lower C ₂ -C ₆ The alkyl-substituted hydroxyl group or has a hydroxyl group substituted with, for example, a halogen group, which is a hydrogen group which is substituted with a methyl group, for example, a halogen group. The term "halogen" as used herein, without further limitation, refers to one of fluorine, chlorine, bromine or iodine. The term "lower alkyl" as used herein, without further limitation, refers to a C ₁ -C ₆ group and includes a methyl group. The term "lower alkyl" may be further limited, for example, "lower alkyl of C ₂ -C ₆ ", which does not include a methyl group. The term "lower alkyl", unless otherwise limited, refers to both a linear alkyl group and a branched alkyl group.

The structure of diacetyl dianthracene alcohol is as shown in the following formula (VIII).

Further, within the scope of the present invention, there is a derivative of diacetyl dianhydrodehydric alcohol, for example, which has one or two methyl groups substituted with a lower alkyl group of C ₂ - C ₆ and a part of an ethyl group, Hydrogen having one or two substituents attached to the epoxy ring substituted with a lower alkyl group, or having a methyl group attached to the same carbon having an ethyl hydrazine group substituted with a lower alkyl group or having, for example An oxime group substituted with a halogen group which is substituted with a hydrogen group, for example, a halogen group.

The structure of dicyclohexanol is as shown in the following formula (IX). Dibromodusol can be formed by the reaction of hydrobromic acid with dulcitol at elevated temperatures, followed by crystallization of the dibromodusol. Some of the properties of dibromodusol are described in NE Mischler et al., "Dibromodusol", Cancer Treat. Rev. 6: 191-204 (1979), and are incorporated by reference. In particular, dibromodusol, as an alpha , omega-dibrominated hexitol, dibromodusol is assigned to many biochemical and biological similar drugs, such as dibromomannitol and mannitol Malilan. The activation of dibromodusol to dicyclohexyloxybutanol occurs in the body, and the diaconol can represent a major active form of the drug; this means that dibromogalactitol has many precursor properties. Dibromodusol absorbed by the oral route is rapid and quite complete. In melanoma, breast lymphoma (Hodgkins and non-Hodgkin's), colorectal cancer, acute lymphocytic leukemia, dibromocortisol has a known activity; and, dibromo Dulcitol has been shown to reduce the incidence of central nervous system leukemia, non-small cell lung cancer, cervical cancer, bladder cancer, and metastatic angioendothelioma.

Furthermore, it is within the scope of the invention to have a derivative of dicyclohexyl alcohol, for example Hydrogen having one or more hydroxyl groups substituted with a lower alkyl group, or having one or two bromo groups substituted with another halogen group such as chlorine, fluorine or iodine.

As described above, and as generally mentioned below, the method applied to the present invention Or the alkylated hexitol derivatives of the compositions, the BH3 analogs and other therapeutically active derivatives and analogs may be optionally substituted with one or more groups which do not significantly affect the derivative or The pharmacological activity of the analog. These groups are generally known in the art. The following definitions of some commonly used groups (which may be used as arbitrary substituents) are provided; however, as long as the chemical and pharmacological requirements for any substituent are met, the omission from any of these definitions cannot be considered to imply such A group cannot be used as an arbitrary substituent.

The term "alkyl" as used herein, refers to an unbranched, branched or cyclic saturated hydrocarbon residue of 1 to 20 carbon atoms, or a combination thereof, which may be optionally substituted; The base residue contains only unsubstituted C and H. Typically, the unbranched or branched saturated hydrocarbyl residue is from 1 to 6 carbon atoms and is referred to as "lower alkyl." When the alkyl residue is cyclic and comprises a ring, it will be understood that the hydrocarbyl residue comprises at least three carbon atoms which are the smallest to form a ring. The term "alkenyl" as used herein refers to an unbranched, branched or cyclic hydrocarbon residue having one or more carbon-carbon double bonds. The term "alkynyl" as used herein, refers to an unbranched, branched or cyclic hydrocarbon residue having one or more carbon-carbon triple bonds; the residue may also comprise one or more Double key. With regard to the use of "alkenyl" or "alkynyl", the presence of multiple double bonds does not result in an aromatic ring. The terms "hydroxyalkyl", "hydroxyalkenyl" and "hydroxyalkynyl" as used herein mean, respectively, an alkyl group, an alkenyl group or an alkyne containing one or more hydroxyl groups (as substituents). A radical; as described below, further substituents may be optionally included. The term "aryl" as used herein refers to a monocyclic moiety or a fused bicyclic moiety having the properties of well-known aromaticity; examples include phenyl and naphthyl which may be optionally substituted. The term "hydroxyaryl" as used herein refers to an aryl group containing one or more hydroxyl groups as a substituent; as further mentioned below, further substituents may optionally be included. The term "heteroaryl" as used herein refers to a monocyclic or fused bicyclic system having aromatic character and comprising one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. In the 5-membered ring and the 6-membered ring, the inclusion of heteroatoms allows for aromaticity. A typical heteroaromatic system comprises a monocyclic C ₅ -C ₆ heteroaromatic group such as pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, a triazolyl, triazinyl, tetrazolyl, tetrazinyl and imidazolyl group, and a fused bicyclic moiety formed by fusing these monocyclic rings having a benzene ring or having any heteroaromatic monocyclic group One of a heteroaromatic group to form a C ₈ -C ₁₀ bicyclic group, such as an anthracenyl group, a benzimidazolyl group, a carbazolyl group, a benzotriazolyl group, an isoquinolyl group, a quinolyl group, a benzothiazole group Base, benzofuranyl, pyrazolylpyridyl, quinazolinyl, quinoxalinyl, morpholine and other ring systems known in the art. Any single ring system or fused ring double ring system having aromatic characteristics is included in this definition depending on the distribution of delocalized electrons throughout the ring system. This definition also encompasses a bicyclic group in which at least the ring directly attached to the residue of the molecule has an aromatic character, including a delocalized electron distribution of aromatic character. Typically the ring system contains from 5 to 12 ring member atoms and up to four heteroatoms, wherein the heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur. Frequently, the monocyclic heteroaryl contains 5-6 ring members and up to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; often, the bicyclic heteroaryl The group contains 8-10 ring members and up to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The number and position of heteroatoms in the heteroaromatic ring structure is a well-known limitation based on aromaticity and stability, wherein stability at physiological temperatures without rapid degradation requires that the heteroaromatic group be stable enough to be exposed to water. The term "hydroxyheteroaryl" as used herein refers to a heteroaryl group containing one or more hydroxyl groups (as substituents); as further mentioned below, further substituents may optionally be included . The terms "haloaryl" and "haloaryl" as used herein, mean aryl and heteroaryl, each substituted with at least one halo group, wherein "halo" refers to a halo, The halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine. Usually, the halogen is selected from the group consisting of chlorine, bromine and iodine; as described below, further may be further included Substituents. The terms "haloalkyl", "haloalkenyl" and "haloalkynyl" as used herein mean alkyl, alkenyl and alkynyl groups, respectively substituted with at least one halo group, wherein "Halo" means a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine. Typically, the halogen is selected from the group consisting of chlorine, bromine and iodine; Further substituents may be optionally included as described below.

The term "optionally substituted" as used herein means that the particular group or group referred to as an arbitrary substituent may have no non-hydrogen substituent, or the particular group. The group or group may have one or more non-hydrogen substituents consistent with the chemical and pharmacological activities of the molecule produced. If not otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the group describing the unsubstituted form; less than the maximum number of such substituents may be present. One of the optional substituents is attached via a double bond, such as a carbonyl oxygen (C=O), on which the optional substituent is attached to the carbon atom, the group occupies two available valences, so based on the available valence The number is reduced by the total number of substituents that can be included. The term "substituted" as used herein, whether used as a moiety "optionally substituted" or otherwise used, when used to modify a particular group, moiety or radical, means one or more hydrogens. Atoms are each independently substituted with the same or different substituents (including singular or plural).

Useful substituents for a substituted saturated carbon atom in a particular group, moiety or radical include, but are not limited to, -Z ^a , =O, -OZ ^b , -SZ ^b , =S ^- , -NZ ^c Z ^c , =NZ ^b , =N-OZ ^b , trihalomethyl, -CF ₃ , -CN, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O) ₂ Z ^b , -S(O) ₂ NZ ^b , -S(O ₂ )O ^- , -D(O ₂ )OZ ^b , -OS(O ₂ )OZ ^b , -OS(O ₂ )O ^- , -OS( O ₂ )OZ ^b , -P(O)(O ^- ) ₂ , -P(O)(OZ ^b )(O ^- ), -P(O)(OZ ^b )(OZ ^b ), -C(O) Z ^b , -C(S)Z ^b , -C(NZ ^b )Z ^b , -C(O)O ^- , -C(O)OZ ^b , -C(S)OZ ^b , -C(O)NZ ^c Z ^c , -C(NZ ^b )NZ ^c Z ^c , -OC(O)Z ^b , -OC(S)Z ^b , -OC(O)O ^- , -OC(O)OZ ^b , -OC( S) OZ ^b , -NZ ^b C(O)Z ^b , -NZ ^b C(S)Z ^b , -NZ ^b C(O)O ^- , -NZ ^b C(O)OZ ^b , -NZ ^b C( S) OZ ^b , -NZ ^b C(O)NZ ^c Z ^c , -NZ ^b C(NZ ^b )Z ^b , -NZ ^b C(NZ ^b )NZ ^c Z ^c , wherein Z ^a is selected from the group consisting of a group consisting of a cycloalkyl group, a heteroalkyl group, a cycloheteroalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; each Z ^{b is} each hydrogen or Z ^a ; each Z ^b Z ^c are each or, or, the two Z ^c 's Combining with a nitrogen atom bonded to them to form a 4, 5, 6 or 7 membered cycloheteroalkyl ring structure, which may optionally contain from 1 to 4 identical or different heteroatoms, which are selected From the group consisting of nitrogen, oxygen and sulfur. As a specific example, -NZ ^c Z ^c is intended to include -NH ₂ , -NH-alkyl, -N-pyrrolidinyl and -N-morpholinyl, but is not limited to these specific options and is included in the art. Other options known in the art. Similarly, as another specific example, a monosubstituted alkyl group means a -alkyl-O-alkyl group, an alkylene-heteroaryl group, an alkylene group-cycloheteroaryl group, a -alkylene group. -C(O)OZ ^b , -alkyl-C(O)NZ ^b Z ^b and -CH ₂ -CH ₂ -C(O)-CH ₃ , but are not limited to these specific options, and are included in Other options known in the art. The one or more substituent groups are bonded together with the atoms bonded to them to form a cyclic ring comprising a cycloalkyl group and a cycloheteroalkyl group, but the invention is not limited thereto.

Likewise, useful substituent groups for a substituted unsaturated carbon atom in a particular group, moiety or radical include, but are not limited to, -Z ^a , halo, -O ^- , -OZ ^b , -SZ ^b , -S ^- , -NZ ^c Z ^c , trihalomethyl, -CF ₃ , -CN, -OCN, -SCN, -NO, -NO ₂ , -N ₃ , -S(O) ₂ Z ^b , -S(O ₂ ) O ^- , -S(O ₂ )OZ ^b , -OS(O ₂ )OZ ^b , -OS(O ₂ )O ^- , -P(O)(O ^- ) ₂ , -P(O)(OZ ^b ) (O ^- ), -P(O)(OZ ^b )(OZ ^b ), -C(O)Z ^b , -C(S)Z ^b , -C(NZ ^b )Z ^b , -C(O O ^- , -C(O)OZ ^b , -C(S)OZ ^b , -C(O)NZ ^c Z ^c , -C(NZ ^b )NZ ^c Z ^c , -OC(O)Z ^b ,- OC(S)Z ^b , -OC(O)O ^- , -OC(O)OZ ^b , -OC(S)OZ ^b , -NZ ^b C(O)OZ ^b , -NZ ^b C(S)OZ ^b , -NZ ^b C(O)NZ ^c Z ^c , -NZ ^b C(NZ ^b )Z ^b , and -NZ ^b C(NZ ^b )NZ ^c Z ^c , where Z ^a , Z ^b and Z ^c are as above Defined.

Likewise, substituent groups useful for the substituted nitrogen atom in the heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -Z ^a , halo, -O ^- , -OZ ^b , -SZ ^b , -S ^- , -NZ ^c Z ^c , trihalomethyl, -CF ₃ , -CN, -OCN, -SCN, -NO, -NO ₂ , -S(O) ₂ Z ^b , -S(O ₂ )O ^- , - S(O ₂ )OZ ^b , -OS(O ₂ )OZ ^b , -OS(O ₂ )O ^- , -P(O)(O ^- ) ₂ , -P(O)(OZ ^b )(O ^- ) , -P(O)(OZ ^b )(OZ ^b ), -C(O)Z ^b , -C(S)Z ^b , -C(NZ ^b )Z ^b , -C(O)OZ ^b , -C (S)OZ ^b , -C(O)NZ ^c Z ^c , -C(NZ ^b )NZ ^c Z ^c , -OC(O)Z ^b , -OC(S)Z ^b , -OC(O)OZ ^b , -OC(S)OZ ^b , -NZ ^b C(O)Z ^b , -NZ ^b C(S)Z ^b , -NZ ^b C(O)OZ ^b , -NZ ^b C(S)OZ ^b ,- NZ ^b C(O)NZ ^c Z ^c , -NZ ^b C(NZ ^b )Z ^b , and -NZ ^b C(NZ ^b )NZ ^c Z ^c , wherein Z ^a , Z ^b and Z ^c are as defined above .

The compounds described herein may contain one or more optically active centers and/or double bonds, and thus, stereoisomers may exist, such as double bond isomers (ie, geometric isomers such as E and Z), An enantiomer or a diastereomeric isomer. The present invention encompasses each isolated stereoisomeric form (e.g., the enantiomerically pure isomer, the E and Z isomers, and for stereo, in varying degrees of optical purity or percentages of E and Z). Other alternatives to isomers) and mixtures of stereoisomers, including racemic mixtures, mixtures of diastereoisomers And a mixture of E and Z isomers. Thus, the chemical structures described herein contain all possible enantiomers and stereoisomers of the indicated compounds, which comprise stereoisomeric pure forms (eg, purely geometrically, purely enantiomerically Or pure diastereoisomers) and mixtures of enantiomers and stereoisomers. Enantiomeric and stereoisomeric mixtures can be decomposed into enantiomers of their composition or stereoisomers using separation techniques or optically active techniques well known to those skilled in the art. In varying degrees of optical purity, the invention encompasses each isolated stereoisomeric form as well as mixtures of stereoisomers, including racemic mixtures. It also contains various diastereomeric stereoisomers. Other structures may depict a particular isomer, but are merely for convenience and are not intended to limit the invention to the depicted olefin isomers. When the chemical name does not specify an isomeric form of the compound, it is expressed as either a possible isomeric form or a mixture of compounds of these isomeric forms.

The compound may also exist in several tautomeric forms, one of the tautomers depicted herein is for convenience only, and it is also to be understood that other tautomeric forms are included. Thus, the chemical structures described herein contain illustrative compounds of all possible tautomeric forms. The term "tautomer" as used herein refers to isomers which are very easily changed to another such that they can be in equilibrium at the same time; the equilibrium state can strongly favor the mutual variation One kind of structure, depending on stability considerations. For example, ketones and enols are a compound of two tautomeric forms.

The term "solvate" as used herein means a compound formed by solubilization (a combination of solvent molecules having molecules or ions of a solute) or an aggregate composed of solute ions or molecules (ie, the present invention) The compound has one or more solvent molecules). When water is the solvent, the corresponding solvate is a "hydrate". Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other aqueous species. It will be understood by one of ordinary skill in the art that pharmaceutically acceptable salts and/or precursors of the present compounds may also exist in a solvate form. The solvate is usually formed by hydration (partial preparation of the present compound or by natural absorption of water by the anhydrous compound of the present invention).

The term "ester" as used herein means any ester of the present compound, wherein any -COOH functional group of the molecule is substituted with a -COOR functional group, wherein the R moiety of the ester is any stable to form. a carbon-containing group of an ester moiety, comprising an alkyl group, an alkenyl group, an alkynyl group, A cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group, a heterocycloalkyl group, and a substituted derivative thereof, but the invention is not limited thereto. The hydrolyzable ester of the present compound is a compound in which the carboxyl group is present in the form of a hydrolyzable ester group. That is, these esters are pharmaceutically acceptable and can be hydrolyzed to carboxylic acids in vivo.

In addition to the substituents as described above, the alkyl group, the alkenyl group and the alkynyl group may be exchanged or additionally C ₁ -C ₈ decyl, C ₂ -C ₈ heterofluorenyl, C ₆ - Substituted by a C ₁₀ aryl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₈ heterocyclic group or a C ₅ -C ₁₀ heteroaryl group, each of which may be optionally substituted. Further, in addition, when a group capable of forming a ring having 5 to 8 ring members is present on the same or adjacent atoms, the two groups may be freely attached to the two groups to the substituent groups. The ground is joined to an atom or a plurality of atoms to form such a ring.

"Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" and the like are similarly defined to corresponding a hydrocarbyl (alkyl, alkenyl, and alkynyl) group, but the term 'hetero' refers to a group comprising 1-3 oxygen, sulfur or nitrogen heteroatoms or combinations thereof within a backbone residue; A heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group is formed, respectively, by substituting a specific heteroatom for at least one carbon atom of the corresponding alkyl group, alkenyl group or alkynyl group. Due to chemical stability, it is also understood that such groups do not include more than two adjacent heteroatoms unless otherwise specified, except in the case of nitro groups or sulfonium groups. In the case, an oxygen group is present on N or S.

The term "alkyl" as used herein, includes a cycloalkyl group and a cycloalkylalkyl group. In the group, the term "cycloalkyl" can be used herein to describe a carbocyclic non-aromatic group attached via a ring carbon atom, and "cycloalkylalkyl" can be used to describe a linkage to the alkyl link. The carbon ring of the molecule is a non-aromatic group.

Similarly, "heterocyclyl" can be used to describe a non-aromatic cyclic ring which contains at least a hetero atom (usually selected from nitrogen, oxygen, and sulfur) as a member of a ring, and attached to the molecule via a ring atom, which may be C (carbon chain type) or N (nitrogen chain type); A cycloalkyl group can be used to describe such a group attached to another molecule through a linker. The heterocyclic group can be sufficiently saturated or partially saturated, but non-aromatic. The sizes and substituents which can be used for the cycloalkyl group, the cycloalkylalkyl group, the heterocyclic group and the heterocycloalkyl group are the same as those of the above alkyl group. The heterocyclic group typically comprises 1, 2 or 3 heteromolecules as ring members selected from the group consisting of nitrogen, oxygen and sulfur; in a heterocyclic ring system, the N or S may be based on the bases of these atoms. The regiment is replacing. As this article The terms used also include rings containing one double bond or two as long as the attached ring is not aromatic. The substituted cycloalkyl group and heterocyclic group further comprise a cycloalkyl ring or a heterocyclic ring fused to an aromatic ring or a heteroaromatic ring, and the point at which the group is attached is to the cycloalkyl ring or heterocyclic ring, Not to the aromatic/heteroaromatic ring.

As used herein, "mercapto" includes alkyl, alkenyl, alkynyl, aryl or a group of an arylalkyl radical, said alkyl, alkenyl, alkynyl, aryl or arylalkyl radical being attached to one of two available valence positions of a carbonyl carbon atom, and a hydrazine By a group is meant a corresponding group wherein at least one carbon (other than the carbonyl carbon) has been replaced by a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.

The oxime group and the hydrazine group are bonded to any group or molecule to which they are attached by the valence of the carbonyl carbon atom. Usually, they are a C ₁ -C ₈ fluorene group (which contains a decyl group, an ethyl fluorenyl group, a neopentyl group, and a benzhydryl group) and a C ₂ -C ₈ fluorene group (which contains a methoxyethyl fluorenyl group) , ethoxycarbonyl and 4-pyridylmethyl).

Similarly, "arylalkyl" and "heteroarylalkyl" refer to an aromatic ring system and a heteroaromatic ring system bonded to a bond through a linking group. The linking group is, for example, an alkylene group containing a substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linking group. Typically the linker is a C ₁ -C ₈ alkyl group. These linking groups may contain a carbonyl group to enable them to provide a substituent as a mercapto or heteroindenyl moiety. An aryl or heteroaryl ring in the arylalkyl group or heteroarylalkyl group may be substituted with the same substituent as described above for the aryl group. Preferably, the arylalkyl group comprises a benzene ring optionally substituted by a group defined by an aryl group and a C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group being One or two C ₁ -C ₄ alkyl groups or heteroalkyl groups which are unsubstituted or substituted, wherein the alkyl group or heteroalkyl group can be optionally cyclized to form, for example, cyclopropane, dioxane Ring of a ring or oxolane. Similarly, the heteroarylalkyl group preferably comprises a C ₅ -C ₆ monocyclic heteroaryl group optionally substituted with a group which is as described above for the aryl group and the C ₁ -C ₄ alkylene group. Described as a substituent, the C ₁ -C ₄ alkylene group is unsubstituted or substituted with one or two C ₁ -C ₄ alkyl groups or heteroalkyl groups, or it comprises an optionally substituted benzene ring Or a C ₅ -C ₆ monocyclic heteroaryl group and a C ₁ -C ₄ heteroalkylene group, the C ₁ -C ₄ heteroalkylene group being one or two C ₁ -C ₄ alkyl groups or heteroalkyl groups And unsubstituted or substituted, wherein the alkyl group or heteroalkyl group can be optionally cyclized to form a ring such as cyclopropane, dioxolane or oxolane.

One of the arylalkyl groups or heteroarylalkyl groups is described as a random substituent The substituents may be in the alkyl or heteroalkyl moiety, or in the aryl or heteroaryl portion of the group. The substituents optionally present in the alkyl or heteroalkyl moiety are the same as those described above for the pervasive alkyl group; the substituents optionally present in the aryl or heteroaryl moiety are more than the above The ones described in the base are the same.

"Arylalkyl" groups as used herein are hydrocarbyl groups if they are unsubstituted And in the ring and alkyl or similar linkers are described by the total number of carbon atoms. Thus the benzyl group is a C7-arylalkyl group and the phenylethyl group is a C8-arylalkyl group.

The "heteroarylalkyl group" as described above refers to a moiety containing an aryl group, which is an aryl group. Is attached by a linking group, and differs from "arylalkyl" in that the ring atom of at least one aryl moiety or one atom in the linking group is selected from nitrogen, oxygen and sulfur. Hetero atom. In combination with the linker, the heteroarylalkyl group is described herein in terms of the total number of atoms, and they comprise an aryl group attached through a heteroalkyl link; through a hydrocarbyl linker (eg, a heteroaryl group to which the alkyl group is attached; and a heteroaryl group attached through a heteroalkyl linker. Thus, for example, a C7-heteroarylalkyl group will comprise a pyridylmethyl group, a phenoxy group, and an N-pyrrolylmethoxy group.

As used herein, "alkylene" refers to a divalent hydrocarbyl group; since it is divalent, it can link two other groups together. Generally, it refers to -(CH ₂ ) _n -, wherein n is 1-8, preferably, n is 1-4, and although the specified position, the alkyl group may be substituted by other groups, and may be Other lengths, and open valences do not need to be located at both ends of a chain.

Generally, any alkyl group, alkenyl group, alkyne group, hydrazine contained in the substituent The group or aryl group or arylalkyl group may be optionally substituted by itself with an additional substituent. If the substituents are not otherwise described, the nature of these substituents is similar to those described for the primary substituents themselves.

As used herein, "amino" refers to an NH ₂ , but where the amine group is described as "substituted" or "arbitrarily substituted", the term encompasses NR ' R " wherein each R ' and R "is each H, or a monoalkyl group, an alkenyl group, an alkyne group, a fluorenyl group, an aryl group or an arylalkyl group, and the alkyl group, the alkenyl group, the alkyne group, Each of a fluorenyl group, an aryl group or an arylalkyl group is optionally substituted with a substituent as described herein suitable for the opposite group; the R ' and R " groups and the nitrogen atom attached thereto A 3-membered ring to an 8-membered ring may be optionally formed, and the 3-membered ring to 8-membered ring may be saturated, unsaturated or aromatic, and it contains one to three as ring members each selected from nitrogen, a hetero atom of oxygen and sulfur, and which is optionally substituted with a substituent suitable for the alkyl group, or if NR ' R " is an aromatic group, it is optionally used as a heteroaryl group. The substituents are substituted.

The term "carbocyclic compound", "carbocyclic group" or "carbocyclic ring" as used herein refers to It is a cyclic ring containing only carbon atoms in the ring, and the term "heterocyclic" or "heterocyclic" refers to a ring containing a hetero atom. The carbocyclic group can be sufficiently saturated or partially saturated, but non-aromatic. For example, the carbocyclic group contains a cycloalkyl group. The carbocyclic and heterocyclic structures comprise compounds having a monocyclic, bicyclic or polycyclic ring system; and such systems can incorporate aromatic rings, heterocyclic rings and carbocyclic rings. The hybrid ring system is described in terms of a ring attached to a scaffold of the compound.

The term "heteroatom" as used herein refers to any non-carbon or hydrogen source. Sub, such as nitrogen, oxygen or sulfur. When it is part of the backbone or backbone of the chain or ring, a heteroatom must be at least divalent and is typically selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur.

The term "alkyl fluorenyl" as used herein refers to an alkyl group covalently bonded to a carbonyl group (C=O). The term refers to "lower alkanoyl group" is an alkanoyl group, wherein the alkyl portion of the alkanoyl group is C ₁ -C _6. The alkyl portion of the alkane group can be optionally substituted as described above. The term "alkylcarbonyl" can be used interchangeably. Similarly, the terms "alkenylcarbonyl" and "alkynylcarbonyl" refer to an alkenyl or alkynyl group attached to a carbonyl group, respectively.

The term "alkoxy" as used herein refers to an alkyl group covalently bonded to an oxygen atom; the alkyl group can be considered to be a hydrogen atom replacing a monohydroxy group. The term "lower alkoxy" refers to an alkoxy group in which the alkyl portion of the alkoxy group is a group C ₁ -C _6. The alkyl portion of the alkoxy group can be optionally substituted as described above. The term "haloalkoxy" as used herein refers to an alkoxy group in which the alkyl moiety is substituted by one or more halo groups.

As used herein, the term refers to a "sulfonic acid group" is a sulfonic acid (-SO ₃ H) substituent.

The term "amine sulfonyl" as used herein refers to a substituent having the structure -S(O ₂ )NH ₂ wherein the nitrogen of the NH ₂ moiety of the group is optionally employed as described above. Replace.

The term "carboxy" as used herein refers to a group of the structure -C(O ₂ )H.

As used herein, the term refers to "carbamoyl acyl" is a structural -C (O ₂₎ NH ₂ group, wherein the nitrogen NH ₂ moiety of the group may be optionally substituted as described above.

The terms "monoalkylaminoalkyl" and "dialkylaminealkyl" as used herein refer to the structures -Alk ₁ -NH-Alk ₂ and -Alk ₁ -N(Alk ₂ )(Alk ₃ ). A group wherein Alk ₁ , Alk ₂ and Alk ₃ refer to an alkyl group as described above.

The term "alkylsulfonyl" as used herein refers to a radical of the structure -S(O) ₂ -Alk, wherein Alk refers to an alkyl radical as described above. The terms "alkenylsulfonyl" and "alkynylsulfonyl" are similarly meant to mean a sulfonyl group covalently bonded to an alkenyl group and an alkynyl group, respectively. The term "arylsulfonyl" refers to a group of the structure -S(O) _2- Ar, wherein Ar refers to an aryl group as described above. The term "aryloxyalkylsulfonyl" refers to a group of the structure -S(O) ₂ -Alk-O-Ar, wherein Alk is an alkyl group as described above, and Ar is as above Said aryl. The term "aralkylsulfonyl" refers to a radical of the structure -S(O) _2- AlkAr wherein Alk is an alkyl group as described above and Ar is an aryl group as described above.

The term "alkoxycarbonyl," as used herein, refers to an ester substituent containing an alkyl group, wherein the carbonyl carbon is a point attached to the molecule. One example is ethoxycarbonyl group which is _{CH 3 CH 2 OC (O)} -. Similarly, the terms "alkenyloxycarbonyl", "alkynyloxycarbonyl" and "cycloalkylcarbonyl" refer to similar ester substituents containing an alkenyl group, an alkenyl group or a cycloalkyl group, respectively. . Similarly, the term "aryloxycarbonyl" refers to an ester substituent containing an aryl group wherein the carbonyl carbon is attached to the molecule. Similarly, the term "aryloxyalkylcarbonyl" refers to an ester substituent comprising an alkyl group, wherein the alkyl group itself is substituted with an aryloxy group.

Combinations of other substituents are known in the art and are described, for example, in U.S. Patent No. 8,344,162, the disclosure of which is incorporated herein by reference. For example, the combination of the term "thiocarbonyl" and a substituent containing "thiocarbonyl" includes a carbonyl group in which a double bond of sulfur in the group replaces the oxygen of the normal double bond. The term "alkylidene" and like terms mean an alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group, which according to regulations has two A single carbon atom removes a hydrogen atom such that the group is double bonded to the residue of the structure.

Weikangol and other substituted hexitols have many advantages for the treatment of anti-TKI non-small cell lung cancer (NSCLC) and chronic myelogenous leukemia (CML). These agents inhibit the growth of cancer stem cells (CSC) and are resistant to drugs that deactivate O ⁶ -methylguanine-DNA methyltransferase (MGMT). Wei Kang alcohol is a novel alkylating agents which cause crosslinking of DNA on N ^7.

As described below, in patients with TKIs resistance, Wei Kang alcohol and other substituted hexitols can be used to treat malignant tumors.

One aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor having a polymorphism in a germ cell that is resistant to TKIs, comprising: administering a therapeutically effective amount of a therapeutic agent to The target object is a step of treating the malignant tumor, the therapeutic agent being selected from the group consisting of a derivative or analog of Weikangol, Weikangol, dihydroquinone dihydrated dulcitol, and diacetyl dianthracene A group consisting of a derivative or analog, dibromodusol, and a derivative or analog of dibromodusol.

As described above, the malignant tumor can be chronic myelogenous leukemia (CML) or non-small cell lung cancer (NSCLC), however, as described below, the therapeutic agent can be used to treat other malignancies, including triple negative breast cancer.

In general, confirmation of whether or not a specific target subject has a malignant tumor having a polymorphism of a germ cell that confers resistance to TKIs is performed by performing DNA-paired end tag (DNA-PET) analysis. The connectivity of the PET sequence allows for the detection of deletions. For example, the segment can be selected to be all of a particular size. After the genetic map analysis, the PET sequences are therefore expected to be always a specific distance from each other. Differences from this distance indicate a structural variation between the PET sequences. For example, a deletion in a sequenced genome will be read, and a map that is much larger than the expected map in the reference genome as a reference genome will have a fragment of DNA that is not present in the sequenced genome. This can be used to detect the presence of a deletion, such as the above 2903 bp or another germ cell deletion polymorphism with a deletion that confers resistance to TKIs. Typically, the germ cell DNA deletion polymorphism initiates a splicing variation that results in the expression of an isomer of the BIM protein lacking a BH3 region, thereby inhibiting the induction of apoptosis.

Another aspect of the present invention is to provide a method of combining screening and treatment, the knot Combination: screening for germline deletion polymorphism, and treatment of malignant tumors resistant to TKIs in a target subject if the germ cell deletion polymorphism is found to be present.

Generally, the method comprises the steps of: (1) screening for a germ cell deletion polymorphism in a target subject having a malignant tumor; and (2) if the germ cell deletion polymorphism is found in the malignant tumor In the target object, a therapeutically effective amount of a therapeutic agent is administered to the target subject to treat the malignant tumor, and the therapeutic agent is selected from the group consisting of a derivative or the like of Weikangol, Weikangol, and diethyl hydrazine. A group consisting of a derivative or analog of piranol, diethylene quinone dihydrated cyclohexanol, dibromodusol, and a derivative or analog of dibromodusol.

As described above, the malignant tumor can be chronic myelogenous leukemia (CML), non-small cell lung cancer (NSCLC) or triple negative breast cancer. However, other malignancies can be treated by similar methods (where tyrosine kinase activity is associated with abnormal or uncontrolled cell proliferation).

The method may further comprise: administering (1) a BH3 analog; or (2) a BH3 analog and an anti-tyrosine kinase therapeutic agent to a target subject having a malignant tumor in which a germ cell is deficient in polymorphism; The step of treating the effective amount of both.

Suitable BH3 analogs are mentioned above. A particularly good BH3 analog is ABT-737.

Suitable TKI therapeutic agents include imatinib, bosutinib, nilotinib, and dasatinib, all of which target the Bcr-Abl receptor tyrosine kinase. Generally, imatinib is preferred. Additional TKI therapeutic agents include erlotinib, afatinib, and dacotinib, which are EGFR inhibitors (reversible or irreversible) that actively target native or mutant EGFR; these agents specifically target EGFR tyrosine kinase.

The derivative or analog of Weikangol, Weikangol, or diethyl hydrazine for treating primary anti-TKI tumors can be achieved according to the following principles for improving the therapeutic effect of administration of one or more of these hexitol derivatives. Dehydrated dulcitol, a derivative or analog of Wiconol, a derivative or analog of dibromodusol or dibromodusol (commonly referred to herein as an "alkylated hexitol derivative") ) of the drug.

Accordingly, an aspect of the present invention provides a method of treating a malignant tumor, wherein the malignant tumor is characterized by at least one tyrosine kinase inhibitor (tyrosine kinase inhibitor, TKI) is resistant due to: (1) at least one mutation in a gene that encodes a protein that is a target of at least one TKI; or (2) at least one of a native or mutant state The presence of an additional gene encoding a product of resistance to a therapeutic effect of at least one TKI comprising: administering a therapeutically effective amount of a monoalkylated hexitol derivative. Typically, the alkylated hexitol derivative is a derivative or analog of Weikangol, Weikangol, a dihydroquinone dihydrated cyclohexanol, a derivative or equivalent of diacetyl dianol, or A derivative or analog of dicyclohexanol or dibromodusol.

In an alternative, at least one additional gene in the native or mutant state of the product encoding a resistance to the therapeutic effect of at least one TKI is AHI-1.

As described below, these methods may further comprise: (1) the step of administering a therapeutically effective amount of a BH3 analog to a target subject; (2) the step of administering a therapeutically effective amount of a TKI to a target subject; (3) administering one a step of therapeutically effective amount of a JAK2 inhibitor to a target; (4) a step of administering a therapeutically effective amount of a STAT5 inhibitor to a target; (5) a step of administering a therapeutically effective amount of a Src kinase inhibitor to a target; Or (6) administering a therapeutically effective amount of a combination of a kinase inhibitor to a target subject to treat the malignant tumor; wherein the combination of the kinase inhibitors is a combination selected from the group consisting of: (a a JAK2 inhibitor and a STAT5 inhibitor; (b) a JAK2 inhibitor and a Src inhibitor; (c) a STAT5 inhibitor and a Src inhibitor; and (d) a JAK2 inhibitor, a STAT5 inhibitor And a Src inhibitor to the target. Furthermore, when the method comprises: administering a JAK2 inhibitor, a STAT5 inhibitor, a Src inhibitor or two or more JAK2 inhibitors, a STAT5 inhibitor, and a Src inhibitor to a therapeutically effective amount In the step, the method may further comprise the step of administering a therapeutically effective amount of a BH3 analog or a TKI to the target subject. Suitable BH3 analogs, TKIs, JAK2 inhibitors, STAT5 inhibitors and Src inhibitors for use in these methods are described below.

Another aspect of the present invention is to provide an improved method for the therapeutic use of an alkylated hexitol derivative for treating an anti-TKI tumor by altering the time of administration of the compound and controlling the metabolic rate of the compound. Dose-modifying agents, normal tissue protectants, and other deteriorating agents. Common examples include: changes in the injection schedule (eg, single intravenous injection compared to continuous injection), use of therapeutic antibodies to increase the total number of white blood cells, and to increase the immune response or to prevent anemia caused by myelosuppressive agents Or use a rescue agent (for example, for 5-FU of formazan tetrahydrofolate or thiosulfate for cisplatin treatment). Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: continuous intravenous injections for hours to days; biweekly administration; doses greater than 5 mg/m ² /day; patient-tolerance Sexually increasing dose by 1mg/m ² /day; dose less than 1mg/m ² (greater than 14 days); use of caffeine to regulate metabolism; use of isoniazid to regulate metabolism; selected and intermittent increase Dosing; single single dose and multiple doses from 5 mg/m ² ; or oral doses below 30 mg/m ² or above 130 mg/m ² .

Another aspect of the invention is to provide an improved method of use in the therapeutic use of an alkylated hexitol derivative for the treatment of an anti-TKI tumor by altering the route of administration of the compound. Typical examples include: changing from an oral route to intravenous administration (and vice versa); or using specific routes such as subcutaneous, intramuscular, intraarterial, intraperitoneal, intralesional, intralymphatic, intratumoral, intraspinal, intravascular In the head. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: daily administration; weekly administration for three weeks, weekly administration for two weeks, biweekly administration; biweekly administration for three weeks (1-2 Weekly rest period); intermittent dose escalation; daily dosing for one week, followed by weekly dosing for multiple weeks; use agent to reach 40 mg/m ^{2 for} three days, then 18-21 days for minimum/recovery cycle; The lower level (e.g., 21 days); the agent at a higher level; the agent with a minimum/recovery period of more than 21 days; and the use of an alkylated hexitol derivative as a single therapeutic agent.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by altering the stage of disease in the diagnosis/deterioration of administration of the compound. A general example includes the use of chemotherapy for non-removable topical disease, prophylactic use to prevent metastatic spread or to inhibit disease progression or metastasis to more malignant stages. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include the use of alkylated hexitol derivatives having angiogenesis inhibitors (eg, cancer inhibitors, VEGF inhibitors) to prevent Or limiting metastatic spread, particularly in the central nervous system, using alkylated hexitol derivatives for newly diagnosed diseases, using alkylated hexitol derivatives for recurrent diseases, and using An alkylated hexitol derivative of a pharmaceutically or refractory disease.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by altering the type of patient that is best tolerated or benefit from the use of the compound. Typical examples include: use of pediatric doses for elderly patients, variable doses for obese patients; use of comorbid conditions such as diabetes, cirrhosis or other conditions in which a compound can be uniquely developed. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: patients with high levels of metabolic enzymes, histone deacetylase, protein kinase, and ornithine decarboxylase Patients with low levels of metabolic enzymes, histone deacetylase, protein kinase, or adenine decarboxylase; patients with low or high susceptibility to thrombocytopenia and neutropenia Patients who cannot tolerate GI toxicity; over- or under-expression of jun, GPCR's and signaling proteins, VEGF, prostate specific genes, protein kinases or telomerase.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is accomplished by more accurately identifying the patient's ability to tolerate, metabolize, and utilize the compound. A general paradigm includes: biopsy samples of tumors or normal tissues (eg, glial cells or other cells of the central nervous system) that can also be taken and analyzed for genetic targets to explicitly develop or monitor the use of specific drugs. Unique tumor gene expression morphology or analysis of single nucleotide polymorphisms (SNPs) to improve efficacy or to avoid specific drug sensitivity to normal tissue toxicity. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: diagnostic tools, techniques, kits and assays for identifying a particular genotype of a patient; gene/protein expression wafers and assays; Nucleotide polymorphism (SNPs) assessment; SNPs for histone deacetylase, alanine decarboxylase, GPCR's, protein kinases, telomerase or jun; and identification and measurement of metabolic enzymes and metabolites .

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by professional preparation used before or after the patient with the chemotherapeutic agent. Common examples include: induction or inhibition of metabolic enzymes, specific protection of sensitive normal tissues or organ systems. Specific examples of the invention for treating an alkylated hexitol derivative of a primary anti-TKI tumor include: using colchicine or the like; using a diuretic or a uric acid (for example, probenecid); using uricase; non-oral Use nicotine Indoleamine; sustained release form of nicotinamide; inhibitor of poly ADP ribose polymerase; use of caffeine; methotrexate rescue; infection control; antihypertensives.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by using additional drugs or procedures to prevent or reduce potential side effects or toxicity. Common examples include: use of antiemetic adjuvants, anti-nausea adjuvants, blood adjuvants to limit or prevent neutropenia, anemia, thrombocytopenia, vitamins, antidepressants, for sexual dysfunction Therapeutic agents, as well as other ancillary techniques. Specific examples of the invention for treating an alkylated hexitol derivative of a primary anti-TKI tumor include: using colchicine or the like; using a diuretic or a uric acid (for example, probenecid); using uricase; non-oral Use of nicotinamide; sustained release form of nicotinamide; use of inhibitors of poly ADP ribose polymerase; use of caffeine; methotrexate rescue; use of sustained release of isodecyl alcohol; use of isodecyl alcohol by parenteral; Bone marrow transplantation promoter, blood, platelet injection, Neupogen, G-CSF; GM-CSF; pain control; anti-inflammatory drugs; fluid; corticosteroids; insulin control drugs; antipyretic; anti-nausea therapeutic agents; Laxative therapeutic agent; N-acetyl cysteine; antihistamine.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative, which is to attempt to maximize blood levels of a drug, monitor toxic metabolite production, and monitor drug-drug interaction by monitoring drug levels after administration. Auxiliary drugs that may be beneficial or harmful in terms of function. Typical examples include monitoring of drug plasma protein binding rates, as well as monitoring of other pharmacokinetic or pharmacodynamic variables. Specific examples of inventions for the treatment of alkylated hexitol derivatives of anti-TKI tumors include: multiple determinations of blood levels in the drug; multiple determinations of metabolites in blood or urine.

A further aspect of the present invention is to provide an improved method for the therapeutic use of an alkylated hexitol derivative for treating an anti-TKI tumor, which is carried out by utilizing a unique combination of drugs, which is uniquely used Improvements in efficacy or side effects can be provided in addition to additive or synergistic effects. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: binding to positional isomerase inhibitors; use of pseudonucleosides; use of pseudonucleotides; use of thymidine synthetase inhibitors; Use signaling inhibitors; use cisplatin or platinum analogs; use alkylating agents such as nitrosoururia (BCNU, Gliadel wafers, CCNU, nimustine (ACNU)) , benzodamsten (Treanda); use of an alkylating agent that destroys DNA in different places than the phytonol or another alkylated hexitol derivative (TMZ, BCNU, CCNU, and other alkylating agents) , all destroy DNA on O ⁶ of guanine, and Weikang alcohol cross-links on N ⁷ ); use a monofunctional alkylating agent; use a bifunctional alkylating agent; use anti-tubulin agent; use Antimetabolite; use berberine; use apigenin; use amonafide; use colchicine or its analogues; use genistein; use etoposide; use arabinose cytosine Using camptothecin; using vinca alkaloids; using positional isomerase inhibitors; Use 5-fluorouracil; use curcumin; use NF-κB inhibitor; use rosmarinic acid; use propionate; use tetrandrine; use temozolomide (TMZ); and for example antibody (eg cancer) Combination of Avastin (VEGF inhibitor), Rituxan, Herceptin, Erbitux, biotherapy, combination with cancer vaccine therapy; epigenetic regulation Agent; use of transcription factor inhibitor; use of taxol; use of homoharringtonine; use of pyridoxal; use of spirocyclic guanidine; use of caffeine; use of nicotine guanamine; use of methylglyoxal bis-indole Use of Rho kinase inhibitor; use of 1,2,4-benzotriazine oxide; use of monoalkyl glycerol; use of an inhibitor of Mer, Ax1 or Tyro-3 receptor kinase; use of an inhibitor of ATR kinase Using a Fms kinase, Kit kinase, MAP4K4 kinase, TrkA kinase or TrkB kinase modulator; using tamoxifen (endoxifen); using an mTOR inhibitor; using a MN1a kinase, Mkn1b kinase, Mnk2a kinase or Mnk2b kinase Inhibitor; regulation using a M2 pyruvate kinase Use of a modulator of inositol monophosphate 3 kinase; use of a cysteine protease inhibitor; use of phenformin; use of a Cindbis virus-based vector; use of an analog that plays Smac and inhibits IAPs to promote apoptosis Pseudopeptide; use of a Raf kinase inhibitor; use of a nuclear transfer regulator; use of an acidic neural glutaminase inhibitor and a choline kinase inhibitor; use of a tyrosine kinase inhibitor; use of an anti-CS1 antibody; use PDK1 Inhibitor of protein kinase; use of anti-guanylyl cyclase C (GCC) antibody; use of histone deacetylase inhibitor; use of cannabinoid; use of glycoside-like peptide (glucagon- Like peptide-1, GLP-1) receptor agonist; use inhibitor of Bcl-2 or Bcl-xL; use Stat3 pathway inhibitor; use inhibitor of polo-like kinase 1, Plk1; Use of GBPAR1 activator; use of serine-synamic acid protein kinase and poly(ADP-ribose) polymerase (PARP) activity modulator; use of taxane; use of dihydrofolate reductase inhibitor Using an inhibitor of aromatase; Use of a benzimidazolyl anticancer agent; use of an O6-methylguanine-DNA-methyltransferase (MGMT) inhibitor; use of a CCR9 inhibitor; use an acid sphingomyelinase inhibitor; use a pseudopeptide macrocycle Use of amphoteric acid aminide; use of substituted oxyphosphonazo; use of anti-TWEAK receptor antibody; use of an ErbB3 binding protein; activation of antitumor compounds using a glutathione S-transferase; use of substituted phosphonium Amidoxime; use of an inhibitor of MEKK protein kinase; use of a COX-2 inhibitor; use of cimetidine and a cysteine derivative; use of an anti-IL-6 receptor antibody; use of an antioxidant; use of a microtubule Protein-polymerized isoxazole inhibitors; use of PARP inhibitors; use of aurora protein kinase inhibitors; use of peptides that bind to prostate specific membrane antigens; use of CD19 binding agents; use of benzenediazonium salts; Toll-like receptor (TLR) agonist; use of bridged bicyclic sulfonamide; use of inhibitor of epidermal growth factor receptor kinase; use of a T2 family of ribonuclease with actin-binding activity; Terpene benzoic acid (myrsinoic Acid A) or an analogue thereof; use of a cyclin-dependent kinase inhibitor; use of an inhibitor of interaction between p53 and MDM2; use of an inhibitor of the receptor tyrosine kinase MET; use of ragorazole or pull Gozol analog; inhibitor of AKT protein kinase; use of 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine or L-deoxythymidine; use of HSP90 modulator; use An inhibitor of JAK kinase; an inhibitor of PDK1 protein kinase; a PDE4 inhibitor; an inhibitor of the proto-oncogene c-Met tyrosine kinase; an inhibitor of indoleamine 2,3-dioxygenase; An agent that inhibits the expression of ATDC (TRIM29); a protein-like inhibitor that uses the interaction of a nuclear receptor and a co-activated peptide; an antagonist that uses a XIAP family protein; a tumor-targeted superantigen; an inhibitor that uses Pim kinase Using an inhibitor of CHK1 or CH2 kinase; using an inhibitor of angiopoietin protein 4; using a Smo antagonist; using a nicotinic acetylcholine receptor antagonist; using a farnesyl protein transferase inhibitor; Glycoside A3 receptor antagonist; use cancer vaccine Use a JAK2 inhibitor; or use a Src inhibitor.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative by utilizing an alkylated hexitol derivative as a chemical sensitizer (an improvement in addition or addition to synergy observed in efficacy) When used alone, in combination with other treatments, no detectable activity was observed. use Specific examples of the invention for treating alkylated hexitol derivatives of primary anti-TKI tumors include: as a chemical sensitizer in combination with a positional isomerase inhibitor; as a chemical sensitizer in combination with a pseudonucleoside; a pseudo-nucleotide-bound chemical sensitizer; a chemical sensitizer that binds to a thymidine synthase inhibitor; a chemical sensitizer that binds to a signaling inhibitor; and a chemical that binds to cisplatin or a platinum analog a sensitizer; as a chemical sensitizer in combination with an alkylating agent (eg, BCNU, Griffith implant, CCNU, tredamin (Treanda) or temodar); as an anti-tubulin agent a combined chemical sensitizer; a chemical sensitizer that binds to an antimetabolite; a chemical sensitizer that binds to berberine; a chemical sensitizer that binds to apigenin; and a chemical that binds to naproxen a sensitizer; a chemical sensitizer in combination with colchicine or an analogue thereof; a chemical sensitizer in combination with genistein; a chemical sensitizer in combination with itopride; as an arabinosyl group Chemically induced by cytosine binding Sensitizer; as a chemical sensitizer combined with camptothecin; as a chemical sensitizer in combination with vinca alkaloids; as a chemical sensitizer in combination with a positional isomerase inhibitor; as a 5-fluoro group a uracil-bound chemical sensitizer; a chemical sensitizer that binds to curcumin; a chemical sensitizer that binds to NF-κB inhibitor; and a chemical sensitizer that binds to rosmarinic acid; a chemical sensitizer that binds to acetonide; or a chemical sensitizer that binds to tetrandrine.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method for the therapeutic use of a hexylated hexitol derivative by utilizing an alkylated hexitol derivative as a chemical synergist (an improvement in addition to addition or synergy observed in efficacy) It is carried out when it is used alone, but in combination with other therapeutically unique drugs), with minimal therapeutic activity observed. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: as a chemical potentiator in combination with a positional isomerase inhibitor; as a chemical synergist in combination with a pseudonucleoside; a chemical potentiator that binds to a thymidine synthase inhibitor; acts as a chemical potentiator in combination with a signaling inhibitor; as a chemical synergist in combination with cisplatin or a platinum analog; as an alkylating agent (eg BCNU) a chemical synergist in combination with BCNU, Grind or Teranda; as a chemical synergist in combination with an anti-tubulin agent; as a chemical synergist in combination with an antimetabolite; As a chemical synergist in combination with berberine; as a chemical synergist in combination with apigenin; as a chemical synergist in combination with naproxen; as a chemical synergist in combination with colchicine or its analogues As a chemical synergist in combination with genistein; Iptuce combined chemical synergist; as a synergist with arabinosylcytosine; as a synergist with camptothecin; as a synergist with vinca alkaloids As a chemical potentiator in combination with a positional isomerase inhibitor; as a chemical synergist in combination with 5-fluorouracil; as a chemical synergist in combination with curcumin; as an inhibitor with NF-κB a combined chemical synergist; as a chemical synergist in combination with rosmarinic acid; as a chemical synergist in combination with propylene; as a chemical synergist in combination with tetrandrine.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by considering the drug, treatment, and diagnosis that maximizes benefit to the patient being treated with the compound. Common examples include: pain control, nutritional support, antiemetics, anti-nausea therapy, anti-anemia therapy, anti-inflammatory. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of treatments associated with pain management; use of nutritional support; use of antiemetics; use of anti-nausea therapy; use of anti-anemia therapy; Anti-inflammatory drugs; use of antipyretics; use of immunostimulants.

A further aspect of the invention is to provide an improved method of use in the therapeutic use of an alkylated hexitol derivative for the treatment of anti-TKI tumors by using complementary therapies or to increase effectiveness or reduce side effects The application of the method is carried out. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: hypnosis; acupuncture; physical and mental therapy; herbal drugs produced by synthesis or extraction comprising NF-κB inhibitors (eg, parthenolide) , curcumin, rosmarinic acid); natural anti-inflammatory drugs (including rhein, parthenolide); immune boosters (eg found in echinacea); antimicrobials (eg berberine) Flavonoids, isoflavones and flavonoids (eg apigenin, genistein, genistein, 6 " -O-propanediamine genistein, 6 " -O-acetyl genistin, daidzein, soybean Glycosides, 6 " -O-propanediyl daidinoside, 6 " -O-acetyl dysinium glucoside, daidzein, daidzein, 6 " -O-propanediyl daidzin and 6-O - Ethyl-based flavonoids; application of human kinematics.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by modifying the pharmaceutical material. Typical examples include: salt formation, homogeneous crystal structure, pure isomers. Specific examples of the invention of alkylated hexitol derivatives for treating primary anti-TKI tumors include: salt formation; homogenous crystal structure; pure isomers; increased purity; low residual solvents and heavy metals.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by altering the diluent used to dissolve and release/present the compound for administration. Typical examples include hydrogenated castor oil polyoxyethylene, cyclodextrin for poorly water soluble compounds. Specific examples of the invention for treating an alkylated hexitol derivative against an anti-TKI tumor include: use of an emulsion, dimethyl sulfoxide (DMSO), N-methylformamide (NMF), Dimethylformamide (DMF), dimethylacetamide (DMA), ethanol, benzyl alcohol, water containing glucose for injection, polyoxyethylene castor oil, cyclodextrin, PEG.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by altering the solvent used or required to dissolve the compound for administration or for further dilution. A general example includes: ethanol, dimethylacetamide (DMA). Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of emulsion, dimethyl hydrazine (DMSO), N-methylformamide (NMF), dimethylformate Indoleamine (DMF), dimethylacetamide (DMA), ethanol, benzyl alcohol, water containing glucose for injection, polyoxyethylene castor oil, PEG or salt system.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by altering the materials/excipients, buffers or preservatives required to stabilize and present the chemical compound for proper administration. Typical examples include: mannitol, albumin, EDTA, sodium bisulfite, benzyl alcohol. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of mannitol; use of albumin; use of EDTA; use of sodium hydrogen sulfite; use of benzyl alcohol; use of carbonate buffer; Phosphate buffer; use polyethylene glycol (PEG); use vitamin A; use vitamin D; use vitamin E; use esterase inhibitor; use cytochrome P450 inhibitor; use multi-drug Resistance, MDR) inhibitor; use of an organic resin; use of a detergent; use of perillol or an analogue thereof; or use of a channel to form a receptor activator.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative, which is modified by administration Routes, periods of influence, plasma levels, potential dosage forms of compounds exposed to side effects of normal tissues and metabolic enzymes. Typical examples include: tablets, capsules, topical gels, ointments, patches, embolic agents. Specific examples of the use of the alkylated hexitol derivative include: a tablet; a capsule; a topical gel; a topical ointment; a patch; an embolic agent; a lyophilized dose filler; an immediate release preparation; Use a controlled release formulation; or use a liquid capsule.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is accomplished by varying the dosage form, container/closed system, mixing accuracy, and dosage formulation and presentation. Typical examples include: brown bottles that avoid light, and stoppers with special coatings. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: the use of a brown bottle to avoid illumination; a stopper with a special coating to increase shelf life stability.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is accomplished by using a delivery system to improve the potential properties of the drug product (e.g., convenience, duration of action, reduced toxicity). Typical examples include: nanocrystals, bioerodible polymers, liposomes, sustained release injection gels, microspheres. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of oral dosage forms; use of nanocrystals; use of nanoparticles; use of cosolvents; use of syrup; use of syrup, use of bioerodic Type of polymer; use of liposomes; use of sustained release injection gel; use of microspheres; or use of targeting compositions with epidermal growth factor receptor binding peptides.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative by modifying an initial alkylated hexitol derivative having a covalent, ionic or hydrogen bonded moiety to modify efficacy, toxicity, pharmacokinetics, The pathway of metabolism or administration. Come on. Typical examples include: polymer systems (eg, polyethylene glycol), polylactic acid, polyglycolic acid, amino acids, peptides or multivalent linkers. Specific examples of the invention for treating alkylated hexitol derivatives of primary anti-TKI tumors include: using a polymer system (e.g., polyethylene glycol); using polylactic acid; using polyglycolic acid; using an amino acid; Peptide; use of multivalent linkers; use of immunoglobulins; use of cyclodextrin polymers; use of modified transferrin; use of hydrophobic polymers or hydrophobic-hydrophilic polymers; use of conjugates with partial sodium monophosphate a conjugate having a cell binder with a charged crosslinker; or a There is a conjugate of β-glucuronic acid through a linker.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexitol derivative, which is carried out by altering the initial structure of a molecule having additional chemical functionality that can alter efficacy, reduce toxicity, improve drug performance, Compatible with a particular route of administration or altering the metabolism of the therapeutic agent. Typical examples include: side chain changes to increase or decrease lipophilicity; additional chemical functionality to alter reactivity, electron affinity and binding capacity; salt type. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: side chain changes to increase or decrease lipophilicity; additional chemical functionality to alter reactivity, electron affinity or binding ability; Type of salt.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by modifying the molecule such that cleavage of a portion of the molecule into the body reveals a preferred active molecule followed by improved drug performance with a variant of the active molecule. Typical examples include: enzyme-sensitive esters, dimers, Schiff bases. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of enzyme-sensitive esters; use of dimers; use of Schiff base; use of pyridoxal complexes; use of caffeine complexes Using nitric oxide to release the precursor; using a precursor having a fibroblast activator alpha-cleavable oligopeptide; a precursor using a product reacted with an oxime or an amine formazin; using hexanoic acid a precursor of a salt conjugate; a precursor using a conjugate of a polymer-agent; or a use of a precursor prior to redox activation.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by using additional compounds, biological agents (when administered in the appropriate type, a unique and beneficial effect can be achieved). Common examples include: multidrug resistance inhibitors, specific drug resistance inhibitors, specific selective enzyme inhibitors, signal delivery inhibitors, and repair inhibitors. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: use of multidrug resistance inhibitors; use of specific drug resistance inhibitors; use of specific selective enzyme inhibitors; use of signals Delivery of inhibitors; use of repair inhibitors; or use of positional isomerase inhibitors with non-overlapping side effects.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by using an alkylated hexitol derivative in combination with a sensitizer/potentiator having a biologically reactive modifier. A general example includes the use of a sensitizer/potentiator with a biological response modifier, a cytokine, a therapeutic antibody, a therapeutic antibody, an antisense therapy, or a gene therapy. Specific examples of the invention for treating an alkylated hexitol derivative of a primary anti-TKI tumor include: a combination of a sensitizer/potentiator having a biological reaction modifier; and a sensitizer/potentiation with a cytokine in combination a combination of a sensitizer/potentiator with a therapeutic antibody; a combination of a sensitizer/potentiator with a therapeutic antibody; and an antisense therapy in combination (eg, cancer, Hepatic, rituximab) Sensitizer/potentiator; combination of sensitizer/potentiator with gene therapy; sensitizer/potentiator with ribozyme; sensitizer with RNA interference / synergist.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative by utilizing the selective use of an alkylated hexitol derivative to overcome the developmental or complete resistance of the effective use of biological therapy . Typical examples include: tumors that are resistant to biological response modifiers, cytokines, therapeutic antibodies, therapeutic antibodies, antisense therapy, gene therapy. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: tumors resistant to the effects of bio-reactive modifiers; tumors resistant to cytokine-resistant effects; used to resist lymphokine resistance Tumors affected; tumors that are resistant to the effects of therapeutic antibodies; tumors that are resistant to anti-sense therapy; used to resist the effects of treatment such as cancer, rituximab, carbazone, and erbitux Tumor; a tumor used to combat the effects of resistance to gene therapy; a tumor used to combat the effects of nuclease resistance; or a tumor used to combat the effects of RNA interference.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by using an alkylated hexitol derivative in combination with ionizing radiation, phototherapy, thermotherapy or radio frequency production therapy. Typical examples include: hypoxic sensitizers, radiation sensitizers/protectants, photosensitizers, and radiation repair inhibitors. Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: in combination with ionizing radiation; in combination with a hypoxic sensitizer; in combination with a radiation sensitizer/protecting agent; a combination of agents; used in combination with a radiation repair inhibitor; Used in combination with thiol depletion; in combination with vascular target agents; in combination with radioactive strains; in combination with radionuclides; in combination with radiolabeled antibodies; or in combination with proximity therapy. Improvements in the efficacy of such radiation therapy or the ability to combine the synergistic effects of radiation therapy with alkylated hexitol derivatives are significant.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative, which optimizes its utility by determining various novel mechanisms of action, bio-targets for compounds that are more deeply understood and accurately utilized to better utilize the utility of the molecule ongoing. Specific examples of the invention for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: inhibitors using poly ADP ribose polymerase; use of agents that affect blood vessels; use of agents that promote vasodilation; targeting using oncogenes Drugs; use of signal delivery inhibitors; use of agents that cause EGFR inhibition; use of agents that cause inhibition of protein kinase C; use of agents that cause modulation of phospholipase C; use of agents that cause jun decreasing regulation; use of regulatory tissue protein genes An agent that modulates the expression of VEGF; an agent that modulates the expression of adenosine decarboxylase; an agent that modulates the performance of jun D; an agent that modulates the expression of v-jun; and an agent that modulates the expression of GPCRs; An agent that modulates the expression of protein kinase A; an agent that modulates the expression of telomerase; an agent that modulates the expression of a specific gene of the prostate; an agent that regulates the expression of a protein kinase (except protein kinase A); An agent that degrades the expression of a protein.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative by more accurately identifying and revealing a compound to these selected cell populations (where the cell population can maximize the effect of the compound) . Specific examples of inventions for the treatment of alkylated hexitol derivatives of primary anti-TKI tumors include: resistance to radiation-sensitive cells, resistance to radiation-resistant cells, or resistance to energy depletion of cells.

A further aspect of the invention provides an alkane for use in the treatment of an anti-TKI tumor An improved method of therapeutic use of a hexylated hexitol derivative is carried out by using an agent for increasing the activity of the alkylated hexitol derivative. A general example includes the use of nicotinamide, caffeine, tetrandrine or berberine. Specific examples of the invention for treating an alkylated hexitol derivative of a primary anti-TKI tumor include: using nicotine amide; using caffeine; using tetrandrine; Or use berberine.

These modifications in therapeutic applications of monoalkylated hexitol derivatives can also be used in: (1) treatment of an AHI1- associated malignancy, such as a malignant tumor characterized by a mutation or disorder of AHI1 ; 2) Treatment of triple-negative breast cancer.

Accordingly, another aspect of the present invention is to provide a method for increasing the efficacy and/or reducing side effects of administration of an alkylated hexitol derivative for use in treating a primary anti-TKI tumor, the method comprising the steps of: (1) Identifying at least one factor or parameter associated with the efficacy and/or side effects of the administration of the alkylated hexitol derivative, which is used to treat a primary anti-TKI tumor; and (2) modification The factor or parameter is used to increase the efficacy and/or side effects of administration of the alkylated hexitol derivative for treating the anti-TKI tumor.

Typically, the factor or parameter is selected from the group consisting of: (1) dose adjustment; (2) route of administration; (3) schedule of administration; (4) use of indications; (5) course of disease Stage selection; (6) other indications; (7) selection of patients; (8) patient/disease phenotype; (9) patient/disease genotype; (10) pre/post treatment preparation; (11) Toxicity management; (12) pharmacokinetic/pharmacodynamic monitoring; (13) concomitant administration; (14) chemical sensitization; (15) chemical synergism; (16) post-treatment patient management; (17) selection Sexual medical/treatment support; (18) improvement of drug substance products; (19) diluent system; (20) solvent system; (21) excipient; (22) dosage form; (23) dose kit and packaging; (24) drug delivery system; 25) drug conjugated form; (26) compound analog; (27) precursor; (28) multiple drug system; (29) biotherapeutic potentiation; (30) antibiotic therapy; (31) radiotherapy enhancement; (32) novel mechanism of action; (33) selective target cell population therapy; and (34) use of an agent that increases its activity.

As described above, these modifications in the therapeutic use of monoalkylated hexitol derivatives can also be used in: (1) treatment of an AHI1- associated malignancy, such as a mutation or disorder characterized by AHI1 . Malignant tumors; and (2) treatment of triple-negative breast cancer. Further details regarding the use of alkylated hexitol derivatives in the treatment of AHI1- associated malignancies and in the treatment of triple-negative breast cancer are provided below.

As stated above, the alkylated hexitol derivative is typically a half-lactitol, a monosubstituted galactitol, a dulcitol or a substituted dulcitol, such as Wei Kang alcohol, diethyl hydrazine Alcohol, dibufloxacin and its derivatives and the like, but the invention is not limited thereto. These compounds are precursors to alkylating agents or alkylating agents.

These alkylated hexitol derivatives include, but are not limited to: (1) Weikangol; (2) derivatives of Weikangol, for example, hydrogen having a hydroxyl group substituted with a lower alkyl group, which has a lower alkane a base substituted with hydrogen attached to the epoxy ring, or having a methyl group attached to the same carbon, a carbon having a hydroxyl group substituted with a lower alkyl group or a hydroxyl group substituted with, for example, a halogen group; (3) diacetyl quinone dihydrated cyclohexanol; (4) a derivative of diethylene quinone dihydrated cyclohexanol, For example, it has a methyl group substituted with a lower alkyl group, a methyl group having a lower alkyl group attached to the epoxy ring, or a methyl group attached to the same carbon, the carbon band a hydrazine group substituted with a lower alkyl group or an acetamidine group substituted with, for example, a halogen group; (5) dibromodusol; and (6) a derivative of dibromodusol, for example, One or more hydrogens of a hydroxyl group substituted with a lower alkyl group, or one or two bromo groups substituted with another halogen group (for example, chlorine or fluorine).

When the improvement is made by dose adjustment, the dose adjustment may be, but is not limited to, at least one dose adjustment selected from the group consisting of: (a) continuous intravenous injection for hours to days; b) biweekly administration; (c) a dose greater than 5 mg/m ² /day; (d) a stepwise increase in dose based on patient tolerance from 1 mg/m ² /day; (e) use of caffeine to regulate metabolism (f) use of nicotine strontium to modulate metabolism; (g) selected and intermittent increases in dosing; (h) single and multiple dose escalation from mg/m ² /day in a single dose; (i) an oral dose of less than 30 mg/m ² ; (j) an oral dose of more than 130 mg/m ² ; (k) an oral dose of 40 mg/m ^{2 for} three days, followed by a minimum/recovery period of 18-21 days; (l) The agent is at a lower level of duration (eg 21 days); (m) the agent is at a higher level; (n) the agent is used for a minimum/recovery period of more than 21 days; (o) one is used as a single An alkylated hexitol derivative of a cytotoxic agent; (p) an immediate release agent; (q) a sustained release agent; and (r) a controlled release agent.

The use of an immediate release agent is described in U.S. Patent No. 8,299,052 to Flanner et al., which is incorporated herein by reference. Use of sustained release agents Vergnault et al. are described in U.S. Patent No. 8,303,986, the disclosure of which is incorporated herein by reference. The use of a controlled release agent is described in U.S. Patent No. 8,304,577, the disclosure of which is incorporated herein by reference. The controlled release agent can be obtained by using a biodegradable polymer such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydrogen A crosslinked or bipolar block copolymer of pyran, polycyanoacrylate and water gel, but the invention is not limited thereto.

When the improvement is carried out by a route of administration, the route of administration may be, but not limited to, at least one route selected from the group consisting of: (a) topical administration; (b) oral administration. (c) sustained release of oral delivery; (d) spinal injection; (e) intraarterial injection; (f) continuous infusion; (g) intermittent infusion; (h) intravenous administration, such as intravenous administration for 30 minutes; i) administration by a longer injection; (j) administration by intravenous bolus; and (k) intraperitoneal administration.

When the improvement is carried out by a schedule of administration, the schedule of administration may be, but not limited to, at least one schedule selected from the group consisting of: (a) daily administration; (b) (c) weekly dosing; (c) three weeks of weekly dosing; (d) biweekly dosing; (e) biweekly dosing for three weeks (1-2 weeks rest period); (f) intermittent dose escalation; and (g) ) Daily medication for a week or more.

When the improvement is made by selection of a disease stage, the selection of the stage of the disease may be, but is not limited to, at least one selected from the group consisting of: (a) used in one The appropriate course of disease for anti-TKI tumors; (b) the use of newly diagnosed diseases; (c) the use of recurrent diseases; (d) the use of resistant or refractory diseases; (e) the treatment of an AHI1- associated malignancy Use; (f) use of the treatment of triple-negative breast cancer; and (g) use of the treatment of metastatic disease.

When the improvement is made by selecting a patient, the selected patient can be, but is not limited to, a selected patient achieved by a benchmark selected from the group consisting of: (a Selecting a patient having a condition characterized by a high level of a metabolic enzyme selected from the group consisting of histone deacetylase and ornithine decarboxylase; (b) having A condition of low or high susceptibility conditions selected from the group consisting of thrombocytopenia and neutropenia; (c) selection of patients who cannot tolerate GI toxicity; (d) selection A patient characterized by over- or under-expression of a gene selected from the group consisting of c-Jun, a GPCR, a signaling protein, VEGF, a prostate specific gene, and a protein kinase. Group; (e) select patients based on BIM co-deletions; and (f) select patients with AHI1-based mutations or disorders.

The cell proto-oncogene c-Jun encodes a protein that binds to c-Fos to form an AP-1 early response transcription factor. This proto-oncogene plays a key role in transcription and interacts with a number of proteins that affect transcription and gene expression. It also relates to the proliferation and apoptosis of cells forming part of many tissues, including cells of the endometrium and glandular epithelial cells. G-protein coupled receptors (GPCRs) are important signal transduction receptors. The superfamily of G protein-coupled receptors contains a large number of receptors. These receptors are intact membrane proteins characterized by amino acid sequences containing seven hydrophobic regions, predicted to represent the transmembrane domain of the protein. They are found in a wide range of organisms and involve the transmission of signals to the interior of the cell due to their interaction with the heterotrimeric G protein. They respond to different classes of agents, including fatty analogs, amino acid derivatives, small molecules (such as epinephrine and dopamine), and various sensory stimuli. The properties of many known GPCRs are outlined in S. Watson and S. Arkinstall, "G-Linked Receptor Documentary Series" (Academic Press, London, 1994), and are incorporated by reference. GPCR receptors include, but are not limited to, acetylcholine receptor, β -adrenergic receptor, β ₃ -adrenergic receptor, serotonin (serotonin) receptor, dopamine receptor, adenosine receptor, Second type of vasopressin receptor, vasopressin receptor, calcitonin receptor, calcitonin gene-related receptor, cannabinoid receptor, cholecystokinin receptor, chemokine receptor, cytokine receptor, Gastrin receptor, endothelin receptor, γ-aminobutyric acid (GABA) receptor, galanin receptor, glycosidic receptor, glutamate receptor, progesterone receptor , chorionic gonadotropin receptor, follicle stimulating hormone receptor, thyroid stimulating hormone receptor, gonadotropin releasing hormone receptor, leucotriene receptor, neuropeptide Y receptor, endorphin receptor, Parathyroid hormone receptor, platelet activating factor receptor, prostaglandin (prostaglandin) receptor, somatostatin receptor, thyrotropin releasing hormone receptor, vasopressin and oxytocin receptor.

AHI1 (Abelson-Helper Integration Site-1) is a novel oncogene that has been found to have regulatory abnormalities in some leukemia cell lines, including CML (chronic myeloid leukemia). AHI1 enhances the action of BCR-ABL1 in vivo and induces a number of kinases, including JAK2, STAT5 and Src family kinases, which ultimately mediate the reactivity or resistance of thymidine kinase inhibitors (TKIs). Many studies have shown an overexpression of AHI1 in primary hematopoietic cells: conferring an in vitro growth advantage to such cells, inducing leukemia in vivo, and enhancing the effects of BCR-ABL1. Studies from cells with CML have also shown that AHI1 also contributes to BCR-ABL1-induced malignant transformation by mediating TKI resistance. In addition, mutations in the kinase region of the ABL1 protein contribute to the resistance of imatinib and other TKIs; mutations that are not frequently found are point mutations involving a single amino acid substitution, T315I (TBBalci et al., "In chronic bone marrow AHI1 gene expression level and BCR-ABL1 T315I mutation in patients with leukemia", Hematology 16:357-360 (2011), and is included by reference. The AHI1 locus was initially identified as a common helper proviral integration site in Abelson pre-B cell lymphoma and was shown to be tightly linked to the c-myb proto -oncogene . In the Abelson murine leukemia virus-induced pre-B lymphoma inserted into the AHI1 locus, it was found that there was no significant change in c-myb expression, suggesting that this locus contains at least one other disorder involved in tumor formation. Gene. This gene at this locus is the AHI1 gene. Proviral insertion is found at the 3' end of the gene in the reverse transcription direction, and most of the proviral insertion is placed around or downstream of the last exon of the gene; another insertion is found in the intron 22 of the gene. . In addition, another previously identified proviral insertion site, Mis-2, was found to be mapped in intron 16 of the AHI1 gene. The AHI1 cDNA encodes a protein of a 1047 amino acid residue. The predicted AHI1 protein is a modular protein containing an SH3 motif and seven WD-40 repeats. The AHI1 gene is highly conserved in mammals and encodes two major RNA species, 5 and 4.2 kb, and several other, shorter, splice variants. The AHI1 gene is expressed in mouse embryos and is expressed in organs of several mice and rats; in particular, performance in the brain and testis occurs at a high level. In tumor cells harboring insertional mutations in AHI1 , truncated viral fused transcripts have been identified, including some splice variants with deletions in the SH3 region. In normal intracellular signaling, AHI1 is characterized by several message molecules and is considered to play an important role. Since harboring v-abl deletion retrovirus or c-myc transfected tumor gene, or in a presentation deletion Nf1 of the confirmed AHI1 insertion site, so AHI1 also be involved in tumor development, possibly with other oncogenes (e.g. v -abl and c-myc ) or tumor suppressor gene ( Nf1 ) cooperate. The full-length human AHI1 gene consists of 29 exons (i.e. exons 1 to 33, exons 24, 28, 29 and 32); this stop codon is located in exon 33. However, in exon 24, there is a truncated isomer lacking the SH3 region and consists of 24 exons (exon only 1 to 24) and contains an in-frame stop codon. There is a second truncated isomer consisting of 32 exons (exons 1 to 33, exon 24), however there is a stop codon in exon 28. Some 3' terminal insertional mutations derived from proviral insertions can alter the standard splicing machinery and can force alternative splicing within the viral or intron sequences to access them, thereby deleting the carboxy-terminal region that normally encodes the AHI1 protein. Exon. Genetic evidence suggests that proviral insertional mutations in the AHI1 gene contribute to tumor formation in a number of different cell lines. The AHI1 locus was identified as a common proviral integration site, initially in Abelson ( v-abl- induced) pre-B lymphoma, followed by c-myc- induced T cells in MMTV ^D /myc Tg mice. In lymphoma, this suggests that it may cooperate with some form of these oncogenes to induce tumor formation. In other types of tumors, this locus was also found to be rearranged by proviral insertion, ie in B-cell tumors prior to Eμ/myc Tg mice, and acute bone marrow in Nf1 heterozygous mice In leukemia. Similarly, in the Moloney MuLV-induced rat T cell lymphoma lymphoma (thymoma), the Miss-2 locus was identified as a common proviral insertion site. In fact, these proviral insertion mutations are not random and have been identified in a relatively high proportion of tumors, indicating that the mutations have been selected during the oncogene program and they all involve oncogene programs. In non-deletion retrovirus-inducing tumors, the role of insertional mutagenesis in oncogene programs is supported by several common examples of viral insertion sites that have been found to activate proto-oncogenes. Analysis of RNA in tumors harboring mutations in the AHI1 gene indicates that this mechanism (these insertional mutations can enhance the carcinogenic potential of the AHI1 gene by this mechanism) is truncated by the truncated form of the competent AHI1 RNA. The AHI1 protein is encoded. These truncated RNAs were specific to this tumor analysis and were not found in non-rearranged tumors. These may involve the conversion process. The deletion of the sequence encoded by the carboxy terminus of the protein, including the SH3 region, may significantly affect the interaction of AHI1 with other proteins, possibly converting this molecule to a dominant negative mutant. Alternatively, if the SH3 region binds intramolecularly, or if the SH3 region binds to an inhibitor, the truncated AHI1 protein may represent an abnormally acquired functional mutant. In non-receptor tyrosine kinases, for example, the deletion or mutation of the proto-oncogene c-src or c-abl , his SH3 region usually leads to the activation of its tyrosine kinase oncogene, indicating that the SH3 region Binding to an inhibitor of kinase activity. Thus, deletion of SH3 in AHI1 may reveal some regions and allow for novel protein interactions or may prevent binding of inhibitors. In fact, in tumors, the potential AHI1 cDNA, which is encoded to encode a very truncated protein, has been isolated from normal tissues, indicating that in each tissue, the truncated AHI1 protein is not necessarily Oncogene. Conversely, in certain cell types, inappropriate, dysregulated or increased expression of the truncated AHI1 protein may contribute to the transformation process (X. Jiang et al. " Ahi-1 , a novel coding with WD40" The gene for the repetitive sequence and the model protein of the SH3 region is a targeted target for the integration of Ahi-1 and Miss-2 proviruses, J. Virol. 76: 9046-9059 (2002), and is incorporated by reference) . The AHI1 locus is also involved in the development of acute myeloid leukemia (AML), which occurs in NF-1 heterozygous mice and occurs in Moloney murine (Moloney murine) Leukemia virus, Mo-MuLV) is induced in rat T cell lymphoma. Although the function of the AHI1 protein has not been fully determined, it clearly plays a role in the signal through several pathways. The AHI1 protein is known to have a multiple Src homology 3 (SH3) binding site, an SH3 region, and a plurality of tryptophan-aspartic acid 40 (WD40)-repeat regions. There are at least three human isomers of this protein. The shorter human dimeric isomer lacks the SH3 region, and the human stereoisomer, which is also shorter than the full-length isoform, contains additional coding sequences, and the coding sequence is in one or two isoforms. It is not present in the isomer. Even in normal cells, the AHI1 gene is thus alternatively spliced. However, mutant forms of AHI1 can serve as synergistic oncogenes, particularly in the development of human hematopoietic malignancies. Transcription of AHI1 is considered to be the most active in normal hematopoietic cells of the most native type and then downregulated during their early differentiation. In a wide range of human leukemia cell lines and in cells directly derived from Philadelphia chromosome positive (Ph ⁺ ) but not from Ph ^- leukemia, the marker of AHI1 expression was deregulated and the level of expression was greatly improved. This strongly suggests that changes in the performance of AHI1 are important in the development of Ph ⁺ leukemia. During normal human hematopoietic differentiation, there was an overall 6-fold decrease in the expression of AHI1 from the most native lin ^- CD34 ⁺ CD38 ^- subset to the most mature lin ⁺ CD34 ^- cell. Splicing perturbations were also observed, including the relative upregulation of the one and the two isomers. The dimeric isomer lacks the SH3 region and is a truncated protein with unique properties that may contain functional activity; loss of the SH3 region may disrupt the normal signaling function of the AHI1 protein (X. Jiang et al., "At AHI- In Ph ⁺ human leukemia, the abnormal regulation of genes activated by insertional mutations in a mouse model of leukemia", Blood 103: 3897-3904 (2004), and is incorporated by reference.

In addition, the AHI1 protein and the BCR-ABL fusion protein and others are involved Protein interactions to the regulation of hematopoiesis and hematopoiesis. This interaction is described in LLZhou et al. "AHI-1 interacts with BCR-ABL to modulate BCR-ABL conversion activity and imatinib response to CML stem/precursor cells", J. Exp. Med. 11:2657 -2671 (2005) and include it by reference. Specifically, chronic myelocytic leukemia (CML), which encodes a chimeric oncoprotein (BCR-ABL), is initiated or proliferated by a rare population of CML stem cells that have obtained a BCR-ABL fusion gene, The fitting Oncogenic proteins have been shown to substantially increase tyrosine kinase activity that drives the pathogenesis of CML. This involves, among other effects, the regulation of cell proliferation and apoptosis control through the influence of multiple signaling pathways, including Ras, phospholipidinositol 3-kinase (PI3K), JAK-STAT and NF-κ B pathways. As described above, imatinib mesylate, an inhibitor of BCR-ABL tyrosine kinase, is often used to treat CML, which is affected by the development of resistance to this tyrosine kinase inhibitor, leading to relapse or treatment failure. . Although other tyrosine kinase inhibitors (such as dasatinib and nilotinib) may be useful in cases where drug resistance has progressed or may progress to imatinib, there is still a need to rely on tyrosine alone. The mechanism of specific interaction between acid kinase inhibitors and the BCR-ABL tyrosine kinase prevents the development of drug resistance.

Recent studies have shown that CML stem/precursor cells rarely respond to IM and other tyrosine kinase inhibitors in chronic phase patients and are a key target for the development of imatinib mesylate resistance. group. Such CML stem / progenitor cells having properties genomic instability, and often results in vitro (in vitro) imatinib mesylate resistant mutants.

As described above, in the v-abl-induced mouse pre-B cell lymphoma as a candidate synergistic oncogene, the Ahi-1 gene (in mice) or its retained human homolog ( AHI-1 ) is one. A novel gene identified by a proviral insertional mutation. The mouse Ahi-1 gene encodes a unique protein with an SH3 region, multiple SH3 binding sites, and a WD40-repeat region, all of which are considered to be important mediators of protein-protein interactions, indicating that normal Ahi The -1 protein (in mice) or the human homologous AHI-1 protein has abnormal signal activity, and its deregulation can affect specific cellular signaling pathways. The retentive human homolog AHI-1 has an additional coiled-coil region in its amino terminal region. The expression of the Ahi-1 gene (in mice) or the AHI-1 gene (in humans) has been shown to be regulated in multiple hematopoietic stages in a manner that is highly retained between mice and humans. In general, these genes, in both mouse and human, are expressed at their highest levels in most of the original hematopoietic cells and then rapidly downregulated as the cells begin to differentiate. In general, deregulation of AHI-1 expression has occurred in many human leukemia cell lines, particularly in a CML cell line (K562) and in Philadelphia chromosome positive (Ph ⁺ BCR-ABL ⁺ ) primary leukemia cells, but Not Ph ^- cells, especially in highly concentrated leukemia stem cells from patients with CML. In addition, the level of BCR-ABL transcripts is highly increased in the same CML stem cell population, suggesting that its synergistic activity on AHI-1 and BCR-ABL can be important in the early stages of leukemia formation. A permanent amplification mutant of a stem cell that regulates abnormality.

The overexpression of the mouse gene Ahi-1 alone in native hematopoietic cells was found to confer an advantage in in vitro proliferation and induce lethal leukemia in vivo; these effects are enhanced by BCR-ABL . In BCR-ABL -transduced primitive human umbilical cord blood and native leukemia cells obtained from CML patients, the stable inhibition of the homologous human gene AHI-1 by small interfering RNA (siRNA) was reduced in vitro. ( in vitro ) growth autonomy, so it is expected that such cells will reduce the production of leukemia. One option for siRNA is the siRNA molecule, which is described in A. Ringrose et al., "Evidence for the carcinogenic effects of AHI-1 in leukemia variants of Sezary syndrome, human cutaneous T-cell lymphoma", Leukemia 20: 1593-1601 (2006) and include it by reference. The oligonucleotides encoding these siRNAs are 5'-GATCCCCGTGATGATCCCGACACTATTTCAAGAGAATAGTGTCGGGATCATCACTTTTTA-3' (SEQ ID NO: 12) and 5'-AGCTTAAAAAGTGATGATCCCGACACTATTCTCTTGAAATAGTGTCGGGATCATCA CGGG-3' (SEQ ID NO: 13). In addition, overexpression of Ahi-1 (in mice) induced abnormal differentiation (including phylogenetic switching). Therefore, the excessive expression of Ahi-1 in mice alone in IL-3-dependent hematopoietic cells results in strong transforming activity in vitro and in vivo, and this is an additive having a BCR-ABL effect. Overexpression of Ahi-1 confers a growth advantage on mouse hematopoietic stem/precursor cells and enhances BCR-ABL . This overexpression is monitored by Q-RT-PCR analysis of mRNA transcripts. Further, although the level of performance is less than in the Ahi-1 cells were transduced, the BCR-ABL to the transduced cells alone do not transfer and Ahi-1 itself, it has been observed to improve the performance of Ahi-1.

In addition, the human homologue AHI- in K562 cells was investigated to restore the growth control to a certain extent by the inhibition of Ahi-1 expression and to reduce the growth factor-dependent proliferation, the size of the formed colonies, and the ability to form a representative strain from a single cell. 1. The effect of inhibition or overexpression of a cell line derived from a patient having CML and characterized by a highly increased expression of AHI-1 . In contrast, overexpression of AHI-1 resulted in a dramatic increase in colony forming ability compared to control cells; the recovery of AHI-1 gene or AHI-1 protein in cells was inhibited by AHI-1 inhibition. Defect reversal of siRNA interference. In AHI-1 , similar results were seen as changes in performance in vivo.

Similarly, in vivo, inhibition of AHI-1 expression in native BCR-ABL -transduced human CB cells and primary CML stem/precursor cells reduced their growth autonomy. This inhibition is accomplished by using lentiviral RNA interference. The results indicate that AHI-1 can play a role in the overproduction of bone marrow cells in CML.

In addition, in the pre-treatment of lin ^- CD34 ⁺ cells from patients with subsequent clinical response to both imatinib mesylate therapy (both responders and non-responders), or prior to the patient in the acute phase of transformation AHI-1 transcript levels were assessed in the treatment of lin ^- CD34 ⁺ cells. An increase in the level of AHI-1 expression was observed in lin ^- CD34 ⁺ stem/progenitor cells from all patient samples compared to lin ^- CD34 ⁺ normal BM cells. The cells from the imatinib mesylate non-reactant showed higher levels of AHI-1 transcript than the cells from the responder. This overexpression may be inhibited by lentiviral RNA interference. In a transduced primary CML cell from a non-responder or in an acute transformation phase compared to a transduced primary CML cell from a responder to imatinib mesylate, in a lentiviral RNA interference There is a greater reduction in the induced community forming cells.

In a BCR-ABL - transduced BaF3 cell line survey Ahi-1 synergy, the BCR-ABL - transduced cell line wherein the BaF3 p210 ^BCR-ABL - The level of performance can be by exposure to doxycycline and Variable underground tone. In both in vitro liquid suspension culture and in vitro liquid suspension culture, a decrease in the expression of BCR-ABL protein in the presence of doxycycline resulted in a corresponding decrease in growth factor independence of BaF3 cells; this indicates that BCR-ABL The reduction in protein expression is associated with a decrease in carcinogenic potential. Similarly, in semi-solid cultures in the absence of IL-3, the decreasing regulation of BCR-ABL expression completely inhibits community-forming cell formation. However, the introduction of Ahi-1 in cells with inhibition of BCR-ABL results in their continued growth in liquid suspension culture to have fewer Annexin V ⁺ anti-apoptotic cells, compared to BCR-ABL alone. Transduced cells produce more factor-independent colony forming cells. This is consistent with an increase in the carcinogenic potential caused by Ahi-1 expression in these cells. Taken together, these results demonstrate the ability of Ahi-1 to downregulate BCR-ABL to reverse in vitro growth defects and provide evidence for the regulation of Ahi-1 in BCR-ABL vector transformation.

In addition, it was also demonstrated that the co - expression of Ahi-1 in BCR-ABL -induced cells suffered from tyrosine phosphorylation of BCR-ABL and increased activation of JAK2 and STAT5. Specifically, even in the presence of doxycycline, tyrosine phosphorylation of p210 ^{BCR-ABL was} not significantly inhibited in cells that had been co-transduced by both Ahi-1 and BCR-ABL . Similarly, in co-transduced cells compared to cells transduced only with BCR-ABL , BCR-ABL protein expression was also inhibited to a lesser extent, and in cells transduced with BCR-ABL only. In the comparative co-transduced cells, Ahi-1 protein expression was found to be relatively high. In BCR-ABL -induced cells and Ahi-1- co-transduced BCR-ABL -induced cells compared with BaF3, there was also increased JAK2, STAT5, NF-κB p65 (on Ser-563 and Ser-468) And the level of phosphorylation of Src (on Tyr-416). In addition, phosphorylation of the most downstream protein was down-regulated when BCR-ABL was inhibited by doxycycline, but JAK2 was continuously observed in co-transduced cells in the presence of IL-3 and doxycycline. Continuous phosphorylation of STAT5. In the absence of IL-3, phosphorylation of JAK2 and STAT5 is reduced in co-transduced cells when BCR-ABL expression is inhibited. Similarly, although not so obvious, the discovery of sustained phosphorylation of Src was observed, particularly in Ahi-1 ⁺ BCR-ABL cells in the presence of IL-3, indicating that the IL-3 message was The pathway increases the mediation of the activity of JAK2 and STAT5, and Ahi-1 exerts a regulatory role in the activity of Src.

In addition, a physical interaction was detected between AHI-1 and ABL in CML cells by immunoprecipitation. In K562 cells using an anti-phosphotyrosine antibody, tyrosine phosphorylated p210 ^BCR-ABL can be detected. This protein complex is also associated with tyrosine phosphorylated JAK2. An antigenic peptide derived from the AHI-1 sequence specifically blocks the ability of the AHI-1 antibody to precipitate both tyrosine phosphorylated BCR-ABL and tyrosine phosphorylated JAK2; an unrelated peptide is not produced influences. This interaction complex has also been found to be regulated by the tyrosine kinase activity of BCR-ABL, as treatment with cells with imatinib mesylate leads to the inability to detect tyrosine phosphorylation of BCR-ABL. And both tyrosine phosphorylated JAK2. These results indicate that AHI-1 and BCR-ABL can interact to form a complex involving JAK2 phosphorylated by tyrosine.

Simultaneous interaction of BCR-ABL and AHI-1 with JAK2 mediates imatinib mesylate sensitivity/resistance in BCR-ABL+ cells. In the experiment, BCR-ABL -transduced BaF3 cells and cells co-transduced with Ahi-1 were treated with different doses of imatinib mesylate in the presence or absence of IL-3 for mesylate. BCR-ABL -transduced cells showed a significant decrease in the output response of the community-forming cells treated with Martinini. However, BaF3 cells co-conducted with both BCR-ABL and Ahi-1 did not respond to imatinib mesylate and produced as many colony-forming cells in the presence of IL-3, as well as by the same The cells produced cannot be treated with imatinib mesylate. Although these cells are more sensitive to imatinib mesylate treatment than cells in the presence of IL-3, in the formation of IL-3 deficiency in the formation of cells, co-transduced cells for metformin Acid imatinib also showed greater resistance. These results indicate that Ahi-1 is able to overcome IM-induced growth inhibition in BCR-ABL ⁺ cells when IL-3 signals are activated in these cells. Similar results were seen in human K562 cells with respect to overexpression or inhibition of AHI-1 . Excessive performance results in greater resistance to imatinib mesylate treatment, while inhibition by lentiviral RNA interference results in increased sensitivity to imatinib mesylate. However, even in the presence of lentiviral RNA interference, overexpression reverted to imatinib mesylate resistance. In cells with overexpression of AHI-1 , Western-blot analysis revealed increased tyrosine phosphorylation of BCR-ABL, JAK2, and STAT5, and in cells with inhibition of AHI-1 expression. The levels of these phosphorylated proteins are reduced; phosphorylation of BCR-ABL, JAK2 and STAT5 is increased when AHI-1 construct plastids are reintroduced into cells that have undergone lentiviral RNA interference. Furthermore, AHI-1 is expressed in BCR-ABL ⁺ K562 cells that not only regulates phosphorylation of BCR-ABL, JAK2, and STAT5, but also regulates protein expression of these genes, as evidenced by: significantly increasing these excesses Performance of AHI-1- expressing protein; reduced inhibition of AHI-1 expression; and responsiveness in cells that have rescued AHI-1 inhibition by AHI-1 by introducing AHI-1 to construct plastids.

Consistent with these observations, lin ^- CD34 ⁺ CML stem/precursor cells have sensitivity to imatinib mesylate, dasatinib and nilotinib and have no inhibition of AHI-1 expression. Inhibition of AHI-1 expression is increased in sensitivity to all three tyrosine kinase inhibitors; however, in all cases, the cells are for dasatinib compared to the other two tyrosine kinase inhibitors. With more sensitivity, these results suggest that AHI-1 plays an important role in the modulation of imatinib mesylate and other selective BCR-ABL tyrosine kinase inhibitors in BCR-ABL ⁺ CML cells. The role.

An important observation is that co - expression of Ahi-1 in BCR-ABL -induced cells can rescue growth factor-independent cell growth inhibited by down-regulation of BCR-ABL . Interestingly, this GF-independent remodeling with the introduction of Ahi-1 appears to be regulated by sustained phosphorylation of BCR-ABL, rather than its sustained expression, as these effects induce BCR-ABL inhibition in vitro. The performance of co-transduced cells was observed. These results indicate that the physical interaction between Ahi-1 (in mice) or AHI-1 (in humans) and BCR-ABL stabilizes a protein-protein interaction complex, which interacts with protein-proteins. The complex continues to activate BCR-ABL tyrosine kinase activity and further alters the specific downstream BCR-ABL signaling pathway that releases cell proliferation and apoptosis control. In the BCR-ABL -induced cells of Ahi-1 with co-delivery in the presence of a GF stimulator with IL-3, this is further due to the recognition of JAK2 as a related protein in this interaction complex and JAK2- Support for enhanced activity of the STAT5 pathway is supported. It is known that the BCR-ABL signal closely mimics the signaling pathway of the cytokine receptor, and its IL-3/GM-CSF receptor activation and the BCR-ABL oncogenic protein can induce tyrosine of many proteins. Phosphorylation chain reactions, including JAK2 and STAT5, are common substrates. Interestingly, BCR- ABL-expressing cells have many similarities to cells induced by IL-3 stimulators or cells with forced IL-3 overexpression. It has been shown that BCR-ABL can interact with the beta chain of the common IL-3/GM-CSF receptor to substantially activate JAK2. In particular, increased phosphorylation of STAT5, previously thought to be an immediate function of a BCR-ABL oncoprotein, has now been shown to occur primarily in primary CML CD34 ⁺ precursor cells as an IL-3 autostimulation. The result of BCR-ABL-induced activation leads to activation of STAT5. It has been reported that targeted cleavage of the STAT5A and STAT5B genes reduces the number of bone marrow precursor cells, indicating a nonredundant role for STAT5 in native normal hematopoiesis. It is further suggested that the activation of JAK2 and STAT5 pathways, the autocrine secreted product of GM-CSF can contribute to IM and NL resistance in BCR-ABL ⁺ precursor cells, and the inhibition of STAT5 expression by shRNA method Significantly reduced community formation of CD34 ⁺ CML precursor cells in vitro. In addition, JAK2 is known to interact with the C-terminal region of BCR-ABL, and recent studies have shown that mouse hematopoietic cells transformed with the T315I mutant of BCR-ABL can be treated with a JAK2 inhibitor (eg (E)-N-Benzyl-2-cyano-3-(3,4-dihydroxyphenyl)-propenylamine (AG490)) to induce apoptosis. Together, these results indicate that activation of the JAK2-STAT5 pathway in CML stem/precursor cells may be an important mechanism contributing to the response of BCR-ABL-targeted therapy, and as a novel vector for this pathway Ahi- Identification of 1/AHI-1 indicates that AHI-1 binds alone or in combination with JAK2 and STAT5 as potential additional therapeutic targets. A potential mechanism for the physical interaction between Ahi-1/AHI-1 and BCR-ABL is revealed based on its molecular structure, which is compatible with specific protein-protein interactions. If Ahi-1 is phosphorylated by tyrosine (Ahi-1 contains two potential tyrosine phosphorylation sites), Ahi-1 can pass through its SH3 region or its SH3 binding site (ie, the SH3 region of a protein). Interaction with SH3 binding sites of other proteins) or interaction with BCR-ABL via the SH2 region of BCR-ABL. In addition, Ahi-1 can be bound to the SH2-containing protein of a matrix of BCR-ABL, thus forming a complex. It is well known that BCR-ABL is widely phosphorylated by tyrosine, providing numerous and potential applications. Containing docking sites for SH2 region proteins. In addition, Ahi-1 can interact with multiple regions of BCR-ABL, as evidenced by other BCR-ABL interacting proteins. These results, that is, in the presence of IL-3, the co - expression of Ahi-1 in BCR-ABL -transduced cells can completely rescue imatinib mesylate-induced inhibition of cell growth, indicating that Ahi- 1 may not be a direct matrix of a BCR-ABL tyrosine kinase, but a modular protein that forms a stable protein interaction complex with other tyrosine phosphorylated proteins to regulate IL-3- Dependent BCR-ABL and JAK2-STAT5 activity. Furthermore, this protein interaction complex appears to be disrupted by inhibition of tyrosine phosphorylation of BCR-ABL by imatinib mesylate. Furthermore, it has been observed that in Ahi-1 coexisting in the presence of IL-3, BCR-ABL- induced cells are observed to have an increased phosphorylation of Src, indicating that when BCR-ABL and AHI-1 are co-expressed Other kinases are also activated by IL-3 stimulators. This finding also explains the observation that CML precursor cells with AHI-1 inhibition undergo a more complex response to dasatinib, a more potent thymidine kinase inhibitor that also inhibits Src activity. More suppression.

Therefore, another aspect of the present invention is to provide a thymic nucleus Glycokinase inhibitor (TKIs)-resistant germ cells are a method of treating malignant tumors in a target subject of a polymorphic malignant tumor, comprising administering: (1) a therapeutically effective amount of a therapeutic agent to a target subject to treat the a malignant tumor; and (2) a therapeutically effective amount of a JAK2 inhibitor to a target subject for treating the malignant tumor, the therapeutic agent being selected from the group consisting of Weikangol and Weikangol a group of analogs or analogues, diacetyl sulphate, a derivative or analog of dihydroquinone dihydro fulmeol, a derivative or analog of dibromodusol and dibromodusol group.

The JAK2 inhibitor can be, but is not limited to, (E)-N-benzyl-2-cyano-3-(3,4- Dihydroxyphenyl)-acrylamide (AG490), ruxolitinib, tofacitinib, tofacitinib citrate, N-tert-butyl-3-(5- Methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)anilino)pyrimidin-4-ylamine)benzenesulfonamide (TG-101348), (S)-5-chloro -N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) , N-(-Cyanomethyl-)-4-(2-(4-morpholinylanilino)pyrimidin-4-yl)benzamide (CYT387), baricitinib, (S ,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)-propenylamine (WP1066), S-Roserolinib, N- tert-Butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidin-4-ylamine)benzenesulfonamide (TG101209), N- [3-(4-Methyl-1-piperazinyl)phenyl]-8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazole [1,5-a] Pyridin-2-amine (CEP33779), 8-(3,5-difluoro-4-(morpholinyl)phenyl)-2-(1-(piperidin-4-yl)-1H-pyrazole -4-yl)quinoxaline (NVP-BSK805), (S)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H -pyrazol-3-ylamine)nicotinonitrile (AZ 960), 3-(4-chloro-2-fluorobenzyl)-2-methyl-N- ( 3-methyl-1H-pyrazol-5-yl)-8-(morpholinylmethyl)imidazo[1,2-b]pyridazine-6-amine (LY2784544), 1-cyclopropyl-3- (3-(5-(morpholinyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea (AT9283), paclitinib (SB1518) , (S)-N-(4-(2-((4-morpholinyl)amino)pyrimidin-4-yl)phenyl)pyrrolidin-2-carboxamide (XL019), and N-un -Butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)anilino)pyrimidin-4-ylamine)benzenesulfonamide (TG101348). Other JAK2 inhibitors are known in the art and are described in U.S. Patent No. 8,367,078, issued to U.S. Pat. -pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one, 3-[5-[(4-oxy-4-phenyl-but-2-ylidene) Amino]pentylimido]-1-phenyl-butan-1-one, 2-(diethylaminomethyl)-4-[4-[3-(diethylaminomethyl)-4 -hydroxy-phenyl]hex-3-en-3-yl]phenol, 2-dibutoxyphosphonium oxyvaleronitrile, ruthenium (+3) cation trihydroxylate, and 4-[(1S)-6 , 7-Diethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]cyanobenzene. Nonetheless, other JAK2 inhibitors are described in U.S. Patent No. 8,354,408, to B.S. , 2-d] pyrimidin-2-amine, 7-(4-aminophenyl)-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, N-(4-(2-(4-morpholinoanilinyl)thiazinium[3,2-d]pyrimidin-7-yl)phenyl)-propenylamine, 7-(3-aminophenyl)- N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, N-(3-(2-(4-morpholinylanilino))[3,2-d Pyrimidin-7-yl)phenyl)-acrylamide, methyl 2-(4-morpholinylanilino)thiazin[3,2-d]pyrimidin-7-carboxylate, 7-(4- Amino-3-methoxyphenyl)-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, 4-(2-(4-morpholinylanilinyl) Thiazin[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N,N-dimethyl-3-(2-(4-morpholinylanilino)pyridinium [3,2-d Pyrimidin-7-yl)benzenesulfonamide, 1-ethyl-3-(2-methoxy-4-(2-(4-morpholinoanilino))pyridinium [3,2-d]pyrimidine -7-yl)phenyl)urea, N-(4-(2-(4-morpholinoanilino))pyridinium [3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 2-methoxy-4-(2-(4-morpholinylanilino)thiazino[3,2-d]pyrimidin-7-yl)phenol, 2-cyano-N-(3-(2- (4-morpholinylanilino)thiazolidin[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(-cyanomethyl-)-2-(4-morpholinylaniline Thio[3,2-d]pyrimidin-7-carboxamide, N-(3-(2-(4-morpholinylanilino))[3,2-d]pyrimidin-7-yl Phenyl)methanesulfonamide, 1-B 3-(4-(2-(4-morpholinylanilino))thien[3,2-d]pyrimidin-7-yl)-2-(trifluoromethoxy)phenyl)urea, N-(3-nitrophenyl)-7-phenylthiazin[3,2-d]pyrimidin-2-amine, 7-iodo-N-(3-nitrophenyl)thiazide [3, 2-d]pyrimidin-2-amine, N1-(7-(2-ethylphenyl)thiazole[3,2-d]pyrimidin-2-yl)benzene-1,3-diamine, tert-butyl 3-(2-(4-morpholinoanilino)thiazole[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N1-(7-iodothiazin[3,2-d Pyrimidin-2-yl)benzene-1,3-diamine, 7-(4-amino-3-(trifluoromethoxy)phenyl)-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, N -(3-(2-(4-morpholinoanilino)thiazolo[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(-cyanomethyl-)-N- (3-(2-(4-Morpholinylanilino)thiazino[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(-cyanomethyl-)-N- (4-(2-(4-Morpholinylanilinyl)thiazin[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(3-(5-methyl-2) -(4-morpholinylanilino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 4-(5-methyl-2-(4-? Polinylanilino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)benzenesulfonate Amine, N-(4-(5-methyl-2-(4-morpholinylanilino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-iodo-N-(4-morpholinylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(2-isopropylphenyl)-N-(4- Morpholine phenyl)thiazole[3,2-d]pyrimidin-2-amine, 7-bromo-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, N7 -(2-isopropylphenyl)-N2-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidine-2,7-diamine, N7-(4-isopropylphenyl) -N2-(4-morpholinylphenyl)thiazole[3,2-d]pyrimidine-2,7-diamine, 7-(5-amino-2-methylphenyl)-N-(4-morpholine Phenyl)thiazin[3,2-d]pyrimidin-2-amine, N-(-cyanomethyl-)-4-(2-(4-morpholinylanilino)pyridinium [3,2-d Pyrimidine-7-yl)benzamide Amine, 7-iodo-N-(3-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, 7-(4-amino-3-nitrophenyl)-N- (4-morpholinylphenyl)thiazole[3,2-d]pyrimidin-2-amine, 7-(2-methoxypyridin-3-yl)-N-(4-morpholinylphenyl)thiazide [3,2-d]pyrimidin-2-amine, (3-(7-iodothiazepine [3,2-d]pyrimidin-2-ylamine)phenyl)methanol, N-tert-butyl-3- (2-(3-morpholinylanilino)thiazole[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-tert-butyl-3-(2-(3-(hydroxyl) Anilino)thiazin[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4-morpholinylphenyl)-7-(4-nitrophenylthio)-5H -pyrrolo[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(3,4,5-trimethoxyaniline)thiazine [3,2-d]pyrimidine -7-yl) benzenesulfonamide, 7-(4-amino-3-nitrophenyl)-N-(3,4-dimethoxyphenyl)thiazide [3,2-d]pyrimidine- 2-Amine, N-(3,4-dimethoxyphenyl)-7-(2-methoxypyridin-3-yl)thiazide [3,2-d]pyrimidin-2-amine, N-tert -butyl-3-(2-(3,4-dimethoxyaniline) thiazide [3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(2-aminopyrimidine-5 -yl)-N-(3,4-dimethoxyphenyl)thiazide [3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7-(2 ,6-dimethoxypyridin-3-yl)thiazole[3,2-d]pyrimidin-2-amine; N-(3,4- Methoxyphenyl)-7-(2,4-dimethoxypyrimidin-5-yl)thiazide [3,2-d]pyrimidin-2-amine, 7-iodo-N-(4-(? Phenylmethyl)phenyl)thiazole[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(4-(morpholinyl)anilinyl)thiazide [3 , 2-d]pyrimidin-7-yl)benzenesulfonamide, 2-cyano-N-(4-methyl-3-(2-(4-morpholinylanilinyl)thiazide [3,2- d]pyrimidin-7-yl)phenyl)acetamidine, ethyl 3-(2-(4-morpholinoanilino)thiazinium [3,2-d]pyrimidin-7-yl)benzoate ,7-bromo-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazide [3,2-d]pyrimidin-2-amine, N-(3-(2) -(4-(2-(pyrrolidin-1-yl)ethoxy)anilino)thiazinium [3,2-d]pyrimidin-7-yl)phenyl)acetamidamine, N-(-cyanomethyl -)-3-(2-(4-morpholinoanilino)thiazolidin[3,2-d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2- (4-morpholinylanilino)thiazole[3,2-d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2-(4-(1-ethylpipe) Pyridin-4-yloxy)anilino)thiazolidin[3,2-d]pyrimidin-7-yl)benzenesulfonamide, tert-butyl 4-(2-(4-(morpholinyl)aniline) Thiazin[3,2-d]pyrimidin-7-yl)-1H-pyrazole-1-carboxylate, 7-bromo-N-(4-((4-ethylpiperazin-1-yl) )methyl)phenyl)thiazin[3,2-d]pyrimidin-2-amine, N- Tert-Butyl-3-(2-(4-((4-ethylpiperazin-1-yl)methyl)anilinyl)thiazin[3,2-d]pyrimidin-7-yl)benzenesulfonate Amine, N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-7-(1H-pyrazol-4-yl)thiazide [3,2-d]pyrimidine- 2-Amine, N-(-cyanomethyl-)-3-(2-(4-(morpholinyl)anilino)thiazolidin[3,2-d]pyrimidin-7-yl)benzamide , N-tert-butyl-3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)anilino)thiazin[3,2-d]pyrimidin-7-yl)benzene Sulfonamide, tert-butylpyrrolidin-1-yl)ethoxy)anilino)thiazolidin[3,2-d]pyrimidin-7-yl)benzylaminoformate, 3-(2- (4-(2-(pyrrolidin-1-yl)ethoxy)anilino)thiazin[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(3-chloro-4 -fluoro Phenyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazin[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2 -(4-(1-ethylpiperidin-4-yloxy)anilino)thiazin[3,2-d]pyrimidin-7-yl)-1H-pyrazole-1-carboxylate, 7- (Benzo[d][1,3]dioxy-5-yl)-N-(4-(morpholinyl)phenyl)thiazide[3,2-d]pyrimidin-2-amine, uncle -butyl 5-(2-(4-(morpholinyl)anilino)thiazinium [3,2-d]pyrimidin-7-yl)-1H-indole-1-carboxylate, 7-( 2-aminopyrimidin-5-yl)-N-(4-(morpholinyl)phenyl)thiazide[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2-( 4-(morpholinemethyl)anilino)thiazolidin[3,2-d]pyrimidin-7-yl)-5,6-di-hydropyridine-1(2H)-carboxylate, tert-butyl 4 -(2-(4-(morpholinyl)anilinyl)thiazide [3,2-d]pyrimidin-7-yl)benzylaminoformate, N-(3-(2-(4- (morpholinylmethyl)anilino)thiazin[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(4-(2-(4-(morpholinyl))phenylamino) Thiazin [3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(3-(2-(4-(morpholinyl)anilinyl)thiazide [3,2- d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-(4-(4-methylpiperazin-1-yl)phenyl)-N-(4-(morpholinyl)phenyl Thiazin [3,2-d]pyrimidin-2-amine, N-(2-methoxy-4-(2-(4-) (morpholinylmethyl)anilino)thiazin[3,2-d]pyrimidin-7-yl)phenyl)acetamide, 7-bromo-N-(3,4,5-trimethoxyphenyl)thiazide哢[3,2-d]pyrimidin-2-amine, (3-(2-(3,4,5-trimethoxyaniline) thiazide [3,2-d]pyrimidin-7-yl)phenyl) Methanol, (4-(2-(3,4,5-trimethoxyaniline) thiazide [3,2-d]pyrimidin-7-yl)phenyl)methanol, (3-(2-(4-?) Phenylanilino)thiazin[3,2-d]pyrimidin-7-yl)phenyl)methanol, (4-(2-(4-morpholinoanilino))pyridinium [3,2-d]pyrimidine -7-yl)phenyl)methanol, N-(pyrrolidin-1-yl)ethoxy)anilino)thiazolidin[3,2-d]pyrimidin-7-yl)benzyl)methanesulfonamide, tert-Butyl 3-(2-(4-(morpholinyl)anilino)thiazolidine [3,2-d]pyrimidin-7-yl)benzylaminoformate, N-(4-( Morpholine methyl)phenyl)-7-(3-(piperazin-1-yl)phenyl)thiazol[3,2-d]pyrimidin-2-amine, 7-(6-(2-morpholine) Ethylamino)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)thiazide [3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl) -N-(4-(pyrrolidin-1-yl)ethoxy)phenyl)thiazol[3,2-d]pyrimidin-2-amine, 7-(2-isopropylphenyl)-N- (4-(pyrrolidin-1-yl)ethoxy)phenyl(thiazin[3,2-d]pyrimidin-2-amine, 7-(4-(aminomethyl)phenyl)-N-( 4-(morpholinemethyl)phenyl)thiophene [3,2-d]pyrimidine-2-amine, N-(4-(1-ethylpiperidin-4-yloxy)phenyl)-7-(1H-pyrazol-4-yl)thiazide [3,2-d]pyrimidin-2-amine, N-(2,4-dimethoxyphenyl)-7-phenylthiazin[3,2-d]pyrimidin-2-amine, 7-bromo- N-(3,4-Dimethoxyphenyl)thiazide [3,2-d]pyrimidin-2-amine, or N-(3,4-dimethoxyphenyl)-7-phenylthiazide [ 3,2-d]pyrimidine-2-amine. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 8,309,718, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in Pyrazolyl-N-heteroarylpyrimidin-2-amine. Despite this, other JAK2 kinase inhibitors are described in the United States by Menet et al. U.S. Patent No. 8,242,274, which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 8,158,616, the disclosure of which is incorporated herein in Sulfosyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cycloazetidine-3-yl}acetonitrile. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 8,138,199, the disclosure of which is incorporated herein by reference. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 8,053,433 to Rodgers et al. And [2,3-b]pyrimidin-5-yl-amine. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 7,897,600 to Burkholder et al. Base-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinylmethyl)imidazo[1,2-b]pyridazine-6-amine. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 7,598,257 to Rodgers et al. An aryl substituted pyrrolo[2,3-b]pyrimidine. Nonetheless, other JAK2 kinase inhibitors are described in U.S. Patent No. 7,355,677, the disclosure of which is incorporated herein by reference in its entirety in its entirety, in And [2,3-b]pyrimidin-4-ylamines. Other JAK2 kinase inhibitors are known in the art.

The method can further comprise the step of administering a therapeutically effective amount of a BH3 analog to the target subject. Alternatively, the method may further comprise the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject.

A further aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor having a polymorphism of a germ cell which confers resistance to thymidine kinase inhibitors (TKIs), which comprises administering (1) a therapeutically effective amount of a therapeutic agent to a target subject to treat the malignant tumor; and (2) a therapeutically effective amount of a STAT5 inhibitor to the target subject for treating the malignant tumor, the therapeutic agent being selected from the group consisting of Derivatives or analogues of Weikangol, Weikangol, Dihydroquinone, Derivatives, Derivatives or Analogs of Dihydrostilbene, Dibromodusol and Dibromodusol a group of derivatives or analogs.

STAT5 inhibitors include, but are not limited to, N ' -((4-oxy-4H-gram-3-yl)methenyl)nicotine oxime and pimozide. Other STAT 5 inhibitors are disclosed in U.S. Patent Application Publication No. 2011/0144043, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire disclosure , ranitidine phenol acyl hydrazine, solanine α (solanine alpha), fluoro Los satin (as fluoxetine) hydrochloride, isobutyl cyclophosphamide, hydroxynaphthoic acid send Vanni (pyrvinium pamoate), moricizine (moricizine) Hydrochloride, 3,3'-oxybis[tetrahydrothiophene, 1,1,1',1'-tetraoxy], 2-(1,8-naphthyridin-2-yl)phenol, and 3- (2-Hydroxyphenyl)-3-phenyl-N,N-dipropylpropionamide.

The method can further comprise the step of administering a therapeutically effective amount of a BH3 analog to the target subject. Alternatively, the method may further comprise the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject.

A further aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor having a polymorphism of a germ cell which confers resistance to thymidine kinase inhibitors (TKIs), which comprises administering (1) a therapeutically effective amount of a therapeutic agent to a target subject to treat the malignant tumor; and (2) a therapeutically effective amount of a Src inhibitor to the target subject to treat the malignant tumor, the therapeutic agent being selected from the group consisting of Derivatives or analogues of Weikangol, Weikangol, Dihydroquinone, Derivatives, Derivatives or Analogs of Dihydrostilbene, Dibromodusol, and Dibromo-Hualidol A group consisting of derivatives or analogs of alcohols.

Src inhibitors include dasatinib, saracatinib, bosutinib, N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2 -yl)acetamide (KX2-391), CGP76030, and 4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d] Pyrimidin-4-ylamine)-N-(3-(trifluoromethyl)phenyl)benzamide (NVP-BHG712). Src kinase inhibitors are described in M. Missbach et al., "Substituted 5,7-diphenyl-pyrrolo[2,3-d]pyrimidine: potent inhibitor of tyrosine kinase c-Src", Bioorg . Med. Chem. Lett. 10: 945-949 (2000) and to include it by reference. Other Src inhibitors are known in the art and are described in U.S. Patent No. 8,389,525 to Desai et al. α -[[6-(4-bromophenyl)-3-cyano-4-(trifluoromethyl)-2-pyridyl]thio]-phenylacetic acid, 1,4-dihydro-2- [[[4-(Methoxycarbonyl)phenyl]methyl]thio]-5-methyl-4-oxy-thiazin-[2,3-d]pyrimidine-6-carboxylic acid, 6- Hydroxy-7-oxy-7H-benzo[e]acridine-4-sulfonic acid, 7-ethoxy-11H-indole[1,2-b]quinoxaline-11-one, 5-bromo- 1,3-Dihydro-3-hydroxy-3-[2-oxy-2-(5,6,7,8-tetrahydro-2-naphthyl)ethyl]-2H-indol-2-one , 1-(4-fluorophenyl)-2-(9H-thioxan-9-yl)-1,3-butanedione, 2-[[(2-chloro-6-fluorophenyl) Methyl]thio]-3-(3-pyridyl)-4(3H)-quinazolinone, 2,7-dinitro-fluorene-9H-purin-9-one, and 3-(9H- Indole-9-ylmethyl)ester-3,4-tetrahydrothiazole dicarboxylic acid. U.S. Pat. Hangauer, Jr. U.S. Pat. Hangauer, Jr. U.S. Patent No. 8, which is filed by et al. 088, No. 768, And include it by reference, It describes naphthyl Src inhibitor scaffolds, Isoquinolinyl Src inhibitor scaffold and sulfhydryl Src inhibitor scaffold. U.S. Patent No. 8, filed by Byzova et al. 080, No. 252, Include it by reference, It describes 3-(4, as a Src inhibitor 5, 6, a 7-tetrahydro-2-ylmethylene)-2-indolone derivative, Contains 2-oxy-3 (4, 5, 6, 7-tetrahydro-1-H-indol-2-yl-methylalkenyl)-2, 3-dihydro-1-H-indole-5-sulfonic acid dimethylamine, And 2-oxy-3 (4, 5, 6, 7-tetrahydro-1-H-indol-2-yl-methylalkenyl)-2, 3-Dihydro-1H-indole-5-sulfonic acid amine. U.S. Patent No. 8, filed by Honold et al. 058, No. 283, And include it by reference, It describes 7H-pyrido[3, as a Src inhibitor 4-d]pyrimidine-8-ones. U.S. Patent No. 7, filed by Bebbington et al. 982, No. 037, And include it by reference, It describes a pyrazole compound as a Src kinase inhibitor. U.S. Patent No. 7, filed by Bebbington et al. 951, No. 820, And include it by reference, It describes a triazole compound as a Src kinase inhibitor. U.S. Patent No. 7, filed by Boschelli et al. 919, No. 625, And include it by reference, It describes 4-anilino-3-carbonitrile as a Src inhibitor, Contains 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-carbonitrile. U.S. Patent No. 7, filed by Aronov et al. 842, No. 712, And include it by reference, It describes oxazolinone as a Src inhibitor. U.S. Patent No. 7, filed by Fukumoto et al. 842, No. 701, And include it by reference, Described as a pyrazoloquinolone derivative as a Src inhibitor, Containing 3-amino-2-(2-chloro-5-hydroxyphenyl)-7-(3-morpholin-4-ylpropoxy)-2, 5-dihydro-4H-pyrazolo[4, 3-c]quinolin-4-one, 3-amino-2-(2-chloro-5-hydroxyphenyl)-7-(2-morpholin-4-ylethoxy)-2, 5-dihydro-4H-pyrazolo[4, 3-c]quinolin-4-one, 3-amino-2-(5-hydroxy-2-methylphenyl)-7-(3-morpholin-4-2, 5-dihydro-4H-pyrazolo[4, 3-c]quinolin-4-one, 3-amino-2-(5-hydroxy-2-ylpropoxy)tolyl)-7-(2-morpholin-4-ylethoxy)-2, 5-dihydro-4H-pyrazolo[4, 3-c]quinolin-4-one. U.S. Patent No. 7, filed by Honold et al. 786, No. 113, And include it by reference, It describes a heterocyclic aminoformate derivative as a Src inhibitor, Contains (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-carbamic acid isopropyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid isopropyl ester, (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-carbamic acid 2, 2-dimethyl-propyl ester, {2-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid ethyl ester, {2-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid allyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid ethyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid allyl ester, (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-carbamic acid benzyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-aminoformic acid isobutyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid 2-chloro-benzyl ester, (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-carbamic acid ethyl ester, (2-phenyl-1H-pyrrolo[2, 3-br]pyridin-5-yl)-carbamic acid 2-chloro-benzyl ester, (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-carbamic acid allyl ester, (2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-aminocarbamic acid isobutyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid 2, 2-dimethyl-propyl ester, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid benzyl ester, {2-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid isopropyl ester, {2-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-carbamic acid benzyl ester, {2-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-aminoformic acid isobutyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-ammonium carboxylate, [2-(4-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid allyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-br]pyridin-5-yl]-carbamic acid 2-chloro-benzyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid benzyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid 2, 2-dimethyl-propyl ester, [2-(4-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid 2, 2-dimethyl-propyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid ethyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-carbamic acid allyl ester, [2-(3-Ethylamino-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-aminocarbamic acid isobutyl ester, (2-phenyl-3H-imidazo[4, 1-b-pyridyl-6-yl)-carbamic acid 1-methyl-propenyl ester, (2-phenyl-1H-imidazo[4, 5-b]pyridin-6-yl)-urethane isopropyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridine-6-yl)-carbamic acid cyclohexyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-aminocarbamic acid isobutyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid allyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid tert-butyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid cyclopentyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-urethane, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid sec-butyl ester, (2-phenyl-3H-imidazo[4, 1-b-pyridyl-6-yl)-carbamic acid 1-ethyl-propyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid 2, 2, 2-Trifluoro-1-methyl-ethyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid 2, 2-dimethyl-propyl ester, (2-phenyl-3H-imidazo[4, 5-phenyl]pyridin-6-yl)-carbamic acid 1-phenyl-ethyl ester, (2-phenyl-1H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid propyl ester, (2-phenyl-3H-imidazo[4, 1-b-pyridyl-6-yl)-carbamic acid 1-methyl-prop-2-ynyl ester, (2-phenyl-3H-imidazo[4, 1-b-pyridyl-6-yl)-carbamic acid 1-methyl-but-2-ynyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid cyclobutyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid 1, 3-dimethyl-butyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid 1, 2-dimethyl-propyl ester, {2-[3-(3-Methoxy-propionylamino)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, (2-phenyl-3H-imidazo[4, (b)pyridin-6-yl)-carbamic acid (E)-1-methyl-but-2-enyl ester, (2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-carbamic acid 1, 2-dimethyl-propenyl ester, {2-[4-(2-Diethylamino-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, 2-[3-(2-methoxy-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, {2-[4-(2-Methoxy-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, [2-(3-nitro-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-proline isopropyl ester, {2-[4-(4-Methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, {2-[3-(2-hydroxy-ethyl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, [2-(4-nitro-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-Aminosulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-Methylsulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3-Amino-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-Amino-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3-Ethylamino-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3-methanesulfonylamino-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3-Methylsulfinyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3-Methanesulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-methanesulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(4-Methanesulfinyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(3, 4-difluoro-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, (2-{4-[Bis-(2-methoxy-ethyl)-amino]-3-fluoro-phenyl}-3H-imidazo[4, 5-b]pyridin-6-yl)-urethane isopropyl ester, 3-(6-isopropoxycarbonylamino-3H-imidazo[4, 5-b]pyridin-2-yl)-benzoic acid, {2-[3-(2-Methoxy-I-methoxymethyl-ethylaminemethanyl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, {2-[3-(3-Methoxy-propylaminemethanyl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-ammonium formate, (2-Thien-2-yl-3H-imidazo[4, 5-b]pyridin-6-yl)-urethane isopropyl ester, (2-thiophen-3-yl-3H-imidazo[4, 5-b]pyridin-6-yl)-urethane isopropyl ester, [2-(2-methyl-pyridin-4-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(6-Methyl-pyridin-3-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(1H-benzimidazolyl-5-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium formate, [2-(2-Chloro-pyridin-4-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-ammonium carboxylate, And {2-[2-(3-methoxy-propylamino)-pyridin-4-yl]-3H-imidazo[4, 5-b]pyridine-6-yl}-carbamic acid isopropyl ester. U.S. Patent No. 7, filed by Boyd et al. 776, No. 878, And include it by reference, It describes a heterocyclic benzylamino derivative as a Src inhibitor, Containing (1-phenyl-ethyl)-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-amine, Benzyl-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-amine, {2-[3-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridine-5-yl}-(2-methyl-benzyl)-amine, Benzyl-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-amine, (2-methyl-benzyl)-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-amine, N-[3-(5-benzylamino-1H-pyrrolo[2, 3-b]pyridin-2-yl)-phenyl]-acetamide, N-{3-[5-(2-methyl-benzylamino)-1H-pyrrolo[2, 3-b]pyridin-2-yl]-phenyl}-acetamide, N-[4-(5-benzylamino-1H-pyrrolo[2, 3-b]pyridin-2-yl)-phenyl]-acetamide, And N-{4-[5-(2-methyl-benzylamino)-1H-pyrrolo[2, 3-b]pyridin-2-yl]-phenyl}-acetamide. U.S. Patent No. 7, filed by Bebbington et al. 691, No. 853, And include it by reference, It describes a pyrazole compound as a Src kinase inhibitor. U.S. Patent No. 7, filed by Engh et al. 655, No. 601, And include it by reference, It discloses 3-phenyldihydropyrimido[4, as a Src kinase inhibitor A derivative of 5-d]pyrimidinone. U.S. Patent No. 7, filed by Bebbington et al. 625, No. 913, And include it by reference, Described as a pyrazole compound as a Src kinase inhibitor, Containing (5-methyl-2H-pyrazol-3-yl)-(6-phenyl-2-anilino-pyrimidin-4-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-anilino-pyrimidin-4-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylanilino)-6-phenyl-pyrimidin-4-yl]-amine, [2-(4-Cyanomethylphenylamino)-6-phenyl-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3-ylmethylamino)-pyrimidin-4-yl]-amine, [2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3-chlorophenyl)amino-6-(3, 4, 5-trimethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-Methyl-2H-pyrazol-3-yl)-[2-(4-aminesulfonylphenylamino)-6-(3, 4, 5-trimethoxyphenyl)-pyrimidin-4-yl]-amine, [2-(benzimidazol-2-ylamine-)-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3-chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-amine , [2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine, [5-(furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-anilino-pyrimidin-4-yl)-amine, [2-(4-chlorophenyl)amino-5, 6-Dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5, 6-Dimethyl-2-anilino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(benzimidazol-2-ylamine)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, And (6-methoxymethyl-2-anilino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine. US Patent No. 7, which Lee applied for, 622, No. 472 discloses Src inhibitors, Containing N-(2-chloro-6-tolyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amine Base]-5-thiazole carboxamide. U.S. Patent No. 7, filed by Honold et al. 618, No. 964, And include it by reference, Described as a benzamide derivative as a Src kinase inhibitor, Contains 2-chloro-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, 2-Chloro-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-benzamide, 2-methoxy-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, 2, 4-dichloro-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, 2-Chloro-6-methyl-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridine-5-yl]-4-methoxy-benzamide, 2-methyl-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, 2-Chloro-5-methoxy-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-benzamide, 2, 4-Dichloro-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-benzamide, 4-methoxy-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-benzamide, 3, 5-dimethoxy-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl-benzamide, 3, 5-dimethoxy-N-(2-phenyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-benzamide, N-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridine-5-yl}-2-methyl-benzamide, 2-methoxy-N-{2-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2, 3-b]pyridin-5-yl}-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-2-chloro-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridine-5-yl]-2, 4-dichloro-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-2-methoxy-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-2-chloro-6-methyl-benzamide, N-[2-(3-acetamido-phenyl)-1H-pyrrolo[2, 3-b]pyridin-5-yl]-2-chloro-5-methoxy-benzamide, 2-Chloro-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-6-methyl-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-bromo-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-methyl-5-nitro-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-chloro-5-nitro-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-N-{2-[3-(3-methoxy-propionamido)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 5-amino-2-methyl-N-(2-phenyl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 5-amino-2-chloro-N-(2-phenyl-3H-imidazole [4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-N-{2-[4-(2-diethylamino-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 2-Chloro-N-{2-[4-(2-methoxy-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 2-Chloro-N-{2-[3-(2-methoxy-ethoxy)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 2-Chloro-N-[2-(3-nitro-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(4-morpholin-4-yl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 2-Chloro-N-{2-[3-(2-hydroxy-ethyl)-phenyl]-3H-imidazo[4, 5-b]pyridin-6-yl}-benzamide, 3-[6-(2-Chloro-benzylguanidino)-3H-imidazo[4, 5-b]pyridin-2-yl]-benzoic acid, 3-(6-(2-chlorobenzylamino)-3H-imidazo[4, 5-b]pyridin-2-yl)-N-(3-methoxy-propyl)-benzamide, 3-(6-(2-chlorobenzylamino)-3H-imidazo[4, 5-b]pyridin-2-yl)-N-isopropyl-benzamide, 2-Chloro-N-(2-{3-[2-methoxy-1-methoxymethyl-ethylaminemethanyl]-phenyl}-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-N-[2-(3-methylsulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(4-aminosulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(4-nitro-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(4-methylsulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(3-methanesulfinylidene-phenyl)-3H-imidazo[4, 5-b]pyridine-6-yl]-benzamide, 2-Chloro-N-[2-(4-methanesulfonyl-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, N-[2-(3-Amino-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-2-chloro-benzamide, N-[2-(3-acetamido-phenyl)-3H-imidazo[4, 5-b]pyridin-6-yl]-2-chloro-benzamide, N-(2-{4-[bis-(2-methoxy-ethyl)-amino]-3-fluoro-phenyl}-3H-imidazo[4, 5-b]pyridin-6-yl)-2-chloro-benzamide, 2-Chloro-N-(2-thiophen-2-yl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-N-(2-thiophen-3-yl-3H-imidazo[4, 5-b]pyridin-6-yl)-benzamide, 2-Chloro-N-[2-(2-methyl-pyridin-4-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, 2-Chloro-N-[2-(6-methyl-pyridin-3-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, N-[2-(1H-benzimidazolyl-5-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-2-chloro-benzamide, 2-Chloro-N-[2-(6-morpholin-4-yl-pyridin-3-yl)-3H-imidazo[4, 5-b]pyridin-6-yl]-benzamide, And 2-chloro-N-{2-[2-(3-methoxy-propylamino)-pyridin-4-yl]-3H-imidazo[4, 5-b]pyridine-6-yl}-benzamide. U.S. Patent No. 7, filed by Xiao et al. 583, No. 767, And include it by reference, It describes a substituted pyrazole compound as a Src inhibitor. U.S. Patent No. 7, filed by Honold et al. 550, No. 589, And include it by reference, It describes 6-(2-alkyl-phenyl)-pyrido[2, as a Src inhibitor. 3-d]pyrimidine, Containing 2-(4-morpholin-4-yl-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine, 2-(3-acetamido-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine, 2-(3-methanesulfonylamino-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine, 2-(4, 4-dioxy-3, 4-dihydro-2H-4 λ *6*-benzo[1, 4] Oxythiazol-6-ylamine)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine, 2-(4-morpholin-4-yl-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 2-(3-acetamido-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 2-(3-methanesulfonylamino-anilino)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, And 2-(4, 4-dioxy-3, 4-dihydro-2H-4 λ *6*-benzo[1, 4] Oxythiazol-6-ylamine)-6-(2-trifluoromethyl-phenyl)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-guanamine. U.S. Patent No. 7, filed by Bebbington et al. 531, No. 536, And include it by reference, It describes a pyrazole compound as a Src kinase inhibitor. U.S. Patent No. 7, filed by Engh et al. 494, No. 993, And include it by reference, It discloses 7-amino-3-phenyl-dihydropyrimido[4, A decylamine derivative of 5-d]pyrimidinone. U.S. Patent No. 7, filed by Boschelli et al. 479, No. 561, And include it by reference, It describes 4-(2, as a Src inhibitor 4-Dichloro-5-methoxyphenyl)amino-6-methoxy-7-{[5-substituted-amino)methyl]-3-furanyl}-3-carbonitrile, Contains 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furanyl}- 3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-{5-[(dimethylamino)methyl]-3-furanyl {-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-(morpholin-4-ylmethyl)]-3-furanyl]-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-phenylpiperazin-1-yl)methyl]-3-furanyl}- 3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(2, 4-Dimethoxyphenyl) piperazin-1-yl]methyl}-3-furanyl)-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-(pyrrolidin-1-ylmethyl)-3-furanyl]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-(piperidin-1-ylmethyl)-3-furanyl]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-{5-[(diethylamino)methyl]-3-furanyl)-6-methoxyquinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-{5-[(4-ethylpiperazin-1-yl)methyl]-3-furanyl)-6-methoxyquin Porphyrin-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl] Methyl}-3-furanyl)quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]-3- Furanyl}quinoline-3-carbonitrile, 7-{5-[(4-Butylpiperazin-1-yl)methyl]-3-furanyl}-4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl] Methyl}-3-furanyl)quinoline-3-carbonitrile, 7-{5-[(4-Benzylpiperazin-1-yl)methyl]-3-furanyl}-4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(2-phenylethyl)piperazin-1-yl]methyl}- 3-furyl)quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-{5-[(dipropylamino)methyl]-3-furanyl}-6-methoxyquinoline-3-carbonyl Nitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-{5-[(1, 1-dithiomorpholin-4-yl)methyl]-3-furanyl}-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(1-oxothiomorpholin-4-yl)methyl]-3-furanyl} Quinoline-3-carbon nitrogen, 7-{5-[(4-Cyclohexylpiperazin-1-yl)methyl]-3-furanyl}-4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}- 3-furyl)quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-pyridin-4-ylpiperazin-1-yl)methyl]-3-furan }}quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(4-methylphenyl)piperazin-1-yl]methyl}-3- Furyl)quinoline-3-carbonitrile, 7-(5-{[4-(4-Chlorophenyl)piperazin-1-yl]methyl}-3-furanyl)-4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-(5-{[4-(4-hydroxyphenyl)piperazin-1-yl]methyl}-3-furanyl)-6 -methoxyquinoline-3-carboxonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-({4-[4-(trifluoromethyl)phenyl]piperazin-1-yl }methyl)-3-furanyl]quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-(thiomorpholin-4-ylmethyl)-3-furanyl]quinoline-3- Carboxonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-(5-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-3-furanyl )-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-}5-[(4-isopropylpiperazin-1-yl)methyl]-3-furanyl}-6-methoxy Quinoline-3-carboxonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methyl-1, 4-diazepan-1-yl)methyl]-3-furanyl)quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(2-methoxyethyl)piperazin-1-yl]methyl} -3-furanyl)quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-(5-{[4-{2-hydroxyethyl)piperazin-1-yl]methyl}-3-furanyl-6 -methoxyquinoline-3-carboxonitrile, 4-[(2, 4-dichloro-5-methoxyphenyl)amino]-7-(5-{[4-(2, 6-Dimethylphenyl)piperazin-1-yl]methyl}-3-furanyl)-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-[5-({4-[3-(diethylamino)propyl]piperazin-1-yl}methyl)-3- Furanyl]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(5-{[4-(pyridin-4-ylmethyl)piperazin-1-yl]methyl} -3-furanyl)quinoline-3-carbonitrile, And 4-[(2, 4-dichloro-5-methoxyphenyl)amino]-7-(5-{[4-(2, 6-Dimethylphenyl)piperazin-1-yl]methyl}-3-furanyl)-6-methoxyquinoline-3-carbonylcarbonitrile. U.S. Patent No. 7, filed by Davies et al. 473, No. 691, And include it by reference, It describes a pyrazole compound as a Src inhibitor. U.S. Patent No. 7, filed by Boschelli et al. 417, No. 148, And include it by reference, It discloses 4-anilino-3-carbonitrile as a Src inhibitor, Contains 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-[2-(4-ethyl-1-piperazinyl)ethoxy]-6-methoxy-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-7-[(1-ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile, 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile , 4-[(2, 4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-propyl-1-piperazinyl)propoxy]-3-carbonitrile, 4-[(2, 4-dichlorophenyl)amino]-6-methoxy-7-[(1methylpiperidin-4-yl)methoxy]-3-carbonitrile, 6-Methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-[(3, 4, 5-trimethoxyphenyl)amino]quinoline-3-carboxonitrile, 4-[(2-Chloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3- Carboxonitrile, 6-Methoxy-4-[(5-methoxy-2-methylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonyl Nitrile, 4-[(2, 4-dimethylphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile, 6-methoxy-4-[(5-methoxy-2, 4-xylyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile, And 4-[(2, 4-Dichloro-5-ethoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile. U.S. Patent No. 7, filed by Davies et al. 390, No. 815, And include it by reference, It describes a pyrazole compound as a Src inhibitor. U.S. Patent No. 7, filed by Benish et al. 285, No. 556, And include it by reference, Described as a thiopurine pyridine compound as a Src inhibitor, Contains 2-thiazole formaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 1H-imidazole-4-carbaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-chlorobenzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-bromobenzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-fluorobenzaldehyde (6, 7-dimethylthiazide [3, 2-d]pyrimidin-4-yl)indole, 1-(3-pyridyl)ethanone (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-methyl-2-thiophenecarboxaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-propoxybenzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-propoxybenzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 1H-吲哚-5-formaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Acetaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-(methylthio)benzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Propionaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Butyraldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Valeraldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Tetrahydro-3-furanaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-cyclohexene-1-carbaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, E-2-butenal (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, Phenylacetaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-bromothiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(3-thienyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (pyridyl[3', 2': 4, 5] thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (pyridyl[3', 2': 4, 5] thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (pyridyl[3', 2': 4, 5] thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-carboxybenzaldehyde (7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-pyridinecarboxaldehyde (6-phenylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-ethylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-propyl thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-fluorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-fluorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-methanethiononylphenyl) thiazide-[3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-methanethiononylphenyl) thiazide-[3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(3-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(3-chlorophenyl) thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(2-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(2-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(2-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(2-chlorophenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-methyl-6-phenylthiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (7-methyl-6-phenylthiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (7-methyl-6-phenylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (7-methyl-6-phenylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-iodo-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-iodo-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-iodo-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-iodo-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-methyl-6-(3-thienyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (7-methyl-6-(3-thienyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (7-methyl-6-(3-thienyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (7-methyl-6-(3-thienyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(2-chlorophenyl) 7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(2-chlorophenyl)7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(2-chlorophenyl)7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-iodothiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-iodothiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-iodothiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-iodothiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-methoxyphenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-methoxyphenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(4-methoxyphenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(4-methoxyphenyl)thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(4-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(4-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(3-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(3-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(3-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(3-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(2-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(2-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(2-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(2-methoxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(4-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(4-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(4-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(3-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(3-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(3-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(3-hydroxymethylphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-methyl-6-(trans-2-styryl)-thiazide [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (7-methyl-6-(trans-2-styryl)-thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (7-methyl-6-(trans-2-styryl)-thiazide [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(4-carboxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(4-carboxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(4-carboxyphenyl)-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-hydroxy-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-hydroxy-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-hydroxy-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-hydroxy-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-hydroxy-1-[3-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-hydroxy-1-[3-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-hydroxy-1-[3-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-hydroxy-1-[3-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-carboxy-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-carboxy-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-carboxy-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-carboxy-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-cyclohexyl-1-hydroxy)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-cyclohexyl-1-hydroxy)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-cyclohexyl-1-hydroxy)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-cyclohexyl-1-hydroxy)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-benzyl-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-benzyl-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-benzyl-1-phenyl)methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-hydroxymethyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-hydroxymethyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-hydroxymethyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-hydroxy-1-[3, 4, 5-trimethoxyphenyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-hydroxy-1-[3, 4, 5-trimethoxyphenyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-hydroxy-1-[3, 4, 5-trimethoxyphenyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-hydroxy-1-[3, 4, 5-trimethoxyphenyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-hydroxy-1-[3-pyridyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-hydroxy-1-[3-pyridyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-hydroxy-1-[3-pyridyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (6-(1-hydroxy-1-[3-pyridyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (6-(1-hydroxy-1-[2-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 4-carboxybenzaldehyde (6-(1-hydroxy-1-[2-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (6-(1-hydroxy-1-[2-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole, And 3-hydroxy-4-methoxybenzaldehyde (6-(1-hydroxy-1-[2-thienyl])methyl-7-methylthiazolidine [3, 2-d]pyrimidin-4-yl)indole. U.S. Patent No. 7, filed by Boschelli et al. 276, No. 519, And include it by reference, It describes thiazolidine as a Src inhibitor [3, 2-b]pyridine-6-carboxonitrile and thiazide [2, 3-b]pyridine-5-carboxonitrile, Contains 3-bromo-7-[(2, 4-dichloro-5-methoxyphenyl)amino]thiazide [3, 2-b]pyridine-6-carboxonitrile, 7-[(2, 4-Dichloro-5-methoxyphenyl)amino]-3-(4-methylnonylphenyl) thiazide [3, 2-b]pyridine-6-carboxonitrile, 7-[(2, 4-Dichloro-5-methoxyphenyl)amino]-3-{4-[(dimethylamino)methyl]phenyl}thiazide [3, 2-b]pyridine-6-carboxonitrile, 7-[(2, 4-Dichloro-5-methoxyphenyl)amino]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}thiazide [3, 2-b]pyridine-6-carboxonitrile, And 7-[(2, 4-Dichloro-5-methoxyphenyl)amino]-3-[4-(morpholin-4-ylmethyl)phenyl]thiazide [3, 2-b]pyridine-6-carboxonitrile. U.S. Patent No. 7, filed by Aronov et al. 262, No. 200, And include it by reference, It describes an oxazolinone compound as a Src inhibitor. U.S. Patent No. 7, filed by Arnost et al. 226, No. 920, And include it by reference, It describes an aminotriazole compound as a Src inhibitor. U.S. Patent No. 7, filed by Honold et al. 189, No. 732, And include it by reference, It describes the pyrido[2, as a Src inhibitor. 3-d]pyrimidine dichloro-phenyl derivative, Contains 6-(2, 6-Dichloro-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2, 6-Dichloro-phenyl)-2-[4-(2-hydroxy-ethoxy)-anilino]-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2, 6-Dichloro-phenyl)-2-(3-methanesulfonylamino-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2, 6-Dichloro-phenyl)-2-[3-(2-hydroxy-ethylsulfonyl)-anilino]-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2, 6-Dichloro-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-anilino]-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, And 6-(2, 6-Dichloro-phenyl)-2-(3-methylsulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-guanamine. U.S. Patent No. 7, filed by Honold et al. 169, No. 781, Include it by reference, It describes an imidazole derivative as a Src inhibitor, Contains 2-(2, 6-Dichlorophenyl)-4-(3-bromophenyl)-5-(2-[4-(2-diethylamino-ethoxy)anilino]pyrimidin-4-yl)-N --H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-chlorophenyl)-5-(2-[4-(2-diethylamino-ethoxy)anilino]pyrimidin-4-yl)-N- -H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-chlorophenyl)-5-(2-[4-(2-hydroxyethoxy)phenyl-amino]pyrimidin-4-yl)-N-- H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-chlorophenyl)-5-(2-[4-dimethylaminophenyl-amino]pyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-chlorophenyl)-5-(2-[4-(N-(2-hydroxyethyl)-aminesulfonyl)anilino]-pyrimidine-4- Base)-N--H-imidazole, 2-(2, 6-Dichloro-4-hydroxymethylphenyl)-4-(3-chlorophenyl)-5-(2-[4-(2-diethylaminoethoxy)-anilino]pyrimidine- 4-yl)-N--H-imidazole, 2-(2, 6-Dichloro-4-hydroxymethylphenyl)-4-(3-chlorophenyl)-5-(2-[4-(2-hydroxyethoxy)-anilino]pyrimidin-4-yl) -N--H-imidazole, 2-(2, 6-Dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-chlorophenyl)-5-(2-[4-(2-diethylamino)ethoxy)- Anilinopyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-chlorophenyl)-5-(2-[4-methylsulfinyl-anilino]pyrimidine-4 -yl)-N--H-imidazole, 2-(2, 6-Dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-chlorophenyl)-5-(2-[4-(N-(2-hydroxyethyl))-amine sulfonate Mercapto)anilino]pyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(4-chlorophenyl)-5-(2-[4-(2-diethylaminoethoxy)anilino]pyrimidin-4-yl)-N- -H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(4-chlorophenyl)-5-(2-[4-hydroxyphenyl-amine]pyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(4-chlorophenyl)-5-(2-[4-methoxyphenyl-amine]pyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(4-chlorophenyl)-5-(2-[4-ethoxyphenyl-amine]pyrimidin-4-yl)-N--H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-ethynylphenyl)-5-(2-[4-(2-diethylamino-ethoxy)anilino]pyrimidin-4-yl)-N- -H-imidazole, 2-(2, 6-Dichlorophenyl)-4-(3-ethynylphenyl)-5-(2-[4-(2-hydroxyethoxy)-anilino]pyrimidin-4-yl)-N--H- Imidazole, And 2-(2, 6-Dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-ethynylphenyl)-5-(2-[4-(2-diethylaminoethoxy)- Anilinopyrimidin-4-yl)-N--H-imidazole. U.S. Patent No. 7, filed by Honold et al. 163, No. 941, Include it by reference, It describes the pyrido[2, as a Src inhibitor. 3-d]pyrimidine-7-carboxylic acid, Containing 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(3H-imidazol-4-yl)-ethyl]-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylguanamine, 6-(2-bromo-phenyl)-2-(3-methylsulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylguanamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(3-methylsulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-hydroxy-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methoxy-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (3-dimethylamino-propyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (3-dimethylamino-2, 2-dimethyl-propyl)-guanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-acetamido-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid amine-mercaptomethyl-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-1-methyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid methylamine-methylmethyl-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-propyl)-guanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid dimethylamine-methylmethyl-decylamine, 6-(2-Bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (3-methylamino-propyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-hydroxy-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (3-hydroxy-propyl)-decylamine, (S)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2, 3-dihydroxy-propyl)-guanamine, (R)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2, 3-dihydroxy-propyl)-guanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methanesulfinyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(2-hydroxy-ethanesulfinyl)-ethyl]-guanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-morpholin-4-yl-ethyl)-guanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(2-oxy-imidazolin-1-yl)-ethyl]-decylamine, (R)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [3-(2-oxy-pyrrolidin-1-yl)-propyl]-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (3-morpholin-4-yl-propyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(pyridin-2-ylamine)-ethyl]-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid [2-(3H-imidazol-4-yl)-ethyl]-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (1, 5-dimethyl-1H-pyrazol-3-ylmethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid ((S)-pyrrolidin-2-ylmethyl)-decylamine, 6-(2-bromo-phenyl)-2-(3-methylsulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methylamino-ethyl)-decylamine, 6-(2-Bromo-phenyl)-2-[4-(2-diethylamino-ethoxy)-anilino]-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2, 3-d]pyrimidin-7-carboxylic acid piperidin-4-yl decylamine, 6-(2-bromo-phenyl)-2-(3-methylsulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (2-methylamino-ethyl)-decylamine, (R)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carboxylic acid piperidin-3-ylguanamine, (S)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carboxylic acid piperidin-3-ylguanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carboxylic acid piperidin-4-yl decylamine, 1-[6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carbonyl]semicarbazone, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid N'-(2-dimethylamino-ethenyl)-indole, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (1-methyl-piperidin-4-yl)-decylamine, (S)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carboxypyrrolidin-3-ylguanamine, (R)-6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidin-7-carboxypyrrolidin-3-ylguanamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (1-nitro-bicyclo[2. 2. 2]oct-3-yl)-nonylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (1H-pyrazol-3-yl)-nonylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2,3-d]pyrimidin-7- Carboxylic acid (2-methyl-2H-pyrazol-3-yl)-decylamine, 6-(2-bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2,3 -d]pyrimidine-7-carboxylic acid (4-aminoformamido-1H-pyrazol-3-yl)-decylamine, 6-(2-bromo-phenyl)-2-(4-morpholine-4 -yl-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-[4-(2-diethylamino-B Oxy)-anilino]-pyrido[2,3-d]pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-(3-methylsulfonyl-anilinoyl) - Pyrido[2,3-d]pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-(4-aminesulfonyl-anilino)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-(3-methylamine sulfonylmethyl-anilino)-pyrido[2,3-d Pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-[3-(2-hydroxy-ethanesulfonyl)-anilino]-pyrido[2,-3- d]pyrimidine-7-carboxylic acid decylamine, 6-(2-bromo-phenyl)-2-(3-methanesulfonyl-anilino)-pyrido[2,3-d]pyrimidin-7-carboxylate Acid amide, 6-(2-bromo- 2-(3-methanesulfonyl-anilino)-pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-[4-( 2-Diethylamino-ethoxy)-anilino]-pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-[4-(2 -hydroxy-ethoxy)-anilino]-pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-[4-(2-ethylamino) -ethoxy)-anilino]-pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-(3-methanesulfinyl-anilino - Pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-[3-(2-hydroxy-ethanesulfonyl)-anilino]- Pyrido[2,3-d]pyrimidin-7-carboxonitrile, 6-(2-bromo-phenyl)-2-(4-morpholin-4-yl-phenylamino)-pyrido[2,3- d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(3-methanesulfonylamino-anilino )-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-[4- (2-hydroxy-ethoxy)-anilino]-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2 -bromo-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-anilino]-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonate Amino-ethyl)-guanamine, 6-(2-bromo-phenyl)-2-(3-methoxy-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-guanamine, 2-(3-acetamido-anilino)-6-(2-bromo-phenyl)-pyrido[2,3-d Pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4,4-dioxo-3,4-di Hydrogen-2H-4 λ *6*-benzo[1,4]oxathia-6-ylamine)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonylamine) -ethyl)-decylamine, 6-(2-bromo-phenyl)-2-[3-(2-hydroxy-ethylsulfonyl)-anilino]-pyrido[2,3-d] Pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(3-hydroxymethyl-2,3-dihydro- Benzo[1,4]dioxin-6-ylamine)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-methanesulfonyl-amino-ethyl)-guanamine, 6-(2-Bromo-phenyl)-2-(4-fluoro-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (piperidin-2-ylmethyl)-indole Amine, 6-(2-bromo-phenyl)-2-(4-methanesulfinylidene-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-hydroxy-ethyl) - decylamine, 6-(2-bromo-phenyl)-2-(3-methanesulfinylidene-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2- Hydroxy-ethyl)-guanamine, 6-(2-bromo-phenyl)-2-[3-(2-hydroxy-ethylaminesulfonyl)-anilino]-pyrido[2,3-d Pyrimidine-7-carboxylic acid (2-hydroxy-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-[4-(2-hydroxy-ethylaminesulfonyl)-anilinyl ]-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-hydroxy-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(4-methanesulfinyl) -anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-phenyl)-2-(3 -methanesulfinyl-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-phenyl -2-[4-(2-hydroxy-ethoxy)-anilino]-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine ,6-(2-Bromo-phenyl)-2-(3-methanesulfonyl-anilino)-pyrido[2,3-d]pyrimidin-7-carboxylic acid (2-aminosulfonyl-B -p-amine, 6-(2-bromo-phenyl)-2-(3-hydroxymethyl-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-hydroxy- Ethyl)-guanamine, 6-(2-bromo-phenyl)-2-(3-hydroxymethyl-anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-amine Sulfomethyl-ethyl)-nonylamine, 6-(2-bromo-phenyl)-2-(4,4-dioxo-3,4-dihydro-2H-4 λ *6*-benzo[ 1, 4] Oxythiazol-6-ylamine)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (2-aminosulfonyl-ethyl)-decylamine, 6-(2-bromo-benzene 2-(4,4-dioxo-3,4-dihydro-2H-4 λ *6*-benzo[1,4]oxathia-6-ylamine)-pyrido[2, 3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine hydrochloride, 6-(2-bromo-phenyl)-2-(3-methanesulfonylamino)- Anilino)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine hydrochloride, and 2-(3-acetamido-anilino) -6-(2-Bromo-phenyl)-pyrido[2,3-d]pyrimidine-7-carboxylic acid (pyrrolidin-2-ylmethyl)-decylamine hydrochloride. U.S. Patent No. 7,129,351, issued to U.S. Pat. [4-(2-Diethylamino-ethoxy)-anilino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2- Ketone, and (-)-3-(2-bromo-phenyl)-7-[4-(2-diethylamino-ethoxy)-anilino]-1,4-dimethyl-3, 4-Dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. U.S. Patent No. 7,115,739 to the name of U. U.S. Patent No. 7,098,330, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the U.S. Patent No. 7,091,345, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the the the U.S. Patent No. 7,087,603, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the U.S. Patent No. 7,008,948, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the U.S. Patent No. 6,989,385, the disclosure of which is incorporated herein by reference in its entirety by reference in its entirety in its entirety in the the the the the the the the the the the the the啉-4-yl}-(5-methyl-2H-pyrazole-3-yl)-amine, [2-(methylanilino)-quinazolin-4-yl]-(5-methyl -2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl)-{2-[N-methyl-N-(pyridin-3-ylmethyl)amine (2-quinazolin-4-yl}-amine, (5-methyl-2H-pyrazol-3-yl)-(2-anilino-quinazolin-4-yl)-amine, (2- Benzylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)amine, (2-cyclohexylamino-quinazolin-4-yl)-(5 -methyl-2H-pyrazol-3-yl)-amine, [2-(2,3-dihydrobenzo[1,4]dioxin-6-ylamine)-quinazolin-4-yl ]-(5-Methyl-2H-pyrazol-3-yl)-amine, (2-cyclohexylmethylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazole-3 -yl)-amine, [2-(1H-carbazol-6-ylamine)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5 -methyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine, [2-(3-chloroanilino)- Quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-chloroanilino)-quinazoline 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-fluorobenzylamino)-quinazolin-4-yl]-(5- Methyl-2H-pyrazol-3-yl)-amine, {2-[2-(2-hydroxyethyl)anilino]-quinazolin-4-yl}-(5-methyl-2H-pyridyl Zyrid-3-yl)-amine, [2-(4-cyanomethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amine, [2-(3-hydroxymethylanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3-hydroxyaniline) )-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-(2-aniline - quinazolin-4-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylanilino)-quinazolin-4-yl] -Amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(6-methoxypyridin-3-ylamine)-quinazolin-4-yl]-amine, (5 -cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-5-ylamine)-quinazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazole 3-yl)-[2-(1H-indol-6-ylamine)-quinazolin-4-yl]-amine, [2-(4-acetamido-3-methylanilino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, [2-(4-chloro-3-methylanilino)-quinazoline- 4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyridyl) Zyrid-3-yl)-[2-(4-ethylphenylamino)-quinazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[ 2-(4-propylphenylamino)-quinazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(2- Hydroxyethyl)anilino]-quinazolin-4-yl}-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-(2-anilino-quinazolin-4-yl) -amine, [2-(2-cyclohexylethylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, [2-(4- Carboxymethoxyaniline)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, [2-(4-cyanomethylphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, [2-(benzothiazol-6-ylamine)-quinazolin-4-yl ]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylaniline) , quinazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(2-phenoxyethylamino)-quinazoline-4 -yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(thiophene-2-methylamino)-quinazolin-4-yl]-amine, [2- (4-carboxymethylanilino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazole- 3-yl)-[2-(1H-indazol-5-ylamine)-quinazolin-4-yl] -amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine, (5-cyclopropyl -2H-pyrazol-3-yl)-[2-(3-methoxycarbonylanilino)-quinazolin-4-yl]-amine, [2-(3-carboxyaniline)-quinazoline 4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-ethyl Phenylamino)-quinazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dimethylanilino)-quin Oxazolin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyaniline)-quinazolin-4-yl] -amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyaniline)-quinazolin-4-yl]-amine, (5-methyl-2H -pyrazol-3-yl)-(2-anilino-5,6,7,8-tetrahydroquinazolin-4-yl)-amine, [2-(biphenyl-3-ylamine)-quin Oxazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3- Phenylpropan-1-ylamine)-quinazolin-4-yl]-amine, [2-(4-acetamido-3-methylanilino)-quinazolin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-2-ylamine)-quinazoline 4-yl]-amine, [2-(3-methylanilino)-quinazolin-4-yl]-(5-A -2H-pyrazol-3-yl)-amine, [2-(2-chloro-5-methylanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazole 3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(morpholin-1-yl)anilino]-quinazolin-4-yl }-amine, [2-(benzothiazol-6-ylamine)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3 ,4-dimethylanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3-ethylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3-methoxyaniline)-quinazolin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamido-3-cyanoanilino)-quinazolin-4-yl]-(5-methyl -2H-pyrazol-3-yl)-amine, [2-(2-methoxybiphenyl-5-ylamine)-quinazolin-4-yl]-(5-methyl-2H-pyridyl Zoxa-3-yl)-amine, [2-(4-acetamidoanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-tert-Butoxycarbonylamino-anilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-( 4-cyanoanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl) -[2-(6-oxy-6,10-dihydro-4aH-benzo[c]gram-2-ylamine)-quinazoline啉-4-yl]-amine, [2-(biphenyl-3-ylamine)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [ 2-(4-Methoxycarbonylmethyl-3-methylanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2- (4-carboxymethyl-3-methylanilino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-amino) Phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-bromophenylamino)-quinazoline 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-isobutylammonium-anilino)-quinazolin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, (5-ethyl-2H-pyrazol-3-yl)-[2-(5-ethyl-2H-pyrazol-3-yl) Amine)-quinazolin-4-yl]-amine, (1H-carbazol-3-yl)-(2-anilino-quinazolin-4-yl)-amine, (1H-carbazole-3- -[2-(3-Trifluoromethylanilino)-quinazolin-4-yl]-amine, (1H-carbazol-3-yl)-[2-(4-trifluoromethyl) Alkylamino)-quinazolin-4-yl]-amine, [2-(adamantan-2-ylamine)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine (1H-carbazol-3-yl)-(2-methyl-phenyl-amino-quinazolin-4-yl)-amine, [2-(2-chloro-phenyl)-amino group -quinazolin-4-yl]-(1H-indazol-3-yl)-amine, (1H-carbazole 3-yl)-[2-(2-trifluoromethylanilino)-quinazolin-4-yl]-amine, [2-(4-cyanomethylphenylamino)-quinazoline啉-4-yl]-(1H-indazol-3-yl)-amine, [2-(4-chloroanilino)-5,6,7,8-tetrahydroquinazolin-4-yl]- (5-Methyl-2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl)-(2-anilino-6,7,8,9-tetrahydro -5H-cycloheptadin-4-yl)-amine, [2-(benzimidazol-2-ylamine)-7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4 -d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (7-benzyl-2-anilino-5,6,7,8-tetrahydro- Pyrido[3,4-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine, [6-benzyl-2-(4-chloroanilino)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(benzene And imidazol-2-ylamine)-6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyridyl Zyrid-3-yl)-amine, (6-benzyl-2-anilino-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5- Methyl-2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl)-(2-anilino-5,6,7,8-tetrahydro-pyridine [3,4-d]pyrimidin-4-yl)-amine, [2-(4-cyanomethylphenylamino)-quinazolin-4-yl]-(1H-pyrazolo[3, 4-b] Acridine-3-yl)-amine, [2-(4-cyanobenzylamino)-quinazolin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl -Amine, [2-(4-cyanomethylphenylamino)-quinazolin-4-yl]-(4-fluoro-1H-indazol-3-yl)-amine, [2- (4-cyanoanilino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine, and [2-(4-cyanobenzylamino)-quinazoline- 4-yl]-(1H-indazol-3-yl)-amine. U.S. Patent No. 6,987,116 to Boschelli et al., which is hereby incorporated by reference, which is incorporated herein by reference in its entirety in the the the the the the the the the the -b]pyridine-5-carbonylnitrile. U.S. Patent No. 6,696,452, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the U.S. Patent No. 6,664,247, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the the the the the [2-(naphthalen-2-ylsulfonyl)-6-phenylpyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3- Methoxycarbonyl-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalene-2 - sulfamoyl)-pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2-(naphthalen-2-yl) Sulfomethyl)-pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[5-methyl-2-(naphthalen-2-ylsulfonyl)- Pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2-(naphthalen-2-ylsulfonyl)-pyrimidin-4-yl ]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-(morpholin-4-yl)-2-(naphthalen-2-ylsulfonyl)-pyrimidine-4- Amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-(1-methylpiperazin-4-yl)-2-(naphthalene-2yl-sulfonyl)- Pyrimidin-4-yl]-amine, [6-(2,6-dimethylphenyl)-2-(naphthalen-2-yl-sulfonyl)-pyrimidin-4-yl]-(5-methyl-2H -pyrazol-3-yl)-amine, [6-(2-tolyl)-2-(naphthalen-2-ylsulfonyl)-pyrimidin-4-yl]-(5-A -2H-pyrazol-3-yl)-amine, [2-(4-acetamido-phenylsulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfonyl)-6-phenyl-pyrimidine-4 -yl]-amine, [2-(4-isobutylamine-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amine, [6-(4-methylpiperazin-1-yl)-2-methylsulfonyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine ,(5-Methyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionamido-phenylsulfonyl)-pyrimidin-4-yl]-amine, [ 2-(4-Cyclopropanolamine-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-A -2H-pyrazol-3-yl)-{6-phenyl-2-[4-(propan-1-sulfonylamino)-phenylsulfonyl]-pyrimidin-4-yl}-amine , [2-(4-ethanesulfonylamino-phenylsulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amine, [2-(4-acetamidophenyl-sulfonyl)-6-(2-tolyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl -Amine, [2-(4-isobutanecarbonylamino-phenyl-sulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3- Amine, [2-(4-acetamido-phenyl-sulfonate) 5-(methyl-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-ethylamino)-benzene -sulfonyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [6-(3-ethyl Amidinophenyl)-2-(4-acetamido-phenyl-sulfonyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-Isopropanesulfonylamino-phenyl-sulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amine, {2-[4-(2-dimethylamino-acetamido)-phenylsulfonyl]-6-phenyl-pyrimidin-4-yl}-(5-methyl-2H-pyridyl Zyrid-3-yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyridyl Zyrid-3-yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-(5-A -2H-pyrazol-3-yl)-amine, [2-benzylsulfonyl-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl)-amine, [2-benzylsulfonyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3 -yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine, [2-(4-methoxy-benzylsulfonyl)- 6-(4-Methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-ethylamino) -Phenyl-sulfonyl)-6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H- Pyrazol-3-yl)-[6-phenyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidin-4-yl]-amine, [2-(3-chloro-) Benzylsulfonyl)-6-(piperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-methyl-2H -pyrazol-3-yl)-{2-[4-(morpholinsulfonyl)-benzylsulfonyl]-6-morpholin-4-yl-pyrimidin-4-yl}-amine, {6 -(2-methoxy-ethylamino)-2-[4-(morpholinsulfonyl)-benzylsulfonyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazole -3-yl)-amine, {6-(4-methylpiperazin-1-yl)-2-[4-(morpholinsulfonyl)-benzylsulfonyl]-pyrimidin-4-yl} -(5-methyl-2H-pyrazol-3-yl)-amine, [6-methoxymethyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidine-4- [-] 5-(4-methyl-2H-pyrazol-3-yl)-amine, [2-(4-methoxycarbonyl-phenyl-sulfonyl)-6-methoxymethyl-pyrimidine- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3,5-dimethoxy-benzylsulfonyl)-6-morpholin-4- -Pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-( 3,5-Dimethoxy-benzylsulfonyl)-6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-Methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2-(naphthalen-2-yl-methylsulfonyl)-pyrimidin-4-yl]-amine {2-(4-Ethylamino-phenyl-sulfonyl)-6-[4-(3-dimethylamino-propoxy)phenyl]-pyrimidin-4-yl}-(5 -methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamidophenylsulfonyl)-6-(morpholin-4-yl)-pyrimidin-4-yl] -(5-methyl-2H-pyrazol-3-yl)-amine, [6-hydroxymethyl-2-(4-propylamido-phenyl-sulfonyl)-pyrimidin-4-yl] -(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamido-phenyl-sulfonyl)-pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl)-amine, [6-(1-butoxycarbonyl)-2-(4-propionamido-phenyl-sulfonyl)pyrimidin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, and [6-methoxycarbonyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidin-4-yl] -(5-Methyl-2H-pyrazol-3-yl)-amine. U.S. Patent No. 6,660,731, the disclosure of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the U.S. Patent No. 6,653,301, the disclosure of which is incorporated herein by reference in its entirety by reference in its entirety in the the the the the the the the the the the the the [2-(naphthalen-2-ylsulfonyl)-6-phenylpyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3- Methoxycarbonyl-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalene-2 - sulfamoyl)-pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2-(naphthalen-2-yl) Sulfomethyl)-pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[5-methyl-2-(naphthalen-2-ylsulfonyl)- Pyrimidin-4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2-(naphthalen-2-ylsulfonyl)-pyrimidin-4-yl ]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-(morpholin-4-yl)-2-(naphthalen-2-ylsulfonyl)-pyrimidine-4- Amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[6-(1-methylpiperazin-4-yl)-2-(naphthalen-2-ylsulfonyl) -pyrimidin-4-yl]-amine, [6-(2,6-dimethylphenyl)-2-(naphthalen-2-ylsulfonyl)-pyrimidin-4-yl]-(5-methyl-2H -pyrazol-3-yl)-amine, [6-(2-tolyl)-2-(naphthalen-2-ylsulfonyl)-pyrimidin-4-yl]-(5-A -2H-pyrazol-3-yl)-amine, [2-(4-acetamido-phenylsulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine, (5-methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfonyl)-6-phenyl-pyrimidine-4 -yl]-amine, [2-(4-isobutylammonium-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl )-Amine, [6-(4-methylpiperazin-1-yl)-2-methylsulfonyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine, (5-methyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionamido-phenylsulfonyl)-pyrimidin-4-yl]-amine , [2-(4-Cyclopropanecarbonylamine-phenylsulfonyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5 -methyl-2H-pyrazol-3-yl)-{6-phenyl-2-[4-(propan-1-sulfonylamino)-phenylsulfonyl]-pyrimidin-4-yl} -amine, [2-(4-ethanesulfonylamino-phenylsulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl -Amine, [2-(4-acetamidophenyl-sulfonyl)-6-(2-tolyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3 -yl)-amine, [2-(4-isobutanecarbonylamino-phenyl-sulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazole- 3-yl)-amine, [2-(4-acetamido-phenyl) -sulfonyl)-5-methyl-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamide) -Phenyl-sulfonyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [6-( 3-Ethylaminophenyl)-2-(4-acetamido-phenyl-sulfonyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine, [2-(4-isopropanesulfonylamino-phenyl-sulfonyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3- Amine, {2-[4-(2-dimethylamino-acetamido)-phenylsulfonyl]-6-phenyl-pyrimidin-4-yl}-(5-methyl- 2H-pyrazol-3-yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, [2-benzylsulfonyl-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5 -methyl-2H-pyrazol-3-yl)-amine, [2-benzylsulfonyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyridyl Zyrid-3-yl)-amine, [2-(3-chloro-benzylsulfonyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5- Methyl-2H-pyrazol-3-yl)-amine, [2-(4-methoxy-benzylsulfonate) 6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-B Amidino-phenyl-sulfonyl)-6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl -2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidin-4-yl]-amine, [2-(3- Chloro-benzylsulfonyl)-6-(piperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-A -2H-pyrazol-3-yl)-{2-[4-(morpholinsulfonyl)-benzylsulfonyl]-6-morpholin-4-yl-pyrimidin-4-yl}-amine {6-(2-Methoxy-ethylamino)-2-[4-(morpholinsulfonyl)-benzylsulfonyl]-pyrimidin-4-yl}-(5-methyl-2H -pyrazol-3-yl)-amine, {6-(4-methylpiperazin-1-yl)-2-[4-(morpholinsulfonyl)-benzylsulfonyl]-pyrimidine-4 -yl}-(5-methyl-2H-pyrazol-3-yl)-amine, [6-methoxymethyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidine 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-methoxycarbonyl-phenyl-sulfonyl)-6-methoxymethyl -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3,5-dimethoxy-benzylsulfonyl)-6-morpholine 4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine [2-(3,5-Dimethoxy-benzylsulfonyl)-6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl -Amine, (5-methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2-(naphthalen-2-yl-methylsulfonyl)-pyrimidine-4- Amine, {2-(4-acetamido-phenyl-sulfonyl)-6-[4-(3-dimethylamino-propoxy)phenyl]-pyrimidin-4-yl }-(5-Methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamidophenylsulfonyl)-6-(morpholin-4-yl)-pyrimidine- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [6-hydroxymethyl-2-(4-propionamido-phenyl-sulfonyl)-pyrimidine- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-acetamido-phenyl-sulfonyl)-pyrimidin-4-yl]-( 5-methyl-2H-pyrazol-3-yl)-amine, [6-(1-butoxycarbonyl)-2-(4-propionamido-phenyl-sulfonyl)pyrimidine-4- [-]-(5-methyl-2H-pyrazol-3-yl)-amine, and [6-methoxycarbonyl-2-(4-propionylamino-phenyl-sulfonyl)-pyrimidine- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine. U.S. Patent No. 6,653,300, the disclosure of which is incorporated herein by reference in its entirety by reference in its entirety in the the the the the the the the the the the 2-(naphthalen-2-yloxy)-quinazolin-4-yl]-amine, (5-methyl-2H-pyrazol-3-yl)-(2-phenoxy-quinazoline- 4-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-quinazoline 4-yl]-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenoxy)-quinazolin-4-yl]-amine, [ 2-(3-Methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3,4-dimethyl Oxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(benzo[1,3]dioxy-5 -yloxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(3-methoxycarbonylphenoxy)-quinazoline啉-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl -quinazolin-4-yl)-amine, (2-benzyloxymethyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (2 -benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine, (5-cyclopropyl-2H-pyrazole- 3-yl)-(2-methyl-quinazolin-4-yl)-amine, [2-(4-chlorophenoxymethyl)-6,7,8,9-tetrahydro-5H-cyclo Heptapurid-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-5,6,7,8-tetrahydro -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(2-chlorophenoxymethyl)-6-methyl-pyrimidine-4 -yl]-(5-phenyl-2H-pyrazol-3-yl)-amine, [2-(2-chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5 -(furan-2-yl)-2H-pyrazol-3-yl]-amine, (6-methyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-phenyl-2H- Pyrazol-3-yl)-amine, [5-(furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenoxymethyl-pyrimidin-4-yl -Amine, [5-(furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenylsulfonylmethyl-pyrimidin-4-yl)-amine, [6-Methyl-2-(4-methyl-phenylsulfonylmethyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine, [5 -(furan-2-yl)-2H-pyrazol-3-yl]-[6-methyl-2-(4-methyl-phenylsulfonylmethyl)-pyrimidin-4-yl]-amine , [2-(4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine, [2- (4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H- Zyrid-3-yl]-amine, (6-ethyl-2-phenylsulfonylmethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine, (6-ethyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine, [6-ethyl-2-(4- Fluorophenoxymethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [6-ethyl-2-(1-methyl-1-benzene) -ethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-6-methyl- Pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl] -(5-methyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-6-methoxymethyl-pyrimidin-4-yl]-(5 -methyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2- -2H-pyrazol-3-yl]-amine, (5-methyl-2H-pyrazol-3-yl)-(2-phenylsulfonylmethyl-5,6,7,8- Tetrahydro-quinazolin-4-yl)-amine, [2-(4-methylphenylsulfonylmethyl)-6,7,8,9-tetrahydro-5H-cyclohepta Pyridine-4- ]]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(1-methyl-1-phenyl-ethyl)-6,7,8,9-tetrahydro- 5H-cycloheptadin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(2,6-dichloro) -5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [7-benzyl-2-( 2,6-Dichlorobenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl -Amine, [6-benzyl-2-(4-chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]- (5-Methyl-2H-pyrazol-3-yl)-amine, [2-(4-chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(2,6-dichlorobenzyl)-6-methyl-pyrimidine-4- [-] 5-(5-methyl-2H-pyrazol-3-yl)-amine, [2-(2,6-dichlorobenzyl)-5,6-dimethyl-pyrimidin-4-yl]- (5-Methyl-2H-pyrazol-3-yl)-amine, (1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl ]-amine, (7-fluoro-1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine, (5-fluoro -1H-carbazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine, (5-methyl-1H-pyrazol-3-yl )-[2-(2-Phenyl-cyclopropyl)-quinazolin-4-yl]-amine, [6-ethyl-2-(1-methyl-1-phenyl-ethyl)- Pyrimidin-4-yl]-(5-methyl-1H-pyrazol-3-yl)-amine, [6-methyl-2-(1-methyl-1-phenyl-ethyl)-pyrimidine- 4-yl]-(5-methyl-1H-pyridyl Zyrid-3-yl)-amine, [6-methyl-2-(1-phenyl-cyclopropyl)-pyrimidin-4-yl]-(5-methyl-1H-pyrazol-3-yl) -amine, and [6-ethyl-2-(1-methyl-1-phenyl-propyl)-pyrimidin-4-yl]-(5-methyl-1H-pyrazol-3-yl)- amine. U.S. Patent No. 6,638,926, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the U.S. Patent No. 6,613,736 to Knegtel et al., which is incorporated by reference, which is incorporated herein by reference. U.S. Patent No. 6,610,677, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the U.S. Patent No. 6,503,914 to Benish et al., which is hereby incorporated by reference, which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the Pyrimidin-4-yl)indole, 4-methoxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, 4-pyridinecarboxaldehyde (7-methylthiazolidine [3] , 2-d]pyrimidin-4-yl)indole, 3,4-dimethoxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, 3,5-di Methoxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, 3-chlorobenzaldehyde (7-methylthiazepine [3,2-d]pyrimidine-4-腙, 3,4-dihydroxybenzaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 3-pyridinecarboxaldehyde (7-methylthiazolidine [3,2- d]pyrimidin-4-yl)indole, 2-thiophenecarboxaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 1H-pyrrole-2-carbaldehyde (7-methylthiazolidine) [3,2-d]pyrimidin-4-yl)indole, 2-furaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 3-hydroxybenzaldehyde (7- Methylthiazinium [3,2-d]pyrimidin-4-yl)indole, 3-thiophenecarboxaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 1H-imidazole-2 - formaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)anthracene, 4-ethoxybenzaldehyde (7-methylthiazolidine [3,2-d] Pyridin-4-yl)indole, 4-hydroxy-3-nitrobenzaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 3-ethoxy-4-hydroxybenzene Aldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 3-hydroxy-4-methoxybenzaldehyde (7-methylthiazolidine [3,2-d]pyrimidine- 4-yl)indole, 3-fluorobenzaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 4-hydroxy-3-methoxybenzaldehyde (7-methyl) Thiazin[3,2-d]pyrimidin-4-yl)indole, 3-chloro-4-hydroxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, 4 -Fluorobenzaldehyde (6-phenylthiazin[3,2-d]pyrimidin-4-yl)-indole, 3-pyridinecarboxaldehyde (thiazin[3,2-d]pyrimidin-4-yl)indole, 5-methyl-1H-imidazole-4-carbaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 5-methyl-2-thiophenecarboxaldehyde (7-methylthiazolidine) [3,2-d]pyrimidin-4-yl)indole, 4-cyanobenzaldehyde (7-methylthiazepine [3,2-d]pyrimidin-4-yl)indole, 3-cyanobenzaldehyde ( 7-Methylthiazinium [3,2-d]pyrimidin-4-yl)indole, 3-methoxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, 3-ethoxybenzaldehyde (7-methylthiazol[3,2-d]pyrimidin-4-yl)indole, cyclopropanecarboxaldehyde (7-methylthiazolidine [3,2-d]pyrimidine-4-腙, 3-pyridinecarboxaldehyde (7-bromothiazol[3,2-d]pyrimidin-4-yl)indole, and 3-pyridyl Pyridinaldehyde (6-phenylthiazinium [3,2-d]pyrimidin-4-yl)indole. U.S. Patent No. 6,100,254, issued to U.S. Pat.

The method can further comprise the step of administering a therapeutically effective amount of a BH3 analog to the target subject. Alternatively, the method may further comprise the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject.

A further aspect of the present invention provides a method of treating a malignant tumor in a subject having a malignant tumor having a polymorphism of a germ cell which confers resistance to thymidine kinase inhibitors (TKIs), which comprises administering (1) a therapeutically effective amount of a therapeutic agent to a target subject to treat the malignant tumor; and (2) a therapeutically effective amount of a combination of a kinase inhibitor to the target subject to treat the malignant tumor, wherein the therapeutic agent is Derived from a derivative or analog of Weikangol, Weikangol, a derivative or analog of dihydroquinone dihydrated cyclohexanol, dibromodusol, and two a group consisting of a derivative or analog of bromocortisol; the combination of the kinase inhibitors is a combination selected from the group consisting of: (1) a JAK2 inhibitor and a STAT5 inhibitor; (2) a JAK2 inhibitor and a Src inhibitor; (3) a STAT5 inhibitor and a Src inhibitor; and (4) a JAK2 inhibitor, a STAT5 inhibitor, and a Src inhibitor.

The method can further comprise the step of administering a therapeutically effective amount of a BH3 analog to the target subject. Alternatively, the method may further comprise the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject.

The description of a specific kinase inhibitor as a JAK2 inhibitor, a STAT5 inhibitor or a Src inhibitor does not exclude that the kinase inhibitor is cited or described as an inhibitory activity towards another kinase, such as one or more JAK2, STAT5, Src or kinase activity associated with the BCR-ABL fusion protein.

Where the improvement is by analysis of a patient or disease phenotype, the analysis of the patient or disease phenotype may be, but is not limited to, an analysis of the patient or disease phenotype achieved by a method, The method is selected from the group consisting of: (a) using a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm a particular genotype of the patient; (b) using a method of measuring the marker The marker is a protein selected from the group consisting of a histone deacetylase, an adenine decarboxylase, a VEGF, a gene product of a specific gene of a prostate, a protein product of a jun, a protein kinase, a desmosome a group consisting of nucleoprotein-3 and a novel epitope derived from apoptotic protease; (c) a dose of the mimetic compound; and (d) a state of the low dose pretest enzyme.

In the sample from the target subject, the measurement of protein desmoglein-3, which is a marker of tumor metastasis to lymph nodes, and the amount based on desmoglein-3, the selection of appropriate therapies is described by Gutkind et al. U.S. Patent Application Publication No. 2012/0087892, which is incorporated herein by reference.

The measurement of a novel epitope of apoptotic protease derived as an indicator of apoptosis, including apoptosis induced by an antitumor agent, is described in US Patent Application Publication No. 2012/0028266 by Wells et al. Include it by reference.

When the improvement is performed by analysis of a patient or disease genotype, the analysis of the patient or disease genotype may be, but is not limited to, an analysis method of a disease or disease genotype achieved by a method, The method is selected from the group consisting of: (a) using a diagnostic tool, diagnostic technique, diagnostic kit, or diagnostic test to confirm a particular genotype of the patient; (b) using a gene chip; Using gene expression analysis; (d) using single nucleotide polymorphism (SNP) analysis; and (e) measuring the level of a metabolite or a metabolizing enzyme.

The use of gene chips is described in AJ Lee & S. Ramaswamy, "DNA microarrays in biological discovery and patient care" in Essentials of Genomic and Personalized Medicine (GS Ginsburg & HF Willard, eds., Academic Press, Amsterdam, 2010), ch. 7, pp. 73-88, and is included by reference.

When the method is used for single nucleotide polymorphism (SNP) analysis, it is selected from the group consisting of histone deacetylase, avian acid decarboxylase, VEGF, a prostate specific gene, c-Jun The SNP analysis can be performed on the gene of a group consisting of a protein kinase. The use of SNP analysis is described in S. Levy and Y.-H. Rogers, "DNA sequencing for the discovery of human genetic variation" in Essentials of Genomic and Personalized Medicine (GSGinsburg & HF Willard, eds., Academic Press , Amsterdam, 2010), ch. 3, pp. 27-37, and is included by reference.

Still, other gene bundle techniques can be used, such as copy number variation. Analysis and analysis of DNA methylation. Copy number variation analysis is described in C. Lee et al., "Copy number variation and human health" in Essentials of Genomic and Personalized Medicine (GS Ginsburg & HF Willard, eds., Academic Press, Amsterdam, 2010), ch. Pp.46-59, and include it by reference. DNA methylation analysis is described in S. Cottrell et al., "DNA methylation analysis: providing new insights into human disease," in Essentials of Genomic and Personalized Medicine (GS Ginsburg & HF Willard, eds., Academic Press, Amsterdam, 2010), ch. 6, pp. 60-72, and is included by reference.

When the improvement is made by pre-/post-treatment preparation, the pre-/post-treatment preparation may be, but is not limited to, a method selected from pre-/post-treatment preparations of the group consisting of: (a) use Colchicine or an analogue thereof; (b) using a uric acid; (c) using uricase; (d) non-oral use of nicotinamide; (e) using a sustained release form of nicotine amide; f) using an inhibitor of poly ADP ribose polymerase; (g) using caffeine; (h) using methotrexate rescue; (i) infection control; and (j) using an antihypertensive agent.

Urinary acid drugs include, but are not limited to, probenecid, benzbromarone, and sulfinothrazol. A particularly good diuretic is probenecid. A uric acid-suppressing drug comprising probenecid, which may also have diuretic activity.

Inhibitors of poly ADP ribose polymerase are described in GJ Southan & C. Szabó, "Poly ADP ribose inhibitors", Curr. Med. Chem. 10:321-240 (2003), and are incorporated herein by reference. And comprising nicotinamide, 3-aminobenzamide, substituted 3,4-dihydroisoquinolin-1(2H)-ones and isoquinoline-1(2H)-ones, benzo Imidazole, hydrazine, pyridazine-1 (2H)-ketones, quinazolinones, isoindolinones, phenanthridines and other compounds.

Hyperthyroidism rescues leucovorin (hyperthyroid tetrahydrofolate) to amines The cast of patients with methyl folate. Formazan tetrahydrofolate is a simplified form of folic acid that bypasses dihydrofolate reductase and restores hematopoietic function. Formazan tetrahydrofolate can be administered intravenously or orally.

In an alternative, wherein the pre-/post treatment is the use of a uric acid, the uric acid drug is probenecid or an analog thereof.

When the improvement is carried out by toxicity management, the toxicity management may be, but is not limited to, a method selected from the group consisting of toxicity management of: (a) using colchicine or an analogue thereof; b) using a uric acid; (c) using uricase; (d) non-oral use of nicotinamide; (e) using a sustained release form of nicotine amide; (f) using a poly ADP ribose polymerase Inhibitors; (g) use of caffeine; (h) use of methotrexate rescue; (i) use of sustained release of isodecyl alcohol; (j) non-oral use of isodecyl alcohol; (K) use of bone marrow transplantation; l) using a blood cell stimulating agent; (m) using blood or platelet injection; (n) administering a drug selected from the group consisting of Neupogen ^® , G-CSF and GM-CSF (o) applying a pain control technique: (p) administering an anti-inflammatory agent; (q) administering a liquid; (r) administering a corticosteroid; (s) administering an insulin controlling drug; (t) administering an antipyretic agent; (u) administering an anti-nausea therapeutic agent; (v) administering an antidiarrheal therapeutic; (w) administering N-acetylcysteine; (x) administering an antihistamine; and (y) administering An agent that reduces stomach toxicity.

Whirlpool blood is a granulocytic colony-stimulating factor (G-CSF) analog produced by recombinant DNA technology for stimulating proliferation and differentiation of granules, and is used for therapeutic hooliganism. Leukopenia; G-CSF can be used in a similar method. GM-CSF is a granule-macrophage colony stimulating factor and stimulates stem cells to produce granules (eosinophilic, neutrophilic and basophilic) and monocytes; its administration is useful for preventing or treating infections.

Anti-inflammatory agents are well known in the art and comprise corticosteroids and non-steroidal anti-inflammatory agents (non-steroidal anti-inflammatory agents, NSAIDs). Corticosteroids with anti-inflammatory activity include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone. Prednisone), methylprene cortisol, triamcinolone, fluocinolone acetonide, and fludrocortisone. Non-steroidal anti-inflammatory agents include, but are not limited to, acetyl salicylic acid (aspirin), sodium salicylate, magnesium choline trisalicylate, bis-alginic acid, diflunisal, sulfasalazine ), olsalazine, acetaminophen phenol, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen Ibuprofen), naproxen, flurbiprofen, ketoprofen, fenoprofen, phenpromazine, mefenamic acid, Meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, Etodolac, nimesulide, aceclofenac, alclofenac, alminoprofen, amfenac, anpyridin Ampiroxicam, apazone, araprofen, azapropazone, bendazac, phenoxazole, benzalamine (be Nzydamine), bermofolfen, benzpiperylon, bromfenac, bucloxic acid, bumadizone, butibufen Carprofen (carprofen), cimicoxib, cinmetacin, cinnoxicam, clidanac, clofezone, clonixin, chlorine Clopirac, darbufelone, deracoxib, droxicam, eltenac, enfenamic acid, eplezole Eprizole), esflurbiprofen, ethoxyaniline, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac ), fenclozic acid, fenclozine, fendosal, fentiazac, feprazone, filenadol, fluoride Flobufen, florifenine, flosulide, flufenic acid, flufenamic acid, flufenisal, flunixin Fluroprofen, fluprofen, fluproquazone, furofenac, ibufenac, imrecoxib, guanidine Indoprofen, isofazolac, isoxepac, isoxicam, licofelone, lobprofen, lornoxicam Lomoxicam), lonazolac, loxoprofen, lumaricoxib, mabuprofen, miroprofen, mofflower, mofezolac, morazone ), nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaproxen, opanosin (orpanoxin), oxacinol, oxindanac, oxpinac, oxybutyrazolone, pamicogrel, parcetasal, parecoxib (parectasal) Parecoib), parsalmide, pelubiprofen, pemedolac, phenylbutyrazole, pirazolac, pirprofen, puprofen Pranoprofen, salicin, salicylamine, salicin salicylic acid, satigrel, sudoxicam, suprofen, he Talmetacin, talniflumate, tazofelone, tebufelone, tenidap, tenoxicam, tepoxaline, Tiaprofenic acid, tiaramide, tilmacoxib, tinoridine, tiopinac, thioloprofen, tolfenamic acid (tolfenamic) Acid), triflusal, tropesin, ursolic acid, valdecoxib (valdecoxib), ximoprofen, zaltoprofen, zidometacin, and zomepirac, as well as salts, solvates, analogs, homologs, organisms Bioisosteres, hydrolysates, metabolites, leads and their precursors.

The clinical application of corticosteroids is described in BP Schimmer and KL Parker, "Adrenocorticotropic hormone; Adrenal corticosteroids and their synthetic analogues; Inhibitors of the synthesis and action of adrenocortical hormones" in Goodman &Gilman's The Pharmacological Basis of Therapeutics (LL Brunton, ^{ed., 11 th ed.,} McGraw-Hill, New York, 2006), ch.59, pp.1587-1612, and by reference included.

Anti-nausea therapeutics include, but are not limited to, ondansetron, metoclopramide, promethazine, cyclizine, hyoscine, dronabinol ( Dronabinol), dimenhydrinate, diphenhydramine, hydroxyzine, medizine, dolasetron, granisetron, palonosetron Palonosetron), ramosetron, domperidone, habopol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, Cortisol, dexamethasone, lorazepam and thiethylperazine.

Antidiarrheal therapeutic agents include, but are not limited to, phenethidine, difenoxine, loperamide, codeine, racecadotril, octreotide, and berberine.

N-acetyl cysteine is an antioxidant and chlorinating agent that also provides bioavailable sulfur.

Agents for reducing gastric toxicity include, but are not limited to, rust alcohol (C. Areche et al., "The gastric protective activity of rust alcohol in mice and rats: on gastric secretion, endogenous prostaglandins and non-protein thiol Effect, J. Pharm. Pharmacol. 60:245-251 (2008)), and is incorporated by reference.

When the improvement is by pharmacokinetic/pharmacodynamic monitoring, the pharmacokinetic/pharmacodynamic monitoring can be, but is not limited to, a method selected from the group consisting of: (a) determining plasma levels multiple times; and (b) measuring at least one metabolite in blood or urine multiple times.

Typically, the determination of plasma levels or the determination of at least one metabolite in blood or urine is accomplished by immunoassay. Methods for performing immunoassays are well known in the art and include radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), competitive immunoassay, and immunization using lateral flow assays. Analytical methods, as well as other test methods.

When the improvement is carried out by concomitant administration, the concomitant drug may be, but not limited to, a concomitant selected from the group consisting of: (a) using a pseudonucleoside; (b) using a pseudonucleoside Acid; (c) using a thymidine synthetase inhibitor; (d) using a signaling inhibitor; (e) using cisplatin or a platinum analog; (f) using an alkylating agent; (g) using an anti-tubulin agent (h) using an antimetabolite; (i) using berberine; (j) using apigenin; (k) using colchicine or an analogue thereof; (1) using genistein; (m) using iodo (n) use arabinosylcytosine; (o) use camptothecins; (p) use vinca alkaloids; (q) use positional isomerase inhibitors; (r) use 5-fluoro Uracil; (s) use curcumin; (t) use NF-κB inhibitor; (u) use of rosmarinic acid; (v) use of acesulfame; (w) use of metformin; (x) use of imatinib; (y) use of dasatinib; (z) use of nilotinib (aa) using epigenetic regulators; (ab) using transcription factor inhibitors; (ac) using taxol; (ad) using homoharringtonine; (ae) using pyridoxal; Use spirocyclic guanidine; (ag) use caffeine; (ah) use nicotine guanamine; (ai) use methylglyoxal bis-indole oxime; (aj) use Rho kinase inhibitor; (ak) use 1, 2,4-benzotriazine oxide; (al) using a monoalkyl glycerol; (am) using an inhibitor of Mer, Ax1 or Tyro-3 receptor kinase; (an) using an inhibitor of ATR kinase; (ao) using a Fms kinase, Kit kinase, MAP4K4 kinase, TrkA kinase or TrkB kinase modulator; (ap) tamoxifen; (aq) using an mTOR inhibitor; (ar) using a nk1a kinase, Mkn1b Inhibitor of kinase, Mnk2a kinase or Mnk2b kinase; (as) using a modulator of M2 pyruvate kinase; (at) using a modulator of inositol monophosphate 3 kinase; (au) using a cysteine protease inhibitor ; (av) use of phenformin; (aw) use of Cindbis virus-based vectors; (ax) use of a peptide that acts as an analog of Smac and inhibits IAPs to promote apoptosis; (ay) inhibition using a Raf kinase (az) using a nuclear transfer regulator; (ba) using an acidic neuroglutaminase inhibitor and a choline kinase inhibitor; (bb) using a tyrosine kinase inhibitor; (bc) using an anti-CS1 antibody (bd) using an inhibitor of PDK1 protein kinase; (be) using an anti-guanylate cyclase C (GCC) antibody; (bf) using a histone deacetylase inhibitor; (bg) using cannabinoid; Bh) use a glycoside-like peptide (GLP-1) receptor agonist; (bi) use an inhibitor of Bcl-2 or Bcl-xL; (bj) use a Stat3 pathway inhibitor; (bk) use a polo-like Inhibitor of kinase (Plk1); (bl) using GBPAR1 activator; (bm) using serine-synamic acid protein kinase and modulator of poly ADP ribose polymerase (PARP) activity; (bn) using taxane; (bo) using an inhibitor of dihydrofolate reductase; (bp) using an inhibitor of aromatase; (bq) using a benzimidazolyl anticancer agent; (br) using an O6-methylguanine-DNA-A Base transferase (MGMT) inhibition (bs) using a CCR9 inhibitor; (bt) using an acid sphingomyelinase inhibitor; (bu) using a pseudopeptide macrocycle; (bv) using a cholinate aminate; (bw) using a substituted oxyphosphorus Ring class (bx) using an anti-TWEAK receptor antibody; (by) using an ErbB3 binding protein; (bz) activating an antitumor compound using a glutathione S-transferase; (ca) using a substituted phosphodiamine; Cb) using an inhibitor of MEKK protein kinase; (cd) using a COX-2 inhibitor; (ce) using cimetidine and a cysteine derivative; (cf) using an anti-IL-6 receptor antibody; Use an antioxidant; (ch) use a tubulin-polymerized isoxazole inhibitor; (ci) use a PARP inhibitor; (cj) use an aurora protein kinase inhibitor; (ck) use a binding to the prostate special a peptide of a membrane antigen; (cl) a CD19 binder; (cm) a benzenediazonium salt; (cn) a terpenoid receptor (TLR) agonist; (co) a bridged bicyclic sulfonamide (cp) using an inhibitor of epidermal growth factor receptor kinase; (cq) using a T2 family of ribonuclease having actin-binding activity; (cr) using terpene benzoic acid or an analogue thereof; (cs) Using a cyclin-dependent kinase inhibitor; (ct) using an inhibitor of interaction between p53 and MDM2; (cu) using an inhibitor of the receptor tyrosine kinase MET; (cv) using Gozodazole or ragozol analog; (cw) using an inhibitor of AKT protein kinase; (cx) using 2'-fluoro-5-methyl-β-L-arabinofuranosyl uridine or L-deoxy Thymidine; (cy) using an HSP90 modulator; (cz) using an inhibitor of JAK kinase; (da) using an inhibitor of PDK1 protein kinase; (db) using a PDE4 inhibitor; (de) using an inhibitor of the proto-oncogene c-Met tyrosine kinase; (df) using a guanamine 2,3-dioxo Inhibitor of synthase; (dg) an agent that inhibits the expression of ATDC (TRIM29); (dh) a protein-like inhibitor that uses the interaction of a nuclear receptor and a co-activated peptide; (di) antagonism using a XIAP family protein (d) using tumor-targeting superantigen; (dk) using an inhibitor of Pim kinase; (dl) using an inhibitor of CHK1 or CHK2 kinase; (dm) using an inhibitor of angiopoietin protein 4; (dn) Use Smo antagonists; (do) use nicotinic acetylcholine receptor antagonist; (dp) use farnesyl protein transferase inhibitor; (dq) use adenosine A3 receptor antagonist; (dr) use a cancer vaccine; (ds) a JAK2 inhibitor; and (dt) a Src inhibitor.

These concomitants, in addition to the monoalkylated hexitol derivative, are linked to the same BH3 analog as described above.

Further, as described further below, the monoalkylated hexitol derivative can be used together with an agent which modulates the expression of the AHI1 gene or modulates the activity of the AHI1 protein.

Positional isomerase inhibitors include, but are not limited to, irinotecan, topotecan, camptothecin, lamellarin D, amsacrine, itopride, y Topiramate phosphate, teniposide, doxorubicin and 4-[2-(3,5-dioxo-1-piperazinyl)-1-methylpropyl]piperazine-2, 6-diketone (ICRF-193).

Pseudonucleosides include, but are not limited to, cytarabine, gemcitabine, and fludarabine; other pseudonucleosides are known in the art.

Pseudonucleotides include, but are not limited to, tenofovir fumarate and adefovir dipivoxil (adefovir dipivoxil); other pseudonucleotides are known in the art.

Thymidine synthetase inhibitors include, but are not limited to, raltitrexed, pemetrexed, nolatrexed, ZD9331, GS7094L, fluorouracil, and BGC 945.

Signal delivery inhibitors are described in AVLee et al., "New Mechanisms of Signal Delivery Inhibitors: Downregulation of Receptor Tyrosine Kinases and Blockade of Signal Transactivation", Clin. Cancer Res. 9: 516s ( 2003) and include it as a whole by reference.

Alkylating agents include, but are not limited to, Shionogi 254-S, amphoteric amine analogs, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine, Bella Bstrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, ethyl phenylpyrimidine-139 (Chinoin-139) , ethyl phenylpyrimidinetrione-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) ₂ , diphenyl sirolimus, diplatin cell inhibitor, Erba mitomycin derivative, Chugai DWA-2114R, ITI E09, ermustine, Erbamont FCE-24517, female Estramustine phosphate sodium, fotemustine, Unimed G-6-M, ethyl phenylpyrimidinetrione GYKI-17230, hepsul-fam, ifosfamide, isopropylplatinum Iproplatin), lomustine, maloamine, melphalan, mitolactol, Nippon Kayaku N K-121, NCI NSC-264395, NCI NSC-342215, Platinum oxalate, Upjohn PCNU, Prednistatin, anterior cell PTT-119, ramustine, semustine, SmithKline SK&F -101772, Yakult Honsha SN-22, sultromastine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol , as described in U.S. Patent No. 7,446,122, the disclosure of which is incorporated herein by reference.

Anti-tubulin agents include, but are not limited to, vinca alkaloids, taxanes, podophyllotoxin, halichondrin B, and homoohichondrin B.

Antimetabolites include, but are not limited to, amine methyl folate, pemetrexed, 5-fluoro Uracil, capecitabine, arabinosylcytosine, gemcitabine, 6-thiol oxime, pentostatin, alanosine, AG2037 (Pfizer), 5-FU-protein Original (5-FU-fibrinogen), acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl Cytosine, arabinose cytosine phosphonate stearate, arabinose cytosine conjugate, Lilly DATHF, Merrill-Dow DDFC, deazaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, deoxyfluorouridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, fluorouridine, fludarabine phosphate, N-(2'-furyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolazine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, amine methyl folate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC -612567, Warner-Lambert PALA, piritrexim, plicamycin, Asahi Chem Ical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitor, tyrosine protein kinase inhibitor, Taiho UFT And you are born (uricytin).

Berberine has antibacterial activity and prevents and inhibits the expression of pro-inflammatory cytokines and E-selectin, while increasing the performance of adiponectin.

Apigenin is a flavonoid that reverses the counter-effect of cyclosporine and has chemical protective activity, either alone or in combination with sugar.

Colchicine is a tricyclic alkaloid that exerts its activity by being linked to the protein tubulin. Analogs of colchicine include, but are not limited to, colchicine, N -desyltin, colchicine, dedecolcolcine, N -ethylidene iodine colchicol, trimethyl colchicine Acid (trimethylcolchicinie acid, TMCA) methyl ether, N -acetyl colchicol, TMCA ethyl ether, isocolchicine, isocolchicine, iso-TMCA methyl ether, original colchiceine, TMCA, N -benzylhydrazine TMCA, colchicosamide, colchicine, colchicolin and colchinoic acid (MHZweig and CFChignell, "some colchicine analogues, vinblastine sulfate and rat brain "Interaction of podophyllotoxin in tubulin", Biochem. Pharmacol. 22: 2141-2150 (1973) and B. Yang et al., "Synthesis and biological evaluation of cyclic C-modified colchicine analogues", Bioorg. Med. Chem. Lett. 20: 3831-3833 (2010)), both of which are included by reference.

Genistein is an isoflavone whose chemical name is 5,7-dihydroxy-3-(4-hydroxyphenyl) ketone-4-one. Genistein has many biological activities, including activation of PPARs, inhibition of several tyrosine kinases, inhibition of positional isomerases, antioxidant activity, activation of Nrf2 antioxidant responses, activation of estrogen receptor-beta, and lactation Inhibition of the animal hexose transporter GLUT2.

Itopride is a primary anti-cancer agent that acts primarily as a positional isomerase II inhibitor. Itopex forms a ternary complex of DNA and the positional isomerase II enzyme, preventing re-engagement of the DNA strand, and thus inducing DNA strand breakage and promoting apoptosis of the cancer cell.

Arabinosylcytosine is a nucleoside analog that replaces ribose with arabinose. It can be part of DNA and also inhibits both DNA and RNA polymerase and nucleotide reductase. It is particularly useful in acute myeloid leukemia and acute lymphocytic leukemia.

Camptothecins include camptothecin, homocamptothecin, topotecan, irinotecan, DB 67, BNP 1350, exatecan, lurototecan, ST 1481 and CKD 602. In cancer cells, these compounds act as positional isomerase I inhibitors and prevent DNA synthesis.

Vinca alkaloids include vinblastine, vincristine, vindesine, and vinorelbine.

Positional isomerase inhibitors include positional isomerase I inhibitors as well as positional isomerase II inhibitors. The position isomerase I inhibitor comprises the camptothecins and flavonoid D. The position isomerase II inhibitor comprises, in addition to the naphthophene and its derivatives and analogs, it contains idopride, tenipocil, doxorubicin, daunorubicin, bishydroxyindole , anthraquinone, ellipticines and gold tricarboxylic acid. Many plant-derived naturally occurring phenolic compounds, such as genistein, quercetin and resveratrol, exhibit inhibitory activities towards positional isomerase I and positional isomerase II.

5-fluorouracil is a one-base analog that acts as a thymidine synthase inhibitor, thereby inhibiting DNA synthesis. When deprived of sufficient thymidine, the cancer cells die rapidly by a program called thymine starvation.

Curcumin is considered to have anti-tumor, anti-inflammatory properties, antioxidants, anti-ischemic properties, anti-arthritic properties and anti-amyloid properties, and also has hepatoprotective activity.

NF-κB inhibitors include, but are not limited to, bortezomib.

Rosmarinic acid is a naturally occurring phenolic antioxidant that also has anti-inflammatory activity.

Propionin is an inhibitor of polyamine biosynthesis by competitive inhibition of S -adenosylmethionine decarboxylase.

Isomerization is activated via several possible novel mechanisms of action. It has a cell cycle-specific effect, including blockade of G(O)/G1 blockage by AML cell lines and G2/M due to HT-29 colorectal cell lines. It also stimulates apoptosis through a number of mechanisms, including upregulation of p21 and p27 and downregulation of Bcl-2 in primary AML cells, and upregulation of Bak and Bax in AML cells (DKO is not sensitive to chemotherapy), And a novel apoptosis-dependent pathway in K562 cells. Hyperthyroidism also has an effect on the granulosa, but does not alter the expression of Bcl-2, Bax and Bid proteins. Methionin also stimulates the cleavage of pro-apoptotic proteases 3, 8, 9 and PARP in HL-60 bone marrow cells. Hyperthyroidism is also targeted to multiple cellular targets, which may be synergistic and complementary. For example, it promotes the differentiation of human myeloid leukemia cells with a diminished regulation of c-myb gene expression. In W256 cells, microtubule assembly, glycogen synthase kinase-3 beta (GSK-3 β ) (at 5-50 nM), CDK1/cyclin B, and CDK5/p25 (tau tubulin phosphorylation), It also promotes inhibition of DNA and RNA synthesis. In addition, hyperthyroidism reduces β -catenin and c-myc (HL-60 cells, but not in K562), inhibits Wnt pathway by inhibiting GSK-3 β , and down-regulates β -catenin and c-myc protein expression. . Methionin also promotes upregulation of CD11b, promotes bone marrow differentiation, and upregulates Ahi-1 (causing phosphorylation of c-Myb) in Jurkat cells. In addition, formazan showed an angiogenic effect including reduction of VEGF protection, VCAM-1, tubule preparation in HUVEC, and apoptosis of ECV304 cells.

Imatinib is an inhibitor of the receptor tyrosine kinase enzyme ABL and is used to treat chronic myelogenous leukemia, gastrointestinal stromal tumors and other highly proliferative diseases.

Dasatinib is an inhibitor of the BCR/ABL and Src family of tyrosine kinases and is used to treat chronic myeloid leukemia and acute lymphocytic leukemia.

Nilotinib is another tyrosine approved for the treatment of chronic myelogenous leukemia Acid kinase inhibitors that inhibit the kinases BCR/ABL, KIT, LCK, EPHA3, and many other kinases. The use of nilotinib is described in US Patent Application Publication No. 2011/0028422 by Aloyz et al., which is incorporated herein by reference.

Epigenetic modulators include polyamine-based epigenetic regulators, such as polyamines A regulator of basal epigenetics, described in SK Sharma et al., "Modulators of Polyamine Small Molecular Epigenetics," Med. Chem. Commun. 3: 14-21 (2012), and described in LGWang & JW Chiao, "Chemical prophylactic activity of prostate cancer through epigenetic regulation of phenethyl isothiocyanate (Review)", Int. J. Oncol. 37: 533-539 (2010), Both are included by reference.

The transcription factor inhibitor comprises 1-(4-hexaphenyl)-2-propan-1-one, 3-fluoro-4-[[2-hydroxy-2-(5,5,8,8-tetramethyl) -5,6,7,8,-tetrahydro-2-naphthyl)ethinyl]amino]-benzoic acid (BMS 961), 4-[5-[8-(1-methylethyl)- 4-phenyl-2-quinolinyl]-1 H -pyrrolo-2-benzoic acid (ER-50891), 7-vinyl-2-(3-fluoro-4-hydroxyphenyl)-5- Benzooxazolone (ERB 041), as well as other compounds. Transcription factor inhibitors are described in T. Berg, "Inhibition of Transcription Factors with Small Organic Molecules", Curr. Opin. Chem. Biol. 12: 464-471 (2008), and are incorporated by reference.

Tetrandrine has a chemical structure of 6,6',7,12-tetramethoxy-2,2'-dimethyl- 1β- berbaman, and it has anti-inflammatory, immune and anti-allergic effects. A calcium channel blocker similar to quinidine for antiarrhythmic effects. It has been isolated from powder defense and other Asian herbs.

The VEGF inhibitor contains bevacizumab (cancer), which is for VEGF a monoclonal antibody; itraconazole; and suramin; and batimastat and marimastat, which are matrix metalloproteinase inhibitors, and cannabinoids and their derivatives .

Cancer vaccines are under development. Usually, the pair occurs in cancer cells (not happening in A normal protein) of a protein or multiple proteins, the cancer vaccine is based on an immune response. The cancer vaccine includes a vaccine for metastatic hormone-refractory prostate cancer, a tumor phage for kidney cancer, CimaVax-EGF for lung cancer, MOBILAN, and cancer for expression (for example, breast cancer, colon cancer, bladder cancer, and ovarian cancer). Neuvenge of Her2/neu, Stimuvax for breast cancer, And others. Cancer vaccines are described in S. Pejawar-Gaddy and O. Finn, "Cancer Vaccines: Achievements and Challenges", Crit. Rev. Oncol. Hematol. 67: 93-102 (2008), and are incorporated by reference.

The use of methylglyoxal bis-indenyl hydrazine in cancer therapy has been described in D.D. Von Hoff, "MGBG: Teaching a New Use of Old Drugs", Ann. Oncol. 5:487-493 (1994), and including it by reference.

Use of Rho kinase inhibitors, such as (R)-(+)-N-(4-pyridyl)-4-(1-amine B Benzomethamine, diuretic acid, 4-[2(2,3,4,5,6-pentafluorophenyl)propenyl]cinnamic acid, (+)-trans-4-(1-amine Ethyl)-1-(4-pyridylaminecarbamimidyl)cyclohexane, (+)-10 trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4- (1-Aminoethyl)cyclohexanecarboxamide, and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-amine Ethyl)benzamide is described in U.S. Patent No. 6,930,115, the disclosure of which is incorporated herein by reference.

Use of 1,2,4-benzotriazine oxides, for example: 3-hydroxy-1,2,4-benzotriazine 1,4-dioxide, 3-amino-7-trifluoromethyl-1,2,4-benzotriazine 1-oxide, 3-amino-7-aminecarbamyl-1, 2,4-benzotriazine 1-oxide, 7-acetamido-3-amino-1,2,4-benzotriazine 1-oxime, 3-amino-6(7)fluorenyl -1,2,4-benzotriazine 1,4-dioxide, 1,2,4-benzotriazine dioxide, 7-chloro-3-hydroxy-1,2,4-benzo Triazine 1,4-dioxide, 7-nitro-3-amino-1,2,4-benzotriazine 1,4-dioxide, 3-(3-N,N-diethylamine Propylamino)-1,2,4-benzotriazine 1,4-dioxide, 7-nitro-3-(2-N,N-diethylaminoethylamino)-1,2, 4-benzotriazine 1,4-dioxide, 7-allyloxy-1,2,4-benzotriazine 1,4-dioxide, 7-(3-N-ethylethyl hydrazine Amino-2-ethyloxypropoxy) 1,2,4-benzotriazine 1,4-dioxide, 7-nitro-1,2,4-benzotriazine 1,4- Dioxide. 3-propyl-1,2,4-benzotriazine 1,4-dioxide, and 3-(1-hydroxyethyl)-1,2,4-benzotriazine 1, 4-Dioxide, as described in U.S. Patent No. 6,277,835, the disclosure of which is incorporated herein by reference.

The use of alkyl glycerol is described in U.S. Patent No. 6,121,245, the disclosure of which is incorporated herein by reference.

The use of an inhibitor of the Mer, Ax1 or Tyro-3 receptor tyrosine kinase is described in U.S. Patent Application Publication No. 2012/0230991, the disclosure of which is incorporated herein by reference. These inhibitors may be antibodies, including monoclonal antibodies or fusion proteins.

The use of inhibitors of ATR kinase is described in the United States by Charrier et al. Patent Application Publication No. 2012/0177748, which is incorporated herein by reference. Inhibitors of these ATR kinases are substituted pyridine compounds such as 2-amino-N-phenyl-5-(3-pyridyl)pyridine-3-carboxamide, 5-(4-(methylsulfonyl) Phenyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine, and 5-(1-ethanesulfonyl-3,6-dihydro- 2H-Pyridin-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine.

Regulate one or more Fms kinases, Kit kinases, MAP4K4 kinase, TrkA The use of a compound which is active by kinase or TrkB kinase is described in U.S. Patent Application Publication No. 2012/0165329, the disclosure of which is incorporated herein by reference. These compounds contain (6-methoxy-pyridin-3-ylmethyl)[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyrimidin-2-yl]-amine ,(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyrimidine-2- y]-amine, and (5-fluoro-6-methoxy-pyridin-3-ylmethyl)-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl) -pyrimidin-2-yl]-amine. Compounds that inhibit Trk kinase, particularly TrkA, are described in U.S. Patent Application Publication No. 2011/0301133, the disclosure of which is incorporated herein by reference.

The use of hamoxifen is described in the US Patent Application by Ahmad et al. Open No. 2012/0164075 and include it by reference.

The use of an mTOR inhibitor is described in US Patent by Burke et al. Application No. 2012/0129881 is incorporated by reference. Suitable mTOR inhibitors include, but are not limited to, 40-O-(2-hydroxyethyl) rapamycin. These mTOR inhibitors can be used with Raf kinase inhibitors, as described in U.S. Patent Application Publication No. 2011/0301184, the disclosure of which is incorporated herein by reference. Raf kinase inhibitors are also described in U.S. Patent Application Publication No. 2010/0286178, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in 3-[5-(2-Methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-decylamine, propane-1- Sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-decylamine, propane-1-sulfonic acid [3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-nonylamine, N-[3-(5-cyano- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide, N-[3-(5 -Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-benzene 3-fluoro-benzenesulfonamide, pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4 -difluoro-phenyl]-decylamine, and N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl) -2,4-difluoro-phenyl]-guanamine. In malignant cells, these mTOR inhibitors can also be used with compounds that increase the level of pAkt, as described in U.S. Patent Application Publication No. 2009/0274698, the disclosure of which is incorporated herein by reference. Many compounds that increase pAkt levels are described, including chemotherapeutic agents, analogs of rapamycin, and other agents. The use of mTOR inhibitors is also described in U.S. Patent No. 8,268,819, the disclosure of which is incorporated herein by reference.

A nkla kinase, Mnk1b kinase, Mnk2a kinase or Mnk2b kinase The use of inhibitors is described in U.S. Patent Application Publication No. 2012/0128686, the disclosure of which is incorporated herein by reference. These compounds contain thiazolidin. Additional thienopyrimidine inhibitors of one or more of these kinases are described in U.S. Patent Application Publication No. 2011/0212103 by Heckel et al., and the disclosure of U.S. Patent Application Publication No. 2011/0212102 by Lehmann-Lintz et al. No. Both are included by reference.

The use of a modulator of M2 pyruvate kinase is described in U.S. Patent Application Publication No. 2012/0122885, the disclosure of which is incorporated herein by reference. Suitable modulators of M2 pyruvate kinase include, but are not limited to, 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(3,5-dimethylphenyl)- 1H-imidazole-5-sulfonamide, 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(5-methoxyphenyl)-1H-imidazole-5-sulfonamide And N-(4-methoxyphenyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-H-imidazole-5-sulfonamide.

The use of a modulator of inositol monophosphate 3 kinase is described in US Patent Application Publication No. 2012/0122838 by Ren et al., which is incorporated herein by reference. Inhibitors of the phosphoinositide 3 kinase are also described in U.S. Patent Application Publication No. 2010/0209420, the disclosure of which is incorporated herein by reference in its entirety in its entirety in 2009/0209340, and is incorporated by reference; these inhibitors contain pyridopyrimidinones. The inhibitor of phosphoinositide 3 kinase is also described in U.S. Patent No. 8,242,104 to Blaquiere et al. Internal; these inhibitors contain oxyzazepine. Inhibitors of phosphoinositide 3 kinase are also described in Ren et al., U.S. Patent No. 8,193,182; these inhibitors comprise isoquinoline-1(2H)-ketones. Inhibitors of the phosphoinositide 3 kinase are also described in U.S. Patent No. 7,928,428, the disclosure of which is incorporated herein by reference.

The use of a half-cysteine protease inhibitor is described in US Patent Application Publication No. 2012/0114765 by Cao et al., which is incorporated herein by reference. Suitable cysteine protease inhibitors include, but are not limited to, 1-[5-(2,4-dichlorophenylsulfonyl)-4-nitro-2-thienyl]ethanone, 1-[5- (2,4-difluorophenylsulfonyl)-4-nitro-2-thienyl]ethanone, and 1-{4-nitro-5-[2-(trifluoromethyl)benzene Sulfosyl]-2-thienyl} ethyl ketone.

The use of phenformin is described in U.S. Patent Application Publication No. 2012/0114676, the disclosure of which is incorporated herein by reference.

The use of the Sindbis virus vector is described in US Patent Application Publication No. 2011/0318430 to Meruelo et al., which is incorporated herein by reference. These vectors are capable of binding to higher levels of parenchymal tumors that exhibit high affinity lamelin receptors.

The use of a peptidomimetic which acts as an analog of Smac and inhibits IAPs and promotes apoptosis is described in US Patent Application Publication No. 2011/0305777, the disclosure of which is incorporated herein by reference.

The use of a nuclear transfer modulator, particularly an inhibitor of Crm1, is described in U.S. Patent Application Publication No. 2011/0275607, the disclosure of which is incorporated herein by reference. These inhibitors of Crm1 include, but are not limited to, (Z)-3-[3-(3-chlorophenyl)[1,2,4]-triazol-1-yl]-ethyl acrylate, (E)- 3-[3-(3-Chlorophenyl)[1,2,4]-triazol-1-yl]-ethyl acrylate, (Z)-3-[3-(3-chlorophenyl)- [1,2,4]-triazol-1-yl]-isopropyl acrylate, (E)-3-[3-(3-chlorophenyl)-[1,2,4]-triazole-1 -yl]-isopropyl acrylate, (Z)-3-[3-(3-chlorophenyl)-[1,2,4]-triazol-1-yl] -t -butyl acrylate, ( Z)-3-[3-(3-chlorophenyl)-[1,2,4]-triazol-1-yl] -t -butyl acrylate, (E)-3-[3-(3 -Chlorophenyl)-[1,2,4]-triazol-1-yl]-N-phenyl-propenylamine, (E)-N-(2-chlorophenyl)-3-[3- (3-chlorophenyl)-[1,2,4]-triazol-1-yl]-propenylamine, (4-{(E)-3-[3-(3-chlorophenyl)[1 , 2,4]-triazol-1-yl]-acrylamido}-phenyl-)-carbamic acid t -butyl ester, (E)-3-[3-(3-chlorophenyl)- [1,2,4]-triazol-1-yl]-N-(4-methoxyphenyl)-propenylamine, (E)-3-[3-(3-chlorophenyl)-[1 , 2,4]-triazol-1-yl]-N-methyl-N-phenyl-propenylamine, and (E)-N-(4-aminophenyl)-3-[3-(3 -Chlorophenyl)-[1,2,4]-triazol-1-yl]-propenylamine.

The use of a tyrosine kinase inhibitor is described in US Patent Application Publication No. 2011/0206661, which is directed to a trimethoxyphenyl inhibitor of tyrosine kinase and is described in U.S. Patent Application Publication No. 2011/0195066, which is directed to a quinoline inhibitor of tyrosine kinase, both of which are included by reference. The use of a tyrosine kinase inhibitor is also described in U.S. Patent Application Publication No. 2011/053, 968, the disclosure of which is incorporated herein by reference. The use of tyrosine kinase inhibitors is also described in U.S. Patent Application Publication No. 2010/0291025, which is incorporated herein by reference, which is assigned to the s the The use of a tyrosine kinase inhibitor is also described in U. The classes of compounds also inhibit mTOR and adiponectases (such as modulators of phosphoinositide 3 kinase). The use of tyrosine kinase inhibitors is also described in U.S. Patent No. 8,242,270 to Lajeunesse et al., which is incorporated by reference; these tyrosine kinase inhibitors are 2-aminothiazole-5-arylcarboxylates Amines.

The use of an acidic neural glutaminase inhibitor and a choline kinase inhibitor is described in U.S. Patent Application Publication No. 2011/0256241, the disclosure of which is incorporated herein by reference.

The use of anti-CS1 antibodies is described in U.S. Patent Application Publication No. 2011/0165154, the disclosure of which is incorporated herein by reference.

The use of protein kinase CK2 inhibitors is described in U.S. Patent Application Publication No. 2011/0152240, which is incorporated herein by reference. These protein kinase CK2 inhibitors comprise pyrazolopyrimidines. Additional protein kinase CK2 inhibitors, including tricyclic compounds, are described in U.S. Patent Application Publication No. 2011/0071136, the disclosure of which is incorporated herein by reference in its entirety by reference in its entirety in Kinase or other kinase. Additional protein kinase CK2 inhibitors, including heterocyclic substituted indoleamines, which are also described in U.S. Patent Application Publication No. 2011/0071115, to Haddach et al. Agent It can also inhibit Pim kinase or other kinases.

The use of an anti-guanylate cyclase C (GCC) antibody is described in U.S. Patent Application Publication No. 2011/0110936, the disclosure of which is incorporated herein by reference.

The use of a histone deacetylase inhibitor is described in U.S. Patent Application Publication No. 2011/0105474 by the name of the entire disclosure of the entire disclosure of the entire disclosure. These histone deacetylase inhibitors include, but are not limited to, (E)-N-hydroxy-3-{4-[(E)-3-(4-methyl-piperazin-1-yl)-3-oxo -propenyl]-phenyl}-propenylamine, (E)-N-hydroxy-3-{3-[(E)-3-(4-methyl-piperazin-1-yl)-3- Oxy-propenyl]-phenyl}-propenylamine, (E)-N-hydroxy-3-{3-[(E)-3-oxy-3-(4-phenyl-piperazine-1 -yl)-propenyl]-phenyl}-propenylamine, (E)-3-[3-((E)-3-[1,4']dipiperidinyl-1'-yl-3- Oxy-propenyl)-phenyl]-N-hydroxy-propenylamine, (E)-N-hydroxy-3-{3-[(E)-3-oxy-3-(cis-3,4 ,5-trimethyl-piperazin-1-yl)-propenyl]-phenyl}-propenylamine, (E)-3-{3-[(E)-3-((1S,4S)- 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-oxy-propenyl]-phenyl}-N-hydroxy-propenylamine, (E)- N-hydroxy-3-{4-[(E)-3-oxy-3-(4-phenyl-piperazin-1-yl)-propenyl]-phenyl}-propenylamine, (E) -3-[4-((E)-3-[1,4']dipiperidinyl-1'-yl-3-oxy-propenyl)-phenyl]-N-hydroxy-propenylamine, (E)-N-hydroxy-3-{4-[(E)-3-oxy-3-(cis-3,4,5-trimethyl-piperazin-1-yl)-propenyl]- Phenyl}-propenylamine, (E)-N-hydroxy-3-{4-[(E)-3-oxy-3-((1S,4S)-5-methyl-2,5 -diazo-bicyclo[2.2.1]hept-2-yl)-propenyl]-phenyl}-propenylamine, (E)-N-hydroxy-3-{5-[(E)-3-oxo 3-(4-phenyl-piperazin-1-yl)-propenyl]-pyridin-2-yl}-propenylamine, (E)-N-hydroxy-3-{5-[(E) -3-(4-methyl-piperazin-1-yl)-3-oxy-propenyl]-pyridin-2-yl}-propenylamine, (E)-N-hydroxy-3-{6- [(E)-3-Oxo-3-(4-phenyl-piperazin-1-yl)-propenyl]-pyridin-2-yl}-propenylamine, (E)-N-hydroxy-3 -{6-[(E)-3-(4-Methyl-piperazin-1-yl)-3-oxy-propenyl]-pyridin-2-yl}-propenylamine, (E)-3 -(6-{(E)-3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propenyl}-pyridin-2-yl)-N- Hydroxy-acrylamide, (E)-3-{6-[(E)-3-(4-benzylindolyl-piperazin-1-yl)-3-oxy-propenyl]-pyridine-2- }---hydroxy-propenylamine hydrochloride, (E)-3-(6-{(E)-3-[4-(2-chloro-phenyl)-piperazin-1-yl] -3-oxy-propenyl}-pyridin-2-yl)-N-hydroxy-propenylamine hydrochloride, (E)-N-hydroxy-3-{6-[(E)-3-oxy 3-(4-phenyl-piperidin-1-yl)-propenyl]-pyridin-2-yl}-acrylamide hydrochloride, (E)-N-hydroxy-3-{6-[( E)-3-oxo-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propenyl]-pyridin-2-yl}- Acrylamide Hydrochloride, (E)-3-(6-{(E)-3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-3-oxy-propene Base Pyridin-2-yl)-N-hydroxy-propenylamine hydrochloride, and (E)-3-{6-[(E)-3-(4-benzyl-piperazin-1-yl)-3 -oxy-propenyl]-pyridin-2-yl}-N-hydroxy-acrylamide hydrochloride. Additional histone deacetylase inhibitors, including spirocyclic derivatives, are described in U.S. Patent Application Publication No. 2011/039840, the disclosure of which is incorporated herein by reference. Precursors of histone deacetylase inhibitors are described in U.S. Patent No. 8,227,636, the disclosure of which is incorporated herein by reference. The histone deacetylase inhibitor is described in U.S. Patent No. 8,222,451 to Kozikowski et al., which is incorporated herein by reference. A histone deacetylase inhibitor, comprising a disubstituted aniline compound, is also described in U.S. Patent No. 8,119,685, the disclosure of which is incorporated herein by reference. A histone deacetylase inhibitor, comprising an aryl-fused spiro compound, is also described in U.S. Patent No. 8,119,852, the disclosure of which is incorporated herein by reference.

The use of cannabinoids is disclosed in U.S. Patent Application Publication No. 2011/0086113, the disclosure of which is incorporated herein by reference. Suitable cannabinoids include, but are not limited to, tetrahydrocannabinol and cannabidiol.

The use of a glycoside-like peptide (GLP-1) receptor agonist is described in U.S. Patent Application Publication No. 2011/0046071, the disclosure of which is incorporated herein by reference. A suitable GLP-1 receptor agonist is exendin-4.

The use of an inhibitor of the anti-apoptotic protein Bcl-2 or Bcl-xL is described in US Patent Application Publication No. 2011/0021440, the disclosure of which is incorporated herein by reference.

The use of the Stat3 pathway inhibitor is described in U.S. Patent Application Publication No. 2010/0310503, the disclosure of which is incorporated herein by reference. These Stat3 pathway inhibitors include, but are not limited to, 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-dione, 2-ethylindolyl-7-chloro-naphtho [2,3-b]furan-4,9-dione, 2-ethylindol-7-fluoro-naphtho[2,3-b]furan-4,9-dione, 2-ethyl oxime value Naphtho[2,3-b]furan-4,9-dione, and 2-ethyl-naphtho[2,3-b]furan-4,9-dione.

The use of inhibitors of polo-like kinase (Plk1) is described in U.S. Patent Application Publication No. 2010/0278833, the disclosure of which is incorporated herein by reference. These inhibitors include, but are not limited to, thiophene-imidazopyridine, which contains 5-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[ 2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxyindole Amine, 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, 1- (5-Aminomethylindol-4-{[2-(trifluoromethyl)benzyl)oxy}-2-thienyl)-N-(2-methoxyethyl)-1H-imidazole [4,5-c]pyridine-6-carboxyguanamine, 1-(5-aminocarbamimid-4-{[2-(trifluoromethyl)benzyl)oxy}-2-thienyl) -N-(2-morpholin-4-ylethyl)-1H-imidazo[4,5-c]pyridine-6-carboxamide, 5-{6-[diethylamino)methyl]- 1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, 5-{6- [(Cyclopropylamino)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene -2-carboxamide, 5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{ [2-(Trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, and 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridine-1 -yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, but the invention is not limited thereto.

The use of the GBPAR1 activator is described in U.S. Patent Application Publication No. 2010/0261758, which is incorporated herein by reference. These GBPAR1 activators include, but are not limited to, heterocyclic guanamines. These compounds include, but are not limited to, N-(3,5-dichlorophenyl)-3-methyl-N-naphthalen-2-ylmethyl-isonicotinamine, (3,5-dichlorophenyl) -N-(2-methoxybenzyl)-3-methyl-isonicotinamine, 3-methyl-N-phenyl-N-pyridin-3-ylmethyl-isonicotinamine, N-naphthalen-2-ylmethyl-1-oxy-N-phenyl-isonicotinamine decylamine, N-(3,5-dichlorophenyl)-3-methyl-N-(2-tri Fluoromethoxybenzyl)-isonicotinamide, 4-methyl-oxazole-5-carboxylic acid benzyl-phenylamine, N-benzyl-N-phenylisonicotinamine, N -benzyl-N- p -tolylisonicotinamide, N-benzyl-2-fluoro-N-phenylisonicotinamine, N-benzyl-3,5-dichloro-N- Phenyl-isonicotinamide, N-benzyl-2-chloro-N-phenyl-isonicotinamine, N-benzyl-2-chloro-6-methyl-N-phenyl- Isonicotinicinamide, N-benzyl-3-methyl-N-phenyl-isonicotinamine, N-benzyl-3-chloro-N-phenyl-isonicotinamine, N- Benzyl-2,5-dichloro-N-phenyl-isonicotinamide, N-benzyl-2-methyl-N-phenyl-isonicotinamine, N-benzyl-2-cyanide --N-phenyl-isonicotinamide, N-benzyl-N-phenethyl-isonicotinamine, N-benzyl-N-(2-fluoromethoxy-phenyl)- Isoniazid guanamine, and N-benzyl Base-N-(4-chlorophenyl)-isonicotinamine. Additional GBPAR1 activators are described in U.S. Patent Application Publication No. 2010/0048579, the disclosure of which is incorporated herein by reference.

The use of modulators of serine-synamic acid protein kinase and poly ADP ribose polymerase (PARP) activity is described in US Patent Application Publication No. 2009/0105233 by Chua et al., and is described in US patent by Drygin et al. Application No. 2010/0173013, both of which are incorporated by reference. The serine-synamic acid protein kinase may be, but not limited to, CK2, CK2 α2 , Pim-1, CDK1/cyclin B, c-RAF, Mer, MELK, DYRK2, Flt3, Flt3 (D835Y), Flt4, HIPK3, HIPK2 and ZIPK.

The use of a taxane is described in U.S. Patent Application Publication No. 2010/0166872, the disclosure of which is incorporated herein by reference. The taxane can be, but is not limited to, paclitaxel or docetaxel (docitaxel).

The use of inhibitors of dihydrofolate reductase is described in U.S. Patent Application Publication No. 2010/0150896, the disclosure of which is incorporated herein by reference. Inhibitors of these dihydrofolate reductases include, but are not limited to, diaminoquinazolines.

The use of inhibitors of aromatase is described in U.S. Patent Application Publication No. 2010/0111901, the disclosure of which is incorporated herein by reference. Inhibitors of these aromatics include, but are not limited to, triazoles.

The use of benzimidazolyl anticancer agents is described in U.S. Patent Application Publication No. 2010/009869, the entire disclosure of which is incorporated herein by reference. The benzimidazolyl anticancer agent may be, but not limited to, (E)-3-[1-(3-dimethylamino-2,2-dimethyl-propyl)-2-isopropyl-1H- Benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2-butyl-1-(3-dimethylamino-2,2-dimethyl-propyl) -1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-dimethylamino-2,2-dimethyl-propyl)-2 -(2-methylsulfonyl-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-dimethylamino)- 2,2-Dimethyl-propyl)-2-ethoxymethyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3 -dimethylamino-2,2-dimethyl-propyl)-2-isobutyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[ 1-(2-diethylamino-ethyl)-2-isobutyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2-butyl 1-(2-diethylamino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2-but-3-ynyl- 1-(3-Dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2- But-3-enyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E ) -3-[2-but-3-enyl-1-(2-diethylamino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)- 3-[2-but-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxyl -Acetylamine, (E)-3-[1-(3-dimethylamino-2,2-dimethyl-propyl)-2-(3,3,3-trifluoro-propyl -1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)-2-(3,3,3 -trifluoro-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)-2 -ethoxymethyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-dimethylamino-2,2-dimethyl -propyl)-2-methyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)- 2-(2,2-Dimethyl-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-N-hydroxy-3-[1-(3- Isopropylamino-propyl)-2-(3,3,3-trifluoro-propyl)-1-H-benzimidazol-5-yl]-propenylamine, (E)-3- [2-(2,2-Dimethyl-propyl)-1-(2-isopropylamino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-Diisopropylamino-ethyl)-2-(2,2-dimethyl-propyl)-1H-benzimidazol-5-yl]-N -hydroxy-propenylamine, (E)-3-[1-(2-diisopropylamino-ethyl)-2-isobutyl-1H-benzimidazol-5-yl]-N-hydroxyl - acrylamide, (E)-3-[1-(3-dimethyl -2,2-dimethyl-propyl)-2-hex-3-enyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1 -(3-dimethylamino-2,2-dimethyl-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzimidazol-5-yl]-N -hydroxy-propenylamine, (E)-3-[2-cyclohexyl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazol-5-yl ]-N-hydroxy-propenylamine, (E)-3-[2-bicyclo[2.2.1]hept-5-en-2-yl-1-(3-dimethylamino-2,2-di Methyl-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)-2-hexyl 3-alkenyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diisopropylamino-ethyl)-2- hex-3-enyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2-hex-3-enyl-1-(2-isopropyl) Amino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[2-hex-3-enyl-1-(3-isopropyl) Amino-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-ethylamino-ethyl)-2-hexyl- 3-alkenyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)-2-hexyl-1H -benzimidazol-5-yl]-N-hydroxy- Acrylamide, (E)-N-hydroxy-3-[1-(3-isopropylamino-propyl)-2-(2,4,4-trimethyl-pentyl)-1H-benzene And imidazol-5-yl]-propenylamine, (E)-3-[2-(2,2-dimethyl-propyl)-1-(3-isopropylamino-propyl)-1H -benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diisopropylamino-ethyl)-2-(3,3,3- Trifluoro-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, and (E)-N-hydroxy-3-[2-isobutyl-1-(2- Isopropylamino-ethyl)-1H-benzimidazol-5-yl]-propenylamine.

The use of O6-methylguanine-DNA-methyltransferase (MGMT) inhibitors is described in U.S. Patent Application Serial No. 2010/0093, the entire disclosure of which is incorporated herein by reference. Suitable MGMT inhibitors include, but are not limited to, O ⁶ -benzylguanine, O ⁶ --2-fluoropyridylmethylguanine, O ⁶ --3-iodobenzylguanine, O ⁶ --4-bromobenzene Bismuth, O ⁶ -5-iodophenylguanine O ⁶ -benzyl-8-oxoguanine, O ⁶ -( p -chlorobenzyl)guanine, O ⁶ -( p -methylbenzyl Guanine, O ⁶ -( p -bromobenzyl)guanine, O ⁶ -( p -isopropylbenzyl)guanine, O ⁶ -(3,5-dimethylbenzyl)guanine, O ⁶ -( p - n -butylbenzyl)guanine, O ⁶ -( p -hydroxymethylbenzyl)guanine, O ⁶ -benzylhypoxanthine, N ² -ethylindenyl-O ⁶ -benzylguanine, N ² -acetamido-O ⁶ -benzyl-8-oxy-guanine, 2-amino-6-( p -methyl-benzyl-thio)anthracene, 2- Amino-6-(benzyloxy)-9-[(ethoxycarbonyl)methyl]anthracene, 2-amino-6-(benzyloxy)-9-(neopentyloxymethyl)anthracene , 2-amino-6-(benzyl-thio)anthracene, O ⁶ -benzyl-7,8-dihydro-8-oxoguanine, 2,4,5-triamino-6-benzyl Oxypyrimidine, O ⁶ -benzyl-9-[(3-oxy-5 α -andostan-17β-yloxycarbonylmethyl]guanine, O ⁶ -benzyl-9-[(3- Oxy-4-androstane-17β-yloxycarbonyl ) Methyl (guanine, 8-amino -O ⁶ - -benzylguanine (8 -BG amine), 2,4 diamino-6-benzyloxy-5-nitropyrimidine, 2 4-diamino-6-benzyloxy-5-nitropyrimidine, and 2-amino-4-benzyloxy-5-nitropyrimidine.

The use of a CCR9 inhibitor is described in U.S. Patent Application Publication No. 2010/007596, the entire disclosure of which is incorporated herein by reference. These CCR9 inhibitors include, but are not limited to, benzylsulfonylhydrazine.

The use of an acid sphingomyelinase inhibitor is described in U.S. Patent Application Publication No. 2010/0022482, the disclosure of which is incorporated herein by reference. Typically, these compounds are biphenyl derivatives.

The use of the peptidomimetic macrocycles is described in U.S. Patent Application Publication No. 2009/0275519, the disclosure of which is incorporated herein by reference.

The use of cholinate amides is described in U.S. Patent Application Publication No. 2009/0258847, the disclosure of which is incorporated herein by reference. These cholinate aminations include, but are not limited to, substituted 4-(3-hydroxy-10,13-hydroxymethyl-hexadecahydro-cyclopenta(a)-phenanthrene-17-yl) valerate.

The use of substituted oxyphosphonazo rings is described in U.S. Patent Application Publication No. 2009/0202540, which is incorporated herein by reference. The oxynitride ring may be, but is not limited to In the case of isocyclic phosphoniumamine and cyclophosphamide.

The use of anti-TWEAK receptor antibodies is described in US Patent Application by Culp Please disclose No. 2009/0074762 and include it by reference. The TWEAK receptor is a member of the tumor necrosis factor receptor superfamily and, in many parenchymal tumors, is expressed on the surface of cancer cells.

The use of ErbB3 binding protein is described in US Patent by Zhang et al. Application No. 2008/0269133 is hereby incorporated by reference.

Use of a glutathione S-transferase activation (GST-activated) anti-tumor compound It is described in U.S. Patent Application Publication No. 2008/0166428, the disclosure of which is incorporated herein by reference. A preferred GST-activating antitumor compound is canfosfamide.

The use of substituted phosphodiamines is described in the US by Ma et al. U.S. Patent Application Publication No. 2008/0125398, which is incorporated herein by reference in its entirety, which is incorporated to Tetra-(2-chloroethyl)-phosphoramide, and is described in U.S. Patent Application Publication No. 2008/0125397, the disclosure of which is hereby incorporated by reference in Oxy-2-[(pyridin-3-ylmethyl)amino]ethyl}sulfonyl)ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphoramide . The use of substituted phosphodiamines is also described in U.S. Patent Application Publication No. 2008/0039429, the disclosure of which is incorporated herein by reference in Phosphine diamine.

The use of inhibitors of MEKK protein kinase is described by Sikorski et al. U.S. Patent Application Publication No. 2006/0100226, which is incorporated herein by reference. These inhibitors include, but are not limited to, 2-thiopyrimidinone such as 2-[3-(3,4-dichloro-benzylamino)-benzylsulfonyl]-4-(3-methoxy-benzene 6-oxy-1,6-dihydro-pyrimidine-5-carboxonitrile, 2-[3-(3,4-dichloro-benzylamino)-benzylsulfonyl]-4- (3,4-dimethoxy-phenyl)-6-oxy-1,6-dihydro-pyrimidine-5-carboxonitrile, and 2-[3-(3,4-dichloro-benzylamine) Benzylsulfonyl-4-(4-methoxy-3-thiophen-2-yl-phenyl)-6-oxy-1,6-dihydro-pyrimidine-5-carboxonitrile.

The use of COX-2 inhibitors is described in US Patent by Masferrer et al. Application No. 2004/0072889 is hereby incorporated by reference. Suitable COX-2 inhibitors include, but are not limited to, celecoxib, parecoxib, droxax, rofecoxib, ettoco Ford, valdecoxib and melocica.

The use of cimetidine and N-acetyl cysteine is described by Weidner U.S. Patent Application Publication No. 2003/0158118, which is incorporated herein by reference. Derivatives of cimetidine or N-acetyl cysteine can also be used.

The use of a primary anti-IL-6 receptor antibody is described in the United States by Nakamura et al. Patent Application Publication No. 2002/0131967, which is incorporated herein by reference. The antibody can be an anthropomorphic antibody.

The use of an antioxidant is described in U.S. Patent Application Publication No. 2001/0049349, the disclosure of which is incorporated herein by reference. Suitable antioxidants include, but are not limited to, pyrrolidine dithiocarbamic acid, pbucoco(4,4'-(isopropyliminodithio)bis(2,6-di- t -butylphenol) , vitamin C, vitamin E and 6-hydroxy-2,5,7,8-tetramethyl ketone-2-carboxylic acid.

The use of a tubulin-polymerized isoxazole inhibitor is described by Sun et al. It is described in U.S. Patent No. 8,269,017, which is incorporated herein by reference. Suitable tubulin-polymerized isoxazole inhibitors include, but are not limited to, 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isodine Zin-4-yl)-phenyl)acetamidine hydrochloride, 2-amino-3-hydroxy-N-(2-methoxy-5-[5-(3,4,5-trimethoxybenzene) Isooxazol-4-yl)-phenyl)propanamide hydrochloride, 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxybenzene) Isooxazol-4-yl)-phenyl)propanamide, 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)- Isoxazol-4-yl)-phenyl)-4-(methylthio)butanamine hydrochloride, 2-amino-N-(2-methoxy-5-[5-(3,4) ,5-trimethoxyphenyl)-isoxazol-4-yl)-phenyl)butanamine, 2-amino-N-(2-methoxy-5-[5-(3,4,5) -trimethoxyphenyl)-isoxazol-4-yl)-phenyl)-3-phenylpropanamide hydrochloride, 2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxyphenyl)-isoxazol-4-yl)-phenyl)-4-methylpentanylamine hydrochloride, 2-amino-N-(2-methoxy -5-[5-(3,4,5-Trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide hydrochloride , 1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylaminecarbamyl}-2-yl -propyl-ammonium chloride, 1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl]-phenylaminecarbamyl }-2-Methyl-butyl-ammonium chloride, 2-hydroxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazole-4 -yl]-phenylamine-mercapto}-propyl-ammonium chloride, 2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[5-(3,4,5 -trimethoxyphenyl)-isoxazol-4-yl]-phenylaminecarbamyl}-ethyl-ammonium chloride, C-{2- Methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl]-phenylaminecarbamyl}-C-phenyl-methyl-ammonium chloride , 2-(1H-indol-2-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl]- Phenylamine, mercapto}}-ethyl-ammonium chloride, 2-benzofuran-2-yl-1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl) )-isoxazol-4-yl]-phenylaminecarbamyl}-ethyl-ammonium chloride, 2-carboxy-1-{2-methoxy-5-[5-(3,4,5 -trimethoxyphenyl)-isoxazol-4-yl]-phenylaminecarbamyl}-ethyl-ammonium chloride, 3-carboxy-1-{2-methoxy-5-[5-( 3,4,5-trimethoxyphenyl)-isoxazol-4-yl]-phenylamine-methylhydrazino}-propyl-ammonium chloride, 3-aminoformamido-1-{2-methoxy 5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl]-phenylaminecarbamyl}-propyl-ammonium chloride, 2-aminocarbazinyl 1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl]-phenylamine-methylhydrazino}-ethyl-chlorination Ammonium, and 2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-isoxazol-4-yl] -Phenylaminemethanyl}-ethyl-ammonium chloride.

The use of pyridazinone PARP inhibitors is described in the United States by Branca et al. Patent No. 8,268,827, which is incorporated herein by reference. Pyridazinone PARP inhibitors include, but are not limited to, 6-{4-fluoro-3-[(3-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl 3--3-yl-2,3-dihydropyridazine-1-n-ion trifluoroacetate, 6-{3-[(4-cyclohexyl-3-oxopiperin-1-yl)carbonyl ]-4-fluorobenzyl}-4,5-dimethyl-3-oxy-2,3-dihydropyridazine-1-n-iontrifluoroacetate, 6-{3-[(4 -cyclopentyl-3-oxopiperin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one, 6-{4-fluoro Generation-3-[(3-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazine-3(2H)-one hydrochloride, 4- Ethyl-6-{4-fluoro-3-[(3-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}pyridazine-3(2H)-one trifluoroacetate ,6-{3-[(4-Cyclohexyl-3-oxopiperin-1-yl)carbonyl]-4-fluorobenzyl}-4-ethylpyridazine-3(2H)-one trifluoro Acetate, 3-{4-fluoro-3-[(4-methyl-3-oxopiperin-1-yl)carbonyl]benzyl}-4,5-dimethyl-6-oxy -1,6-dihydropyridazine-1-n-ion trifluoroacetate, 3-(4-fluoro-3-{[4-(4-fluorobenzyl)-3-oxopiperazine- 1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxy-1,6-dihydropyridazine-1-n-iontrifluoroacetate 6-(3-{[4-(2-Chlorophenyl)-3-oxopiperin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo Base-2,3-dihydropyridazine-1-n-ion trifluoroacetate, 6-(3-{[4-(3-chloro-4-fluorophenyl)-3-oxopiperazine -1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxy-2,3-dihydropyridazine-1-n-ion trifluoroacetate, and 6 -(3-{[4-(3,4-difluorophenyl)-3-oxopiperin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl- 3-oxy-2,3-dihydropyridazine-1-n-ion trifluoroacetate. Other PARP Inhibitors are described in U.S. Patent No. 8,143,447, the disclosure of which is incorporated herein by reference.

The use of aurora protein kinase inhibitors is described in U.S. Patent No. 8,268,811, the disclosure of which is incorporated herein by reference. The aurora protein kinase inhibitors include, but are not limited to, thiazoles and pyrazoles. The use of aurora protein kinase inhibitors is also described in U.S. Patent No. 8,129,399, the disclosure of which is incorporated herein by reference.

The use of a peptide (PSMA) that binds to a prostate specific membrane antigen is described in US Patent No. 8,258,256 to Denmeade et al., which is incorporated herein by reference.

The use of a CD19 binding agent is described in U.S. Patent No. 8,242,252, the disclosure of which is incorporated herein by reference. These CD19 binding agents include, but are not limited to, anti-CD19 antibodies.

The use of a benzenediazonium salt is described in U.S. Patent No. 8,242,109, the disclosure of which is incorporated herein by reference.

The use of a steroid agonist (TLR) agonist is described in U.S. Patent No. 8,242,106, the disclosure of which is incorporated herein by reference. Suitable TLR agonists include, but are not limited to, (1E,4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidin-1-carbonyl)phenyl)-3H-benzo [b] Azaindole-4-carboxyguanamine.

The use of a bridged bicyclic sulfonamide is described in U.S. Patent No. 8,242,103, issued to hereby incorporated by reference in its entirety herein in

The use of an inhibitor of epidermal growth factor receptor (EGFR) kinase is described in U.S. Patent No. 8,242,080 to Kuriyan et al. Typically, these inhibitors of EGFR kinase target an asymmetrically activated dimer interface.

The use of the ribonucleic acid of the T2 family with actin-binding activity is described in U.S. Patent No. 8,236,543, the disclosure of which is incorporated herein by reference. Typically, in an active or passive ribonucleic acid form, the ribonucleic acid binds to actin.

The use of terpene benzoic acid or its analogs is described in U.S. Patent No. 8,232,318, the disclosure of which is incorporated herein by reference.

Use of an inhibitor of a cyclin-dependent kinase by Shipps et al. It is described in U.S. Patent No. 8,227,605; these inhibitors include, but are not limited to, 2-aminothiazole-4-carboxyguanamine. The use of an inhibitor of a cyclin-dependent kinase is also described in US Patent No. 7,700,773 to Mallams et al., which is incorporated by reference; these inhibitors include but are not limited to pyrazolo[1,5- a] 4-cyano, 4-amino and 4-aminomethyl derivatives of pyridine, pyrazolo[1,5-c]pyrimidine and 2H-carbazole compounds, and imidazo[1,2-a] 5-Cyano, 5-amino and 5-aminomethyl derivatives of pyridine and imidazo[1,5-a]pyrazine compounds.

The use of an inhibitor of interaction between p53 and MDM2 through Wang It is described in U.S. Patent No. 8,222,288, the disclosure of which is incorporated herein by reference.

Use of an inhibitor of the receptor tyrosine kinase MET by Dinsmore et al It is described in U.S. Patent No. 8,222,269, incorporated herein by reference. Inhibitors of these receptor tyrosine kinases MET include, but are not limited to, 5H-benzo[4,5]cyclohepta[1,2-b]pyridine derivatives. Inhibitors of the receptor tyrosine kinase MET are also described in U.S. Patent No. 8,207,186, the disclosure of which is incorporated herein by reference. These compounds include, but are not limited to, benzocycloheptapyridine, which comprises a 5H-benzo[4,5]cyclohepta[1,2-b]pyridine derivative.

The use of ragorazole or ragozol analogs is described by Williams et al. U.S. Patent No. 8,217,076, incorporated herein by reference.

The use of the inhibitor of the protein kinase AKT is described by Furuyama et al. It is described in U.S. Patent No. 8,207,169, the disclosure of which is incorporated herein by reference in its entirety in the the the the the the the the the the the the the the the the 1,6] Pyrido[2,3-b]pyrazine.

2'-Fluoro-5-methyl-β-L-arabinose furanosyluridine or L-deoxythymidine The use of glucosides is described in U.S. Patent No. 8,207,143, the disclosure of which is incorporated herein by reference.

The use of compounds that modulate HSP90 activity is described by Ying et al. National Patent No. 8,188,075, which is incorporated herein by reference. These compounds include, but are not limited to, substituted triazoles, including 3-(2-hydroxyphenyl)-4-(naphthalen-1-yl)-5-thiol triazole, 3-(2,4-dihydroxybenzene 4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-thiol triazole, 3-(2,4-dihydroxyphenyl)-4-(2 -methyl-4-bromophenyl)-5-thiol triazole, 3-(3,4-dihydroxyphenyl)-4-(6-methoxy-naphthalene-1- 5-)thiol triazole, 3-(3,4-dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-thiol triazole, 3-(3 ,4-dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-thiol triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl) 4-(5-methoxy-naphthalen-1-yl)-5-thiol triazole, 3-(3,4-dihydroxyphenyl)-4-(6-isopropoxy-naphthalene-1 -yl)-5-thiol triazole, 3-(2,4-dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-thiol triazole, 3-(2, 4-dihydroxyphenyl)-4-(2-methyl-6-ethylphenyl)-5-thiol triazole, 3-(2,4-dihydroxyphenyl)-4-(2,6 -diisopropylphenyl)-5-thiol triazole, 3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-thiol Azole, and 3-(2,4-dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-thiol triazole.

The use of inhibitors of JAK kinase or PDK kinase is described by Guerin et al. It is described in U.S. Patent No. 8,183,245, which is incorporated herein by reference. The JAK kinase comprises JAK1, JAK2, JAK3 and TYK2. Suitable inhibitors of these classes of kinases include, but are not limited to, 5-(1-methyl-1H-pyrazol-4-yl)-3-(6-piperazin-1-ylpyrazin-2-yl)-1H -pyrrolo[2,3-b]pyridine, 5-(1-methyl-1H-pyrazol-4-yl)-3-[6-(piperidin-4-yloxy)pyrazine-2- -1H-pyrrolo[2,3-b]pyridine, 3-[6-(cyclohexyloxy)pyrazin-2-yl]-5-(1-methyl-1H-pyrazole-4- -1H-pyrrolo[2,3-b]pyridine, N-methyl-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3 -b]pyridin-3-yl]-N-piperidin-4-ylpyrazin-2-amine, 3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-5- (1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, 3-{6-[(3R)-piperidin-3-yloxy]pyrazin-2-yl} -5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, and 3-{6-[(3S)-piperidin-3-yloxy]pyrazine- 2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine.

Inhibition of phosphodiesterase type IV (PDE4) The use of the agent is described in U.S. Patent No. 8,158,672, the disclosure of which is incorporated herein by reference. The inhibitor of PDE4 comprises a fluoroalkoxy-substituted 1,3-dihydroisodecyl compound.

Use of an inhibitor of c-Met proto-oncogene receptor tyrosine kinase Zhuo et al. are described in U.S. Patent No. 8,143,251, incorporated herein by reference. These inhibitors include, but are not limited to, triazole triazines containing [1,2,4]triazolo[4,3-b][1,2,4]triazine. Inhibitors of the C-Met proto-oncogene receptor tyrosine kinase are also described in U.S. Patent No. 8,106,197, the disclosure of which is incorporated herein by reference.

The use of indoleamine 2,3-dioxygenase inhibitors is described by Combs et al. It is described in U.S. Patent No. 8,088,803, the disclosure of which is incorporated herein by reference.

Use of agents that inhibit ATDC (TRIM29) performance through Simeone et al. It is described in U.S. Patent No. 8,088,749, incorporated herein by reference. These agents comprise oligonucleotides that function via RNA interference.

The use of a protein-like inhibitor of the interaction of a nuclear receptor and a co-activated peptide is described in U.S. Patent No. 8,084,471, the disclosure of which is incorporated herein by reference. These inhibitors include, but are not limited to, 2,3',3 " -trisubstituted biphenyls.

The use of XIAP family protein antagonists is described by Chen et al. Japanese Patent No. 7,910,621, which is incorporated herein by reference. These antagonists include, but are not limited to, enbehenic acid.

The use of tumor-targeted superantigens is described in the US by Hedlund et al. No. 7,763,253, and is incorporated by reference.

The use of an inhibitor of Pim kinase is described in U.S. Patent No. 7,750,007, the disclosure of which is incorporated herein by reference. These inhibitors include, but are not limited to, imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine compounds.

The use of an inhibitor of CHK1 or CHK2 kinase is described in U.S. Patent No. 7,732,436, the disclosure of which is incorporated herein by reference. These inhibitors include, but are not limited to, indole hydrazine and its acid amine salts.

The use of an inhibitor of angiopoietin protein 4 is described in U.S. Patent No. 7,740,846, the disclosure of which is incorporated herein by reference. These inhibitors include, but are not limited to, antibodies, including monoclonal antibodies.

The use of an inhibitor of Smo is described in U.S. Patent No. 7,691,997, the disclosure of which is incorporated herein by reference. Smo (Smoothened) is a medium that is transmitted by the hedgehog signal. Suitable inhibitors include, but are not limited to, 5-(1,1-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H -1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole, 5-(3,3-difluorocyclobutyl )-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2] Oct-1-yl)-1,2,4-oxadiazole, 5-(1-fluoro) -1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl }Bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole, 2-(1,1-difluoroethyl)-5-(4-{4-methyl-5 -[2-(Trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxa Diazole, 2-(3,3-difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2 , 4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole, and 2-(1-fluoro-1-methylethyl)- 5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]xin- 1-yl)-1,3,4-oxadiazole.

The use of nicotinic acetylcholine receptor antagonists was revealed by Cooke et al. U.S. Patent No. 7,652,038, incorporated herein by reference. Nicotinic acetylcholine receptor antagonists include, but are not limited to, mecamylamine, hexamethonium, dihydro-beta-erionine, d-tubocurarine ), pempidine, chlorisondamine, erysodine, trimethaphan camsylate, pentolinium, bungarotoxin, amber Alkali, tetraethylammonium, trimethaphan, isoamyl chloride, and trimethidinium.

The use of a farnesyl protein transferase inhibitor is described in U.S. Patent No. 7,557,107, the disclosure of which is incorporated herein by reference. These farnesyl protein transferase inhibitors comprise a tricyclic compound.

The use of adenosine A3 receptor antagonists is described in U.S. Patent No. 6,326,390, the disclosure of which is incorporated herein by reference. These adenosine A3 receptor antagonists include tricyclic non-xanthine antagonists and triazoloquinazolines.

U.S. Patent Application Publication No. 2010/0069458, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in the the the the the the the the the Used together: (1) ACE inhibitors include, but are not limited to, benazepril, enazepril, captopril, enalapril, osinopril, lisinopri Lisinopril, moexipril, quinapril, ramipril, perindopril and trandolapril; (2) adenosine Kinase inhibitors include, but are not limited to, 5-iodotubericidin; (3) Adrenal cortical antagonists include, but are not limited to, mitotane; (4) AKT pathway inhibitors (protein kinase B inhibition) Agents include, but are not limited to, deguelin and 1,5-dihydro-5-methyl-1- β -D-ribofuranoside-1,4,5,6,8-pentazaindene- 3-amine; (5) angiogenesis inhibitors include, but are not limited to, nicotinic acid fumagillin, shikonin, konivic acid, ursolic acid; suramin; salidom Omide), lenalidomide lenalidomide; pyridazines including but not limited to 1-(4-chloroanilino)-4-(4-pyridylmethyl)pyridazine, 1-(4-methylaniline)-4- (4-pyridylmethyl)pyridazine, 1-(3-chloroanilino)-4-(4-pyridylmethyl)pyridazine, 1-anilino-4-(4-pyridylmethyl)pyridazine, 1 -benzylamino-4-(4-pyridylmethyl)pyridazine, 1-(4-methoxyanilino)-4-(4-pyridylmethyl)pyridazine, 1-(3-benzyloxyaniline) 4-(4-pyridylmethyl)pyridazine, 1-(3-methoxyanilino)-4-(4-pyridylmethyl)pyridazine, 1-(2-methoxyanilinyl}-4 -(4-pyridylmethyl)pyridazine, 1-(4-trifluoromethylaniline)-4-(4-pyridylmethyl)pyridazine, 1-(4-fluoroaniline)-4-(4-pyridine Methyl)pyridazine, 1-(3-hydroxyanilino)-4-(4-pyridylmethyl)pyridazine, 1-(4-hydroxyanilino)-4-(4-pyridylmethyl)pyridazine, 1-(3-Aminoanilino)-4-(4-pyridylmethyl)pyridazine, 1-(3,4-dichloroanilino)-4-(4-pyridylmethyl)pyridazine, 1- (4-bromoanilino)-4-(4-pyridylmethyl)pyridazine, 1-(3-chloro-4-methoxyanilino)-4-(4-pyridylmethyl)pyridazine, 1- (4-cyanoaniline)-4-(4-pyridylmethyl)pyridazine, 1-(3-chloro-4-fluoroaniline)-4-(4-pyridylmethyl)pyridazine, 1-(3- Methylaniline)-4-(4-pyridyl) Pyridylmethyl)pyridazines, and other azines disclosed in PCT Patent Application Publication No. WO 98/035958, the entire disclosure of which is incorporated by reference in its entirety by reference in its entirety in Application for the publication of isoquinoline No. WO 00/09495, including by its entirety, including 1-(3,5-dimethylanilino)-4-(pyridin-4-ylmethyl)-iso quinoline; through Bold et al disclosed in PCT Patent application Publication No. WO 00/59509 phthalazine class number, and by reference in its entirety is included, comprising E -1- (3- methylaniline) -4- [ (2-(pyridin-3-yl)vinyl]pyridazine, Z -1-(3-methylanilino)-4-[(2-(pyridin-3-yl)vinyl]pyridazine, 1-( 3-methylaniline)-4-[(2-(pyridin-3-yl)ethyl]pyridazine, 1-(3-methylanilino)-4-[{2-(pyridin-4-yl)ethylene Pyridazine, 1-(4-chloro-3-trifluoromethylaniline)-4-[(2-(pyridin-3-yl)ethyl]pyridazine, 1-(4-chloroanilino) 4-[(2-(pyridin-3-yl)ethyl]pyridazine, 1-(3-chlorobenzylamino)-4-[(2-(pyridin-3-yl)ethyl]pyridazine , 1-(4-Chloro-3-trifluoromethylaniline)-4-[3-(pyridin-3-yl)propyl]pyridazine, 1-(4-chloroanilino)-4-[3 -(pyridin-3-yl) Pyridazine, 1-(3-chloro-5-trifluoromethylaniline)-4-[3-(pyridin-3-yl)propyl]pyridazine, and 1-(4-tert-butyl) Aniline)-4-[3-(pyridin-3-yl)propyl]pyridazine; and monoclonal antibodies; (6) angiogenesis-inhibiting steroids include, but are not limited to, anecortave, anal cortisol, hydrocortisone, 11 α - table hydrocortisone (11 α -epihydrocotisol), transdermal estrone (cortexolone), 17 α - hydroxyprogesterone, testosterone cortex (corticosterone), deoxycorticosterone testosterone (desoxycorticosterone), Testosterone, estrone, and dexamethasone; (7) antiandrogens include, but are not limited to, nilutamide and bicalutamide; (8) antiestrogens Including but not limited to toremifene, letrozole, testolactone, anastrozole, bicalutamide, flutamide, exemestane ( Exemestane), tamoxifen, fulvestrant, and raloxifene; (9) antihypercalcification agents include, but are not limited to, gallium (III) nitrate hydrate and glutathione Pamidronate disodium; (1 0) Apoptosis inducers include, but are not limited to, 2-[[3-(2,3-dichlorophenoxy)propyl]amino]-ethanol, gambogic acid, and embellin And arsenic trioxide; (11) ATI receptor antagonists include, but are not limited to, valsartan; (12) Aurora kinase inhibitors include, but are not limited to, binucleine 2; (13) aromatase inhibitors include Not limited to: (a) steroids include, but are not limited to, atamestane, exemestane, and formestane; and (b) non-steroids include, but are not limited to, aminoacetophenone, roqueimine (roglethimide), pyridophenacridone, trilostane, testosterone, clonazole, vorozole, fadrozole, anastrozole and letrozole (14) bisphosphonates include, but are not limited to, etidronic acid, clodronic acid, tiludronic acid, alendronic acid, ibandronic acid (ibandronic acid), risedronic acid and zoledronic acid; (15) Bruton tyrosine kinase inhibitors include but not For terreic acid; (16) phosphatase inhibitors include, but are not limited to, cypermethrin, deltamethrin, fenvalerate, and tyrosine phosphorylation inhibitors 8 (tyrphostin 8); (17) CaM kinase II inhibitors include, but are not limited to, 5-isoquinoline sulfonic acid 4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]- 3-oxy-3-(4-phenyl-1-piperazinyl)propyl]phenyl ester, and N-[2-[[[3-(4-chlorophenyl)-2-propenyl]] Methyl]amino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxy-benzenesulfonamide; (18) CD45 tyrosine phosphatase inhibitors include but are not limited to [ [2-(4-Bromophenoxy)-5-nitrophenyl]hydroxymethyl]-phosphonic acid; (19) CDC25 phosphatase inhibitors include but are not limited to 2,3-bis[(2-hydroxyethyl) (20) CHK kinase inhibitors include, but are not limited to, debrominated hymenial disine; (21) compounds that target/decrease a protein or adipokinase activity; or protein or fat phosphatase Active; or further anti-angiogenic compounds including, but not limited to, protein tyrosine kinases and/or serine and/or threonine kinase inhibitors or lipokinase inhibitors, including but not limited to: (a) The compound targets, reduces or inhibits the activity of vascular endothelial growth factor receptor (VEGFR) or vascular endothelial growth factor (VEGF), including but not limited to 7H-pyrrolo[2,3 a -d pyrimidine derivative comprising: [6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- -yl]-(R)-1-phenyl-ethyl)-amine (referred to as AEE788), BAY 43-9006, and isoquinoline compounds disclosed in PCT Patent Application Publication No. WO 00/09495, for example ( 4-tert-Butyl-phenyl)-94-pyridin-4-ylmethyl-isoquinolin-1-yl)-amine; (b) Compound targeting, reducing or inhibiting the platelet-derived growth factor receptor ( The activity of platelet-derived growth factor-receptor (PDGFR), including but not limited to: N-phenyl-2-pyrimidine-amine derivatives, for example, imatinib, SU101, SU6668, and GFB-111; (c) compound target To reduce or inhibit the activity of the fibroblast growth factor-receptor (FGFR); (d) to target, reduce or inhibit the first type of insulin-like growth factor receptor (insulin-like growt) The activity of h factor receptor 1, IGF-1R), including but not limited to 4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivatives, is disclosed in WO 02/ a compound of 092599 and a derivative thereof; (e) a compound that targets, reduces or inhibits the activity of the Trk receptor tyrosine kinase family; (f) a compound that targets, reduces or inhibits the Axl receptor tyrosine kinase family (g) the compound targets, reduces or inhibits the activity of the c-Met receptor; (h) the compound targets, reduces or inhibits the activity of the Ret receptor tyrosine kinase; (i) the compound targets, reduces Or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase; (j) compound targeting, reducing or inhibiting the activity of the C-kit receptor tyrosine kinase, including but not limited to imatinib; (k) compound Targeting, reducing or inhibiting the activity of members of the c-Abl family and its gene fusion products, such as BCR-Abl kinases, such as N-phenyl-2-pyrimidine-amine derivatives including, but not limited to, imatinib, 6- (2,6-Dichlorophenyl)-2-[(4-fluoro-3-tolyl)amino]-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)- -one (PD180970), methyl -4- [N- (2 ', 5 ' - dihydroxy benzyl) amine Benzoate (Tyrphostin AG957), 4-[[(2,5-dihydroxyphenyl)methyl]amino]benzoic acid tricyclo[3.3.1.13,7]non-1-yl ester (Ade) Asaphostin or NSC 680410), 6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfonylanilino)pyrido[2,3-d] Pyrimidine-7-one (PD173955), and desatinib; (1) compound targeting, reducing or inhibiting protein kinase C (PKC) and Raf family of serine kinase/synamic acid kinase Members, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family members or members of the PI(3) kinase family or PI(3)-kinase-associated kinase family, and/or the cyclin-dependent kinase (cyclin) The activity of members of the -dependent kinase (CDK) family, and in particular those of the stellate derivatives disclosed in U.S. Patent No. 5,093,330, such as but not limited to militalin; examples of further compounds include, for example, UCN-01 , safingol, sorafenib, Bryostatin 1 , Perifosine, Ilmofosine, 3-[3-[2,5 - dihydro-4- (1-methyl -1 H - indol-3-yl) -2,5-dioxo -1 H - pyrrole-3 ] -1 H - indol-1-yl] propyl dithiocarbamate imidate (RO 318220), 3 - [ (8 S) -8 - [( Dimethylamino) methyl] -6,7 ,8,9-tetrahydropyrido[1,2- a ]indole-10-yl]-4-(1-methyl-1 H -indol-3-yl)-1 H -pyrrole-2, 5-diketone (RO 320432), 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxy-5H-indole[2,3 -a]pyrrolo[3,4-c]carbazole (GO 6976), Isis 3521, (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro- 4,9:16,21-dimethyl-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacy clohexadecene-1,3(2H) -dione (LY333531), LY379196, isoquinoline compound, such as disclosed in PCT Patent Application Publication No. WO 00/09495; farnesyl transferase inhibitors include, but are not limited to, tipifarnib and Lonafarnib, 2-(2-chloro-4-iodo-anilino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide (PD184352), And QAN697, a PI3K inhibitor; (m) a compound that targets, reduces or inhibits the activity of a protein tyrosine kinase such as, but not limited to, imatinib mesylate, Tyrphostin, pyrimidinyl Amine Methionine and its derivatives; tyrosine phosphorylation inhibitors are preferably low molecular weight (Mr < 1500) compounds, or pharmaceutically acceptable salts thereof, especially one selected from the group consisting of benzalmalononitrile or A compound consisting of a group of S-aryl phenylmalononitriles or a double-substrate quinoline compound, more particularly any one selected from the group consisting of tyrosine phosphorylation inhibitor A23/RG-50810 (Tyrphostin A23/RG -50810), Tyrphostin AG 99, Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+) enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556, Tyrphostin AG957 and adaphostin ( a compound of the group consisting of 4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester or NSC 680410); (n) compound targeting, reducing or inhibiting the receptor The activity of the epidermal growth factor family of tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers), such as but not limited to those generally and specifically disclosed in the preceding examples , protein or monoclonal antibody: PCT patent application filed by Traxler et al. WO 97/02266 (for example (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)-amino]-7H-pyrrolo-[2,3-d U.S. Patent Application Publication No. EP 0 564 409 to Zimmermann, PCT Patent Application Publication No. WO 99/03854 to Zimmermann et al., and European Patent Application Publication No. EP 0520722 to Barker et al. European Patent Application Publication No. EP 0 566 226, filed by et al., and the European Patent Application Publication No. EP 0 877 722, filed on Sep. PCT Patent Application Publication No. WO 98/10767, filed by McMahon et al., PCT Patent Application Publication No. WO 97/30034, filed by s. PCT Patent Application Publication No. WO 97/38983, filed on Jun. No. No. No. No. No. No. No. No. No. No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No 6,7-bis(2-methoxyethoxy)-4-quinazolinamine (CP 358774 or erlotinib) or Gibson et al Application of PCT patent application Publication No. WO 96/33980 including, but not limited to, N - (3-chloro-4-fluoro - phenyl) -7-methoxy-6- (3-morpholin-4 PCT Patent No. PCT Patent Application Publication No. WO 95/03283, which is incorporated herein by reference, and which is incorporated herein to -Tolyl-amino)-quinazoline (ZM105180); monoclonal antibodies include, but are not limited to, trastuzumab and cetuximab; and other small molecule inhibitors include, but are not limited to, carnitinib ( Canertinib), pelitinib, lapatinib and 7H-pyrrolo-[2,3-d]pyrimidine derivatives, which are disclosed in PCT Patent Application Publication No. WO 03/013541 by Bold et al. (22) A compound that targets, decreases or inhibits the activity of a protein or a fat phosphatase, including but not limited to an inhibitor of phosphatase 1, phosphatase 2A, PTEN or CDC25, such as but not limited to okadaic acid or a derivative thereof; (23) the process of cell differentiation inducing compounds include, but are not limited to, retinoic acid (retinoic acid), α - tocopherol (α -tocopherol), γ- tocopherol, delta-tocopherol, α - triene Tocopherol α -tocotrienol), γ- and δ- tocotrienols tocotrienols; (24) cRAF kinase inhibitor include, but are not limited to, 3- (3,5-dibromo-4-hydroxy-benzylidene) -5- Iodo-1,3-dihydroindol-2-one, and 3-(dimethylamino)-N-[3-[(4-hydroxybenzylidyl)amino]-4-methyl] - Benzalamine; (25) cyclin-dependent kinase inhibitors include, but are not limited to, N9-isopropyl-ornomostar; olomoucine; benzoic acid (purvalanol B), roascovitine, Ken Keponlonone and 1-butanol (purvalanol A); (26) cysteine protease inhibitors include, but are not limited to, N-[(1S)-3-fluoro-2-oxy-1-(2) - phenyl]ethyl)propyl]amino]-2-oxy-1-(phenylmethyl)ethyl]-4-morpholincarbamoyl; (27) DNA incorporation includes but not Limited to pucamycin and dactinomycin; (28) DNA strand cleavage agents include, but are not limited to, bleomycin; (29) E3 ligase inhibitors include, but are not limited to, N-((3, 3,3-Trifluoro-2-trifluoromethyl)propanyl)amine benzenesulfonamide; (30) EDG binding agent includes but is not limited to FTY720; (31) endocrine hormones include but are not limited to leuprolide Lin (leuprolide) and Acetate Megestrol acetate; (32) farnesyl transferase inhibitors include, but are not limited to, α -hydroxyfarnesylphosphonic acid, 2-[[(2S)-2-[[(2S,3S)-2- [[(2R)-2-amino-3-thiolpropyl]amino]-3-methylpentyl]oxy]-1-oxy-3-phenylpropyl]amino]-4 - (Methanesulfonyl)-1-methylethylbutyrate (2S), and manumycin A; (33) Flk-1 kinase inhibitors include, but are not limited to, 2-cyano-3 -[4-hydroxy-3,5-bis(1-methylethyl)phenyl]-N-(3-phenylpropyl)-(2-E)-2-propenylamine; (34)Flt -3 inhibitors include, but are not limited to, N-benzylindolyl-spirulina, militalin, and N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro) Benz-2-oxo-1H-indol-3-yl)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (sunitinib); (35) The gonadotropin agonist includes, but is not limited to, abarelix, goserelin, and goserelin acetate; (36) heparinase inhibitors include, but are not limited to, thio Phosphate pentose pentose (PI-88); (37) histone deacetylase (HDAC) inhibitors include, but are not limited to, disclosed in PCT Patent Application Publication No. Compound of WO 02/22577, which includes, but is not limited to, N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino) ]methyl]phenyl]-2E-2-propenylamine, octyl benzalkonium hydroxamic acid, 4-(2-amino-phenylaminemethanyl)-benzyl]-carbamic acid pyridine-3 -methyl methyl ester and its derivatives, butyric acid, pyroxamide, trichostatin A, oxamflatin, histone deacetylase (apicidin), depsipeptide, depudecin ), trapoxin, HC toxin, and sodium phenylbutyrate; (38) HSP90 inhibitors include but are not limited to: 17-propenylamine; 17-desmethoxylatine 17-demethoxygeldanamycin (17AAG); a geldanamycin derivative; other geldanamycin-related compounds; radicicol; and 5-(2,4-dihydroxyl) -5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-oxazole-3-carboxylic acid ethylamine; (39) I κ B α inhibitor IKKs) Including but not limited to 3-[(4-methylphenyl)sulfonyl]-(2E)-2-acrylonitrile; (40) insulin receptor tyrosine kinase inhibitors include, but are not limited to, hydroxy-2-naphthyl Phosphonic acid; (41) cJ Un N-terminal kinase inhibitors include, but are not limited to, pyridone and epigallocatechin gallate; (42) microtubule binding agents include, but are not limited to, vinblastine sulfate; Vincristine sulfate; vindesine; vinorelbine; docetaxel; paclitaxel; dissolvmolides; colchicine; and epothilones and derivatives thereof, for example Epothilone B or a derivative thereof; (43) mitogen-activated protein (MAP) kinase inhibitors include, but are not limited to, N-[2-[[[3-(4-chlorophenyl)) -2-propenyl]methyl]amino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxy-benzenesulfonamide; (44) MDM2 inhibitors include but are not limited to Trans- 4-iodo, 4'-boranyl-chalcone; (45) MEK inhibitors include, but are not limited to, bis[amino[2-aminophenyl)thio]methenyl]-succinonitrile; 46) Amethionine amino-peptidase inhibitors include, but are not limited to, bengamide and its derivatives; (47) MMP inhibitors include, but are not limited to, actinoin (Actinonin); Gallocatechin gallate; collagen pseudopeptide and non-synaptic Inhibitor; tetracycline derivatives such as hydroxamate, bamastat, malimastat, primomastat, TAA211, N-hydroxy-2(R)-[[(4-methoxy) Phenyl)sulfonyl](3-methylpyridine)amino]-3-methylbutanamine hydrochloride (MMI270B) and AAJ996; (48) NGFR tyrosine kinase inhibitors include, but are not limited to, Tyrphostin AG 879; (49) p38 MAP kinase inhibitors include, but are not limited to, 3-(dimethylamino)-N-[3-[(4-hydroxybenzhydryl)amino]-4-methyl]]-phenyl 50amine; (50) p56 tyrosine kinase inhibitors include, but are not limited to, 9,10-dihydro-3-hydroxy-1-methoxy-9,10-dioxo-2-indolecarboxaldehyde, and Tyrphostin 46; (51) PDGFR tyrosine kinase inhibitors include, but are not limited to, Tyrphostin AG 1296, Tyrphostin 9, 2-amino-4-(1H-indol-5-yl)-1,3-butadiene-1,1 , 3-tricarbonitrile and imatinib; (52) phospholipid 醯 inositol-3 kinase inhibitors include, but are not limited to, wortmannin and quercetin dihydrate; (53) phosphatase inhibitors include are not limited to, cantharidic acid (cantharidic acid), cantharidin (cantharidin) and (E) -N- [4- (2- carboxyvinyl) acyl benzyl] amine Gan acyl -L- α - bran (54) Platinum agents include, but are not limited to, carboplatin, cisplatin, platinum oxalate, satraplatin, and ZD0473; (55) protein phosphatase inhibitors include but not Limited to: (a) PP1 inhibitors and PP2A inhibitors include, but are not limited to, cantharidin and cantharidin; (b) tyrosine phosphatase inhibitors include, but are not limited to, LP-bromotetrazide oxalate, benzylphosphonic acid, And (5R)-4-hydroxy-5-(hydroxymethyl)-3-(1-oxyhexadecyl)-2(5H)-furanone; (56) PKC inhibitors include but are not limited to -[1 -[3-(Dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrolo-2,5-dione, nerve Sphingosine, staurosporine, Tyrphostin 51, and hypericin; (57) PKC delta kinase inhibitors include, but are not limited to, lysin (rottlerin); (58) polyamines Synthetic inhibitors include, but are not limited to, ( RS )-2,5-diamino-2-(difluoromethyl)pentanoic acid (DMFO); (59) proteasome inhibitors include, but are not limited to, anamycin A (aclacinomycin A), gliotoxin and bortezomib; (60) PTP1B inhibitors include but are not limited to (E)-N-[4-(2-carboxyvinyl)benzylidene]glycine Mercapto-L- α -glutaminyl-L-leucine; (61) protein tyrosine kinase inhibitors include but are not limited to: Tyrphostin AG 126, Tyrphostin AG 1288, Tyrphostin AG 1295, Geld And genistein; (62) SRC family tyrosine kinase inhibitors include but are not limited to 1-(1,1-dimethylethyl)-3-(1-naphthyl)-1H-pyrazolo[ 3,4-d]pyrimidine-4-amine, and 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidine -4-amine; (63) Syk tyrosine kinase inhibitors include, but are not limited to, piceatannol; (64) Janus (JAK-2 and / or JAK-3) tyrosine kinase inhibitors include but Not limited to Tyrphostin AG 490, and 2-naphthyl vinyl ketone; (65) inhibitors of Ras oncogene isoforms include but are not limited to (2S)-2-[[(2S)-2-[(2S, 3S) -2-[(2R)-2-amino-3-thiolpropyl]amino]-3-methylpentyl]oxy]-1-oxy-3-phenylpropyl]amino ]-4-(Methanesulfonyl)-butyric acid 1-methylethyl ester (L-744832), DK8G557, and tififinib; (66) Retinoids include, but are not limited to, isotretinoin (isotretinoin) And retinoic acid (tretinoin); (67) ribonucleotide reductase inhibitors include but not Urea and 2-hydroxy to hydroxy -1H- isoindole-1,3-dione; (68) RNA polymerase II elongation inhibitor include, but are not limited to, 5,6-dichloro--1- β -D- ribofuranoside Glycoside benzimidazole; (69) S-adenosine methionine decarboxylase inhibitors include, but are not limited to, 5-mercapto-1-tetralone-2'-mercaptopurine, and others disclosed by Stanek Compounds of U.S. Patent No. 5,461,076, the disclosure of which is incorporated herein by reference in its entirety; Compounds that target, decrease or inhibit the activity or function of a serine/glycine amino acid kinase include, but are not limited to, everolimus, temsirolimus, zotarolimus, Rapamycin, derivatives and analogs of rapamycin, deforolimus, AP23841, sirolimus, and everolimus; (72) somatostatin receptor antagonists include But not limited to octreotide and pasireotide (SOM230); (73) sterol biosynthesis inhibitors include, but are not limited to, terbinadine; (74) telomerase inhibitor package But not limited to telomestatin; and (75) positional isomerase inhibitors include, but are not limited to: (a) positional isomerase I inhibitors include, but are not limited to, topotecan, gimatecan , irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-16614, macromolecular camptothecin conjugate (described by Angelucci et al. PCT Patent Application Publication No. WO 99/17804), 10-hydroxycamptothecin acetate, idopride idamycin hydrochloride, teniposide, doxorubicin, epirubicin hydrogen Chloride, bishydroxyhydrazine hydrochloride, and daunorubicin hydrochloride; and (b) positional isomerase II inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, comprising liposomal formulations thereof; Daunorubicin, comprising its liposome formulation; epirubicin; idamycin; nemorubicin; bishydroxyindole; loxophone; etatopes; Eni (eniposide); (76) VEGFR tyrosine kinase inhibitors include, but are not limited to, 3-(4-dimethylaminobenzylmercapto)-2-indanone; and (77) RANKL inhibition Agents include, but are not limited to, denosumab.

When the improvement is carried out by chemical sensitization, the chemical sensitization may include, but is not limited to, a combination of an alkylated hexitol derivative as a chemical sensitizer and an agent selected from the group consisting of In the group consisting of: (a) a positional isomerase inhibitor; (b) a pseudonucleoside; (c) a pseudonucleotide; (d) a thymidine synthase inhibitor; (e) signal transmission inhibition (f) cisplatin or platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; An analogue of colchicine or colchicine; (m) genistein; (n) etatopril; (o) arabinose cytosine; (p) camptothecin; (q) vinca alkaloid; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; and (v) propyl hydrazine.

When the modification is carried out by chemical synergism, the chemical synergism may include, but is not limited to, a combination of an alkylated hexitol derivative as a chemical synergist and an agent selected from the group consisting of In the group consisting of: (a) pseudonucleosides; (b) pseudonucleotides; (c) thymidine synthase inhibitors; (d) signal delivery inhibitors; (e) cisplatin or platinum (f) alkylating agent; (g) anti-tubulin agent; (h) antimetabolite; (i) berberine; (j) apigenin; (k) colchicine or colchicine similar (l) genistein; (m) idopride; (n) arabinosylcytosine; (o) camptothecin; (p) vinca alkaloids; (q) positional isomerase inhibitor; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; (v) And (w) a biological treatment.

In an alternative, when the chemical synergistic effect involves a chemical synergistic effect of an alkylating agent which is activated by alkylating a hexitol derivative, the alkylating agent may be selected from the group consisting of BCNU, BCNU tablets. A group consisting of climax, CCNU, bendamidine, cyclohexylnitrosourea, ACNU and temodar.

When the chemically synergistic agent is a biological therapeutic, the biological therapeutic can be, but is not limited to, a biological treatment selected from the group consisting of cancer, Hepatic, rituximab and Erbitux. Things.

When the improvement is performed by post-treatment management, the post-treatment management may be, but is not limited to, a method selected from the group consisting of: (a) a therapy associated with pain management; (b) (c) nutritional support; (c) administration of an antiemetic; (d) primary anti-emetic therapy; (e) administration of a primary anti-inflammatory agent; (f) administration of an antipyretic; and (g) administration of an immunostimulating agent.

When the improvement is performed by selective medical/post-treatment support, the selective medical/post-treatment support may be, but is not limited to, a method selected from the group consisting of: (a) hypnosis; b) acupuncture; (c) physical and mental therapy; (d) an herbal drug produced by synthesis or extraction; and (e) application of human kinematics.

In an alternative, when the method is an herbal medicine produced by synthesis or extraction, the herbal medicine produced by synthesis or extraction may be selected from the group consisting of: (a) an NF-κ B An inhibitor; (b) a natural anti-inflammatory agent; (c) an immunostimulant; (d) an antimicrobial; and (e) a flavonoid, isoflavone or flavonoid.

When the herbal drug produced by the synthesis or extraction is an NF-κB inhibitor, the NF-κB inhibitor may be selected from the group consisting of parthenolide, curcumin and rosmarinic acid. When the herbal drug produced by the synthesis or extraction is a natural anti-inflammatory agent, the natural anti-inflammatory agent may be selected from the group consisting of rhein and parthenolide. When the herbal drug produced by synthesis or extraction is an immunostimulating agent, the immunostimulating agent may be a product found in echinacea or separated from echinacea. When the herbal drug produced by the synthesis or extraction is an antimicrobial drug, the antimicrobial drug may be berberine. When the herbal drug produced by synthesis or extraction is a flavonoid or flavonoid, the flavonoid, isoflavone or flavonoid may be selected from apigenin, genistein, apigenenin, genistein, genistein. , 6 " -O-propanediyl genistein, 6 " -O-acetyl generin, daidzein, daidzin, 6 " -O-propanedithioglycoside, 6 " -O-B A group consisting of thioglycoside, xanthophyll, daidzein, 6 " -O-propanediylxanthine, and 6-O-ethylidene-flavonoid.

When the improvement is carried out by a drug substance product modification, the drug substance product improvement may be, but not limited to, an improvement of a drug substance product selected from the group consisting of: (a) salt formation; b) as a homogeneous crystal structure; (c) as a pure isomer; (d) increased purity; (e) a low residual solvent content; (f) A formulation having a low residual solvent content.

When the modification is carried out by using a diluent, the diluent may be, but not limited to, a diluent selected from the group consisting of: (a) an emulsion; (b) dimethyl (DMSO); (c) N-methylformamide (NMF); (d) dimethylformamide (DMF); (e) dimethylacetamide (DMA); (f) ethanol; (g) benzyl alcohol; (h) water containing glucose for injection; (i) polyoxyethylene castor oil; (j) cyclodextrin; and (k) PEG.

When the modification is carried out by using a solvent system, the solvent system may be, but not limited to, a solvent system selected from the group consisting of: (a) an emulsion; (b) DMSO; c) NMF; (d) DMF; (e) DMA; (f) ethanol; (g) benzyl alcohol; (h) water containing glucose for injection; (i) polyoxyethylene castor oil; (j) PEG ; and (k) salt system.

When the modification is carried out by using an excipient, the excipient may be, but not limited to, an excipient selected from the group consisting of: (a) mannitol; (b) albumin; (c) EDTA; (d) sodium hydrogen sulfite; (e) benzyl alcohol; (f) carbonate buffer; (g) phosphate buffer; PEG; (i) vitamin A; (j) vitamin D; (k) vitamin E; (1) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibitor; o) an organic resin; (p) a detergent; (q) perillol or an analogue thereof; and (r) an activator of a channel-forming receptor.

Suitable esterase inhibitors include, but are not limited to, ebelactone A and erbene lactone B.

Suitable cytochrome P450 inhibitors include, but are not limited to, 1-aminobenzotriazole, N-hydroxy-N'-(4-butyl-2-methylphenyl)carboxamidine, ketoconazole, methoxalin ( Methoxsalen), metyrapone, roquefortine C, proadifen, 2,3',4,5'-tetramethylstilbene, and doxycycline ( Troleandomycin).

Suitable MDR inhibitors include, but are not limited to, 5'-methoxyphile, INF 240, INF 271, INF 277, INF 392, INF 55, respine, and GG918. MDR inhibitors are described in M. Zloh & S. Gibbons, "Molecular Similarity of MDR9 Inhibitors", Int. J. Mol. Sci. 5: 37-47 (2004), and are incorporated by reference.

Suitable organic resins include, but are not limited to, a partially neutralized polyacrylic acid, as It is described in U.S. Patent No. 8,158,616, the disclosure of which is incorporated herein by reference.

Suitable detergents include, but are not limited to, nonionic detergents such as a polysorbate or a poloxamer, and through Bj Rn et al. are described in PCT Patent Application Publication No. WO/1997/039768, which is incorporated herein by reference.

The use of an antitumor agent to improve the delivery of an anti-tumor agent, or an analogue thereof, is described in US Patent Application No. 2012/0219541, the disclosure of which is incorporated herein by reference.

The use of an activator for a channel-forming receptor is described in U.S. Patent Application Publication No. 2010/0311678, the disclosure of which is incorporated herein by reference. Activators for such channel-forming receptors include, but are not limited to, capsaicin, lidocaine, eugenol, arvanil (N-arachidontyl vanillamine), cannabinoids (anandamide) ), 2-aminoethoxydiphenylborate, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-high vanillic acid (PPAHV), olvanil , N-oleyl dopamine, N-arachidonic acid dopamine, 6'-iodoresiniferatoxin (6'-IRTX), C ₁₈ N-mercaptoethanolamine, such as 12-peroxyhydroxyl a lipoxygenase derivative of an arachidonic acid, an inhibitor cysteine knot (ICK) vanillotoxins, piperine, N-[2-(3,4-dimethyl Benzyl)-3-(neopentyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide, N-[2-( 3,4-Dimethylbenzyl)-3-(neopentyloxy)propyl]-N'-(4-hydroxy-3-methoxybenzyl)thiourea, SU200 N-(4- t -butylbenzyl)-N'-(4-hydroxy-3-methoxybenzyl)thiourea), transacin, cinnamaldehyde, propenyl-isothiocyanate, diallyl Disulfide l disulfide), icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, mustard oil, ATP, 2-methylthio-ATP, 2' and 3'-O- (4-Benzylbenzylbenzyl)-ATP, ATP-5'-O-(3-thiotriphosphate), menthol, eucalyptol, linalool, geraniol ), as well as hydroxycitronellal.

When the modification is carried out by using a dosage form, the dosage form may be, but is not limited to, a dosage form selected from the group consisting of: (a) a tablet; (b) capsule; (c) topical gel; (d) topical ointment; (e) patch; (f) embolic agent; (g) lyophilized dose filler; (h) immediate release formulation; (i) Release preparation; (j) controlled release preparation; and (k) liquid capsule.

Formulations of pharmaceutical compositions in tablets, capsules and topical gels, topical ointments or embolic agents are well known in the art and are described, for example, by Griffin et al. in U.S. Patent Application Publication No. 2004/0023290, the disclosure of which is incorporated by reference. Include it.

Formulations of a pharmaceutical composition as a patch (e.g., a transdermal patch) are well known in the art and are described, for example, in U.S. Patent No. 7,728,042, the disclosure of which is incorporated herein by reference.

Lyophilized dose fillers are also well known in the art. A common method for preparing such lyophilized dose fillers for dibromodusol and its derivatives comprises the following steps:

(1) dissolving the drug into water for injection, and pre-cooling to below 10 ° C, diluting to a final volume with cold water for injection to yield a 40 mg/mL solution;

(2) sterilizing the bulk solution through a 0.2-μm filter paper into a receiving container under aseptic conditions, and the preparation and filtration should be completed within 1 hour;

(3) Filling the nominal 1.0 mL filtered solution into a sterile vial;

(4) After filling, place all the small glass bottles in the rubber stopper inserted in the “freeze-drying position”, and load into the pre-cooling lyophilizer, set the shelf temperature of the lyophilizer at +5 ° C and maintain 1 hour; then the shelf temperature was adjusted to -5 ° C for 1 hour, and the condenser was set to -60 ° C and turned on;

(5) The glass vial is then frozen to -30 ° C or below and maintained for no less than 3 hours, usually 4 hours;

(6) then opening the vacuum, the shelf temperature is adjusted to -5 ° C, and primary drying for 8 hours; the shelf temperature is again adjusted to -5 ° C and drying for at least 5 hours;

(7) After the condenser is turned on (set at -60 ° C) and vacuum, the second drying is started. In the secondary drying, the shelf temperature is controlled at +5 ° C for 1 to 3 hours (usually 1.5 hours), followed by It is carried out at 25 degrees for 1 to 3 hours (usually 1.5 hours) and finally at 35-40 degrees for at least 5 hours (usually 9 hours) or until the product is completely dried.

(8) The vacuum is removed by a filtered inert gas such as nitrogen. The vial was stoppered in a lyophilizer.

(9) Remove the vial from the lyophilizer chamber and close the seal with an aluminum flip, visually inspect and label all vials with the approved label.

The immediate release formulation is described in U.S. Patent No. 8,148,393, the disclosure of which is incorporated herein by reference. The immediate release formulation may, for example, comprise a conventional film ingot.

Sustained release formulations are described in U.S. Patent No. 8,178,125, the disclosure of which is incorporated herein by reference. The sustained release preparation may, for example, comprise a microemulsion or a liquid crystal.

Controlled release formulations are described in U.S. Patent No. 8,231,898 to Oshlack et al., which is incorporated herein by reference. The controlled release formulation may, for example, comprise a matrix of a controlled release material. Such controlled release materials may comprise hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac and oils such as hydrogenated castor oil or hydrogenated vegetable oils. However, in accordance with the present invention, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material capable of imparting controlled release of the ketone alkylating agent can be used. Preferred controlled release polymers comprise alkyl celluloses such as ethyl cellulose, acrylic and methacrylic polymers and copolymers, and cellulose ethers, especially hydroxyalkyl celluloses (eg, hydroxypropylmethyl) Cellulose) and carboxyalkyl cellulose. Preferred acrylic and methacrylic polymers and copolymers comprise methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, amine alkyl acrylate Methyl ester copolymer, polyacrylic acid, polymethacrylic acid, alkylamine copolymer of methacrylate, polymethyl methacrylate, polymethacrylic anhydride, polymethyl acrylate, polyacrylamide, polymethyl Acrylic acid anhydride, and epoxy propyl methacrylate copolymer.

When the improvement is made by using a dose kit and packaging, the dosage sleeve The kits and packages may be, but are not limited to, a dosage kit and a package selected from the group consisting of: a brown bottle that avoids illumination, and a use to increase shelf life stability. Special coated stoppers.

When the improvement is carried out by using a drug delivery system, the drug delivery system can be, but is not limited to, a drug delivery system selected from the group consisting of: (a) an oral dosage form; (b) (c) nanoparticle; (d) cosolvent; (e) slurry; (f) syrup; (g) bioerodible polymer; (h) liposome; (i) sustained release injection gel (j) microspheres; and (k) a targeting composition having an epidermal growth factor receptor binding peptide.

Nanocrystals are described in U.S. Patent No. 7,101,576 to Hovey et al., which is incorporated herein by reference.

Nanoparticles for drug delivery are described in U.S. Patent No. 8,258,132, the disclosure of which is incorporated herein by reference. Typically, such nanoparticles have an average particle size of less than about 1000 nanometers (nm) of active ingredient, more preferably less than about 400 nm, and most preferably less than about 250 nm. The nanoparticle can be coated with a surface stabilizer such as gelatin, casein, phosphatides, dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzyl chloride, stearin. Calcium acid, glyceryl monostearate, cetearyl alcohol, polyethylene glycol emulsion wax, sorbitan ester, polyoxyethylene alkyl ether (for example, polyethylene glycol ether such as polyethylene glycol 1000) , polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (such as commercially available Tweens®, such as Tween 20® and Tween 80® (ICI Speciality Chemicals)); polyethylene glycol (such as carbon wax 3550®) And 934® (Union Carbide), polyoxyethylene stearate, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, calcium carboxymethylcellulose, carboxymethyl fibers Sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, three Ethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), with oxidation 4-(1,1,3,3-tetramethylbutyl)-phenol polymer of olefin and formaldehyde (also known as tyloxapol, superione and triton), Polo Sham (eg Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamine (eg Tetronic 908®, also known as poloxamine 908®, which is a a tetrafunctional block copolymer obtained by increasing the order of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), a dialkyl ester of sodium sulfosuccinate (such as Aerosol OT®, which is a dioctyl ester of sodium monosulfonated succinate (Cyanamide)), sulfosuccinic acid Dioctyl sodium sulfosuccinate (DOSS), sodium docusate (Ashland Chem. Co., Columbus, Ohio); fatty acid sulfate (Duponol) P®, which is sodium lauryl sulfate (DuPont); Nuclear X-200®, which is a monoalkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110®, a mixture of sucrose stearate and sucrose distearate (Croda I Nc.); p-isodecylphenoxy-poly-(dehydroglycerol), also known as Olin-IOG® or surfactant 10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40 ® (Croda, Inc.); with its SA9OHCO, which is C ₁₈ H ₃₇ CH ₂ (CON(CH ₃ )--0CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ (Eastman Kodak Company), 癸醯Amides -N- methyl glucose group, n - decyl β-D- glucopyranoside, n - decyl β-D- glucoside pyran malt, n - dodecyl β-D- pyran Glucoside, n -dodecyl β-D-maltoside, heptyl-N-methyl-glucosamine, n -heptyl-β-D-glucopyranoside, n -heptyl β- D-glucosinolate, n -hexyl β-D-glucopyranoside, thiol-N-methylglucosamine, n -fluorenyl β-D-glucopyranoside, octyl-N- Methyl glucosamine, n -octyl β-D-glucopyranoside, and octyl β-D-thioglucopyranoside, but the present invention is not limited thereto. Nanoparticles for drug delivery are also described in US Patent Application Publication No. 2010/209479, the disclosure of which is incorporated herein by reference. These nanoparticles contain carbon nanoparticles such as carbon nanotubes.

A pharmaceutically acceptable co-solvent is described in U.S. Patent No. 8,207,195, to Navratil et al., which is incorporated herein by reference in its entirety and in its entirety, including but not limited to water, methanol, ethanol, 1-propanol, isopropanol, 1- Butanol, isobutanol, t -butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, toluene, xylene (s), ethylene glycol, dichloromethane, 1,2-di Ethyl chloride, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, pyridine, dioxane, and diethyl ether.

A slurry for use in a pharmaceutical formulation is described in U.S. Patent Application Publication No. 2006/0229277, which is incorporated herein by reference.

Syrups for use in pharmaceutical preparations are described in U.S. Patent No. 8,252,930, the disclosure of which is incorporated herein by reference. Such syrups may comprise the active ingredient and a syrup type composition (e.g., a sugar or sugar alcohol) and a mixture of ethanol, water, glycerin, propylene glycol, and polyethylene glycol. Such liquid preparations may contain, if desired, coloring agents, flavoring agents, preservatives, saccharin, and carboxymethylcellulose or other thickening agents.

The bio-erosion-type polymer is described in U.S. Patent No. 7,318,931, the disclosure of which is incorporated herein by reference. A bioerodible polymer decomposes an organism placed inside, which is measured as the molecular weight of the polymer decreases over time. The molecular weight of the polymer can be determined by a variety of methods including size exclusion chromatography (SEC) and is generally expressed as a weight average molecular weight or a number average molecular weight. If the pH of the phosphate buffered saline (PBS) is 7.4 and the temperature is 37 ° C, the polymer is bioerodible, and its weight average molecular weight is measured by SEC for a period of six months. Reduce by at least 25%. Useful bioerodible polymers include polyesters such as polycaprolactone, polyglycolic acid, polylactic acid, and polyhydroxybutyric acid; polyanhydrides such as polyadipate anhydride and polymaleic anhydride; polydioxanone; Polyamines; polyamines; polyurethanes; polyester decylamines; polyorthoesters; polyacetals; polyketals; polycarbonates; polyorthoester carbonates; polyphosphazenes; polymalic acid; polyamino acids ; polyvinylpyrrolidine; polymethyl vinyl ether; polyalkylene oxalate; polyalkyl succinate; polyhydroxy cellulose; chitin; chitosan; and copolymers and mixtures thereof .

Liposomes are well known as drug delivery vehicles. The preparation of liposomes is described in the European Patent Application Publication No. EP 1332755 by Weng et al., which is incorporated herein by reference. The liposome can comprise a short oligopeptide sequence capable of targeting the EGFR receptor, as described in U.S. Patent Application Publication No. 2012/0213844, which is incorporated herein by reference. Alternatively, the liposome can comprise a nuclear localization signal/fusion peptide The conjugates are formed into a target liposome complex, as described in U.S. Patent Application Publication No. 2012/0183596, the disclosure of which is incorporated herein by reference.

Sustained release injection gels are known in the art and are described, for example, in B. Jeong et al., "Drug release from biodegradable injection thermosensitive hydrogels of PEG-PLGA-PEG triblock copolymers. , J. Controlled Release 63: 155-163 (2000), and include it by reference.

The use of microspheres for drug delivery is known in the art and is described, for example, in H. Okada & H. Taguchi, "Biodegradable Microspheres in Drug Delivery", Crit. Rev. Ther. Drug Carrier Sys. 12: 1-99 (1995) and includes it by reference.

The use of a targeting composition having an epidermal growth factor receptor-binding peptide is described in U.S. Patent Application Publication No. 2010/0151003, the entire disclosure of which is incorporated herein by reference.

When the modification is carried out by using a drug conjugated form, the conjugated form of the drug may be, but not limited to, a drug conjugated form selected from the group consisting of: (a) a polymer system (b) polylactic acid; (c) polyglycolic acid; (d) amino acid; (e) peptide; (f) multivalent linker; (g) immunoglobulin; (h) cyclodextrin polymerization (i) modified transferrin; (j) hydrophobic polymer or hydrophobic-hydrophilic polymer; (k) conjugate having a partial ester of sodium phosphate; (1) having a charged crosslinker a conjugate of a cell binder; and (m) a conjugate having beta-glucuronic acid through a linker.

Polylactic acid conjugates are well known in the art and are described, for example, in R. Tong & C. Cheng, "Controllable Synthesis of Camptothecin-Polylactic Acid Conjugates and Nanoconjugates", Bioconjugate Chem. 21: 111-121 (2010), which is incorporated by reference.

Polyglycolic acid conjugates are also well known in the art and are described, for example, by PCT Patent Application Publication No. WO 2003/070823, the disclosure of which is incorporated herein by reference.

Multivalent linkers are known in the art and are described, for example, in U.S. Patent Application Publication No. 2007/0207952, the disclosure of which is incorporated herein by reference. For example, a multivalent linker can comprise a thiol group for reaction with a reactive cysteine and a plurality of nucleophilic groups (eg, NH or OH) or an electrophilic group (eg, an activated ester), which allows A plurality of biologically active moieties are attached to the linker.

The conjugates of the immunoglobulins are disclosed in U.S. Patent No. 4,925,662, the disclosure of which is incorporated herein by reference. The conjugate is prepared by using a crosslinking agent such as carbodiimide, glutaraldehyde, or diethyl propylene glycol.

The cyclodextrin polymer, its conjugate having a therapeutically active agent, and its administration with the granules are described in U.S. Patent Application Publication No. 2012/0213854, which is incorporated herein by reference.

A conjugate having a modified transferrin is described in U.S. Patent Application Publication No. 2011/0288023, the disclosure of which is incorporated herein by reference.

A conjugate having a hydrophobic polymer or a hydrophobic-hydrophilic polymer is described in U.S. Patent Application Publication No. 2011/0268658, which is incorporated herein by reference. These polymers may comprise a single peptide, a double peptide or a tripeptide. These polymers may also include polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid, PLGA), polycaprolactone ( Polycaprolactone, PCL), polydioxanone (PDO), polyanhydride, polyorthoester or chitosan.

A conjugate having a partial ester of sodium monophosphate is described in U.S. Patent Application Publication No. 2010/227, the entire disclosure of which is incorporated herein by reference.

A conjugate having a cell binder incorporating a charged cross-linking agent is described in U.S. Patent No. 8,236,319, the disclosure of which is incorporated herein by reference.

A conjugate having β-glucuronic acid via a linker is depicted by Jeffrey It is described in U.S. Patent No. 8,039,273, incorporated herein by reference.

Suitable reagents for crosslinking a combination of many functional groups are known in the art. For example, an electrophilic group can react with a number of functional groups, including those found in proteins or polypeptides. Various combinations of reactive amino acids and electrophiles are known in the art and can be used. For example, N-terminal cysteine, comprising a thiol group, can be reacted with a halogen or maleimide. Thiol groups are known to have a reactivity containing a large amount of a coupling agent, such as an alkyl halide, a vinylidene derivative, a maleimide, an aziridine, an acrylonitrile derivative, such as an aryl halide, and Other aromatizing agents. These are described in G.T. Hermanson, "Bio-Grafting Technology" (Academic Press, San Diego, 1996), pp. 146-150, and are incorporated by reference. The reactivity of the cysteine residue can be optimized by appropriate selection of adjacent amino acid residues. For example, a histidine residue adjacent to the cysteine residue will increase the reactivity of the cysteine residue. Combinations of other reactive amino acids and electrophilic reagents are known in the art. For example, maleimide can be reacted with an amine group, such as the epsilon-amine group of the side chain of lysine, particularly at a higher pH range. Aryl halides can also be reacted with such amine groups. The haloacetyl derivative can react with the imidazolyl side chain nitrogen of histidine, the thioether group of the side chain of methionine, and the .ε (epsilon).-amine group of the side chain of lysine. . Many other electrophiles are known to react with the ε-amine groups of the lysine side chain, including but not limited to isothiocyanates, isocyanates, decyl azides, hydroxy amber imidates, chlorination Sulfonium, epoxy compounds, ethylene oxide, carbonates, imidates, carbodiimides and anhydrides. These are described in G.T. Hermanson, "Bio-Grafting Technology" (Academic Press, San Diego, 1996), pp. 137-146, and are incorporated by reference. In addition, electrophiles are known to react with carboxylate side chains such as those of aspartame and glutamic acid, such as diazonanes and diazonium compounds, carbonyl diimidazoles and carbon bismuth. Imine. These are described in G.T. Hermanson, "Bio-Grafting Technology" (Academic Press, San Diego, 1996), pp. 152-154, and are incorporated by reference. Furthermore, electrophiles are known to react with hydroxyl groups such as those in the side chains of serine and physic acid, including reactive haloalkane derivatives. These are described in G.T. Hermanson, "Bio-Grafting Technology" (Academic Press, San Diego, 1996), pp. 154-158, and are incorporated by reference. In another alternative embodiment, the relative positions of the electrophile and the nucleophilic group (ie, the molecular activity of the electrophile) are reversed such that the protein has There is an amino acid residue having an electrophilic group which is reactive with a nucleophilic group and the targeting molecule comprises one of the nucleophilic groups. This involves the reaction of an aldehyde (electrophile) having hydroxylamine (nucleophilic group), as described above, but more generally than its reaction; other groups can be used as electrophiles and nucleophiles. Suitable groups are well known in organic chemistry without further elaboration.

Additional combinations of reactive groups for crosslinking are known in the art. For example, the amine group may be combined with isothiocyanate, isocyanate, decyl azide, N-hydroxysuccinimide (NHS) ester, sulfonium chloride, aldehyde, glyoxal, The epoxy compound, ethylene oxide, carbonate, alkylating agent, imidate, carbodiimide and anhydride are reacted. The thiol group may be combined with a halomethyl or alkyl halide derivative, a maleimide, an aziridine, an acrylonitrile derivative, a oxime or other sulfur which is formed by oxidizing and forming a mixed disulfide. The alcohol group reacts. The carboxyl group can be reacted with a diazane, a diazonium compound, a carbonyl diimidazole, or a carbodiimide. The hydroxyl group may be combined with an epoxy compound, ethylene oxide, carbonyldiimidazole, N,N'-disuccinimide carbonate, N-hydroxysuccinimide chloroformate, periodate (for Oxidation, alkyl halogen or isocyanate reacts. The aldehyde group and the ketone group may be a group reactive with a hydrazine, a Schiff base, and other groups in a reductive amination reaction or a Mannich condensation reaction. Nonetheless, other reactions suitable for crosslinking reactions are known in the art. Such cross-linking reagents and reactions are described in G.T. Hermanson, "Bio-Grafting Technology" (Academic Press, San Diego, 1996) and are incorporated by reference.

When the modification is carried out by using a compound analog, the compound analog may be, but not limited to, a compound analog selected from the group consisting of: (a) a change in a side chain to increase or Reducing lipophilicity; (b) increasing the chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding ability; and (c) variation in salt type.

When the improvement is carried out by using a precursor system, the precursor system may be, but is not limited to, a precursor system selected from the group consisting of: (a) using an enzyme-sensitive ester; b) using a dimer; (c) using a Schiff base; (d) using a pyridoxal complex; (e) using a caffeine complex; (f) using a nitric oxide to release a precursor; (g) using a fibrinogen activator alpha-cleavable oligopeptide precursor; (h) using a precursor of the product reacted with an oxime or an amine methacrylate; (i) using a hexanoate conjugate precursor; (j) using a polymer-agent conjugate Previously driven; and (k) used to be activated by redox activation.

The term "precursor" as used herein refers to a compound that is transformed in vivo to produce a disclosed compound or a pharmaceutically acceptable form of the compound. In some embodiments, a precursor is a compound that can be converted under physiological conditions or by solvolysis of a biologically active compound as described herein. Thus, the term "precursor" refers to a precursor of a pharmaceutically acceptable biologically active compound. When administered to a target subject, a precursor may be inactive, but its attachment will be converted to the active compound in vivo, for example by hydrolysis (e.g., hydrolysis in blood or tissue). In some cases, a precursor has improved physical and/or transport properties over a starting compound derived from the precursor. In a mammalian organism, the precursor often provides the advantage of solubility, histocompatibility or slow release (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7-9, 21-24), And include it by reference. A discussion of precursors is provided by T. Higuchi et al., "Prodrugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14 and is provided in EB Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987), both of which are included by reference. Typical advantages of a precursor may include, but are not limited to, its physical properties, such as increased water solubility for parenteral administration (in comparison to the physiological pH of the original compound), increased absorption of the digestive tract, or for long term storage. The increase in drug stability.

When the precursor is administered to a subject, the term "precursor" also means a covalently bonded carrier comprising any in vivo release of the active compound. A therapeutically active compound precursor as described herein can be modified by modifying one or more functional groups present in the therapeutically active compound (such a cleavage in a modified manner, whether in routine manipulation or in vivo, Production Raw raw therapeutically active compounds) were prepared. The precursor comprises a compound in which a hydroxyl group, an amine group or a thiol group is covalently bonded to any group, and when the precursor of the active compound is administered to a target object, the group is cleaved to a free hydroxyl group, respectively. a free amine group or a free thiol group. Examples of precursors include, but are not limited to, a formate or benzoate derivative of ethanol or acetamide, a protopamine or benzamide derivative, etc., of a therapeutically active agent having a reactive amine functional group. Wait.

For example, if the pharmaceutically acceptable form of the therapeutically active or therapeutically active agent comprises a monocarboxylic acid functional group, a precursor may comprise an ester formed by substituting a hydrogen atom of a carboxylic acid group with a group, The group is, for example, a C _1-8 alkyl group, a C _2-12 alkanomethoxymethyl group, a 1-(alkyloxy)ethyl group having 4 to 9 carbon atoms, and 1 to 5 carbon atoms. -methyl-1-(alkyloxy)ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy) having 4 to 7 carbon atoms Ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5-8 carbon atoms, N-(alkoxycarbonyl)aminemethyl having 3-9 carbon atoms, having 1-(N-(alkoxycarbonyl)amino)ethyl, 3-mercapto, 4-crotonolactonyl, γ-butyrolactone-4-yl, 4-10 carbon atoms , bis-N,N(C ₁ -C ₂ )alkylamino(C ₂ -C ₃ )alkyl (eg (3-dimethylaminoethyl), aminecaraki-(C ₁ -C ₂ ) alkane , N,N-di(C ₁ -C ₂ )alkylaminemethanyl-(C ₁ -C ₂ )alkyl and piperidinyl-, pyrrolidinyl-, or morpholinyl (C ₂ -C ₃ ) an alkyl group.

Likewise, if the disclosed compound or a pharmaceutically acceptable form of the compound comprises a monoethanol functional group, a precursor can be formed by substitution of a hydrogen atom of an ethanol group having a group, for example, Is (C ₁ -C ₆ ) alkoxymethyl, 1-((C ₁ -C ₆ ))alkyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkane醯oxy)ethyl (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N(C ₁ -C ₆ ) alkoxycarbonylaminomethyl, amber thiol, (C ₁ -C ₆ ) An alkane group, an α -amino group (C ₁ -C ₄ )alkyl group, an aryl group and an α -amino group, or an α -amino group- α -amino group, wherein each α -amine group The groups are each selected from naturally occurring L-amino acids, P(O)(OH) ₂ , P(O)(O(C ₁ -C ₆ )alkyl) ₂ or glycosyl (free radicals derived from Removal of hydroxyl groups in the form of hemiacetals of carbohydrates).

If a disclosed compound or a pharmaceutically acceptable form of the compound comprises a monoamine functional group, in the amine group having a group such as R-carbonyl, RO-carbonyl, NRR ' -carbonyl, a precursor may substituted by a hydrogen atom to form, wherein R and R 'for each (C ₁ -C ₁₀₎ alkyl, (C ₃ -C ₇₎ cycloalkyl, benzyl, or R- carbonyl is a natural α - amine Mercapto or natural alpha -amine sulfhydryl-natural alpha -amine sulfhydryl, C(OH)C(O)OY ¹ (where Y ¹ is H, (C ₁ -C ₆ )alkyl or benzyl), C ( OY ² )Y ³ (wherein Y ² is (C ₁ -C ₄ )alkyl, and Y ³ is (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl,amino (C ₁ -C ₄ )alkyl or mono-N or di-N,N(C ₁ -C ₆ )alkylaminealkyl, C(Y ⁴ )Y ⁵ (where Y ⁴ is H or methyl, and Y ⁵ is Mono-N or di-N,N(C ₁ -C ₆ )alkylamino), morpholinyl, piperidin-1-yl or pyrrolidin-1-yl.

The use of precursor systems is described in T. Järvinen et al., “Precursor Design "Pharmaceutical applications are considered" in Drug Discovery Handbook (SCGad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 17, pp. 733-796, and are incorporated by reference. The use of an enzyme-sensitive ester as a precursor. The use of a dimer as a precursor is described in U.S. Patent No. 7,879,896 to Allegretti et al., the disclosure of which is incorporated by reference. Described in S. Prasad et al., "publishing multiple anticancer peptides as a single precursor using lysine lysine as a simple linker", J. Peptide Sci. 13:458-467 (2007), And the use of the Schiff base as a precursor is described in U.S. Patent No. 7,619,005 to Epstein et al., which is incorporated herein by reference. It is described in U.S. Patent No. 6,443,898 to Unger et al., which is incorporated herein by reference. The use of nitric oxide release precursors is described in N. Nath et al., "JS-K (Nitric Oxide Release Precursor) Regulates β-Linkin/TCF Signals in Leukemia Jurkat Cells: Thionitroso Mechanism Evidence, Biochem. Pharmacol. 80: 1641-1649 (2010), and is incorporated by reference. The use of a fibroblast-activated protein alpha-cleavable oligopeptide precursor is described in U.S. Patent Application Publication No. 2002/0155565, the disclosure of which is incorporated herein by reference. The use of precursors for the reaction with an oxime or monoamine oxime is described in JHLin and JYHLu, "The Role of Pharmacokinetics and Metabolism in Drug Discovery and Development", Pharmacol. Rev .4: 403-449 (1997) and include it by reference. The use of hexanoate conjugates is described in U.S. Patent No. 8,101,661, the disclosure of which is incorporated herein by reference. The use of polymer-agent conjugates is described in R. Satchi et al., "Polymer-Directed Enzyme Prodrug Therapy (PDEPT)," Br. J. Cancer 85: 1070-1076 ( 2001) and include it by reference. The use of precursors prior to redox activation is described in S. H. van Rijt and P. J. Sadler, “The current application and future potential of bioinorganic chemistry in the development of anticancer drugs”, Drug Discov. Today 14: 1089-1097 (2009), and is included by reference.

When the improvement is carried out by using a multi-drug system, the multi-drug system can be, but is not limited to, a multi-drug system selected from the group consisting of: (a) inhibitors of multiple drug resistance (b) specific drug resistance inhibitor; (c) specific selective enzyme inhibitor; (d) signal delivery inhibitor; (e) methotrexate; (f) imatinib; (g) hydroxy urea (h) dasatinib; (i) capitabine; (j) nilotinib; (k) repair inhibitor; and (l) positional isomerase inhibitor with non-overlapping side effects.

Multi-drug resistance inhibitors are described in U.S. Patent No. 6,011,069, the disclosure of which is incorporated herein by reference.

Specific anti-drug inhibitors are described in T. Hideshima et al., "Proteasome inhibitor PS-341 inhibits growth, induces apoptosis and overcomes resistance in human multiple myeloma cells", Cancer Res. 61:3071 -3076 (2001) and include it by reference.

Selective inhibitors of specific enzymes are described in D. Leung et al., "Effective and selective reversible enzyme inhibitors found in complex protein bodies", Nature Biotechnol. 21:687-691 (2003), and Include it by reference.

Inhibition is described in N.M. Martin, "DNA Inhibition and Cancer Therapy", J. Photochem. Photobiol. B 63: 162-170 (2001), and is incorporated by reference.

When the improvement is carried out by biotherapeutic enhancement, the biotherapeutic treatment The potent action can be accomplished by a combination of a sensitizer/potentiator and a therapeutic agent or technique selected from the group consisting of: (a) a biological response modifier; b) cytokines; (c) therapeutic antibodies; (d) therapeutic antibodies; (e) antisense therapy; (f) gene therapy; (g) ribozyme; and (h) RNA interference.

Biological reaction modifiers are described in T.E.G.K. Murthy et al., "Bioreactive Modifications", Int. J. Pharmtech Res. 2: 2152-2160 (2010), and are incorporated herein by reference.

Antisense therapy is described, for example, in B. Weiss et al., "Antisense RNA Gene Therapy for the Study and Regulation of Biological Processes", Cell. Mol. Life Sci. 55: 334-358 (1999) And include it by reference.

Ribozymes are described, for example, in S. Pascolo, "RNA-based Therapy" in Drug Discovery Handbook (SCGad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 27, pp. 1273-1278, and adopted References include it.

RNA interference is described, for example, in S. Pascolo, "RNA-based therapy" in Drug Discovery Handbook (SCGad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 27, pp. 1278-1283, and References include it.

When the biotherapeutic potentiation is combined with the use of a sensitizer/potentiator having a therapeutic antibody, which may be, but is not limited to, a therapeutic antibody selected from bevacizumab (canceriz) Stop), a group consisting of rituximab (rituximab) (rituximab), trastuzumab (He Cancer) and cetuximab (Erbitux).

Where the improvement is effected by the use of anti-biotherapeutic regulation, the anti-biological therapeutic modulation can be, but is not limited to, an anti-TKI tumor that is resistant to a therapeutic agent or technique that is selected from the group consisting of The following group of groups: (a) biological response modifiers; (b) cytokines; (c) therapeutic antibodies; (d) therapeutic antibodies; (e) antisense therapy; (f) gene therapy; (g) ribozyme; and (h) RNA interference.

In another alternative, when the improvement is effected by the use of anti-biotherapeutic regulation, the anti-biotherapeutic regulation can be, but is not limited to, a mutation or abnormality associated with the AHI1 gene that is also resistant to a therapeutic agent or technique. To modulate a related malignancy, the therapeutic agent or technique is selected from the group consisting of: (a) a biological response modifier; (b) a cytokine; (c) a therapeutic antibody; (d) a therapeutic antibody; e) antisense therapy; (f) gene therapy; (g) ribozyme; and (h) RNA interference.

When the anti-biotherapeutic regulation is to combat tumors resistant to therapeutic antibodies, the therapeutic antibody may be, but is not limited to, a therapeutic antibody selected from bevacizumab (cancer), rituximab. A group consisting of monoclonal antibody (rituximab), trastuzumab (He Cancer) and cetuximab (Erbitux).

When the improvement is performed by enhancing radiation therapy, the enhancement of the radiation therapy may be, but not limited to, a radiation therapy enhancing agent or technique selected from the group consisting of: 1 using a hypoxia sensitizer; 2 using a radiation sensitizer / protective agent; 3 use photosensitizer; 4 use radiation repair inhibitor; 5 use thiol consumer; 6 use vascular target; 7 use DNA repair inhibitor; 8 use radioactive strain; 9 use radioactive nucleus; ; and 11 use proximity therapy.

The monoalkylated hexitol derivative can be used in combination with radiation for treating a primary anti-TKI tumor.

Hypoxic sensitizers are described in CCLing et al., "Impact of hypoxic sensitizers at different radiation dose rates", Radiation Res. 109:396-406 (1987), and are incorporated herein by reference. Radiation sensitizers are described in TS Lawrence, "Radiation Sensitizers and Target Therapy", Oncology 17 (Suppl. 13) 23-28 (2003), and are incorporated by reference. Radiation protection agents are described in SB Vuyyuri et al., "Evaluation of D-methionine as a novel oral radiation protectant for the prevention of mucositis", Clin. Cancer Res. 14:2161-2170 (2008), And include it by reference. Photosensitizers are described in RR Allison and CH Sibata, "Tumor Photodynamic Therapeutics Photosensitizers: A Clinical Review", Photodiagnosis Photodynamic Ther. 7: 61-75 (2010), and are incorporated by reference. Radiation repair inhibitors and DNA repair inhibitors are described in M. Hingorani et al., "Assessment of radiation-induced DNA damage enhances the performance of replication-defective adenoviral vectors", Cancer Res. 68: 9771-9778 (2008) And include it by reference. Thiol consuming agents are described in KD Held et al., "After irradiation sensitization of thiol-derived dimethyl fumarate mammalian cells", Radiation Res. 127:75-80 (1991), and Include it by reference. Vascular target agents are described in ALSeynhaeve et al., "Tumor necrosis factor alpha mediated uniform distribution of liposomes in murine melanoma that contributes to better tumor response", Cancer Res. 67:9455-9462 (2007) ).

When the improvement is carried out by a novel mechanism of action, the novel mechanism of action It may be, but is not limited to, a novel mechanism of action with a therapeutic interaction of a target or mechanism selected from the group consisting of: (a) an inhibitor of poly ADP ribose polymerase; b) agents that affect blood vessels; (c) agents that promote vasodilation; (d) oncogene-targeted drugs; (e) signal delivery inhibitors; (f) agents that cause EGFR inhibition; (g) cause protein kinase C An inhibitory agent; (h) an agent that causes a decrease in phospholipase C; (i) an agent that causes jun down regulation; (j) an agent that modulates the expression of a tissue protein gene; (k) an agent that modulates the expression of VEGF; An agent that modulates the expression of adenine decarboxylase; (m) an agent that modulates the performance of jun D; (n) an agent that modulates the expression of v-jun; (a) an agent that modulates the expression of GPCRs; (a) a regulatory protein An agent that exhibits the expression of kinase A; (q) an agent that modulates the expression of a protein kinase (other than protein kinase A); (r) an agent that modulates the expression of telomerase; (s) an agent that modulates the expression of a specific gene of the prostate; And (t) an agent that modulates the expression of histone deacetylase.

Inhibitors of poly ADP ribose polymerase include veliparib (ABT-888), AGO14699, iniparib (BSI-201), carboplatin, gemcitabine, INO-1001, MK4827, nicotinamide, olaparib , paclitaxel, temozolomide, and topotecan, and are described in EA Comen and M. Robson, "Inhibitors of Poly ADP Ribose Polymerase as a Therapeutic Strategy for Breast Cancer," Oncology 24: 55-62 (2010), and Include it by reference. Agents that promote vasodilation include Levosimendan and are described in WG Toller et al., "Levosimendan, a new agent that affects muscle contractility and vasodilators", Anesthesiology 104:556-569 (2006) And include it by reference. EGFR inhibition is described in G. Giaccon and JA Rodriguez, "EGFR inhibitors: what we learned from lung cancer treatment", Nat. Clin. Pract. Oncol. 11: 554-561 (2005), and included by reference. Inside. Protein kinase C inhibition is described in HCS Wannie and SB Kaye, "Protein Kinase C Inhibitors", Curr. Oncol. Rep. 4: 37-46 (2002), and is incorporated by reference. Phospholipase C downregulation is described in AM Martelli et al., "Signaling of phosphoinositide in the nucleus of Friend cells: Phospholipase C beta downregulation is associated with cell differentiation", Cancer Res. 54: 2536-2540 (1994) and is included by reference. The downregulation of Jun (especially c-Jun) is described in AAPZada et al., "C-Jun Expression and Decreasing Regulation of Cell Cycle Regulatory Molecules in Acute Myeloid Leukemia Cells after CD44 Polymerization", Oncogene 22: 2296-2308 (2003) and include it by reference. The role of histone genes as targets for therapeutic intervention is described in B. Calabretta et al., "Variant Expression of G1-Specific Genes in Human Malignant Bone Marrow Cells", Proc. Natl. Acad. Sci. USA 83: 1495-1498 (1986) and include it by reference. The role of VEGF as a target for therapeutic prevention is described in A. Zielke et al., "The VEGF vector angiogenesis of human pheochromocytoma in experimental tumors is related to malignant tumors and by anti-VEGF antibodies And suppression", Surgery 132: 1056-1063 (2002), and includes it by reference. The role of alginate decarboxylase as a target for therapeutic prophylaxis is described in JANilsson et al., "Targeting avian acid decarboxylase to prevent tumor formation in Myc-induced lymphoma," Cancer Cell 7: 433- 444 (2005) and include it by reference. The role of ubiquitin C as a target for therapeutic prevention is described in C. Aghajanian et al., "Phase I clinical trial of the novel proteasome inhibitor PS341 in advanced parenchymal malignancies", Clin. Cancer Res. 8:2505-2511 (2002) and include it by reference. The role of Jun D as a target for therapeutic prevention is described in MMCaffarel et al., "JunD involved in the antiproliferative effect of 9-tetrahydrocannabinol in human breast cancer cells", Oncogene 27: 5033- 5044 (2008) and include it by reference. The role of v-Jun as a target for therapeutic prevention is described in M. Gao et al., "Difference and Antagonism of v-Jun and c-Jun", Cancer Res. 56: 4229-4235 (1996) And include it by reference. The role of protein kinase A as a target for therapeutic prevention is described in PC Gordge et al., "Elevation of protein kinase A and protein kinase C in malignant tumors compared to normal breast tissue", Eur. J. Cancer 12 : 2120-2126 (1996) and included by reference. The role of telomerase as a target for therapeutic prevention is described in EK Parkinson et al., "Terminal enzymes as novel and potential selective targets for cancer chemotherapy", Ann. Med. 35:466- 475 (2003) and include it by reference. The role of histone deacetylase as a target for therapeutic prevention is described in A. Melnick and JDLicht, "Histone Deacetylase as a therapeutic target in hematological malignancies", Curr. Opin. Hematol. 9: 322-332 (2002) and includes it by reference.

When the improvement is carried out by using selective target cell population therapy, the use of the selective target cell population therapy can be, but is not limited to, the use selected from the group consisting of: (a) Resistant to radiation-sensitive cells; (b) to resist radiation-resistant cells; and (c) to resist energy-depleting cells.

This modification can also be carried out by using an alkylation combination with ionizing radiation.

When the improvement is carried out by using an agent for increasing the activity of the alkylated hexitol derivative, and the agent for increasing the activity of the alkylated hexitol derivative may be, but not limited to, An agent selected from the group consisting of (a) nicotinamide; (b) caffeine; (c) tetrandrine; and (d) berberine.

As described above, in view of these findings, mutation, overexpression or dysregulation of the AHI1 gene is associated with many malignant tumors, including chronic myeloid leukemia, and the monoalkylated hexitol derivative can also modulate the AHI1. The gene or agent for the expression or activity of the AHI1 protein is used together. In this alternative, the method further comprises: administering a therapeutically effective amount of an agent that modulates the performance or activity of the AHI1 gene or the AHI1 protein.

In an alternative, the agent that modulates the expression or activity of the AHI1 gene or the AHI1 protein is an agent that modulates the expression of the AHI1 gene. Transcription of the AHI1 gene The regulation of AHI1 expression can be performed horizontally or at the level of translation of the AHI1 gene.

In some embodiments, the inhibitory nucleotide is used to modulate AHI1 expression. These include short interfering RNA (siRNA), microRNA (miRNA) and synthetic hairpin RNA (shRNA); antisense nucleic acid; or complementary DNA (cDNA). In some preferred embodiments, an siRNA is used to target AHI1 expression. Functional interference and the expression of endogenous genes by double-stranded RNA (eg, siRNA) have been demonstrated in a variety of organisms. See, for example, A. Fire et al., "Effective and Special Gene Interference in Double-stranded RNA in Caenorhabditis elegans ", Nature 391: 806-811 (1998); JR Rennerdell and RW Carthew, "dsDNA Use of vector gene interference to demonstrate that frizzled and curl 2 act in the Wingless pathway, Cell 95: 1017-1026 (1998); F. Wianni and M. Zernicka-Goetz, "In early mice There is a special interference in the development of gene function by double-stranded RNA", Nat. Cell Biol. 2: 70-75 (2000). The siRNAs may comprise a hairpin loop containing either a self-complementary sequence or a double-stranded sequence. siRNAs typically have less than 100 base pairs and can be, for example, about 30 bps or less, and can be made by methods known in the art, including the use of complementary DNA strands or synthetic routes. Such double-stranded RNA can be synthesized by in vitro transcription of single-stranded RNA read from both directions of the template and in vitro annealing of sense and antisense RNA strands. In the opposite direction separated by the inverted repeat sequence, the double-stranded RNA targeting AHI1 can also be synthesized by culturing the AHI1 gene from the cDNA vector construct plastid. Following cell transfection, the RNA is transcribed and recombined with complementary strands. The double-stranded RNA targeting AHI1 gene can be introduced into cells (eg, a leukemia cell or other tumor cell) by appropriate constructed plastid transfection. Typically, at the level of translation, RNA interference mediated by siRNA, miRNA or shRNA is mediated; in other words, these interfering RNA molecules prevent translation of the corresponding mRNA molecules, resulting in their degradation. RNA interference can also operate at the level of transcription, preventing transcription of regions relative to the genome of these interfering RNA molecules. The structure and function of these interfering RNA molecules are in known in the art, and are described for example in RFGesteland et al., Eds, "RNA ^{World" (3 rd ed, Cold Spring} Harbor Laboratory Press, Cold Spring Harbor, New York, 2006 ), pp. 535-565, and include it by reference.

For these methods, colonization into vectors and transfection methods are also well known in the art and are described, for example, in J. Sambrook and DR Russell, "Molecular Selection: A Laboratory Manual" (3 ^rd ed., Cold Spring Harbor) Laboratory Press, Cold Spring Harbor, 2001), and includes it by reference.

In addition to double-stranded RNAs, other nucleic acid reagent targets AHI1 can also be used in the methods of the invention, such as antisense nucleic acids. An antisense nucleic acid is a DNA or RNA molecule that is complementary to at least a portion of a particular target mRNA molecule. In this cell, the single antisense molecule hybridizes to that mRNA to form a double stranded molecule. In this double-stranded form, the cell did not translate an mRNA. Thus, an antisense nucleic acid interferes with translation of the mRNA into the protein and, therefore, has a representation of the gene transcribed into that mRNA. Antisense methods have been used in vitro to inhibit the performance of many genes. See, for example, CJ Marcus-Sekura, "Using antisense oligodeoxyribonucleotides to study gene expression techniques", Anal. Biochem. 172:289-295 (1988); JE Hambor et al., "Human cytotoxic T- Use of Epstein-Barr Virus free replicon for antisense RNA vector gene suppression in cell expression strains, Proc. Natl. Acad. Sci. USA 85: 4010-4014 (1988); H Arima et al. "Specific inhibition of the interleukin-10 product by murine macrophages by thiophosphate antisense oligonucleotides", Antisense Nucl. Acid Drug Dev. 8:319-327 (1998) And W.-F. Hou et al., "The effect of antisense deoxyoligonucleotides directed to the individual calcitonin gene transcripts in the proliferation and differentiation of PC12 cells", Antisense Nucl. Acid Drug Dev. 8:295 -308 (1998), all of which are incorporated by reference. Antisense techniques are further described in C. Lichtenstein and W. Nellen, eds., "Antisense Technology: A Practical Approach" (IRL Press, Oxford, 1997), and are incorporated by reference.

AHI1 nucleotide sequences, such as those derived from RNA, are known in the art and comprise a gene sequence recorded in the gene bank NM_001134830.1, NM_001134831.11, NM_001134832.1, and NM_017651.4; These sequences represent transcript variants. Based on known sequences, targeting PAR1 can be readily synthesized by inhibitory nucleotides (eg, siRNA, miRNA or sRNA) using methods well known in the art. Exemplary siRNAs of the invention may have an integer of 29 bps, 25 bps, 22 bps, 21 bps, 20 bps, 15 bps, 10 bps, 5 bps or base pairs between any of these numbers. Tools for designing optimal inhibitory siRNAs are available from DNAengine Inc. (Seattle, WA) and Ambion, Inc. (Austin, TX).

As another alternative, the inhibition of the AHI1 gene or the AHI1 protein The agent that exhibits or is active may be an agent that inhibits the activity of the AHI1 protein. For example, such an agent can be an antibody that binds to the AHI1 protein or one or more receptors that specifically bind to the AHI1 protein. The preparation of such antibodies is well known in the art and does not require further description. In general, although IgG antibodies are generally preferred, the antibodies of the invention may be, for example, any of IgG, IgA, IgD, IgE, IgM or IgY. The antibody may be of any mammalian or avian origin and comprises human, murine (mouse or rat), donkey, sheep, goat, rabbit, camel, horse or chicken. In the same alternative, the antibody can be bispecific. The antibody can be modified by covalent attachment of any type of molecule to the antibody. For example, but not by way of limitation, the antibody derivative comprises an antibody that has been modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidiation, by known protection/ Derivatization of blocking groups, protease cleavage, ligation to a cellular ligand or other protein, or other modifications known in the art. Individual antibodies can be prepared using a variety of techniques known in the art, including the use of fusion tumors, recombinant and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using fusion cell technology, including those known and taught in the art, for example, in Harlow et al., "Antibody: A Laboratory Manual" (Cold Spring Harbor Laboratory Press, 2nd ed. 1988). Hammerling et al., monoclonal antibody and T cell fusion tumor 563-681 (Elsevier, NY, 1981) or by other standard methods known in the art. The term "monoclonal antibody" as used herein is not limited to antibodies produced by fusion tumor technology. The term "monoclonal antibody" refers to an antibody derived from a single expression strain comprising any eukaryotic, prokaryotic or phage display strain, rather than the method by which it is produced. For example, suitable antibodies can be produced by phage display or other techniques. Furthermore, without being limited in this way, human antibodies can be produced by a variety of techniques, including phage display using an antibody library derived from human immunoglobulin sequences and by using a gene-transferred mouse, the gene Transgenic mice are unable to express functional endogenous immunoglobulins, but they can express human immunoglobulin gene complexes. For example, human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. The antibody can also be produced by encoding the antibodies by the expression of the polynucleotide. Furthermore, the antibodies of the invention may be fused to a marker sequence, such as a peptide for ease of purification; The label is a six-histidine acid label. The antibody can also be conjugated to a diagnostic or therapeutic agent by methods known in the art. Techniques for preparing such conjugates are well known in the art.

Other methods for the preparation of these monoclonal antibodies, as well as chimeric antibodies, anthropomorphic antibodies and single chain antibodies, are known in the art. Generally, it is preferred to administer to a human patient, human antibody, chimeric antibody or anthropomorphic antibody.

In another alternative, the agent that modulates the activity of the AHI1 protein is an antagonist that specifically binds to the receptor of the AHI1 protein, and comprises the serotonin receptor 2C, but the invention is not limited thereto.

In still another alternative, the agent that modulates the activity of the AHI1 protein is an antibody that specifically binds to the receptor of the AHI1 protein, and comprises the serotonin receptor 2C, but the invention is not limited thereto.

In still another alternative, the agent that modulates the activity of the AHI1 protein is an agent that inhibits a transcription factor having a binding position in the promoter of the AHI1 gene, comprising RFX1, POU2F1, POU2F1a, Nkx2-5, Evi-1, and RSRFc4 However, the invention is not limited thereto.

Another aspect of the present invention is to provide a composition for increasing the efficacy and/or side effects of an undesired administration therapy using a monoalkylated hexitol derivative for treatment An anti-TKI tumor or a malignant tumor associated with abnormal regulation or mutation of the AHI1 gene, the composition comprising a selection scheme selected from the group consisting of: (i) a modified alkylated hexitol derivative Or a therapeutically effective amount of a derivative, analog or precursor of a monoalkylated hexitol derivative or a modified alkylated hexitol derivative, wherein the unmodified alkylated hexitol derivative is compared to an unmodified alkylated hexitol derivative The modified alkylated hexitol derivative or a derivative, analog or precursor of the modified alkylated hexitol derivative has a malignant tumor associated with an anti-TKI tumor or an abnormal regulation or mutation of the AHI1 gene The treatment increases the therapeutic effect or reduces the side effects; (ii) the composition comprising: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative Or a modified alkylated hexitol derivative a therapeutically effective amount of a derivative, analog or precursor; and (b) at least one additional therapeutic agent, a therapeutic agent that is chemically sensitized, A synergistic therapeutic agent, diluent, excipient, solvent system or drug delivery system wherein the composition has an anti-TKI tumor or with AHI1 compared to an unmodified alkylated hexitol derivative Abnormal regulation of genes or treatment of mutation-associated malignancies increases efficacy or reduces side effects; (iii) monoalkylated hexitol derivatives, a modified alkylated hexitol derivative or incorporated into a dosage form or A therapeutically effective amount of a derivative, analog or precursor of a monoalkylated hexitol derivative or a modified alkylated hexitol derivative, wherein, compared to an unmodified alkylated hexitol derivative, a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative in the dosage form Derivatives, analogs or precursors have increased efficacy or reduced side effects for the treatment of a primary anti-TKI tumor or a malignant tumor associated with abnormal regulation or mutation of the AHI1 gene; (iv) incorporated into a dose set and package Monoalkylated hexitol derivatives, A therapeutically effective amount of a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor thereof, wherein Modified alkylated hexitol derivatives, monoalkylated hexitol derivatives, modified alkylated hexitol derivatives or monoalkylated hexitols incorporated into the dosage kit and package A derivative, analog or precursor of a derivative or a modified alkylated hexitol derivative having increased therapeutic effect or reduced side effects for treatment of a primary anti-TKI tumor or a malignant tumor associated with abnormal regulation or mutation of the AHI1 gene; (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative modified by a bulk drug product A therapeutically effective amount of a derivative, analog or precursor of a substance, wherein the alkylated hexitol derivative modified by the drug substance product, a modification, compared to an unmodified alkylated hexitol derivative Alkylated hexitol derivative or monoalkylated Alcohol derivatives or alcohol derivatives of hexitol derivative alkylating a modified analog or a precursor thereof having anti-TKI for treating tumor or cancer associated with abnormal regulation of the gene or mutation AHI1 increase efficacy or reduce side effects.

As described above, the alkylated hexitol derivative may be, but not limited to, a stilbitol, a derivative or analog of vecanol, dihydroquinone dihydrated dulcitol, diacetyl quinone dihydrated euphorol A derivative or analog, dibromodusol, or a derivative or analog of dicyclohexyl alcohol.

In an alternative, the composition has an increased therapeutic effect or reduced side effects for the treatment of a primary anti-TKI tumor.

In an alternative, the composition has an increased therapeutic effect or a reduced side effect for the treatment of a malignant tumor associated with abnormal regulation or mutation of the AHI1 gene.

In an alternative, the composition comprises a combination comprising: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a derivative, analog or precursor of a modified alkylated hexitol derivative; and (ii) an additional therapeutic agent selected from the group consisting of: (a) a positional isomerase inhibitor (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidine synthase inhibitor; (e) signal delivery inhibitor; (f) cisplatin or platinum analogue; (g) alkylating agent (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; (l) naphthophene; (m) vinca alkaloid; (n) 5 - fluorouracil; (o) curcumin; (p) NF-κB inhibitor; (q) rosmarinic acid; (r) propyl hydrazine; (s) tetrandrine; (t) a JAK2 inhibition Agent (u) a STAT5 inhibitor; and (v) a Src inhibitor.

In these alternatives, when the additional therapeutic agent is an alkylating agent, the alkylating agent can be, but is not limited to, one selected from the group consisting of BCNU, BCNU tablets, CCNU, bendamustine (Treanda), and temodazole (Temodar). A group of alkylating agents.

In another alternative, the composition comprises a combination comprising: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative Or a modified derivative, analog or precursor of an alkylated hexitol derivative; and (ii) a BH3 analog.

In another alternative, the composition comprises a combination comprising: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative Or a modified derivative, analog or precursor of an alkylated hexitol derivative; and (ii) an agent that modulates the expression of the AHI1 gene or modulates the activity of the AHI1 protein.

In still another alternative, the composition comprises a combination comprising: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative Or a modified derivative, analog or precursor of an alkylated hexitol derivative; (ii) an agent that modulates the expression of the AHI1 gene or the activity of the AHI1 protein; and (iii) a BH3 analog.

In another alternative, the composition comprises: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkyl group. a derivative, analog or precursor of a hexitol derivative; and (ii) a chemical sensitizing therapeutic agent selected from the group consisting of: (a) positional isomerase inhibition (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidine synthase inhibitor; (e) signal delivery inhibitor; (f) cisplatin or platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; Alkalin; (l) analog of colchicine or colchicine; (m) genistein; (n) rituxep; (o) arabinosylcytosine; (p) camptothecin; q) vinca alkaloids; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; and (v) acetophenone, a derivative, analog or precursor of the alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative As a chemical sensitizer.

In still another alternative, the composition comprises: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkyl group a derivative, analog or precursor of a hexitol derivative; and (ii) a chemically synergistic therapeutic agent selected from the group consisting of: (a) a pseudonucleoside; b) a pseudonucleotide; (c) thymidine synthase inhibitor; (d) signal delivery inhibitor; (e) cisplatin or platinum analog; (f) alkylating agent; (g) anti-tubulin agent; (h) antimetabolite (i) berberine; (j) apigenin; (k) analog of colchicine or colchicine; (l) genistein; (m) etatopse; (n) arabinose Pyrimidine; (o) camptothecin; (p) vinca alkaloids; (q) positional isomerase inhibitor; (r) 5-fluorouracil; (s) curcumin; (t) NF- κ B inhibitor; (u) rosmarinic acid; (v) acetamidine; and (w) a biological therapeutic wherein the alkylated hexitol derivative, a modified alkylated hexitol derivative Alternatively, a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor is used as a chemical synergist.

In these alternatives, wherein the additional therapeutic agent is a biological therapeutic, the biological therapeutic can be, but not limited to, a group selected from the group consisting of cancer, Hepatic, rituximab and Erbitux. Biotherapeutics.

In still another alternative, the alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative The derivative, analog or precursor is modified by a bulk drug product, wherein the drug substance product modification is selected from the group consisting of: (a) salt formation; (b) as a uniform crystal structure (c) as a pure isomer adjustment; (d) increased purity; (e) a low residual solvent content; and (f) a low residual solvent content.

In still another alternative, the composition comprises: an alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexose a derivative, analog or precursor of an alcohol derivative; and a diluent, wherein the diluent is selected from the group consisting of: (a) an emulsion; (b) dimethyl hydrazine (DMSO) (c) N-methylformamide (NMF); (d) dimethylformamide (DMF); (e) dimethylacetamide (DMA); (f) ethanol; (g) Benzyl alcohol; (h) water containing glucose for injection; (i) polyoxyethylene castor oil; (j) cyclodextrin; and (k) PEG.

In still another alternative, the composition comprises: an alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexose a derivative, analog or precursor of an alcohol derivative; and a solvent system, wherein the solvent system is selected from the group consisting of: (a) an emulsion; (b) DMSO; (c) NMF; (d) DMF; (e) DMA; (f) ethanol; (g) benzyl alcohol; (h) water containing glucose for injection; (i) polyoxyethylene castor oil; PEG; and (k) salt system.

In still another alternative, the composition comprises: an alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexose a derivative, analog or precursor of an alcohol derivative; and an excipient, wherein the excipient is selected from the group consisting of: (a) mannitol; (b) albumin; EDTA; (d) sodium hydrogen sulfite; (e) benzyl alcohol; (f) carbonate buffer; (g) phosphate buffer; (h) PEG; (i) vitamin A; (j) vitamin D; (k) vitamin E; (1) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibitor; (o) organic resin; (p) detergent; (q) perillol or an analogue thereof; and (r) an activator for channel forming receptors.

In still another alternative, the alkylated hexitol derivative, modified alkylated hexitol derivative or monoalkylated hexitol derivative or modified alkylated hexitol derivative, The analog or precursor is incorporated into a dosage form selected from the group consisting of: (a) a tablet; (b) a capsule; (c) a topical gel; (d) Topical ointment; (e) patch; (f) embolic agent; (g) lyophilized dose filler; (h) immediate release formulation; (i) sustained release formulation; (j) controlled release formulation; and (k) liquid capsule.

In still another alternative, the alkylated hexitol derivative, modified alkylated hexitol derivative or monoalkylated hexitol derivative or modified alkylated hexitol derivative, The analog or precursor is incorporated into a dose kit and package selected from a brown bottle that is protected from light and a bottle with a special coating to increase shelf life stability. A group of plugs.

In still another alternative, the composition comprises: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylation a derivative, analog or precursor of a sugar alcohol derivative; and (ii) a drug delivery system, wherein the drug delivery system is selected from the group consisting of: (a) an oral dosage form; (b) a na[beta] Rice crystals; (c) nanoparticles; (d) cosolvent; (e) slurry; (f) syrup; (g) bioerodible polymer; (h) liposome; (i) sustained release injection gel; (j) microspheres; a targeting composition having an epidermal growth factor receptor binding peptide.

In still another alternative to a composition of the invention, the therapeutic agent is a modified alkylated hexitol derivative and the modification is selected from the group consisting of: (a) side chain changes To increase or decrease lipophilicity; (b) an increase in another chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding ability; and (c) variation in salt type.

In still another alternative of a composition of the invention, the therapeutic agent is a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkyl group. A derivative or analog of a hexitol derivative, and the therapeutic agent is present in a composition in a conjugated form of the drug, wherein the conjugated form of the drug is a drug selected from the group consisting of Conjugated forms: (a) a polymer system; (b) polylactic acid; (c) polyglycolic acid; (d) amino acid; (e) peptide; (f) multivalent linker; (g) Immunoglobulin; (h) cyclodextrin polymer; (i) modified transferrin; (j) hydrophobic polymer or hydrophobic-hydrophilic polymer; (k) a conjugate having a partial sodium phosphate monoester; (1) a conjugate having a cell binder added with a charged crosslinking agent; and (m) a total of β-glucuronic acid having a linking agent Yoke.

In still another alternative of a composition of the invention, the therapeutic agent is a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkyl group. A derivative or analog of a hexitol derivative, and the therapeutic agent is in the form of a precursor system, wherein the precursor system is selected from the group consisting of: (a) an enzyme-sensitive ester; (b) dimer; (c) Schiff base; (d) pyridoxal complex; (e) caffeine complex; (f) nitric oxide releasing precursor; (g) fibroblast activation protein a precursor of the α-cleavable oligopeptide; (h) a product of reaction with a deuterating agent or an amine carbamate; (i) a hexanoate conjugate; (j) a polymer-agent conjugate And (k) are driven by redox activation.

In still another alternative of a composition of the invention, the therapeutic agent is a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkyl group. A derivative, analog or precursor of a hexitol derivative, and the composition further comprises at least one additional therapeutic agent to form a multi-drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of Groups: (a) a multidrug resistance inhibitor; (b) a specific drug resistance inhibitor; (c) a specific selective enzyme inhibitor; (d) a signal delivery inhibitor; e) an inhibitor of repair enzyme; and (f) a positional isomerase inhibitor with non-overlapping side effects.

In still another alternative of a composition of the invention, the composition comprises a therapeutic agent and a BH3 analog as described above, the therapeutic agent being a monoalkylated hexitol derivative, a modified alkylated hexitol A derivative or a monoalkylated hexitol derivative or a derivative, analog or precursor of a modified alkylated hexitol derivative.

When the pharmaceutical compositions of the present invention comprise a precursor, the precursors and active metabolites of a compound can be identified using conventional techniques known in the art. See, for example, Bertolini et al, J. Med. Chem., 40, 2011-2016 (1997); Shan et al, J. Pharm. Sci., 86(7), 765-767; Bagshawe, Drug Dev. Res , 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Precursors (Elsevier Press 1985); Larsen, Design and Application of Precursors, Drug Design and Development ( Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991); Dear et al, J. Chromatogr. B, 748, 281-293 (2000); Spraul et al, J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992) And Prox et al., Xenobiol., 3, 103-112 (1992).

When the pharmaceutically active compound in the pharmaceutical compound of the present invention has a sufficiently acidic functional group, a sufficiently basic functional group or a sufficiently acidic functional group and a sufficiently basic functional group, these groups or groups The groups can accordingly react with any of a number of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those prepared by the reaction of a pharmaceutically active compound having an inorganic or organic acid or an inorganic base, for example, comprising a sulfate, a pyrosulfate, a disulfate, a sulfite, Bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, citrate, octoate, Acrylates, formates, isobutyrates, hexanoates, heptanoates, propiates, oxalates, malonates, succinates, suberates, sebacates, Fumar Acid, maleate, butyne-1,4-diate, hexyne-1,6-diate, benzoate, chlorobenzoate, methyl benzoate, dinitro Benzoates, hydroxybenzoates, methoxybenzoates, decanoates, sulfonates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrate, citrate , lactate, β -hydroxybutyrate, glycolate, tartaric acid, methane-sulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid Salts and salts of mandelic acid salts. If the pharmaceutically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, a treatment with a free base of a mineral acid, such as hydrogen. Chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or treatment with a free base of an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid , glycolic acid, salicylic acid, pyranosidic acid (such as glucuronic acid or galacturonic acid), alpha -hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid) An aromatic acid (such as benzoic acid or cinnamic acid), or a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid) or the like. If the pharmaceutically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treatment with a free acid of an inorganic or organic base, such as a Amines (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine And inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

In the case where the medicament is a solid, those skilled in the art can understand that the present invention The compounds and salts of the present invention may exist in different crystalline forms or polymorphic forms, all of which are intended to be within the scope of the invention and the formula.

a unit dose of a specific pharmaceutically active agent contained in the pharmaceutical composition of the present invention The amount, for example, a derivative or analog of Weikangol or Weikangol as described above, will vary depending on factors such as the specific compound, the condition of the disease and its severity, and the target subject needs treatment The characteristics (e.g., weight) can still be determined periodically by those skilled in the art. Generally, such pharmaceutical compositions comprise a therapeutically effective amount of a pharmaceutically active agent and an inert pharmaceutically acceptable carrier or diluent. These compositions are usually prepared, for example, by oral administration or parenteral administration, in unit dosage forms suitable for the route of administration. In a conventional dosage form prepared by combining a therapeutically effective amount of such a pharmaceutically active agent as an active ingredient with a suitable pharmaceutical carrier or diluent according to a conventional method, the pharmaceutically active agent as described above can be administered. These procedures may involve mixing, granulating, compressing, and dissolving ingredients suitable for the desired formulation. The pharmaceutical carrier employed can be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Likewise, the carrier or diluent may contain a time delay or sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate. Separately or with wax, ethyl cellulose, hydroxypropylmethylcellulose, methyl methacrylate, and the like.

Various pharmaceutical forms can be used. Thus, if a solid carrier is employed, in the form of a powder or small granules or in the form of a tablet or lozenge, the preparation may be presented as a tablet, placed in a hard gelatin capsule. The amount of solid carrier may vary, but will generally range from about 25 mg to about 1 g. If a liquid carrier is used, it will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.

To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of a pharmaceutically active agent as described above is dissolved in an aqueous solution of an organic or inorganic acid (e.g., a solution of 0.3 M succinic acid or citric acid). If a soluble salt type is not available, the agent can be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable cosolvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, and the like, in the range of 0-60% of the total volume. In an exemplary embodiment, a compound of formula (I) is dissolved in DMSO and diluted with water. In a suitable aqueous vehicle such as water or isotonic saline or dextrose solution, the composition may also be in the form of a salt-type solution of the active ingredient.

It will be understood that the compositions of the present invention are used in accordance with the particular complex being used, the formulation of the particular composition, the administration and location, the mode of the host and the disease, and/or the condition being treated. The actual dose of the agent will vary. The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to provide an amount of the active ingredient which is effective to achieve the desired therapeutic response for the particular subject, composition, and mode of administration. Not toxic to the target. The selected dosage level will depend on the various pharmacokinetic factors, including the activity of the particular therapeutic agent, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the severity of the condition, and other factors affecting the subject. Health factors, as well as the state of liver and kidney function of the target subject. It also depends on the duration of treatment; other drugs, compounds and/or materials are used in combination with the particular therapeutic agent used; and the age, weight, condition, general health and prior medical history of the target being treated; and similar factors . Determination of optimum dosages are described in the prior art, for example: Remington: The Science and Practice of ^{Pharmacy, Mack Publishing Co., 20 th ed} , 2000.. The optimal dosage for a given condition can be determined by one of ordinary skill in the art using conventional dosimetry assays in view of experimental data for the agent. For oral administration, an exemplary daily dose will generally range from about 0.001 to about 3000 mg/kg body weight (mg/kg of body weight) with repeated course of treatment at appropriate intervals. In some embodiments, the daily dose is from about 1 to 3000 mg/kg of body weight.

A typical daily dose in a patient, once or twice daily, for example, It can be administered twice 3000 mg per day (total dose 6000 mg). In one embodiment, the dosage is between about 1000 and about 3000 mg. In another embodiment, the dosage is between about 1500 and about 2800 mg. In other embodiments, the dosage is between about 2000 and about 3000 mg.

The plasma concentration in the target subject can range from about 100 [mu]M to about Between 1000 μM. In some embodiments, the plasma concentration can be between about 200 [mu]M and about 800 [mu]M. In other embodiments, the concentration is between about 300 [mu]M and about 600 [mu]M. In other embodiments, the plasma concentration can be between about 400 [mu]M and about 800 [mu]M. The predrug is usually administered at a dose level that is chemically equivalent to the fully activated form of the weight level.

The compositions of the present invention may be generally used for the preparation of pharmaceutical compositions. Techniques are made, for example, by conventional techniques such as mixing, dissolving, granulating, dragee forming, suspending, emulsifying, encapsulating, capturing or lyophilizing. In a conventional manner of using one or more physiologically acceptable carriers, the pharmaceutical compositions may be formulated, which may be selected from the excipients and auxiliaries which facilitate the treatment of the active compound into a pharmaceutically acceptable formulation.

The appropriate formulation will depend on the route of administration chosen. For injection, this hair The clearing agent can be formulated in an aqueous solution, preferably in a physiologically compatible buffer, such as a solution of Hanks, a solution of Ringer or a buffer of physiological saline. For mucosal administration, penetrants suitable for the permeation barrier are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compound can be combined with the active compound and the art It is readily formulated by known pharmaceutically acceptable carriers. Such a carrier enables the compound of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions and the like for the oral administration of patients. In the blend with the active ingredient (agent), the pharmaceutical preparation for oral use can be obtained by using a solid excipient, if necessary, obtaining a tablet or a sugar-coated core, optionally grinding the obtained mixture, and adding Suitable additives A mixture of post-processed particles. Suitable excipients include, for example, fillers of saccharides, including lactose, sucrose, mannitol or sorbitol; and cellulosic products such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl fiber , hydroxypropyl methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidine (PVP). If necessary, a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof (for example, sodium alginate) may be added.

The dragee core has a suitable coating. For this purpose, concentrated sugar can be used A solution, which may optionally contain gum arabic, polyvinylpyrrolidone, carboxyvinyl polymer (Carbopol) gel, polyethylene glycol and/or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablet or dragee coating to identify or represent different combinations of therapeutically active agents.

Delicious pharmaceutical preparations include push-fit glue made of gelatin Capsules, as well as soft, sealed capsules and plasticizers made of gelatin (such as glycerin or sorbitol). In a blend having a filler (eg, lactose), a binding agent (eg, starch), and/or a lubricant (eg, talc or magnesium stearate), and optionally a stabilizer, the press-fit capsule can comprise the Active ingredient. In soft capsules, the therapeutically active agent can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration. For oral administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

Pharmaceutical preparations for parenteral administration may comprise aqueous solutions or suspensions. Combined Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain materials which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may contain suitable stabilizers or regulators to increase the solubility or dispersibility of the composition to allow for the preparation of highly concentrated solutions, or may comprise a suspending or dispersing agent. The pharmaceutical preparation for oral use can be obtained by combining a pharmaceutically active agent with a solid excipient, if necessary, obtaining a tablet or a sugar-coated core, randomly grinding the obtained mixture, and processing the particles after adding a suitable auxiliary agent. mixture. Suitable excipients are, in particular, fillers for saccharides, including lactose, sucrose, mannitol or sorbitol; cellulose products such as corn starch, wheat starch, rice starch, potato starch, gelatin, yoghurt gum, methyl fiber , hydroxypropyl methylcellulose, carboxymethyl fiber Sodium and/or polyvinylpyrrolidine (PVP). If necessary, a disintegration modifier such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof (for example, sodium alginate) may be added.

Other components such as stabilizers are, for example, sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, vitamin C, vitamin E, sodium hydrogen sulfite, butyl. An antioxidant of hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl- α -naphthylamine or lecithin can be used. Also, a chelating agent such as EDTA can be used. Other ingredients of pharmaceutical compositions and formulations conventionally used in the art, such as lubricants, colorants or flavoring agents in tablets or pills, can be used. Also, conventional pharmaceutical excipients or carriers can be used. The pharmaceutical excipient can include, but is not necessarily limited to, calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art. Exemplary pharmaceutically acceptable carriers include, but are not limited to, any solvent and/or all solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, and/or isotonicity and/or Or absorb delayed agents and so on. The use of such media and/or agents for pharmaceutically active substances is well known in the art. The use of any of the conventional media, carriers or agents in the compositions of the present invention is contemplated unless it is incompatible with the active ingredients or ingredients. The accessory active ingredient may also be part of the composition, especially as described above. The formulation should meet the sterility, exotherm, general safety and purity standards required by the FDA Bacterial Standards Bureau or other regulatory tissue-modulating drugs.

For intranasal or by inhalation, in the use of pressurized containers or sprayers A suitable propellant is present in the form of an aerosol spray to conveniently deliver the compound used in the present invention, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other Suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to release a metered amount. Capsules and cartridges of gelatin for inhalation or insufflation, etc., may be formulated with a powder mixture of a compound and a suitable powder base such as lactose or starch.

The compound can be formulated for parenteral administration by injection, for example, by single administration Injection or continuous injection. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. In oily or aqueous media The composition may take such forms as suspensions, solutions or emulsions, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.

In a water-soluble form, a pharmaceutical preparation for parenteral administration comprises an active compound An aqueous solution of the substance. In addition, suspensions of therapeutically active agents can be prepared in a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain materials which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may contain suitable stabilizers or agents which increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in the form of a powder of a suitable vehicle. For example, sterile pyrogen-free water before use. The compounds may also be formulated in rectal compositions such as embolic or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the preparations described above, the compound can also be formulated to be effective. Agent. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (for example as an emulsion in an acceptable oil) or an ion exchange resin, or as a poorly soluble derivative, for example, to form a poorly soluble salt.

An exemplary pharmaceutical carrier for a hydrophobic compound is a cosolvent system, It comprises benzyl alcohol, a non-polar surfactant, a water-soluble organic polymer and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is a solution consisting of 3% w/v benzyl alcohol, 8% w/v nonpolar surfactant polysorbate 80 and 65% w/v polyethylene glycol 300 (quantified volume in absolute ethanol). The VPD cosolvent system (VPD: 5W) contained VPD and a 5% aqueous glucose solution, and the dilution ratio of the two was 1:1. This cosolvent system fully dissolves the hydrophobic compound and itself produces low toxicity over systemic administration. Of course, the ratio of the cosolvent system can vary widely without destroying its solubility and toxic properties. In addition, the nature of the cosolvent component can be altered: for example, other low toxicity non-polar surfactants can be used in place of polysorbate 80; the fraction of polyethylene glycol can be varied; other biocompatible polymers Can replace polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides can be grape Replaced by sugar.

Alternatively, other delivery systems for hydrophobic drug compounds can be used. fat Plastosomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Although more toxic is often lost, certain organic solvents such as dimethyl hydrazine can also be used. In addition, the compound can be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials have been established and are known to those skilled in the art. Sustained-release capsules can release the compound for a few weeks to over 100 days depending on its nature. Additional strategies for protein stabilization can be used depending on the chemical nature and biostability of the therapeutic agent.

The pharmaceutical composition may also comprise a suitable solid phase or gel phase carrier or Shape agent. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

A pharmaceutical composition can be administered by a variety of methods known in the art. Medication The pathways and/or modes vary depending on the desired outcome. Depending on the route of administration, the pharmaceutically active agent can be covered by a material to protect the targeting composition or other therapeutic agent from the action of the acid and a compound that renders the agent inactive. Conventional pharmaceutical practice can be used to provide a suitable formulation or composition for administration of the pharmaceutical composition to a subject. Any appropriate administration route can be used, for example, intravenous injection, parenteral administration, intraperitoneal administration, transdermal administration, subcutaneous injection, intramuscular injection, intraurethral administration or oral administration, but the present invention is not limited thereto. The systemic delivery or localized delivery of the pharmaceutical composition can be used in the treatment according to the severity of the treatment of the malignant tumor or other disease, condition or symptom, and other conditions affecting the treatment of the target subject. in the process of. The pharmaceutical composition as described above may be administered with an additional therapeutic agent intended to treat a particular disease or condition, which may be the same disease or condition (the pharmaceutical composition is intended to treat a disease or condition that may be relevant, or even possible Is an unrelated disease or symptom).

The pharmaceutical compositions of this invention may be prepared according to methods well known and frequently performed in the art. See for example, Remington: The Science and Practice of ^{Pharmacy, Mack Publishing Co., 20 th ed} , 2000; and sustained-release and controlled-release drug delivery systems, JRRobinson, ed, Marcel Dekker, Inc., New York,.. 1978. The pharmaceutical composition is preferably manufactured under GMP conditions. Formulations for parenteral administration may, for example, comprise excipients, sterile water or saline, polyolefin-based diols such as polyethylene glycol, oils of vegetable origin or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of such compounds. Other potentially useful parenteral delivery systems for use in the molecules of the invention comprise ethylene-vinyl acetate copolymer particles, osmotic pumps, and implantable infusion systems. The preparation for inhalation may contain an excipient such as lactose, or may be an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be an oily solution for administration. Or gel.

The pharmaceutical composition of the present invention is usually administered to a target subject in many cases. Single dose The time interval between quantities can be weekly, monthly or yearly. The time interval can also be an irregularity as indicated by a therapeutic response or other parameters well known in the art. Alternatively, the pharmaceutical composition may be a sustained release formulation, in which case low frequency administration is necessary. In the topic of pharmaceutically active agents contained in pharmaceutical compositions, the dosage and frequency will vary depending on the half-life. The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered over relatively inactive time intervals over long periods of time. Some target subjects can continue to receive treatment for their lifetime. In therapeutic applications, relatively high doses at relatively short intervals are sometimes necessary in therapeutic applications until the deterioration of the disease is reduced or terminated, and preferably until the target subject shows partial or complete amelioration of the disease symptom. Thereafter, the target object can be given a preventive system.

As stated above, for the purposes of this application, treatment is monitored by observation One or more improved symptoms for treating a disease, condition or symptom, or by observing one or more improved clinical indicators for treating a disease, condition or symptom.

Sustained release formulations or controlled release formulations are well known in the art. E.g, The sustained release or controlled release preparation may be (1) an oral matrix sustained release or controlled release formulation, (2) an oral multi-layer sustained release or controlled release lozenge formulation, (3) an oral multiparticulate sustained release or controlled release Formulation, (4) an oral infusion sustained release or controlled release formulation, (5) an oral chewing sustained release or controlled release formulation or (6) a sustained release or controlled release patch formulation of the skin.

The pharmacokinetic principles of drug controlled release are described, for example, in B.M. Silber Et al., "The pharmacokinetic/pharmacodynamic basis of drug controlled release" in Controlled Drug Delivery: Fundamentals and Applications (J. R. Robinson & V. H. L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 5, pp. 213-251, and is incorporated by reference.

One of ordinary skill in the art can modify the formulation as described above. Formulations for controlled release or sustained release comprising the pharmaceutically active agents of the invention are readily prepared, for example, according to the principles disclosed in VHKLi et al., "The effects of drug properties on the design of sustained release and controlled release systems and drug administration. "In Controlled Drug Delivery: Fundamentals and Applications (JR Robinson & VHLLee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94, and by reference . This preparation typically takes into account the physicochemical properties of the pharmaceutically active agent, such as water solubility, partition coefficient, molecular size, stability, and non-specific binding to proteins and other biomacromolecules. This preparation also takes into account biological factors such as absorption, distribution, metabolism, duration of action, possible side effects and margins of safety of the pharmaceutically active agent. Thus, one of ordinary skill in the art can modify the formulation to a formulation having the desirable characteristics described above for a particular application.

U.S. Patent No. 6,573,292, filed by Nardella, filed by Nardella U.S. Patent No. 6, 921, 722, to U.S. Patent No. 7, 314, 886, to the name of the entire disclosure of U.S. Pat. Methods of using the compositions, and methods of determining the therapeutic effectiveness of such pharmaceutically active agents and pharmaceutical compositions, all of which are incorporated by reference.

Generally, the therapeutically effective amount of diconazole is about 40 mg/m ² . The therapeutically effective amount of diacetyl sulphate or dibromodusol is similar considering the difference in molecular weight.

Typically, the terconazole is administered by a route selected from the group consisting of intravenous and oral. Preferably, the dicolol is administered intravenously. A similar route can be used for diethylene quinone dehydrated dulcitol or dibromodusol.

The method can further comprise the step of administering a therapeutically effective amount of ionizing radiation.

The invention is illustrated by the following examples. This embodiment is for illustrative purposes only. The invention is not intended to limit the invention.

example

Use Weikangol to inhibit the growth of tumor cells

Materials and methods: cell strain and culture conditions: all cells were placed in DMEM (Dulbecco's Modified Eagle's medium; Invitrogen/Gibco) with 10% FBS (fetal bovine serum; Invitrogen/Gibco) and placed at 37 °C. Cultured in a 5% CO ₂ environment and subcultured twice a week during the experimental period.

Drug: 100 mM stock solution was kept at -20 °C before use. Weikangol (DAG; in the figure, the result of DAG is shown as "VAL") is provided by Dema Pharmaceuticals. A 100 mM stock solution was prepared by dissolving the lyophilized powder into phosphate buffered saline (PBS) in the vial of the injection and maintained at 20 °C prior to use.

Growth test: Each cell line (3000 cells/well) was seeded in 100 μL of medium in a 96-well plate (BD Falcon) and cultured overnight. Then, the cells were treated with DAG (concentration: 0.1-100 μM) in fresh medium for 72 hours. The cells were fixed in 2% paraformaldehyde (Sigma-Aldrich) with nuclear dye Hoechst 33342 (1 μg/mL) (Sigma-Aldrich). After gentle washing with PBS, the cells were maintained in fresh PBS and the plates were kept at 4 ° C in the dark before analysis by high content screening (HCS) (ThermoFisher Scientific). Scan and analyze 20 fields of view per well. Growth inhibition is calculated as a percentage of control without solvent and drug; the solvent treated sample is used as a reference. Three replicates were processed each time and the experiment was repeated once.

result

Fig. 1 shows the effect of Weikangol (concentration 0.1 to 100 μM) on the cell line MDA-MB-231. This is an estrogen-independent human breast cancer cell line (T. Hiraga et al., "Bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases", Cancer Res .61:4418-4424 (2001) and include it by reference).

Fig. 2 shows the effect of Weikangol (concentration 0.1 to 100 μM) on the cell line HCC1143. HCC1143 is a triple-negative breast cancer cell line that is specific for PARP or TKIs. Insensitive, and well-known, aggressive cancer metastatic cells (D. Tryfonopoulos et al., "Src: a potential target for the treatment of triple-negative breast cancer", Ann. Oncol. 22: 2234-2240 (2011), and References include it).

Figure 3 shows the effect of Weikangol (concentration 0.1 to 100 μM) on the cell line K562. K562 is a myeloid leukemia cell line (CBLozzio and BBLozzio, "Human chronic myeloid leukemia cell line with positive Philadelphia chromosome", Blood 45:321-224 (1975), and is included by reference); native type K562 itself lacks BIM deletion polymorphism and maintains sensitivity for TKIs (KPNg et al., "A common BIM deficiency in cancer, polymorphism and innate resistance and poor response to tyrosine kinase inhibitors", Nat.Med .18:521-528 (2012) and include it by reference).

Figure 4 shows the effect of Weikangol (concentration 0.1 to 100 μM) on the cell line K562-AHI-1. The cell line K562-AHI-1 carries a mutation in which the expression of AHI1 is dysregulated. This AHI-1 mutation confers TKI imatinib resistance to K562 cells.

result

For the testing of all cell lines, Wei Kang alcohol showed a high degree of cytotoxicity. In particular, in AHI1 in K562-AHI-1, the introduction of mutation by K562 did not significantly attenuate the cytotoxic effect of Weikangol . Furthermore, in the triple negative breast cancer cell line HCC1143, the vegetal alcohol showed a high degree of cytotoxicity, and the triple negative breast cancer cell line HCC1143 was insensitive to PARP or TKIs and is a well-known positive cancer metastatic cell.

Advantages of the invention

The present invention provides a plurality of effective methods and compositions for treating TKI resistant malignancies, particularly in a subject having a germ cell polymorphism, which causes an alternative splicing in the BIM gene. The BIM gene causes the growth of an alternative splicing isoform of BIM, which is an important BH3 region lacking the promotion phase involved in apoptosis. The invention also provides a plurality of effective methods and compositions for treating malignancies associated with cells having abnormal regulation or mutation in the AHI1 gene. These methods and compositions can treat such malignancies without relying on the inhibition of thymidine kinase. It is well tolerated and does not cause significant side effects.

Germ cell polymorphism with the effectiveness of blocking tyrosine kinase inhibitors In the target object, or a target object having a malignant tumor (especially a hyperproliferative disease) associated with a cell having abnormal regulation or mutation in the AHI1 gene, the present invention is for the preparation of an agent for treating many diseases and symptoms The composition and method have industrial applicability and are industrially useful as a pharmaceutical composition.

The patent scope of the method of the present invention provides specific method steps that go beyond the application of the general natural law and require that the steps of practicing the method be different than the specific application of the natural law described or implied in the scope of the patent application. Those steps well known in the art are employed to constrain the scope of the patent application to the specific application recited therein. In some cases, the scope of these patent applications is directed to new ways of using existing drugs.

The description of the present invention in this exemplary embodiment can be suitably carried out in the absence of any element that is not specifically disclosed herein. Therefore, for example, the terms "including", "including", "including", and the like should be interpreted broadly and without limitation. In addition, the terms and expressions used herein are for the purpose of description and not limitation, and the use of the terms and expressions are not intended to exclude other equivalents that are shown and described in the future, or other relevant parts. Different changes are possible in the scope of the request. Therefore, it should be understood that the present invention has been described herein in terms of the preferred embodiments and the features of the present invention. The scope of the disclosure. The invention has been described broadly and generically herein. Each of the narrowly defined species and sub-populations that fall within the scope of the generic name also form part of the invention. These include the generic names described in each of the inventions, which exclude the content of any generic name by a proviso or a negative limitation, whether or not the excluded content is specifically present herein.

In addition, the features and directions of the invention are described in the terms of the Markush group, and educators in this field will judge that the invention is also in the terminology of any individual member or subgroup member of the Markusi form. Narrative. It should also be understood that the above description is for purposes of illustration and not limitation. Many embodiments are apparent to those of ordinary skill in the art in view of the foregoing description. The scope of the invention should be determined by reference to the appended claims and the appended claims The disclosure of all articles and references, including patent publications, is hereby incorporated by reference.

<110> Del Mar Pharmaceuticals Brown, Dennis M. Bacha, Jeffrey A. Garner, William J.

<120> METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS ORMUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF

<130> P6886PC00

<140> PCT/US13/47320

<141> 2013-06-24

<150> US 61/824,672

<151> 2013-05-17

<150> US 61/664,279

<151> 2012-06-24

<160> 13

<170> PatentIn version 3.5

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Claims (209)

A method for treating a malignant tumor, wherein the malignant tumor is characterized by resistance to at least one tyrosine kinase inhibitor (TKI), wherein: (1) at least one mutation in a gene encoding a protein, The protein is a target of at least one TKI; or (2) the presence of at least one additional gene in a native or mutant state, which encodes a product of resistance to a therapeutic effect of at least one TKI, the method comprising : A therapeutically effective amount of a monoalkylated hexitol derivative. The method of claim 1, wherein the at least one additional gene in the native or mutant state of the product encoding the resistance to the therapeutic effect of at least one TKI is AHI-1 . The method of claim 2, wherein the AHI-1 gene mutation is the result of a proviral insertion. The method of claim 1, wherein the resistance to at least one tyrosine kinase inhibitor (TKI) is due to a mutation in the kinase region of the ABL1 protein, which belongs to a TKI Part of the target BCR-ABL fusion protein. The method of claim 1, wherein the alkylated hexitol derivative is selected from the group consisting of a derivative or analog of Weikangol, Weikangol, diacetyl dianol, A group consisting of a derivative or analog of diacetyl dianol, a derivative or analog of dibromodusol and dibromodusol. The method of claim 5, wherein the alkylated hexitol derivative is selected from the group consisting of derivatives or analogs of Wei Kang alcohol and Wei Kang alcohol. The method of claim 6, wherein the alkylated hexitol derivative is Weikang alcohol. The method of claim 5, wherein the alkylated hexitol derivative is selected from the group consisting of a derivative or the like selected from the group consisting of diacetyl dianol and diacetyl dianol. Group Into the group. The method of claim 8, wherein the alkylated hexitol derivative is diacetyl dianol. The method of claim 5, wherein the alkylated hexitol derivative is selected from the group consisting of dibromodusol and a derivative or analog of dibromodusol. The method of claim 10, wherein the alkylated hexitol derivative is dibromodusol. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 12, wherein the BH3 analog is selected from the group consisting of: (a) a peptide; (b) a modified peptide; (c) a triazinyl group Peptides; (d) p-benzoguanamine-based peptipeptides; (e) benzamidine-based p-peptides; (f) ambastadrol; (g) TW37; (h) analogs of TW37 Or a derivative; (i) (-) gossypol; (j) gossypol derivative; (k) isoxazoline derivative; (l) A-385358; (m) analog of A-385358 or derivative; (n) ABT-737; (o) an analog or derivative of ABT-737; (p) ABT-263; (q) an analog or derivative of ABT-263; (r) TM-1206; An analog or derivative of TM-1206. The method of claim 12, wherein the BH3 analog is a BH3 analog, the binding of which occurs between a hydrophobic groove on the binding partner of BH3 and the BH3 analog. The method of claim 12, wherein the BH3 analog is a BH3 analog that adopts a helical structure or a combination of a helical structure attached to a hydrophobic groove located in the binding object. The structure seen by the object. The method of claim 12, wherein the BH3 analog is a BH3 analog having a hydrophobic amino acid residue having a spacing of i, i+3, i+7 and i+11, The i, i+3, i+7, and i+11 interact in four hydrophobic pockets on the binding object of BH3. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 17, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a JAK2 inhibitor to the target subject. The method of claim 19, further comprising the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 19, further comprising: administering a BH3 analog The step of treating the effective amount to the target subject. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a STAT5 inhibitor to the target subject. The method of claim 22, further comprising the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 22, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a Src kinase inhibitor to the target subject. The method of claim 25, further comprising the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 25, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 1, further comprising: a step of administering a therapeutically effective amount of a combination of a kinase inhibitor to a target subject to treat the malignant tumor; wherein the combination of the kinase inhibitors is selected from the group consisting of a combination of the following: (1) a JAK2 inhibitor and a STAT5 inhibitor; (2) a JAK2 inhibitor and a Src inhibitor; (3) a STAT5 inhibitor and a Src inhibitor; 4) A JAK2 inhibitor, a STAT5 inhibitor and a Src inhibitor, to the target subject. The method of claim 28, further comprising the step of administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 28, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. a type of germ cell deficiency with a resistance to thymidine kinase inhibitors (TKIs) A method for treating a malignant tumor in a target of a polymorphic malignant tumor, comprising: administering a therapeutically effective amount of a therapeutic agent to a target subject to treat the malignant tumor, the therapeutic agent being selected from the group consisting of a derivative or analog of phytol, a derivative or analog of dihydroquinone dihydropivoxil, a derivative of dibromodusol and dibromodusol or a group of analogs. The method of claim 31, wherein the malignant tumor is chronic myelogenous leukemia (CML). The method of claim 31, wherein the malignant tumor is non-small cell lung cancer (NSCLC). The method of claim 31, wherein the malignant tumor is a triple negative breast cancer. The method of claim 31, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of Wei Kang alcohol and Wei Kang alcohol. The method of claim 35, wherein the therapeutic agent is Wei Kang alcohol. The method of claim 35, wherein the therapeutic agent is a derivative or analog of Weikangol. The method of claim 37, wherein the derivative or analog of the tilconol is a derivative of Weikangol selected from the group consisting of: (i) a Weikangol a derivative having one or two hydrogen groups of a dihydroxy group of a dicamyl alcohol substituted with a lower alkyl group; (ii) a derivative of Weikangol having one or more substituents substituted with a lower alkyl group Hydrogen of two epoxy rings; (iii) a derivative of Weikangol having one or two methyl groups present in the phytol, and which are attached to the lower order with C ₂ -C ₆ a same carbon of an alkyl-substituted hydroxyl group; and (iv) a derivative of Weikangol having one or two methyl groups present in the phytonol, and which are attached to the same carbon, the ribbon There are hydroxyl groups substituted with a halogen group by substituting hydrogen of a methyl group with a halogen group. The method of claim 31, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dihydroquinone dihydrated dulcitol and diacetyl dianol. The method of claim 39, wherein the therapeutic agent is diacetyl dianol. The method of claim 38, wherein the therapeutic agent is a derivative or analog of diacetyl dianol. The method of claim 41, wherein the derivative or analog of dihydroquinone difollnitol is selected from the group consisting of diacetyl dianthracene derivatized from the group consisting of (i) a derivative of diacetyl dianhydrodehydrin having one or two methyl groups substituted with a lower alkyl group of C ₂ -C _{6 to} the ethyl group; (ii) one a derivative of acetamyl hexahydrocyclohexanol having one or two hydrogens attached to the epoxy ring substituted with a lower alkyl group; (iii) a derivative of diethylene quinone dihydrated cyclohexanol having one Or two methyl groups attached to the same carbon having an acetamyl group substituted with a lower alkyl group of C ₂ -C ₆ ; and (iv) a derivative of diacetyl quinone difoam. It has one or two methyl groups attached to the same carbon having a hydroxyl group substituted with a halogen group by hydrogen replacing the methyl group with a halogen group. The method of claim 31, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dicyclohexanol and dibromodusol. The method of claim 43, wherein the therapeutic agent is dicycloheximide. The method of claim 43, wherein the therapeutic agent is a derivative or analog of dicycloheximide. The method of claim 45, wherein the derivative or analog of dibromodusol is a derivative of dibromodusol selected from the group consisting of: (i) a a derivative of dibromodusol having one or more hydrogens substituted with a lower alkyl group; and (ii) a second A derivative of bromodianol having one or two bromo groups substituted with another halo group selected from the group consisting of chlorine, fluorine and iodine. The method of claim 31, further comprising the step of: determining whether a particular target subject has a malignant tumor having a polymorphism in the germ cell that confers resistance to the TKIs. The method of claim 47, wherein the step of confirming whether a specific target subject has a malignant tumor having a polymorphism in a germ cell that confers resistance to TKIs is by double-end labeling (DNA-PET). The analysis is completed. The method of claim 31, wherein the germ cell DNA deletion polymorphism is a 2903 bp germ cell DNA deletion polymorphism of the BIM gene. The method of claim 49, wherein the germ cell DNA deletion polymorphism initiates a splicing variation, which results in the absence of a BH protein isomer of the BH3 region, thereby inhibiting the induction of apoptosis. . The method of claim 31, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 51, wherein the BH3 analog is selected from the group consisting of: (a) a peptide; (b) a modified peptide; (c) a triazinyl group Peptides; (d) p-benzoguanamine-based peptipeptides; (e) benzamidine-based p-peptides; (f) ambastadrol; (g) TW37; (h) an analog or derivative of TW37; (i) (-) gossypol; (j) gossypol phenol derivative; (k) isoxazoline derivative; (l) A-385358; (m) An analog or derivative of A-385358; (n) ABT-737; (o) an analog or derivative of ABT-737; (p) ABT-263; (q) an analog or derivative of ABT-263; (r) TM-1206; and (s) an analog or derivative of TM-1206. The method of claim 51, wherein the BH3 analog is a BH3 analog, the binding of which occurs between a hydrophobic groove on the binding partner of BH3 and the BH3 analog. The method of claim 51, wherein the BH3 analog is a BH3 analog that adopts a helical structure or a combination of a helical structure attached to a hydrophobic groove located in the binding object. The structure seen by the object. The method of claim 51, wherein the BH3 analog is a BH3 analog having a hydrophobic amino acid residue having a spacing of i, i+3, i+7, and i+11, The i, i+3, i+7, and i+11 interact in four hydrophobic pockets on the binding object of BH3. The method of claim 52, wherein the BH3 analog is a peptide. The method of claim 52, wherein the BH3 analog is a modified peptide. The method of claim 57, wherein the modified peptide is a pinned BID BH3 spiral. The method of claim 52, wherein the BH3 analog is a tri-aziridinyl-like peptide. The method of claim 52, wherein the BH3 analog is a pair of benzoguanamine-based peptides. The method of claim 52, wherein the BH3 analog is a benzamidine-based pseudopeptide. The method of claim 52, wherein the BH3 analog is ambastadrol. The method of claim 52, wherein the BH3 analog is TW37. The method of claim 52, wherein the BH3 analog is an analog or derivative of TW-37. The method of claim 52, wherein the BH3 analog is (-) gossypol. The method of claim 52, wherein the BH3 analog is a gossypol derivative. The method of claim 52, wherein the BH3 analog is A-385358. The method of claim 52, wherein the BH3 analog is an analog or derivative of A-385358. The method of claim 52, wherein the BH3 analog is ABT-737. The method of claim 52, wherein the BH3 analog is an analog or derivative of ABT-737. The method of claim 52, wherein the BH3 analog is ABT-263. The method of claim 52, wherein the BH3 analog is an analog or derivative of ABT-737. The method of claim 52, wherein the BH3 analog is TM-1206. The method of claim 52, wherein the BH3 analog is an analog or derivative of TM-1206. The method of claim 51, wherein the method further comprises: administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 75, wherein the tyrosine kinase inhibitor is selected from the group consisting of imatinib, bosutinib, nilotinib, and dasatinib. The method of claim 76, wherein the tyrosine kinase inhibitor is imatinib. The method of claim 76, wherein the tyrosine kinase inhibitor is selected from the group consisting of erlotinib, afatinib, and dacotinib. The method of claim 51, wherein the method further comprises: administering a therapeutically effective amount of a JAK2 inhibitor to the target subject. The method of claim 79, wherein the JAK2 inhibitor is selected from the group consisting of (E)-N-benzyl-2-cyano-3-(3,4-dihydroxyphenyl)-propene Indoleamine (AG490), rosolidinib, tofacitinib, tofacitinib citrate, N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrole) Pyridin-1-yl)ethoxy)anilino)pyrimidin-4-ylamine)benzenesulfonamide (TG-101348), (S)-5-chloro-N2-(1-(5-fluoropyrimidine) -2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480), N-(-cyanomethyl-)-4- (2-(4-morpholinylanilino)pyrimidin-4-yl)benzamide (CYT387), baricitinib, (S,E)-3-(6-bromopyridine-2 -yl)-2-cyano-N-(1-phenylethyl)-acrylamide (WP1066), S-Roserolinib, N-tert-butyl-3-(5-methyl- 2-(4-(4-Methylpiperazin-1-yl)anilino)pyrimidin-4-ylamine)benzenesulfonamide (TG101209), N-[3-(4-methyl-1-piperazine) Phenyl]-8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine (CEP33779), 8-(3 ,5-difluoro-4-(morpholinylmethyl)phenyl)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (NVP-BSK805) , (S)-5-fluoro-2-(1-(4-fluorophenyl) Ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamine)nicotinonitrile (AZ 960), 3-(4-chloro-2-fluorobenzyl)-2- Methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinylmethyl)imidazo[1,2-b]pyridazine-6-amine (LY2784544), 1- Cyclopropyl-3-(3-(5-(morpholinyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea (AT9283), Paklit (pactinib, SB1518), (S)-N-(4-(2-((4-morpholinyl)amino)pyrimidin-4-yl)phenyl)pyrrolidin-2-carboxamide (XL019) And N-tert-butyl-3-(5-methyl-2-(4-(2-(pyrrolidin-1-yl)ethoxy)anilino)pyrimidin-4-ylamine)benzenesulfonate A group consisting of indoleamine (TG101348). The method of claim 51, wherein the method further comprises the step of administering a therapeutically effective amount of a STAT5 inhibitor to the target subject. The method of claim 81, wherein the STAT5 inhibitor is selected from the group consisting of N ' -((4-oxy-4H-gram-3-yl)methenyl) nicotine and A group of fans. The method of claim 51, wherein the method further comprises the step of administering a therapeutically effective amount of a Src inhibitor to the target subject. The method of claim 83, wherein the Src inhibitor is selected from the group consisting of dasatinib, sectinib, bosutinib, N-benzyl-2-(5-(4- (2-morpholineethoxy)phenyl)pyridin-2-yl)acetamide (KX2-391), CGP76030, and 4-methyl-3-(1-methyl-6-(pyridine-3- a group consisting of -1H-pyrazolo[3,4-d]pyrimidin-4-ylamine)-N-(3-(trifluoromethyl)phenyl)benzamide (NVP-BHG712) Group. The method of claim 51, wherein the method further comprises the step of administering a therapeutically effective amount of a combination of a kinase inhibitor to the target, the combination comprising: (1) a JAK2 inhibitor and a STAT5 inhibition (2) a JAK2 inhibitor and a Src inhibitor; (3) a STAT5 inhibitor and a Src inhibitor; and (4) a JAK2 inhibitor, a STAT5 inhibitor and a Src inhibitor. A method of combining screening and treatment, the combination of which: a germ cell deficiency conferring resistance to TKI therapy Screening for polymorphism and treatment of malignant tumors resistant to TKIs in a target subject if the germ cell deletion polymorphism is found to exist, the method comprising the steps of: (a) targeting a malignant tumor Screening for the germ cell deletion polymorphism in the subject; and (b) if the germ cell deletion polymorphism is found in the target subject having the malignant tumor, administering a therapeutically effective amount of a therapeutic agent to the target subject to treat the In the case of a malignant tumor, the therapeutic agent is selected from the group consisting of a derivative or analog of Weikangol, Weikangol, a dihydroquinone dihydrated cyclohexanol, a derivative or the like of diammonium dihydrated dulcitol, A group consisting of bremerol, and a derivative or analog of dibromodusol. The method of claim 86, wherein the germ cell deletion polymorphism conferring resistance to the TKI therapy is a 2903 bp deletion located in the BIM gene. The method of claim 86, wherein the germ cell DNA deletion polymorphism initiates a splicing variation, which results in the absence of a BH protein isoform of a BH3 region, thereby inhibiting apoptosis induction. . The method of claim 86, wherein the step of screening the germ cell deletion polymorphism in a target subject having a malignant tumor is performed by double-end labeling (DNA-PET) analysis. The method of claim 86, wherein the malignant tumor is chronic myelogenous leukemia (CML). The method of claim 86, wherein the malignant tumor is non-small cell lung cancer (NSCLC). The method of claim 86, wherein the malignant tumor is a triple negative breast cancer. The method of claim 86, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of Wei Kang alcohol and Wei Kang alcohol. The method of claim 93, wherein the therapeutic agent is Wei Kang alcohol. The method of claim 86, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dihydroquinone dihydrated dulcitol and diacetyl dianol. The method of claim 95, wherein the therapeutic agent is diacetyl dianol. The method of claim 86, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dicyclohexanol and dibromodusol. The method of claim 97, wherein the therapeutic agent is dibuvalimide. The method of claim 86, further comprising the step of administering a therapeutically effective amount of a BH3 analog to the target subject. The method of claim 99, wherein the BH3 analog is selected from the group consisting of: (a) a peptide; (b) a modified peptide; (c) a triazinyl group Peptides; (d) p-benzoguanamine-based peptipeptides; (e) benzamidine-based p-peptides; (f) ambastadrol; (g) TW37; (h) analogs of TW37 Or a derivative; (i) (-) gossypol; (j) gossypol phenol derivative; (k) isoxazoline derivative; (l) A-385358; (m) an analog or derivative of A-385358; (n) ABT-737; (o) an analog or derivative of ABT-737; (p) ABT-263; (q) an analog of ABT-263 or a derivative; (r) TM-1206; and (s) an analog or derivative of TM-1206. The method of claim 99, wherein the BH3 analog is a BH3 analog, the binding of which occurs between a hydrophobic groove on the binding partner of BH3 and the BH3 analog. The method of claim 99, wherein the BH3 analog is a BH3 analog which adopts a helical structure or a combination of a helical structure attached to a hydrophobic groove located in the binding object. The structure seen by the object. The method of claim 99, wherein the BH3 analog is a BH3 analog having a hydrophobic amino acid residue having a spacing of i, i+3, i+7, and i+11, The i, i+3, i+7, and i+11 interact in four hydrophobic pockets on the binding object of BH3. The method of claim 100, wherein the BH3 analog is ABT-737. The method of claim 86, wherein the method further comprises: administering a therapeutically effective amount of a tyrosine kinase inhibitor to the target subject. The method of claim 105, wherein the tyrosine kinase inhibitor is selected from the group consisting of imatinib, bosutinib, nilotinib, and dasatinib. The method of claim 106, wherein the tyrosine kinase inhibitor is imatinib. The method of claim 105, wherein the tyrosine kinase inhibitor is selected from the group consisting of In the group consisting of erlotinib, afatinib and dacotinib. A method for treating a malignant tumor in a target subject having a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene, comprising: a step of administering a therapeutically effective amount of a therapeutic agent to a target subject to treat the malignant tumor, the therapeutic agent Is selected from derivatives or analogs of Weikangol, Weikangol, diacetyl dianol, a derivative or analog of diacetyl dianol, dibromodusol and two A group consisting of derivatives or analogs of bromocortisol. The method of claim 109, wherein the malignant tumor is chronic myelogenous leukemia. The method of claim 109, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of Wei Kang alcohol and Wei Kang alcohol. The method of claim 111, wherein the therapeutic agent is Wei Kang alcohol. The method of claim 109, wherein the therapeutic agent is a derivative or analog of Weikangol. The method of claim 113, wherein the derivative or analog of the tilconol is a derivative of Weikangol selected from the group consisting of: (i) a Weikangol a derivative having one or two hydrogen groups of a dihydroxy group of a dicamyl alcohol substituted with a lower alkyl group; (ii) a derivative of Weikangol having one or more substituents substituted with a lower alkyl group a hydrogen of two epoxy rings; (iii) a derivative of Weikangol having one or two methyl groups present in the phytol alcohol, and which are attached to the lower order with C ₂ -C ₆ a same carbon of an alkyl-substituted hydroxyl group; and (iv) a derivative of Weikangol having one or two methyl groups present in the phytonol, and which are attached to the same carbon, the ribbon There are hydroxyl groups substituted with a halogen group by substituting hydrogen of a methyl group with a halogen group. The method of claim 109, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dihydroquinone dihydrodasyl alcohol and diacetyl dianol. group. The method of claim 115, wherein the therapeutic agent is diacetyl dianol. The method of claim 115, wherein the therapeutic agent is a derivative or the like of diammonium dihydrated cyclohexanol. The method of claim 117, wherein the derivative or analog of diacetyl dianhydro decanol is selected from the group consisting of diethylene quinone dihydrated cyclohexanol. (i) a derivative of diacetyl dianhydrodehydrin having one or two methyl groups substituted with a lower alkyl group of C ₂ -C _{6 to} the ethyl group; (ii) one a derivative of acetamyl hexahydrocyclohexanol having one or two hydrogens attached to the epoxy ring substituted with a lower alkyl group; (iii) a derivative of diethylene quinone dihydrated cyclohexanol having one Or two methyl groups attached to the same carbon having an acetamyl group substituted with a lower alkyl group of C ₂ -C ₆ ; and (iv) a derivative of diacetyl quinone difoam. It has one or two methyl groups attached to the same carbon having a hydroxyl group substituted with a halogen group by hydrogen replacing the methyl group with a halogen group. The method of claim 109, wherein the therapeutic agent is selected from the group consisting of derivatives or analogs of dicyclohexanol and dibromodusol. The method of claim 119, wherein the therapeutic agent is dibuvalimide. The method of claim 119, wherein the therapeutic agent is a derivative or analog of dicycloheximide. The method of claim 121, wherein the derivative or analog of dibromodusol is a derivative of dibromodusol selected from the group consisting of: (i) a a derivative of dibromodusol having one or more hydrogens substituted with a lower alkyl group; and (ii) a derivative of dibromodulcitol having one or two substituted with another halo group, The other halogen group is selected from the group consisting of chlorine, fluorine, and iodine. The method of claim 109, further comprising: administering a therapeutically effective amount of an agent that modulates the performance or activity of the AHI1 gene or the AHI1 protein. The method of claim 123, wherein the agent that modulates the expression or activity of the AHI1 gene or the AHI1 protein is an agent that modulates the expression of the AHI1 gene. The method of claim 124, wherein the agent that modulates the expression of the AHI1 gene at the level of transcription modulates the expression of the AHI1 gene. The method of claim 124, wherein the agent that modulates the expression of the AHI1 gene at the level of translation regulates the performance of the AHI1 gene. The method of claim 125, wherein the agent that modulates the expression of the AHI1 gene at the level of transcription is selected from the group consisting of short interfering RNA (siRNA), microRNA (miRNA), and synthetic hairpin RNA ( A group consisting of shRNA), antisense nucleic acids, and complementary DNA (cDNA). The method of claim 127, wherein the agent that modulates the expression of the AHI1 gene at the level of transcription is an siRNA. The method of claim 123, wherein the agent that modulates the expression or activity of the AHI1 gene or the AHI1 protein is an agent that inhibits the activity of the AHI1 protein. The method of claim 129, wherein the agent that inhibits the activity of the AHI1 protein is an antibody that specifically binds to the AHI1 protein. The method of claim 129, wherein the agent that inhibits the activity of the AHI1 protein is an antibody that specifically binds to a receptor of the AHI1 protein. The method of claim 129, wherein the agent that inhibits the activity of the AHI1 protein is an antagonist that specifically binds to the receptor of the AHI1 protein. The method of claim 129, wherein the agent that modulates the expression or activity of the AHI1 gene or the AHI1 protein is an agent that inhibits a transcription factor having a binding position in a promoter of the AHI1 gene. The method of claim 133, wherein the transcription factor having a binding position in the promoter of the AHI1 gene is selected from the group consisting of RFX1, POU2F1, POU2F1a, Nkx2-5, Evi-1, and RSRFC4. Group. A method for increasing the efficacy and/or reducing side effects of administration of an alkylated hexitol derivative for administering a malignant tumor selected from a primary anti-TKI tumor And a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene, the method comprising the steps of: (a) confirming at least one factor or parameter associated with the efficacy and/or side effects of administration of the alkylated hexitol derivative, An alkylated hexitol derivative is used to treat a primary anti-TKI tumor or to treat a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene; and (b) modify the factor or parameter to make the alkyl group The efficacy of the administration of the hexitol derivative is reduced and/or the side effect is reduced, and the alkylated hexitol derivative is used for treating the anti-TKI tumor or the malignant tumor associated with mutation or abnormal regulation of the AHI1 gene. The method of claim 135, wherein the malignant tumor is a primary anti-TKI tumor. The method of claim 135, wherein the malignant tumor is a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene. The method of claim 135, wherein the factor or parameter is selected from the group consisting of: (1) dose adjustment; (2) route of administration; (3) schedule of administration; (4) the use of indications; (5) the choice of the stage of the disease; (6) other indications; (7) selection of patients; (8) patient/disease phenotype; (9) patient/disease genotype; (10) pre/post treatment preparation; (11) toxicity management; 12) pharmacokinetic/pharmacodynamic monitoring; (13) concurrent administration; (14) chemical sensitization; (15) chemical synergism; (16) post-treatment patient management; (17) selective medical/treatment Support; (18) API product improvement; (19) diluent system; (20) solvent system; (21) excipient; (22) dosage form; (23) dose kit and packaging; (24) drug delivery system (25) a conjugated form of the drug; (26) a compound analog; (27) a precursor; (28) a multi-drug system; (29) a biotherapeutic potentiation; (30) anti-biological therapy regulation; (31) radiotherapy enhancement; (32) novel mechanism of action; (33) selective target cell population therapy; and (34) use of an agent that increases its activity. The method of claim 138, wherein the improvement is by dose adjustment, and the dose adjustment is at least one dose adjustment selected from the group consisting of: (a) persistence Intravenous injection for several hours to several days; (b) biweekly administration; (c) dose greater than 5 mg/m ² /day; (d) progressively increasing dose from 1 mg/m ² /day based on patient tolerance; Use caffeine to regulate metabolism; (f) use of isoniazid to regulate metabolism; (g) selected and intermittent increases in dosing; (h) by single increment from mg/m ² /day Single-dose and multi-dose administration; (i) oral dose less than 30 mg/m ² ; (j) oral dose over 130 mg/m ² ; (k) oral dose up to 40 mg/m ^{2 for} three days, followed by 18-21 days Minimum/recovery cycle; (1) the agent at a lower level (eg 21 days); (m) the agent at a higher level; (n) the agent with a minimum/recovery of more than 21 days a cycle; (o) using an alkylated hexitol derivative as a single cytotoxic agent; (p) an immediate release agent; (q) a sustained release agent; and (r) a controlled release agent. The method of claim 138, wherein the improvement is by a route of administration, and the route of administration is at least one route selected from the group consisting of: (a Partial administration; (b) oral administration; (c) sustained release of oral delivery; (d) spinal injection; (e) intraarterial injection; (f) continuous infusion; (g) intermittent infusion; (h) intravenous administration For example, intravenous administration for 30 minutes; (i) administration by a longer injection; (j) administration by intravenous bolus; and (k) intraperitoneal administration. The method of claim 138, wherein the improvement is performed by a timetable for administration, and the schedule of administration is at least one timetable selected from the group consisting of: (a) daily dosing; (b) weekly dosing; (c) three weeks of dosing per week; (d) biweekly dosing; (e) biweekly dosing for three weeks (1-2 weeks of rest); (f) Intermittently increasing dose administration; (g) Daily dosing for one week to many weeks. The method of claim 138, wherein the improvement is by a selection of a stage of the disease, and the selection of the stage of the disease is at least one selected from the group consisting of: (a) for use in an appropriate course of disease for anti-TKI tumors; (b) use of newly diagnosed diseases; (c) use of recurrent diseases; (d) use of resistant or refractory diseases; The use of an AHI1 associated malignant tumor; (f) the use of triple negative breast cancer treatment; and (g) the use of a treatment for metastatic disease. The method of claim 138, wherein the improvement is performed by selecting a patient, and the selected patient is a selected patient achieved by a benchmark selected from the group consisting of A group consisting of: (a) selecting a patient having a condition characterized by a high level of a metabolic enzyme selected from the group consisting of histone deacetylase and alginate decarboxylase. a group; (b) selecting a patient with a low or high susceptibility condition selected from the group consisting of thrombocytopenia and neutropenia; (c) choosing to tolerate GI a patient who is toxic; (d) chooses a patient characterized by over- or under-expression of a gene selected from the group consisting of c-Jun, a GPCR, a signaling protein, VEGF, and a prostate. a group consisting of a gene and a protein kinase; (e) selecting a patient based on a BIM co-deletion; and (f) selecting an AHI1- based mutation or disorder. The method of claim 138, wherein the improvement is performed by analysis of a patient or a disease phenotype, and the analysis of the patient or disease phenotype is selected from the following The method of grouping is achieved by: (a) using a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm the patient's specific genotype; (b) using a marker measurement method, the marker Is a protein selected from the group consisting of histone deacetylase, avian acid decarboxylase, VEGF, a gene product of a prostate specific gene, a gene product of jun, a protein kinase, desmoglein-3 And a group of novel epitopes derived from apoptotic protease; (c) a dose of the mimetic compound; and (d) a state of the low dose pretest enzyme. The method of claim 138, wherein the improvement is performed by analysis of a disease or disease genotype, and the analysis of the disease or disease genotype is performed by one selected from the following The method of grouping is achieved by: (a) using a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm the patient's specific genotype; (b) using a gene chip; (c) using gene expression Analysis; (d) using single nucleotide polymorphism (SNP) analysis; and (e) measuring the level of a metabolite or an metabolic enzyme. The method of claim 138, wherein the improvement is performed by pre-/post-treatment preparation, and the pre-/post-treatment preparation is a pre-/post-selection selected from the group consisting of Method of preparation for treatment: (a) use of colchicine or its analogues; (b) using a uric acid; (c) using uricase; (d) non-oral use of nicotinamide; (e) using a sustained release form of nicotine amide; (f) using a poly ADP ribose polymerization Inhibitor of enzyme; (g) use of caffeine; (h) rescue with methotrexate; (i) infection control; and (j) use of an antihypertensive agent. The method of claim 138, wherein the improvement is performed by toxicity management, and the toxicity management is a method of toxicity management selected from the group consisting of: (a) use Colchicine or an analogue thereof; (b) using a uric acid; (c) using uricase; (d) non-oral use of nicotinamide; (e) using a sustained release form of nicotine amide; f) use of an inhibitor of poly ADP ribose polymerase; (g) use of caffeine; (h) rescue with methotrexate; (i) use of sustained release of isodecyl alcohol; (j) use of isodecyl alcohol for parenteral use (k) using bone marrow transplantation; (1) using a blood cell stimulator; (m) using blood or platelet injection; (n) administering an agent selected from the group consisting of Neupogen®, G-CSF, and GM-CSF; (o) applying a pain control technique; (p) administering an anti-inflammatory agent (q) administering a liquid; (r) administering a corticosteroid; (s) administering an insulin controlling drug; (t) administering an antipyretic; (u) administering an anti-nausea therapeutic; (v) administering a diarrhea a therapeutic agent; (w) administering N-acetylcysteine; (x) administering a primary antihistamine; and (y) administering an agent for reducing gastric toxicity. The method of claim 138, wherein the improvement is by pharmacokinetic/pharmacodynamic monitoring, and the pharmacokinetic/pharmacodynamic monitoring is selected from the group consisting of Group methods: (a) multiple determinations of plasma levels; and (b) multiple determinations of at least one metabolite in blood or urine. The method of claim 138, wherein the improvement is performed by concomitant administration, and the concomitant is a concomitant selected from the group consisting of: (c) using thymidine Synthetase inhibitor; (d) using a signaling inhibitor; (e) using cisplatin or a platinum analog; (f) using an alkylating agent; (g) using an anti-tubulin agent; (h) using an antimetabolite; (i) using berberine; (j) using apigenin; (k) using colchicine or an analogue thereof; (1) using a dye Flavonoids; (m) use of idopride; (n) use of arabinosylcytosine; (o) use of camptothecins; (p) use of vinca alkaloids; (q) use of positional isomerase inhibition (r) using 5-fluorouracil; (s) using curcumin; (t) using NF-κB inhibitor; (u) using rosmarinic acid; (v) using propyl hydrazine; ) using metformin; (x) using imatinib; (y) using dasatinib; (z) using nilotinib; (aa) using epigenetic modulators; (ab) using transcription factor inhibition (ac) using taxol; (ad) using homoharringtonine; (ae) using pyridoxal; (af) using spirocyclic guanidine; (ag) using caffeine; (ah) using nicotine decylamine; (ai) using methylglyoxal bis-indole hydrazine; (aj) Rho kinase inhibitor; (ak) using 1,2,4-benzotriazine oxide; (al) using monoalkyl glycerol; (am) using an inhibitor of Mer, Axl or Tyro-3 receptor kinase; (an) use an inhibitor of ATR kinase; (ao) use a Fms kinase, Kit kinase, MAP4K4 kinase, TrkA kinase or TrkB kinase modulator; (ap) use tamoxifen; (aq) use a mTOR inhibition (ar) using an inhibitor of Mnk1a kinase, Mkn1b kinase, Mnk2a kinase or Mnk2b kinase; (as) using a modulator of M2 pyruvate kinase; (at) using a modulator of inositol monophosphate 3 kinase; (au) use of a cysteine protease inhibitor; (av) use of phenformin; (aw) use of Cindbis virus-based vectors; (ax) use of analogs that act as Smac and inhibit IAPs to promote apoptosis Pseudopeptide; (ay) using a Raf kinase inhibitor; (az) using a nuclear transfer modulator; (ba) using an acidic neuraminidase inhibitor and a choline kinase inhibitor; (bb) using a tyrosine kinase inhibitor; (bc) using an anti-CS1 antibody; (bd) using an inhibitor of protein kinase CK2; (b) using an anti-guanylate cyclase C (GCC) antibody; (bf) Use of histone deacetylase inhibitors; (bg) use of cannabinoids; (bh) use of glycoside-like peptide (GLP-1) receptor agonists; (bi) use of Bcl-2 or Bcl-xL Inhibitor; (bj) use Stat3 pathway inhibitor; (bk) use inhibitor of polo-like kinase (Plk1); (bl) use GBPAR1 activator; (bm) use serine-synamic acid protein kinase and poly ADP ribose a modulator of polymerase (PARP) activity; (bn) a taxane; (bo) an inhibitor of dihydrofolate reductase; (bp) an inhibitor of aromatase; (bq) a benzimidazole-based antibiotic Cancer agent; (br) using an O6-methylguanine-DNA-methyltransferase (MGMT) inhibitor; (bs) using a CCR9 inhibitor; (bt) using an acid sphingomyelinase inhibitor; (bu) using Pseudopeptide macrocycles; (bv) use of choline acid aminide; (bw) use of substituted oxyphosphonazo; (bx) use of anti-TWEAK receptor antibodies; (by) using an ErbB3 binding protein; (bz) activating an antitumor compound using a glutathione S-transferase; (ca) using a substituted phosphodiamine; (cb) using an inhibitor of MEKK protein kinase; (cd) using a COX-2 inhibitor; (ce) using cimetidine and a half cysteine derivative; (cf) using an anti-IL-6 receptor antibody; (cg) using an antioxidant; (ch) using a tubulin-polymerized isoxazole inhibitor; (ci) using a PARP inhibitor; (cj) using an aurora protein kinase inhibitor; (ck) using a peptide that binds to a prostate specific membrane antigen; (cl) Use CD19 binder; (cm) use benzenediazonium salt; (cn) use terpenoid receptor (TLR) agonist; (co) use bridging bicyclic sulfonamide; (cp) use epidermal growth factor receptor An inhibitor of kinase; (cq) a ribonuclease using a T2 family with actin-binding activity; (cr) using terpene benzoic acid or an analogue thereof; (cs) using a cyclin-dependent kinase inhibitor (ct) an inhibitor that uses the interaction between p53 and MDM2; (cu) an inhibitor that uses the receptor tyrosine kinase MET; (cv) uses a ragorazole or a lagozoled analog; w) using an inhibitor of AKT protein kinase; (cx) using 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine or L-deoxythymidine; (cy) using HSP90 modulator; (cz) inhibition using JAK kinase (da) an inhibitor of PDK1 protein kinase; (db) a PDE4 inhibitor; (de) an inhibitor of the original oncogene c-Met tyrosine kinase; (df) a guanamine 2,3- An inhibitor of dioxygenase; (dg) an agent that inhibits the expression of ATDC (TRIM29); (dh) a protein-like inhibitor that uses the interaction of a nuclear receptor and a co-activated peptide; (di) uses a XIAP family protein Antagonist; (dj) use of tumor-targeted superantigen; (dk) inhibitor of Pim kinase; (dl) inhibitor of CHK1 or CHK2 kinase; (dm) inhibitor of angiopoietin protein 4; Dn) use Smo antagonist; (do) use nicotinic acetylcholine receptor antagonist; (dp) use farnesyl protein transferase inhibitor; (dq) use adenosine A3 receptor antagonist; Using a cancer vaccine; (ds) using a JAK2 inhibitor; and (dt) using a Src inhibitor. The method of claim 138, wherein the improvement is performed by concomitant administration, and the concomitant is a concomitant selected from the group consisting of: (i) inhibition using ACE (ii) using an adenosine kinase inhibitor; (iii) using an adrenocortical antagonist; (iv) using an AKT pathway inhibitor; (v) using an angiogenesis inhibitor; (vi) using an angiogenesis-inhibiting steroid; Use anti-androgens; (viii) use anti-estrogens; (ix) use anti-hypercalcemia agents; (x) use apoptosis inhibitors; (xi) use ATI receptor antagonists; (xii) use Aurora kinase inhibitor; (xiii) use of aromatase inhibitor; (xiv) use of bisphosphonate; (xv) use Bruton's tyrosine kinase inhibitor; (xvi) use of phosphatase inhibitor; (xvii) use CaM kinase II inhibitor; (xviii) using a CD45 tyrosine phosphatase inhibitor; (xix) using a CDC25 phosphatase inhibitor; (xx) using a CHK kinase inhibitor; (xxi) using a targeting/decreasing protein or fat a compound that is kinase active; (xxii) a compound that targets, decreases or inhibits the activity of a protein or a fat phosphatase; Xiii) using a compound that induces a cell differentiation process; (xxiv) using a cRAF kinase inhibitor; (xxv) using a cyclin-dependent kinase inhibitor; (xxvi) using a cysteine protease inhibitor; (xxvii) using DNA崁(xxviii) use DNA strand breakage agent; (xxix) use E3 ligase inhibitor; (xxx) use EDG binding agent; (xxxi) use endocrine hormone; (xxxii) use farnesyl transferase inhibitor; Xxxiii) use Flk-1 kinase inhibitor; (xxxiv) use Flt-3 inhibitor; (xxxv) use gonadotropin agonist; (xxxvi) heparinase inhibitor; (xxxvii) use histone deacetylase (HDAC) inhibitor; (xxxviii) use HSP90 inhibitor; (xxxix) use I κ B α inhibitor; (xl) use insulin receptor tyrosine kinase inhibitor; (xli) use c-Jun N-terminal kinase Inhibitor; (xlii) using microtubule binding agent; (xliii) using mitogen-activated protein (MAP) kinase inhibitor; (xliv) using MDM2 inhibitor; (xlv) using MEK inhibitor; Xlvi) use of methionine amino-peptidase inhibitor; (xlvii) use of MMP inhibitor; (xlviii) use of NGFR tyrosine kinase Formulation; (xlix) use of p38 MAP kinase inhibitor; (1) use of p56 tyrosine kinase inhibitor; (li) use of PDGFR tyrosine kinase inhibitor; (lii) use of phospholipid 醯 inositol-3 kinase inhibitor; (liii) using a phosphatase inhibitor; (liv) using a platinum agent; (lv) using a protein phosphatase inhibitor; (lvi) using a PKC inhibitor; (lvii) using a PKC delta kinase inhibitor; (lviii) using a polyamine Synthetic inhibitors; (lix) use proteasome inhibitors; (lx) use PTP1B inhibitors; (lxi) use protein tyrosine kinase inhibitors; (lxii) use SRC family tyrosine kinase inhibitors; (lxiii) use Syk tyrosine kinase inhibitor; (lxiv) using Janus (JAK-2 and / or JAK-3) tyrosine kinase inhibitor; (lxv) using Ras oncogene isomer inhibitor; (lxvi) use class Vitamin A; (lxvii) using a ribonucleotide reductase inhibitor; (lxviii) using an RNA polymerase II elongation inhibitor; (lxix) using an S-adenosine methionine decarboxylase inhibitor; (lxx) a serine/threonine kinase kinase inhibitor; (lxxi) uses the activity or function of targeting, decreasing or inhibiting the activity or function of a serine/synthesis mTOR kinase (lxxii) using a somatostatin receptor antagonist; (lxxiii) using a telomerase inhibitor; (lxxiv) using a positional isomerase inhibitor; (lxxv) using a VEGFR tyrosine kinase inhibitor; Lxxvi) uses a RANKL inhibitor. The method of claim 138, wherein the improvement is performed by chemical sensitization, and the chemical sensitization comprises a combination of alkylation of a hexitol to be used as a chemical sensitizer. And an agent selected from the group consisting of: (a) a positional isomerase inhibitor; (b) a pseudonucleoside; (c) a pseudonucleotide; (d) a thymidine synthase inhibitor (e) signal delivery inhibitor; (f) cisplatin or platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; k) apigenin; (l) an analog of colchicine or colchicine; (m) genistein; (n) rituxep; (o) arabinosylcytosine; (p) camptothecin; (q) vinca alkaloids; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; and (v) propyl hydrazine . The method of claim 138, wherein the improvement is carried out by chemical synergism, and the chemical synergism comprises a combination of alkylation of hexitol as one of the chemical synergists And an agent selected from the group consisting of: (a) a pseudonucleoside; (b) a pseudonucleotide; (c) a thymidine synthetase inhibitor; (d) a signal delivery inhibitor; e) cisplatin or platinum analogue; (f) alkylating agent; (g) anti-tubulin agent; (h) antimetabolite; (i) berberine; (j) apigenin; (k) colchicine Or an analog of colchicine; (1) genistein; (m) idopride; (n) arabinosylcytosine; (o) camptothecin; (p) vinca alkaloids; (q) positional isomerase inhibitors; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosemary Aromatics; (v) acetamidine; and (w) a biological therapeutic. The method of claim 138, wherein the improvement is performed by post-treatment management, and the post-treatment management is a method selected from the group consisting of: (a) Pain management related therapies; (b) nutritional support; (c) administration of an antiemetic; (d) primary anti-vomiting; (e) administration of an anti-inflammatory agent; (f) administration of an antipyretic; An immune booster is administered. The method of claim 138, wherein the improvement is performed by selective medical/post-treatment support, and the selective medical/post-treatment support is selected from the group consisting of Methods: (a) hypnosis; (b) acupuncture; (c) physical and mental therapy; (d) an herbal drug produced by synthesis or extraction; (e) Applying human kinematics. The method of claim 154, wherein the selective medical/post-treatment support is an herbal medicine produced by synthesis or extraction, and the herbal medicine produced by synthesis or extraction is selected from the following Groups: (a) an NF-κB inhibitor; (b) a natural anti-inflammatory agent; (c) an immunostimulant; (d) an antimicrobial; and (e) a flavonoid, isoflavone Or flavonoids. The method of claim 155, wherein the herbal drug produced by synthesis or extraction is an NF-κB inhibitor, and the NF-κB inhibitor is selected from the group consisting of parthenolide and turmeric a group of vegetarian and rosmarinic acids. The method of claim 155, wherein the herbal drug produced by synthesis or extraction is a natural anti-inflammatory agent, and the natural anti-inflammatory agent is selected from the group consisting of rhein and parthenolide The group formed. The method of claim 155, wherein the herbal drug produced by synthesis or extraction is an immune promoter, and the immune promoter is a product found in echinacea or isolated from echinacea. . The method of claim 155, wherein the herbal drug produced by synthesis or extraction is an antimicrobial drug, and the antimicrobial drug is berberine. The method of claim 155, wherein the herbal drug produced by synthesis or extraction is a flavonoid, isoflavone or flavonoid, and the flavonoid or flavonoid is selected from the group consisting of apigenenin, genistein, and dye wood. Glycosides, 6 " -O-propanediamine genistein, 6 " -O-acetyl generin, daidzein, daidzin, 6 " -O-propanedithioglycoside, 6 " -O- A group consisting of acetyl glucoside, daidzein, daidzein, 6 " -O-propanediylxanthine and 6-O-ethylidene-flavonoid. The method of claim 138, wherein the improvement is carried out by modifying a drug substance product, and the drug substance product improvement is an improvement of a drug substance product selected from the group consisting of : (a) salt formation; (b) as a homogeneous crystal structure; (c) as a pure isomer; (d) increased purity; (e) a low residual solvent content; f) A formulation with a low residual solvent content. The method of claim 138, wherein the improvement is carried out by using a diluent, and the diluent is a diluent selected from the group consisting of: (a) a Emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF); (d) dimethylformamide (DMF); (e) dimethyl acetamide (DMA); (f) ethanol; (g) benzyl alcohol; (h) water containing glucose for injection; (i) polyoxyethylene castor oil; (j) cyclodextrin; and (k) PEG. The method of claim 138, wherein the improvement is carried out by using a solvent system, and the solvent system is a solvent system selected from the group consisting of: (a) a Emulsion; (b) DMSO; (c) NMF; (d) DMF; (e) DMA; (f) ethanol; (g) benzyl alcohol; (h) glucose-containing water for injection; (i) poly Oxyethylene castor oil; (j) PEG; and (k) salt system. The method of claim 138, wherein the improvement is carried out by using an excipient, and the excipient is an excipient selected from the group consisting of: a) mannitol; (b) albumin; (c) EDTA; (d) sodium hydrogen sulfite; (e) benzyl alcohol; (f) carbonate buffer; (g) phosphate buffer; (h) PEG (i) vitamin A; (j) vitamin D; (k) vitamin E; (l) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibitor; (o) organic resin; a detergent; (q) perillol or an analogue thereof; and (r) an activator for channel forming receptors. The method of claim 138, wherein the improvement is carried out by using a dosage form, and the dosage form is a dosage form selected from the group consisting of: (a) a tablet; b) capsule; (c) topical gel; (d) topical ointment; (e) patch; (f) embolic agent; (g) lyophilized dose filler; (h) immediate release formulation; (i) sustained release Formulation; (j) a controlled release formulation; and (k) a liquid capsule. The method of claim 138, wherein the improvement is performed by using a dose kit and a package, and the dose set and package are selected from the group consisting of avoiding light browning Color bottles and dose sets and packages using a group of stoppers with special coatings to increase shelf life stability. The method of claim 138, wherein the improvement is performed by using a drug delivery system, and the drug delivery system is a drug delivery system selected from the group consisting of: a) oral dosage form; (b) nanocrystals; (c) nanoparticle; (d) cosolvent; (e) slurry; (f) syrup; (g) bioerodible polymer; (h) liposome (i) a sustained release injection gel; (j) microspheres; and (k) a targeting composition having an epidermal growth factor receptor binding peptide. The method of claim 138, wherein the improvement is carried out by using a drug conjugated form, and the conjugated form of the drug is a drug conjugate selected from the group consisting of Form: (a) a polymer system; (b) polylactic acid; (c) polyglycolic acid; (d) amino acid; (e) peptide; (f) a multivalent linker; (g) an immunoglobulin; (h) a cyclodextrin polymer; (i) a modified transferrin; (j) a hydrophobic polymer or a hydrophobic-hydrophilic polymer; (k) a conjugate having a monophosphate of partial sodium phosphate; (1) a conjugate having a cell binder to which a charged crosslinking agent is added; and (m) a conjugate having β-glucuronic acid through a linking agent. The method of claim 138, wherein the improvement is carried out by using a compound analog, and the compound analog is a compound analog selected from the group consisting of: a) a change in the side chain to increase or decrease lipophilicity; (b) an increase in another chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding ability; and (c) Changes in salt type. The method of claim 138, wherein the improvement is performed by using a precursor system, and the precursor system is a precursor system selected from the group consisting of: ( a) use of enzyme-sensitive esters; (b) use of dimers; (c) use of Schiff base; (d) use of pyridoxal complexes; (e) use of caffeine complexes; (f) use of nitric oxide Release the precursor; (g) using a precursor having a fibroblast activation protein α-cleavable oligopeptide; (h) using a precursor of the product reacted with an oxime or an amine formazan; (i) using hexanoic acid a salt conjugate precursor; (j) a polymer-agent conjugate precursor; and (k) a precursor that is activated by redox activation. The method of claim 138, wherein the improvement is performed by using a multi-drug system, and the multi-drug system is a multi-drug system selected from the group consisting of: (a) inhibitors of multiple drug resistance; (b) specific drug resistance inhibitors; (c) specific selective enzyme inhibitors; (d) signal delivery inhibitors; (e) metformin; Imatinib; (g) hydroxy urea; (h) dasatinib; (i) capitabine; (j) nilotinib; (k) repair inhibitor; and (l) non-overlapping side effects Positional isomerase inhibitor. The method of claim 138, wherein the improvement is performed by a biotherapeutic potentiation, and the biotherapeutic potentiation is achieved by a combination of a sensitizer/potentiator and a therapeutic agent or technique And completed, the therapeutic agent or technique is selected from the group consisting of: (a) biological response modifiers; (b) cytokines; (c) therapeutic antibodies; (d) therapeutic antibodies; (e) antisense therapy; (f) gene therapy; (g) ribozyme; and (h) RNA interference. The method of claim 138, wherein the improvement is performed by using an antibiotic treatment, and the antibiotic treatment is used to resist an anti-TKI tumor that is also resistant to a therapeutic agent or technique. The therapeutic agent or technique is selected from the group consisting of: (a) a biological response modifier; (b) a cytokine; (c) a therapeutic antibody; (d) a therapeutic antibody; (e) an antisense therapy; f) gene therapy; (g) ribozyme; and (h) RNA interference. The method of claim 138, wherein the improvement is performed by using an antibiotic treatment, and the antibiotic treatment is used to resist an abnormality of the AHI1 gene which is also resistant to a therapeutic agent or technique. To modulate a related malignancy, the therapeutic agent or technique is selected from the group consisting of: (a) a biological response modifier; (b) a cytokine; (c) a therapeutic antibody; (d) a therapeutic antibody; e) antisense therapy; (f) gene therapy; (g) ribozyme; and (h) RNA interference. The method of claim 138, wherein the improvement is performed by enhancing radiation therapy, and the enhancement of the radiation therapy is a radiation therapy enhancing agent or technique selected from the group consisting of : (a) use of a hypoxic sensitizer; (b) use of a radiation sensitizer / protectant; (c) use of a photosensitizer; (d) use of a radiation repair inhibitor; (e) use of a mercaptan consumer; f) use of a vascular target agent; (g) use of a DNA repair inhibitor; (h) use of a radioactive strain; (i) use of a radioactive nucleus; (j) use of a radioactive label antibody; and (k) use of a proximity therapy. The method of claim 138, wherein the improvement is performed by using a novel mechanism of action, and the novel mechanism of action is a novel mechanism of action with a therapeutic interaction of a target or mechanism, the label The target or mechanism is selected from the group consisting of: (a) inhibitors of poly ADP ribose polymerase; (b) agents that affect blood vessels; (c) agents that promote vasodilation; (d) oncogene-targeted drugs; (e) signal delivery inhibitors; An agent that inhibits EGFR; (g) an agent that causes inhibition of protein kinase C; (h) an agent that causes a decrease in phospholipase C; (i) an agent that causes jun down regulation; (j) an agent that modulates the expression of a tissue protein gene (k) an agent that modulates the expression of VEGF; (1) an agent that modulates the expression of ornithine decarboxylase; (m) an agent that modulates the performance of jun D; (n) an agent that modulates the expression of v-jun; An agent that modulates the expression of GPCRs; (p) an agent that modulates the expression of protein kinase A; (q) an agent that modulates the expression of a protein kinase (other than protein kinase A); and (r) an agent that modulates the expression of telomerase; s) an agent that modulates the expression of a particular gene in the prostate; and (t) an agent that modulates the expression of histone deacetylase. The method of claim 138, wherein the improvement is performed by using a selective target cell population therapy, and the use of the selective target cell population therapy is selected from the group consisting of Use: (a) to resist radiation-sensitive cells; (b) used to resist radiation-resistant cells; and (c) to resist energy depletion of cells. The method of claim 138, wherein the improvement is carried out by using an agent for increasing the activity of the alkylated hexitol derivative, and the method for improving the alkylation The agent for the activity of the sugar alcohol derivative is selected from the group consisting of (a) nicotinamide; (b) caffeine; (c) tetrandrine; and (d) berberine. A composition for increasing the efficacy and/or side effects of an undesired administration of a therapy using a monoalkylated hexitol derivative for the treatment of a primary anti-TKI tumor or an AHI1 gene A mutation or abnormal regulation associated malignancy, the composition comprising a selection selected from the group consisting of: (a) a modified alkylated hexitol derivative or a monoalkylated hexitol A therapeutically effective amount of a derivative, or a modified alkylated hexitol derivative, analog or precursor thereof, wherein the modified alkylated hexose is compared to an unmodified alkylated hexitol derivative The alcohol derivative or the derivative, analog or precursor of the modified alkylated hexitol derivative has an effect of reducing or reducing side effects on the treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene. (b) The composition comprises: (i) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexose a derivative, analog or precursor of an alcohol derivative And a therapeutically effective amount; and (ii) at least one additional therapeutic agent, a chemical sensitizing therapeutic agent, a chemically potentiating therapeutic agent, a diluent, an excipient, a solvent system, or a drug delivery system, wherein An unmodified alkylated hexitol derivative having increased therapeutic effect or reduced side effects for treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene; (c) incorporation a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative in one dosage form A therapeutically effective amount of an analog, or precursor, wherein the monoalkylated hexitol derivative, a modified alkylation, incorporated into the dosage form is compared to an unmodified alkylated hexitol derivative A derivative, analog or precursor of a hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative having a mutation or abnormality for a primary anti-TKI tumor or a AHI1 gene Regulation related malignant swelling Treatment increases efficacy or reduces side effects; (d) monoalkylated hexitol derivatives, modified alkylated hexitol derivatives or monoalkylated hexoses incorporated into a single dose kit and package A therapeutically effective amount of an alcohol derivative or a derivative, analog or precursor of a modified alkylated hexitol derivative, wherein the dosage set is incorporated as compared to an unmodified alkylated hexitol derivative a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a derivative of a modified alkylated hexitol derivative in the package and package , an analog or a precursor having increased therapeutic efficacy or reduced side effects for treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene; and (e) monoalkylated hexose modified by a drug substance product A therapeutically effective amount of an alcohol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative, analog or precursor thereof, wherein Compared to an unmodified alkylated hexitol derivative, Derivatization of the alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative to the drug substance product The substance, analog or precursor has an increased therapeutic effect or a reduced side effect for the treatment of a primary anti-TKI tumor or a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene. The composition of claim 179, wherein the composition has an increased therapeutic effect or a reduced side effect for treatment with a primary anti-TKI tumor. The composition of claim 179, wherein the composition has an effect of reducing or reducing side effects for treatment of a malignant tumor associated with mutation or abnormal regulation of the AHI1 gene. The composition of claim 179, wherein the composition comprises a combination comprising: (ii) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a mono a derivative, analog or precursor of a modified hexitol derivative or a modified alkylated hexitol derivative; and (ii) an additional therapeutic agent selected from the group consisting of: a) positional isomerase inhibitor; (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidine synthase inhibitor; (e) signal delivery inhibitor; (f) cisplatin or platinum (g) an alkylating agent; (h) an anti-tubulin agent; (i) an antimetabolite; (j) berberine; (k) apigenin; (l) naproxen; (m) vinca alkaloids; (n) 5-fluorouracil; (o) curcumin; (p) NF- κ B inhibitor; (q) rosmarinic acid; (r) acetamidine; (s) tetrandrine; (t) a JAK2 inhibitor; (u) a STAT5 inhibitor; and (v) a Src inhibition Agent. The composition of claim 179, wherein the composition comprises a combination comprising: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a mono a derivative, analog or precursor of a modified hexitol derivative or a modified alkylated hexitol derivative; and (b) a BH3 analog. The composition of claim 183, wherein the BH3 analog is a BH3 analog selected from the group consisting of: (i) a peptide; (ii) a modified peptide; a triazinyl-based peptidomimetic; (iv) p-benzoguanamine-based peptipeptides; (v) benzamidine-based p-peptides; (vi) erbaturab; (vii) TW37; (viii) analogs or derivatives of TW37; (ix) (-) gossypol; (x) gossypol phenol derivative; (xi) isoxazoline derivative; (xii) A-385358; (xiii) A-385358 analog or derivative; Xiv) ABT-737; (xv) an analog or derivative of ABT-737; (xvi) ABT-263; (xvii) an analog or derivative of ABT-263; (xviii) TM-1206; and (xix) An analog or derivative of TM-1206. The composition of claim 179, wherein the composition comprises a combination comprising: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a mono a derivative, analog or precursor of a modified hexitol derivative or a modified alkylated hexitol derivative; and (b) an agent that modulates the expression of the AHI1 gene or modulates the activity of the AHI1 protein. The composition of claim 179, wherein the composition comprises a combination comprising: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a mono a derivative, analog or precursor of a modified hexitol derivative or a modified alkylated hexitol derivative; (b) an agent that modulates the expression of the AHI1 gene or modulates the activity of the AHI1 protein; and (c) A BH3 analogue. The composition of claim 179, wherein the composition comprises: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol a derivative, a derivative, an analog or a precursor of a modified alkylated hexitol derivative; and (b) a therapeutic agent that is chemically sensitized, selected from the group consisting of: (i) a positional isomerase inhibitor; (ii) a pseudonucleoside; (iii) a pseudonucleotide; (iv) a thymidine synthase inhibitor; (v) a signal delivery inhibitor; (vi) cisplatin or platinum Analog (vii) alkylating agent; (viii) antitubulin agent; (ix) antimetabolite; (x) berberine; (xi) apigenin; (xii) colchicine or colchicine Analog; (xiii) genistein; (xiv) itopride; (xv) arabinoxycytosine; (xvi) camptothecin; (xvii) vinca alkaloids; (xviii) 5-fluorouracil; (xix) curcumin; (xx) NF-κB inhibitor (xxi) rosmarinic acid; and (xxii) propyl hydrazine wherein the alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or A derivative, analog or precursor of an alkylated hexitol derivative is modified as a chemical sensitizer. The composition of claim 179, wherein the composition comprises: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol a derivative or a derivative, a derivative or an analog of a modified alkylated hexitol derivative; and (b) a chemically synergistic therapeutic agent selected from the group consisting of: i) positional isomerase inhibitor; (ii) pseudonucleoside; (iii) pseudonucleotide; (iv) thymidine synthase inhibitor; (v) signal delivery inhibitor; (vi) cisplatin or platinum (vii) an alkylating agent; (viii) an anti-tubulin agent; (ix) antimetabolite; (x) berberine; (xi) apigenin; (xii) naphthophene; (xiii) vinca alkaloid; (xiv) 5-fluorouracil; (xv) turmeric (xvi) NF-κB inhibitor; (xvii) rosmarinic acid; (xviii) propyl hydrazine; and (xix) tetrandrine, wherein the alkylated hexitol derivative, a modified alkyl group A derivative, analog or precursor of a hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative is used as a chemical synergist. The composition of claim 179, wherein the alkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylation A derivative, analog or precursor of a hexitol derivative is modified by a bulk drug product, wherein the drug substance product modification is selected from the group consisting of: (i) salt formation; (ii) a uniform crystal structure; (iii) as a pure isomer; (iv) increased purity; (v) a low residual solvent content; and (vi) a low residual solvent content. The composition of claim 179, wherein the composition comprises: a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor; and a diluent, wherein the diluent is selected from the group consisting of: (i) an emulsion; (ii Dimethyl hydrazine (DMSO); (iii) N-methylformamide (NMF); (iv) dimethylformamide (DMF); (v) dimethylacetamide (DMA); Vi) ethanol; (vii) benzyl alcohol; (viii) water containing glucose for injection; (ix) polyoxyethylene castor oil; (x) cyclodextrin; and (xi) PEG. The composition of claim 179, wherein the composition comprises: a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor; and a solvent system wherein the solvent system is selected from the group consisting of: (i) an emulsion; (ii DMSO; (iii) NMF; (iv) DMF; (v) DMA; (vi) ethanol; (vii) benzyl alcohol; (viii) water containing glucose for injection; (ix) polyoxyethylene castor oil; (x) PEG; and (xi) salt system. The composition of claim 179, wherein the composition comprises: a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkylated hexitol derivative derivative, analog or precursor; and an excipient wherein the excipient is selected from the group consisting of: (i) mannitol; Ii) albumin; (iii) EDTA; (iv) sodium hydrogen sulfite; (v) benzyl alcohol; (vi) carbonate buffer; (vii) phosphate buffer; (viii) PEG; (ix) vitamin A (x) vitamin D; (xi) vitamin E; (xii) esterase inhibitor; (xiii) cytochrome P450 inhibitor; (xiv) multidrug resistance (MDR) inhibitor; (xv) an organic resin; (xvi) a detergent; (xvii) perillol or an analogue thereof; and (xviii) an activator of a channel-forming receptor. The composition of claim 179, wherein the alkylated hexitol derivative, modified alkylated hexitol derivative or monoalkylated hexitol derivative or modified alkylated hexose A derivative, analog or precursor of an alcohol derivative is incorporated into a dosage form selected from the group consisting of: (i) a tablet; (ii) a capsule; (iii) Topical gel; (iv) topical ointment; (v) patch; (vi) embolic agent; (vii) lyophilized dose filler; (viii) immediate release preparation; (ix) sustained release preparation; (x) controlled release Formulation; and (xi) liquid capsules. The composition of claim 179, wherein the alkylated hexitol derivative, modified alkylated hexitol derivative or monoalkylated hexitol derivative or modified alkylated hexose Derivatives, analogs or precursors of alcohol derivatives are incorporated into a dosage kit and package selected from a brown bottle that is protected from light and used to increase shelf life stability. A group of stoppers with special coatings. The composition of claim 179, wherein the composition comprises: (a) a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative Or a modified derivative, analog or precursor of an alkylated hexitol derivative; and (b) a drug delivery system, wherein the drug delivery system is selected from the group consisting of: (i) Oral dosage form; (ii) nanocrystals; (iii) nanoparticles; (iv) cosolvents; (v) slurries; (vi) syrups; (vii) bioerodible polymers; (viii) liposomes; Ix) a sustained release injection gel; (x) microspheres; and (xi) a targeting composition having an epidermal growth factor receptor binding peptide. The composition of claim 179, wherein the therapeutic agent is a modified alkylated hexitol derivative, and the modification is selected from the group consisting of: (a) side chains Varying to increase or decrease lipophilicity; (b) an increase in another chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding ability; and (c) change in salt type . The composition of claim 179, wherein the therapeutic agent is monoalkylated a sugar alcohol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified derivative, analog or precursor of an alkylated hexitol derivative, and the therapeutic agent is present in In a composition in a conjugated form of the drug, the conjugated form of the drug is selected from the group consisting of: (i) a polymer system; (ii) polylactic acid; (iii) polyglycolic acid; (iv) amino acid; (v) peptide; (vi) multivalent linker; (vii) immunoglobulin; (viii) cyclodextrin polymer; (ix) modified transferrin; (x) hydrophobic a polymer or a hydrophobic-hydrophilic polymer; (xi) a conjugate having a partial ester of sodium phosphate; (xii) a conjugate having a cell binder added with a charged crosslinking agent; and (xiii) having a pass The conjugate of β-glucuronic acid of the linker. The composition of claim 179, wherein the therapeutic agent is a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkane. A derivative or analog of a hexitol derivative, and the therapeutic agent is in the form of a precursor system, wherein the precursor system is selected from the group consisting of: (i) an enzyme-sensitive ester (ii) dimer; (iii) Schiff base; (iv) pyridoxal complex; (v) caffeine complex; (vi) nitric oxide releasing precursor; (vii) having fibroblast activation protein alpha-cleavable oligopeptide precursor; (viii) and a product of the reaction of a hydrating agent or a monomethyl methacrylate; (ix) a hexanoate conjugate; (x) a conjugate of a polymer-agent; and (xi) a use of a precursor prior to redox activation . The composition of claim 179, wherein the therapeutic agent is a monoalkylated hexitol derivative, a modified alkylated hexitol derivative or a monoalkylated hexitol derivative or a modified alkane. A derivative, analog or precursor of a hexitol derivative, and the composition further comprises at least one additional therapeutic agent to form a multi-drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of a group consisting of: (i) a multidrug resistance inhibitor; (ii) a specific drug resistance inhibitor; (iii) a specific selective enzyme inhibitor; (iv) a signal delivery inhibitor; (v) an inhibitor of repair enzyme; and (vi) a positional isomerase inhibitor having non-overlapping side effects. The composition of claim 179, wherein the alkylated hexitol derivative is selected from the group consisting of a derivative or analog of Weikangol, Weikangol, and diacetyl dianol. A group consisting of a derivative or analog of diacetyl dianol, a dibromodusol, and a derivative or analog of dibromodusol. The composition of claim 200, wherein the alkylated hexitol derivative is Wei Kang alcohol. The composition of claim 200, wherein the alkylated hexitol derivative is a derivative or analog of weikangol. The composition of claim 202, wherein the derivative or analog of the tilconol is a derivative of Weikangol selected from the group consisting of: (i) a Weikangol a derivative having one or two hydrogen groups of a dihydroxy group of a diconical alcohol substituted with a lower alkyl group; (ii) a derivative of a terconazole having one or more linkages substituted with a lower alkyl group Hydrogen in two epoxy rings; (iii) a derivative of Weikangol having one or two methyl groups present in the diconazole and attached to the same carbon, the carbon with C _a lower alkyl-substituted hydroxyl group of ₂ -C ₆ ; and (iv) a derivative of Weikangol having one or two methyl groups present in the phytocol and attached to the same carbon, The carbon has a hydroxyl group substituted with a halogen group by hydrogen replacing a methyl group with a halogen group. The composition of claim 202, wherein the alkylated hexitol derivative is diacetyl dianol. The composition of claim 200, wherein the alkylated hexitol derivative is a derivative or analog of diethylene quinone dihydrated. The composition of claim 205, wherein the derivative or analog of dihydroquinone dihydroxylitol is selected from the group consisting of diacetyl dianol. Derivatives: (i) a derivative of diacetyl dianhydrodehydrin having one or two methyl groups substituted with a lower alkyl group of C ₂ -C _{6 to} the ethyl group; (ii) a a derivative of diacetyl dianhydroquinol having one or two hydrogens attached to the epoxy ring substituted with a lower alkyl group; (iii) a derivative of diacetyl quinone difoamol having One or two methyl groups attached to the same carbon having an acetamyl group substituted with a C ₂ -C ₆ lower alkyl group; and (iv) a diethylene quinone dihydrated cyclohexanol derivative It has one or two methyl groups attached to the same carbon having a hydroxyl group substituted with a halogen group by hydrogen replacing the methyl group with a halogen group. The composition of claim 200, wherein the alkylated hexitol derivative is dipotassium dibromide. The composition of claim 200, wherein the alkylated hexitol derivative is a derivative or analog of dicycloheximide. The composition of claim 208, wherein the derivative or analog of dibromodusol is a derivative of dibromodusol selected from the group consisting of: (i) a derivative of dibromodusol having one or more hydrogens substituted with a lower alkyl group; and (ii) a derivative of dibromodusol having one or two substituted with another halo group a bromo group selected from the group consisting of chlorine, fluorine and iodine.