TW201815395A - Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies - Google Patents

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of malignancies of the central nervous system in pediatric patients, including glioblastoma multiforme (GBM) high grade glioma, and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation and that can induce double-stranded breaks in DNA. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents (e.g. cisplatin) and can possess additive or super-additive effects.

Description

Use of dihydrogalactitol or a derivative or analog thereof for treating pediatric central nervous system malignant diseases Cross-references to related applications

The application of the above-mentioned title is claimed in US Provisional Application No. 62/247,350 to JABacha et al., entitled "Use of Dianhydrogalactitol or Derivatives or Analogs Thereof for Treatment of Pediatric Central Nervous System Malignancies" (Application Date October 28, 2015) The disclosure of the disclosure is hereby incorporated by reference in its entirety.

The present invention relates to a composition and method for treating pediatric central nervous system malignant diseases using di-desaled galactitol, diacetyl hydrazine galactitol, or a derivative or analog thereof, the malignant disease including the medullary mother Cell tumors and highly malignant gliomas, including glioblastoma multiforme.

The search for and discrimination of many life-threatening diseases that afflict humans is still in the process of experimentation, and sometimes it is a process of unexpected gains. Although many advances have been made in improving basic patient care from basic scientific research, there are still specific and successful treatments for life-threatening diseases such as cancer, inflammation, infection, and other conditions. A lot of frustration. Since the National Institutes of Health (NIH) began its "Declaration of Cancer" in the early 1970s, the United States National Cancer Institute (NCI) has produced many types of prevention, diagnosis, and treatment. And strategies and plans to cure cancer and implement them. One of the oldest and most controversial but most successful projects is the synthesis and screening of small chemical entities (<1500 MW) for the biological activity against cancer. The organization of the project is to improve the process from chemical synthesis and biological screening to preclinical research, and to streamline it so that it can be reasonably developed into human clinical trials, hoping to discover many kinds of life-threatening malignant tumors. In addition to screening natural products and extracting from prokaryotes, invertebrates, plant communities, and other sources from all over the world, hundreds of chemical compounds have been synthesized and screened from thousands of chemical compounds from academic and industry sources. It continues to be a novel precursor for discriminating novelty as a significant and promising pharmaceutical achievement. In addition to other programs, it also includes biomedical methods, which use vaccines, medical antibodies, cytokines, lymphokines, tumor vascular development (angiogenesis) inhibitors or genes to stimulate the human immune system, and use cancer to change Antisense therapy for the genetic makeup of cells, and other biological response modifiers.

Work supported by NCI and other government agencies, including domestic and foreign academic or industrial research and development laboratories, has generated a wealth of biological, chemical and clinical information. In addition, a large chemical database has been established, and Highly characterized in vitro and in vivo bioscreening systems that have been successfully applied. However, in these preclinical and clinical programs that have been supported by tens of billions of dollars over the past 30 years, only a few compounds have been identified or found to be successfully used to develop suitable medical products. Despite this, it is still necessary to use in vitro and in vivo biological systems and "decision trees" to further confirm animal testing to achieve clinical trial certification. These plans, biological models, clinical trial methods, and other information developed with this work are still important for the discovery and development of any novel medical agents.

Unfortunately, many of the compounds that have successfully met the preclinical trials and the federal government's regulatory requirements for clinical assessment have not been successful or disappointing in human clinical trials. Many compounds have been found to have cumbersome or specific side effects in human clinical Phase I dose escalation assays used to determine maximum tolerated dose (MTD) and side effects. In some cases, such toxicity or its toxic strength is not discerned or predicted in preclinical toxicity testing. In other cases, chemotherapeutic agents that have potential unique activities for specific tumor types, molecular targets, or biological pathways in vitro and in vivo are still not successfully used in human Phase II clinical trials, and are specifically examined in this trial. Special cancer indications/types will be approved by the government (eg USFDA), IRB approved clinical trial evaluation. In addition, in some cases, potential new agents evaluated in randomized Phase III clinical trials did not demonstrate significant clinical benefit; these examples were extremely frustrating and disappointing. Finally, many compounds have been commercialized, but their final clinical application is still subject to the adverse effects of monotherapy (reaction rate <25%) and troublesome dose-limiting side effects (grades III and IV) (eg, myelosuppressive, Neurotoxicity, cardiotoxicity, gastrointestinal Limitations of toxicity, or other significant side effects.

In many cases, after a lot of time and money spent developing and transferring research compounds to human clinical trials and clinical failures, it is necessary to go back to the lab to recreate better analogs, look for different structures, but may have a related role. Pharmacy, or a method of trying other modified drugs. In some instances, additional Phase I or II clinical trials have been attempted to try to achieve some improvement in the side effects or medical effects of selected patients or cancer indications. In many of these cases, the results are not sufficient to achieve significant improvements for further clinical development into product registration. Even for commercial products, their end use is still limited by the best performance.

Since only a very small number of medical agents are approved for cancer patients, and because cancer is recognized as a combination of many pathogenic diseases, the response and survival of patients undergoing medical interventions is complicated by many factors that affect the success or failure of their treatment. Factors such as disease indications, stages of invasion and metastasis, patient gender, age, health status, past therapy or other diseases, genetic markers that promote or delay medical efficacy, and other factors, are difficult to cure in the short term. fathom. In addition, due to advances in diagnostic techniques, such as mammography for breast cancer and PSA testing for prostate cancer, more patients are diagnosed early. For refractory cancers, the patient's treatment options often reach a level of incompetence, so that other treatments are urgently needed. Even for the most limited patient population, any other treatment opportunity can be valuable. The present invention is directed to the use of the compositions and methods of the present invention to improve the medical benefit of chemical compounds that are administered in suboptimal amounts, including substituted hexitols such as di-dehydrated galactitol.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor that occurs in humans. GBM is involved in glial cells; it accounts for 52% of all functional tissue brain tumors and accounts for 20% of all intracranial tumors. Its frequency in Europe and North America is estimated to be 2 to 3 per 100,000 people.

GBM has a variety of different treatments, including craniotomy with surgery to remove the tumor as much as possible, followed by chemoradiotherapy, bevacizumab for anti-angiogenesis therapy, gamma knife radiosurgery, and Symptomatic treatment with corticosteroids, but its prognosis is extremely poor. The median survival of GBM is only 14 months.

Common symptoms of GBM include convulsions, nausea, vomiting, headache, and hemiparesis. However, the most common symptom of GBM is progressive memory, personality, or neurological deficits caused by cerebral palsy or prefrontal lobes. The type of symptoms produced by GBM will depend on the location of the tumor and will not be affected by its pathology. The tumor quickly develops symptoms at the beginning, but sometimes it has no symptoms until it reaches a considerable size.

The causes of GBM are mostly unknown. For unknown reasons, GBM is good for men. Most glioblastomas occur occasionally without any significant genetic predisposition. No association was found between GBM and several known carcinogenic risk factors including diet, smoking, and exposure to electromagnetic fields. There have been suggestions for a viral cause, possibly SV40 or cytomegalovirus. There may also be some correlation between exposure to free radiation and GBM. In addition, the correlation between PVC exposure and GBM has been proposed; it has also been considered that exposure to lead in the workplace is a possible cause. Brain tumor occurrence and malaria Related to the disease, this means that malaria mosquitoes in the malaria zone may transmit GBM virus or other pathogens.

GBM is also quite common in people over the age of 50, Caucasian or Asian, and patients who have developed lower grade astrocytoma and may develop into more advanced tumors. In addition, patients with one of the following genetic lesions are also associated with an increased incidence of GBM: neurofibromatosis, tuberous sclerosis, Von Hippel-Lindau disease, Li-Fomeni syndrome (Li- Fraumeni syndrome), or Turcot syndrome.

A typical feature of GBM tumors is the appearance of small areas of necrotic tissue surrounded by degeneratively altered cells. These features, along with the presence of proliferating blood vessels, distinguish these malignant diseases from grade 3 astrocytomas without such features.

There are four subtypes of glioblastoma. A large proportion (97%) of the so-called "typical" subtypes have additional copies of the epidermal growth factor receptor (EGFR) gene, and most of these tumors have higher than normal EGFR expression, while the gene TP53 ( A tumor suppressor gene with many anticancer activities, often mutated in glioblastoma, rarely mutates in this subtype. Conversely, pro-neuronal subtypes are often found in TP53 and PDGFRA, which are genes encoding alpha-type platelet-derived growth factor receptors, and in IDH1, which encodes the gene for isocitrate dehydrogenase-1. Rate of change. The mesenchymal subtype is characterized by a high mutation rate or a change in NF1, which is a gene encoding a neurofibromin type 1 gene, which rarely changes in the EGFR gene, and the expression of EGFR is lower than its His subtype.

GBM is usually formed in the white matter of the brain, grows rapidly, and becomes extremely large before symptoms appear. Less than 10% of GBM will form slowly after degeneration of low-grade astrocytoma or degenerative astrocytoma; these tumors are called secondary GBM and are quite good in younger patients. Tumors may extend into the meninges or ventricles, resulting in abnormally high protein content (>100 mg/dL) in cerebrospinal fluid (CSF), and sometimes 10 to 100 cells in the cerebrospinal fluid, mainly lymphocytes. Malignant cells in CSF rarely spread to the spine or cause meningeal glioma; however, the transfer of GBM across the central nervous system is extremely rare. About 50% of GBM tumors occupy more than one leaf of the hemisphere or on both sides. This type of tumor usually originates in the brain and rarely produces bilateral ("butterfly") gliomas through typical permeation of the corpus callosum. Tumors can have different appearances depending on the amount of bleeding or the presence of necrosis or tumor age. CT scans of GBM tumors can often produce non-uniform entities with a low-density center and different rings surrounded by edema to enhance visualization. Physical effects from tumors and surrounding edema may compress the ventricles and cause hydrocephalus.

Cancer cells with stem cell-like properties have been found in glioblastoma. This may be the cause of its traditional treatment of impedance and high recurrence rates.

GBM often has typical features on MRI, but these features are not unique to GBM and may be caused by other conditions. To be clear, when using MRI, GBM often presents a ring-enhanced development lesion. However, other lesions such as abscesses, metastases from outside the central nervous system, tumor-like multiple sclerosis, or other conditions may also Have similar images. Determining the diagnosis of suspected GBM on CT or MRI requires stereotactic biopsy or craniotomy to remove the tumor and confirm it with pathology. Biopsy or partial resection of the tumor may underestimate the tumor grade due to the classification of the major malignant part of the tumor. Tumor blood flow visualization using perfusion MRI and measurement of tumor metabolite concentrations using MR mass spectrometry may increase the value of standard MRI, but pathology remains the gold standard for the diagnosis of GBM.

Based on the following factors, GBM is extremely difficult to treat: (1) tumor cells are very resistant to traditional therapies; (2) the brain is easily damaged by traditional therapies; (3) the brain's self-repairing ability is extremely limited; and (4) many Medical drugs cannot pass through the blood-brain barrier and act on tumors. Symptomatic treatments (including the use of corticosteroids and anticonvulsants) focus on reducing symptoms and improving neurological function in patients. However, these symptomatic therapies do not slow tumor progression and may have significant side effects, including pleomorphic erythema and Steven-Johnson syndrome, when phenytoin administration is synchronized with chemoradiotherapy.

The palliative therapy is usually performed to improve the quality of life and achieve a longer survival period. The palliative therapy can include surgery, radiation therapy, and chemotherapy. The largest possible resection of the largest tumor-free margin is usually accompanied by extracorporeal radiation and chemotherapy. The prognosis of all tumor resection is better.

Surgery is the first step in the treatment of glioblastoma. GBM tumors contained an average of 10 ¹¹ cells and fell to an average of 10 ⁹ cells (99% reduction) after surgery. Surgical biopsy was used for pathological diagnosis, removal of large solid body compression of the brain, removal of disease prior to secondary resistance to radiotherapy and chemotherapy, and prolonged survival. The greater the degree of tumor removal, the better the results. Removal of 98% or more tumors has been associated with significantly longer and healthier survival than removal of less than 98% of tumors. If the surgery is guided by a fluorescent dye called 5-aminoacetamidonic acid, the chances of completely removing the tumor for the first time can be greatly improved. At the time of diagnosis, GBM cells infiltrated through the brain extensively, so despite the “complete resection” of all visible tumors, most GBM patients later developed recurrent tumors near the original site or at distant satellite lesions in the brain. . Other means, including radiation, can be used after surgery to suppress and slow the recurrence of the disease.

After surgery, radiotherapy becomes the central treatment for people with glioblastoma. Key clinical trials conducted in the early 1970s showed that among 303 GBM patients randomized to either radiotherapy or non-radiotherapy, the median survival of those who received radiation was more than double that of those who did not. Later clinical studies attempted to establish a major axis for radiotherapy after surgery. On average, postoperative radiotherapy can shrink tumors to 10 ⁷ cells. Whole brain radiotherapy did not improve the results when compared to more precise and targeted three-dimensional stereotactic radiotherapy. A total radiation dose of 60-65 Gy has been found to be the optimal therapeutic dose.

In GBM, when chemotherapy is used in addition to radiotherapy, there is only a limited improvement in survival compared to the use of radiotherapy alone. In the treatment of other malignant diseases, when chemotherapy is added to the radiotherapy, substantial improvement has been made in survival, which has not been confirmed in GBM cases. One drug that has been associated with radiotherapy is temozolomide (TMZ). TMZ plus radiation has become the standard for most current GBM cases quasi. TMZ appears to act by sensitization of tumor cells to radiation.

However, TMZ often fails due to drug resistance caused by the repair of O ⁶ damage of guanine of DNA molecules caused by the catalytic activity of O ⁶ -methylguanine-DNA methyltransferase (MGMT) enzyme. In addition to MGMT, defective or inhibited DNA mismatch repair (MMR) systems also cause TMZ resistance. The chemotherapy resistance to TMZ caused by the results of MGMT activity is often associated with poor outcomes in patients receiving TMZ, and patients with TMZ or bevacizumab failure will not have much if they have any treatment opportunities. Option.

In addition, cancer stem cells (CSC) are tumor subpopulations of impedance therapy and cause recurrence.

Another medical method involves the use of the monoclonal antibody bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A), and thus acts as an angiogenesis inhibitor. Although bevacizumab can block disease progression, the first line of bevacizumab does not improve overall survival in patients with new diagnoses of GBM (MRGilbert et al., "A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma ," New Engl. J. Med. 370: 699-708 (2014)). In addition, unlike some other malignant diseases that can be treated with bevacizumab, in GBM, increased chemotherapy on bevacizumab does not improve the results of bevacizumab alone. Bevacizumab reduces brain edema and subsequent symptoms, and the benefits from this drug are attributed to its role in combating edema, rather than any action against the tumor itself. Some patients with cerebral edema do not really have any active tumor residuals, but because of previous radiotherapy The edema developed by the continuous effect. This type of edema is difficult to distinguish from the edema caused by the tumor, and both may coexist. Both respond to bevacizumab. However, patients with both Dimensions and Bevacizumab will not have many options even if they have any treatment opportunities.

Another proposed method is gene transfer. Although gene transfer therapy has the potential to kill cancer cells while leaving unharmed healthy cells, this approach still encounters many difficulties in other diseases, including the possibility of inducing other types of malignant diseases and interfering with immune system function.

Other treatments for GBM have also been proposed, including the use of protein therapies, including the soluble CD95-Fc fusion protein APG101, immunotherapy using tumor vaccines, alternating electric fields, and metabolic therapy. The value of these treatments remains to be determined.

In GBM, the median survival is 3 months from the start of diagnosis without any treatment, but usually 1-2 years under treatment. An increase in age (>60 years) leads to a worse prognosis risk. Death usually results from cerebral edema or increased intracranial pressure.

Good initial Karenofsky Performance Status (KPS) and methylation of the promoter of the O ⁶ -methylguanine-DNA methyltransferase (MGMT) gene are associated with longer survival. DNA testing can be performed on glioblastoma to determine whether the promoter of the MGMT gene is methylated. Even in patients under 50 years of age and KPS (Corsiton Status) equal to or greater than 90%, the 5-year survival rate is still only 14%.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 15-30% of all intracranial tumors in children. Highly malignant glioma (HGG) is more common in children than in adults, accounting for only 5%-10% of childhood brain tumors. Although various subject treatments have significantly improved children's 5-year survival rate, the prognosis of MB and HGG recurrence is still poor, with a median overall survival of <1 year. Dimension (TMZ) is commonly used to treat HGG in children; however, there is a lack of clinical evidence, and it has been reported that due to the high performance of the repair protein O ⁶ -methylguanine-DNA methyltransferase (MGMT) (which is resistant to TMZ) Sexual relevance), the results are not good. The status of p53 is also important for prognosis and treatment options for MB (Sonic Hedgehog (SHH) and Type 3 subtypes). P53 mutations in these groups, and especially in recurrent SHH, are associated with treatment resistance and poor prognosis. MB's standard care regimen includes a combination of radiation and chemotherapeutic agents (cisplatin, vincristine, cyclophosphamide, and lomustine) with severe side effects in 100% of patients, and survivors are developing The brain suffers from severe long-term side effects.

Therefore, pleomorphic glioblastoma and medulloblastoma require improved therapies, which provide surviving patients (especially pediatric patients) with improved survival with reduced side effects and functional impairment. See K. Hu et al, VAL-083, a N7 Alkylating Agent, Provides a New Potential Treatment for Glioblastoma Multiforme Because It Bypasses Temozolomide Resistance, "AACR (2012). However, there is no mention of pediatric glioblastoma or Treatment of medulloblastoma in children, and there are still other considerations, including medical tolerance and immature immune system response, which must be resolved in pediatric patients.

There is a particular need for a medical method that can pass through the blood brain barrier (BBB), which suppresses the growth and division of cancer stem cells (CSC), which can be prevented from being inactivated by O ⁶ -methylguanine-DNA methyl convertase (MGMT). There is also a particular need for a medical method that can provide an increased response rate and improved quality of life for patients with such malignant diseases. There is also a particular need for a medical method that is effective against patients who have proven to have failed one or both of Dimension and Bevacizumab. There is also a particular need to improve malignant diseases in pediatric patients, such as highly malignant gliomas (including glioblastoma multiforme), and treatment of medulloblastoma.

Use of a substituted hexitol derivative (such as di-dehydrated galactitol, diethyl hydrazine galactitol, or di-dehydrated galactitol or a derivative of diethyl hydrazine galactitol) Or the like) The treatment of pediatric patients with central nervous system malignancies (such as glioblastoma multiforme or medulloblastoma) may provide an improved therapy for such malignant diseases, which may improve viability and have substantially no side effects. In general, substituted hexitols suitable for use in the methods and compositions of the present invention include galactitols, substituted galactitols, dulcitol, and substituted dulcitol. class. Usually, the substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, derivative of di-dehydrated galactitol, diethylamino-dehydrated galactitol, Derivatives of ethoxylated galactitol, dibromodusol, and derivatives of dibromodusol. A particularly preferred substituted hexitol derivative is dihydrated galactitol (DAG). The substituted hexitol derivatives can be used in conjunction with other medical treatments for such malignant diseases. Dihydrated galactitol is particularly suitable for the treatment of such malignant diseases because it can pass through the blood-brain barrier because it can suppress the growth of cancer stem cells (CSC) and because it can resist the drug by O ⁶ -methylguanine - DNA methyltransferase (MGMT) was inactivated. The substituted hexitol derivative is a pediatric patient suffering from such diseases, which improves the response rate and improves the quality of life.

Di-dehydrated galactitol is a novel alkylating agent that targets N7 of guanine, resulting in inter-strand cross-linking between two guanines of opposite DNA strands.

In particular, dihydrogalactitol has been shown to have substantial potency in inhibiting the growth of glioblastoma multiforme (GBM) cells. In GBM cases, DAG has been shown to be more effective in suppressing the growth of GBM cells than the current selection of TMM for GBM chemotherapy. As detailed below, DAG can effectively cross the blood brain barrier and effectively suppress the growth of cancer stem cells (CSC). The role of the DAG is independent of the MGMT repair machine. DAG activity is also shown to be independent of the MMR repair system. DAG has also shown efficacy in treating medulloblastoma cell lines, as described in further detail below. DAG is less dependent on p53 status than other alkylating agents used in the treatment of medulloblastoma.

Therefore, the composition and method comprising the dehydrated galactitol or its derivative or analog according to the present invention have been confirmed to be effective for treating pediatric central nervous system malignancies, including glioblastoma and medulloblastoma. As described in more detail below, the dehydrated galactitol can be used to treat such malignancies, which can be in a single formulation or in combination with other agents, such as, but not limited to, Dimensions, which can be administered simultaneously or sequentially. The effect of di-dehydrated galactitol is independent of MGMT, and its effect is also independent of MMR mismatch repair and can overcome cisplatin resistance associated with normal p53 activity defects.

A specific medical combination according to the present invention comprises two dehydrated half milk More than sugar alcohol and Dimensions; two dehydrated galactitol and Polo kinase-like inhibitors; two dehydrated galactitol and a preparation for reducing the activity or performance of YB-1; two dehydrated galactitol and Akt inhibitors ; two dehydrated galactitol and RSK inhibitor; two dehydrated galactitol and PARP inhibitor olaparib (olaparib); two dehydrated galactitol and cisplatin or oxaliplatin; Di-dehydrated galactitol and the topoisomerase II inhibitor etoposide. When the two dehydrated galactitol and the Dimensional two preparations are administered sequentially, it is synergistic, usually it is administered for 3 days, and then the second galactitol is administered for 3 days, but when it is administered at the same time. No synergy. For other alternatives, the formulations may be administered simultaneously or sequentially. Other medical combinations are described below.

As described in further detail below, treatment of pleomorphic glioblastoma (GBM) in pediatric patients includes and specifically targets the treatment of such patients with high grade glioma (HGG). This applies to the methods and compositions according to the invention for the treatment of GBM in pediatric patients; such methods and compositions are particularly useful for treating HGG in such patients. One aspect of the methods and compositions of the present invention is the suppression of cancer stem cell (CSC) proliferation.

Therefore, one aspect of the present invention is a method for improving the administration efficacy and/or reducing side effects of a substituted hexitol derivative for treating a central nervous system malignant disease in a pediatric patient, comprising the following steps: (1) discriminating and The at least one factor or parameter relating to the efficacy of administration and/or the occurrence of side effects of a substituted hexitol derivative for treating a central nervous system malignancy in a pediatric patient; and (2) adjusting the factor or parameter for improvement Treatment of pediatric patients The efficacy of the substituted hexitol derivative of the central nervous system malignant disease and/or the reduction of side effects.

Typically, the central nervous system malignancy is selected from the group consisting of medulloblastoma and highly malignant glioma.

Typically the factor or parameter is selected from the group consisting of: (1) dose modulation; (2) administration route; (3) dosing schedule; (4) disease stage selection; (5) patient selection; Patient/disease phenotype; (7) patient/disease genotype (8) preparation before/after treatment; (9) toxicity treatment; (10) pharmacokinetic/pharmacodynamic tracking; (11) drug combination; 12) chemotherapy sensitization; (13) chemotherapy synergy; (14) patient treatment after treatment; (15) alternative medical/medical support; (16) improvement of API products; (17) diluent system; (18) solvent system; (19) excipients; (20) dosage forms; (21) dose sets and packaging; (22) drug delivery systems; (23) drug conjugate types; (24) compound analogs; (25) prodrugs; 26) Multiple drug system; (27) Biomedical agent enhancement method; (28) Biomedical agent resistance regulation method; (29) Enhanced radiation therapy; (30) Novel action mechanism; (31) Selective target cell population Medical method; (32) combined with free radiation; (33) combined with a preparation for enhancing its activity; (34) combined with a preparation for counteracting myelosuppressive effects; and (35) use of the substituted hexitol to pass the blood-brain barrier The preparation of the ability.

As described in detail above, usually, the substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, derivative of didehydrated galactitol, and diethyl hydrazine. A derivative of water galactitol, a diethylene sulfonate dehydrated galactitol, dibromodusol, and a derivative of dibromodusol. Preferably, the substituted hexitol derivative is dihydrated galactitol.

In one of the alternatives to this method, at least two anti-tumions are administered Tumor medical agent. The at least two anti-tumor agents can be administered simultaneously or substantially simultaneously, such as in a single pharmaceutical composition. In another alternative, the at least two anti-neoplastic agents can be administered sequentially. Some possible options for these at least two anti-tumor medical agents include: dihydrogalactitol and Dimensional; di-desogalactitol and Polo-like kinase inhibitors; di-dehydrated galactitol and reduced YB- Formulation of activity or performance; inhibitor of serogalactitol and Akt; dehydrated galactitol and inhibitor of RSK; inhibitor of galactitol and PARP; and galactose Alcohols and preparations that counteract the loss of PTEN function.

Another aspect of the present invention is a composition for improving efficacy and/or reducing side effects in suboptimal administration of a drug when treating a central nervous system malignancy in a pediatric patient using a substituted hexitol derivative, which comprises An option selected from the group consisting of: (i) a medically effective amount of a modified substituted hexitol derivative, or a substituted hexitol derivative or a modified substituted hexitol a derivative, analog, or prodrug of the derivative, wherein the modified substituted hexitol derivative, or the substituted hexitol derivative or the modified substituted hexitol derivative A derivative, an analog, or a prodrug has an improved medical efficacy or a reduced side effect compared to an unmodified substituted hexitol derivative when treating a central nervous system malignant disease in a pediatric patient; (ii) a A composition comprising: (a) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, a substituted hexitol derivative or a modified substituted a derivative of a sugar alcohol derivative, similar , Or prodrug thereof; And (b) at least one other medical agent, a medical agent that is sensitized by chemotherapy, a medical agent that is chemotherapeutic, a diluent, an excipient, a solvent system, a drug delivery system, or a anti-myelosuppressive effect a formulation, or a preparation for increasing the ability of the substituted hexitol to pass through the blood-brain barrier, wherein the composition is compared to an unmodified substituted hexitol derivative in the treatment of a central nervous system malignancy in a pediatric patient Having an improved medical efficacy or reduced side effects; (iii) a medically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or the substituted hexose that has been included in the dosage form a derivative, analog, or prodrug of an alcohol derivative or a modified substituted hexitol derivative, wherein the substituted hexitol derivative, modified substituted hexitol, in the dosage form a derivative, or a substituted hexitol derivative or a modified derivative, analog, or prodrug of a substituted hexitol derivative for treating a central nervous system malignancy in a pediatric patient, compared to Modified Substituted hexitol derivatives have improved medical efficacy or reduced side effects; (iv) a medically effective amount of a substituted hexitol derivative that has been incorporated into a dosage kit and packaged, modified by a substituted a sugar alcohol derivative, or a derivative, analog, or prodrug of the substituted hexitol derivative or modified substituted hexitol derivative, wherein the package has been incorporated into a dosage kit and packaged a substituted hexitol derivative, a modified substituted hexitol derivative, or a substituted hexitol derivative or a modified substituted hexitol derivative derivative, analog, or Prodrugs for treating children In the case of a central nervous system malignant disease, the medical efficacy or reduced side effects are improved compared to the unmodified substituted hexitol derivative; (v) the medically effective amount that has been modified by the drug substance product is replaced a derivative, analog, or prodrug of a hexitol derivative, a modified substituted hexitol derivative, or a substituted hexitol derivative or a modified substituted hexitol derivative a substituted hexitol derivative, a modified substituted hexitol derivative, or a substituted hexitol derivative or a modified substituted hexose, which has been modified by a drug substance product Derivatives, analogs, or prodrugs of alcohol derivatives have improved medical efficacy or reduced side effects compared to unmodified substituted hexitol derivatives in the treatment of central nervous system malignancies in pediatric patients.

Typically, the central nervous system malignancy is selected from the group consisting of medulloblastoma and highly malignant glioma.

As described in detail above, usually the unmodified substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, derivative of seletartarditol, and diethyl Derivatives of decyl dihydrogalactitol, diethylene hydrazine dihydrogalactitol, dibromodusol, and dibromodusol derivatives. Preferably, the unmodified substituted hexitol derivative is dihydrated galactitol.

Another aspect of the invention is a method of treating a central nervous system malignancy in a pediatric patient, comprising the step of administering a therapeutically effective amount of a substituted hexitol derivative to a patient suffering from a malignant disease. As described in detail above, the substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, derivative of seletartarditol, and diethyl hydrazide. Dehydrated galactitol, a derivative of diethylene hydrazine dihydrogalactitol, dibromodusol, and a derivative of dibromodusol. Preferably, the substituted hexitol derivative is dihydrated galactitol.

Typically, when the substituted hexitol derivative is dihydrated galactitol, the medically effective amount of diglycolic galactitol is from about 1 mg/m ² to about 40 mg/m ² . Preferably the two lines to the medical water-galactitol effective amount is about 5mg / m ² to about 25mg / m ² of a dose. Other dosages are described below.

Typically, the substituted hexitol derivative, such as bis-galactositol, is administered by a route selected from the group consisting of intravenous and oral administration. Other possible routes of administration are described below.

The method can further comprise the step of administering a therapeutically effective dose of free radiation. The method can further comprise the step of administering a therapeutically effective amount of Dimensal, Bevacizumab, or a corticosteroid.

The method can further comprise administering a medically effective amount of a tyrosine kinase inhibitor as described below.

The method can further comprise administering a medically effective amount of an epidermal growth factor receptor (EGFR) inhibitor as described below. EGFR inhibitors can affect wild-type binding sites or mutated binding sites, including variant III as described below.

The following invention will be better understood by reference to the specification, the accompanying claims, and the drawings, wherein: FIG. 1 shows the pleomorphic glioblastoma (GBM) mode and its two dehydrated galactitol (VAL) -083) A comprehensive list of reactions.

Figure 2 shows three cell lines: SF188, U251, and T98G (TMZ) resistance and MGMT status. SF188 is a highly malignant glioma cell line in children. In Fig. 2, protein actin was used as a control group. Show the Western dot map.

Figure 3 shows SF188 (top), U251 (middle), and T98G (bottom) using 0.1, 1, 2.5, 5, 10, 25, 50, and 100 μM Dimension (TMZ) and two de-water half The survival result of lactitol (VAL). Two tests were presented for each cell line.

Figure 4 shows that dehydrated galactitol provides more than 95% repressivity in the SF188 community formation assay at 5 μM.

Figure 5 shows that the effect of di-dehydrated galactitol (VAL) in inhibiting SF188 growth in secondary cell spheroid formation is higher than that of Dimension (TMZ). Two dehydrated galactitols were used at 5 μM, and Dimensions were used at 10 μM.

Figure 6 shows that dehydrated galactitol (VAL083) completely inhibits neuronal spheroid formation in primary neuronal spheroids and secondary neuronal spheroids of BT74 cancer stem cells. The second dehydrated galactitol was used at 5 μM.

Figure 7 shows that dehydrated galactitol (VAL083) is more potent than Dimension (TMZ) when SF188 and DAOY cell lines (DAOY is a medulloblastoma cell line) inhibit primary neuronal spheroid formation. Two dehydrated galactitols were used at 5 μM, and Dimensions were used at 10 μM.

Figure 8 shows that dehydrated galactitol provides 100% repressiveness to the formation of DAOY medulloblastoma cells at 5 μM, and to SF188 Community formation of glioblastoma cells provides >80% repressivity.

Figure 9 shows a method for calculating the number of spheroids of glioblastoma multiforme cells (GBM4) including the control group and the two-dehydrated galactitol-treated group (VAL).

Figure 10 shows the inhibition of 10 [mu]M didesaminogalactitol (VAL) on cells of first and second generation GBM4 (patient derived adult GBM cancer stem cells).

Figure 11 shows inhibition of cell spheroids when treated with 10 μM of dehydrated galactitol (VAL) for 1 week in GBM4 and GBM8 (patient-derived adult GBM cancer stem cells) cells.

Figure 12 shows the control effect of di-dehydrated galactitol on human neural stem cells (hNSC). The effect of various concentrations of dihydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) in monolayer hNSC treatment for 72 hours is shown.

Figure 13 is a graph showing various concentrations of di-dehydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) in monolayer aBT001 (adult GBM cells from patients) A pattern that handles the effectiveness of 72 hours.

Figure 14 is a diagram showing the other experiments in which different concentrations of dihydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) were treated in a single layer of hNSC 72 The pattern of the effectiveness of the hour.

Figure 15 shows the dewatering after various concentrations A series of general dose-response curves and S-type dose-response curves for galactitol and Dimensional multi-treated U251, T98G, and SF188 cell lines.

Figure 16 is a list showing the IC50 calculated from the S-type dose effect curve of Figure 15.

Figure 17 is a graph showing the efficacy of sequential administration of di-dehydrated galactitol (VAL-083) and Dimension (TMZ) on pediatric high-grade glioma cell line SF188; treatment with TMZ for 3 days, It was then washed and treated with two dehydrated galactitol for 3 days. This combination completely inhibits neuronal spheroid formation.

Figure 18 is a graph showing the expected mechanism of action of NDA to galactose-targeted N7, which results in cross-linking between the two guanines of the opposite DNA strand.

Figure 19 is a graph showing the efficacy of simultaneous administration of DM188 cells with the combination of Dimensions and di-dehydrated galactitol (VAL). This simultaneous treatment combination does not increase potency compared to the use of di-dehydrated galactitol (VAL) alone.

Figure 20 is a graph showing the efficacy of reducing the formation of colonies when SF188 cells were treated with Simeral and Dihydrogalactitol (VAL).

Figure 21 is a graph showing the efficacy of sequential administration of dehydrated galactitol (VAL-083) and Dimension (TMZ) on pediatric high-grade glioma cell line SF188; treated with TMZ for 3 days, then Washed and treated with two dehydrated galactitol for 3 days; two dehydrated galactitol used two concentrations: 10 μM and 25 μM.

Figure 22 is a graphical representation of the progression of malignant disease recurrence caused by cancer stem cell survival.

Figure 23 is a graph showing the efficacy of the combination of di-dehydrated galactitol (VAL) and Dimension (TMZ) on first and second passage SF188 cells.

Figure 24 is a graph showing that BT74 cancer stem cells did not show significant sensitivity to Dimension.

Figure 25 is a graph showing the efficacy of the second dehydrated galactitol (VAL083) against the freshly isolated aBT001 GBM culture of the first generation.

Figure 26 is a graph showing that dihydrated galactitol is active against tumors exhibiting YB-1 because the DNA repair enzyme is unable to repair the N ⁷ -adduct produced by the treatment with dihydrated galactitol.

Figure 27 is a graph showing inhibition of YB-1 in adult glioblastoma, which may increase sensitivity to Dimension.

Figure 28 shows that YB-1 stays in the nucleus in the presence of the Dimension; the Dimensional multi-system uses 10 μM; the left picture shows the control group; the right picture shows the DMC multi-treatment group; the magnification is 200×.

Figure 29 is a diagram showing the efficacy of administration of Dimensions and di-dehydrated galactitol to reduce the formation of neuronal spheroids in SF188 cells; 10 μM for Dimensional multi-line; 5 μM for di-dehydrated galactitol .

Figure 30 is a graphical representation of inhibition of YB-1 and its interaction with the MGMT pathway in MGMT-positive adult glioblastoma cells.

Figure 31 shows the two dehydrated galactitol and the Dimension The combination made the SF188 cell line less effective in reducing neuronal spheroid formation than in the case of di-dehydrated galactitol alone; the second dehydrated galactitol was used at 5 [mu]M, and the Dimensional multi-line was used at 10 [mu]M.

Figure 32 shows Western blots of U251 and SF188 cells for p-RSK, PLK1, P-YB-1, and actin (as a control). Glioblastoma cell lines were treated with 5 μM of dehydrated galactitol, PBS, or untreated for 72 h, collected, and subjected to Western blot analysis.

Figure 33 shows the effect of pre-treatment of dihydrated galactitol on SF188 and U251 cell lines prior to administration of Polo kinase inhibitor BI6727. After 72 hours of treatment with 5 [mu]M didesaminogalactitol, cells were seeded into 96-well plates, treated with a range of BI6727 for 72 hours, and an untreated control group was used.

Figure 34 is a graph showing the inhibitory effect of di-despartate galactitol on the growth of medulloblastoma cell lines DAOY, ONS76, UW228, and UW426. The medulloblastoma cell line was inoculated into a 96-well plate and treated with a gradually increasing concentration of the second dehydrated galactitol for 72 hours.

Figure 35 is a graph showing the effect of pre-treatment of di-dehydrated galactitol prior to administration of Polo kinase inhibitor BI6727 in medulloblastoma cell lines DAOY, ONS76, UW228, and UW426. After 72 hours of treatment with 5 [mu]M didesaminogalactitol, cells were seeded into 96-well plates, treated with a range of BI6727 for 72 hours, and an untreated control group was used.

Figure 36 is a graph showing the dose-response curve of Example 3 bis dehydrated galactitol in ovarian tumor cell groups, the correlation of which is confirmed The anti-tumor activity of the second dehydrated galactitol is independent of each other and independent of p53.

Figure 37 is a list showing the IC ₅₀ of the two dehydrated galactitol in the human ovarian tumor group of Example 3, the correlation confirming that the anti-tumor activity of the di-dehydrated galactitol is independent of each other and independent of p53. A2780 has wild-type p53 and is MMR-free. 2780CP-16 has a mutated p53 and is a MMR-deficient (lack of MLH1 protein). OVCAR10 has a mutated p53 and is MMR-free. HEY has a mutated p53 and is MMR-free. OVCA-433 has a mutated p53 and is MMR-free.

Figure 38 is a graph showing the activity of the two dehydrated galactitol in Example 3 relative to cisplatin and oxaliplatin (expressed as IC50) in bar graphs, the correlation confirming the dehydrated galactitol resistance Tumor activity and MMR were independent of each other and independent of p53.

Figure 39 is a diagram showing the resistance factor relative to A2780, and the presence of di-dehydrated galactitol in the HEY mode is effective in avoiding cisplatin resistance, while in 2780CP-16, OVCAR-10, and OVCA-433 The degree in the cell line is slightly worse.

Fig. 40 is a graph showing the synergistic activity of the dehydrated galactitol and olaparib administered to the A2780 ovarian cancer cell line in Example 4.

Figure 41 is a graph showing the synergistic effect of the two dehydrated galactitols of Example 5 with cisplatin and oxaliplatin in NSCLC cell line H460 (wild type p53 and wild type EGFR).

Figure 42 is a graph showing the synergism of the two dehydrated galactitols of Example 5 with cisplatin and oxaliplatin in NSCLC cell line A549 (wild type p53 and wild type EGFR).

Figure 43 is a graph showing the synergistic effect of the two dehydrated galactitols of Example 5 with cisplatin and oxaliplatin in NSCLC H1975 (mutated p53 and mutant EGFR having a T790M mutation).

The second dehydrated galactitol (DAG) compound has been shown to have substantial potency in inhibiting the growth of glioblastoma multiforme (GBM) cells. Taking GBM as an example, DAG has been shown to be more effective in suppressing the growth of GBM cells than the chemotherapeutic agent (TMZ) currently selected for the treatment of GBM. As detailed below, DAG can effectively cross the blood brain barrier and effectively suppress cancer stem cell (CSC) growth. The role of the DAG is independent of the MGMT repair machine. DAG activity also appears to be independent of the MMR repair system. DAG also demonstrates the efficacy of treating medulloblastoma cell lines, as described in further detail below. The correlation between DAG and p53 status is lower than that associated with other alkylating agents commonly used in the treatment of medulloblastoma.

Therefore, the composition and method comprising the dehydrated galactitol or its derivative or analog according to the present invention have been confirmed to be effective for treating pediatric central nervous system malignancies, including glioblastoma and medulloblastoma. As described in detail below, the dehydrated galactitol can be administered in a single formulation or in combination with other agents (e.g., but not limited to Dimension), and can be administered simultaneously or sequentially for the treatment of such malignancies. The effect of the second dehydrated galactitol is independent of MGMT, and it is also independent of the role of MMR mismatch repair, and can be overcome Cisplatin resistance associated with defects in normal p53 activity.

Compositions suitable for administration of dehydrated galactitol and its derivatives or analogs for the treatment of pediatric central nervous system malignancies are also described below. The composition may include, for example, other medical agents, prodrugs, conjugates, drug delivery systems, anti-myelosuppressive formulations, or formulations that increase the ability of the substituted hexitol to cross the blood-brain barrier.

The structure of the dehydrated galactitol (DAG) is shown in the following formula (I).

Other substituted hexitols can also be used in the methods and compositions in accordance with the present invention, as described in more detail below. In general, the substituted hexitols suitable for use in the methods and compositions according to the present invention include galactitols, substituted galactitols, dulcitol, and substituted dulcitol. These include di-dehydrated galactitol, diethylidene di-dehydrated galactitol, dibromodusol, derivatives thereof, and the like. Usually, the substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, derivative of di-dehydrated galactitol, diethylamino-dehydrated galactitol, Derivatives of ethoxylated galactitol, dibromodusol, and derivatives of dibromodusol. Preferably, the substituted hexitol derivative is dihydrated galactitol.

These galactitols, substituted galactitols, Phalloids, substituted alkylidene-based alkylating agents or alkylating agents are discussed further below.

Also included within the scope of the invention is a derivative of dihydrated galactitol, which is, for example, one or two hydrogens of two hydroxyl groups of di-dehydrated galactitol are replaced by a lower alkyl group, and two epoxides are attached One or more hydrogens of the ring are replaced by a lower alkyl group, or are present in dihydrated galactitol and the methyl group attached to the same carbon having a hydroxyl group is replaced by a C ₂ -C ₆ lower alkyl group Or, for example, a halogen group, the hydrogen atom on the methyl group is replaced by, for example, a halogen group. The term "halo" as used herein, unless otherwise limited, refers to one of fluorine, chlorine, bromine or iodine. As used herein, the term "lower alkyl" means C ₁ -C ₆ include a methyl group, and without the further limitation. The term "lower alkyl" may be further limited to, for example, "C ₂ -C ₆ lower alkyl", which does not include methyl. The term "lower alkyl", unless otherwise limited, refers to both straight and branched alkyl groups. These groups may be further substituted as needed, as explained below.

The structure of diacetyl hydrazine dehydrated galactitol is shown in the following formula (II).

Also within the scope of the invention is a derivative of diethylaminosodium galactitol, for example, wherein one or two methyl groups as part of the ethyl thiol moiety are C ₂ -C ₆ a lower alkyl substitution, one or two hydrogens attached to an epoxide ring are replaced by a lower alkyl group, or a methyl group attached to the same carbon having an ethyl hydrazine group is replaced by a lower alkyl group or Substituting, for example, a halo group, for example, a hydrogen is replaced by, for example, a halo group.

The structure of dibromodusol is shown in the following formula (III). Dibromodusol can be produced by crystallizing dicyclopentyl alcohol after the temperature-reacting reaction of dulcitol and hydrobromic acid. Some of the properties of dibromodusol are described in N. E. Mischler et al., "Dibromoducitol," Cancer Treat. Rev. 6:191-204 (1979). In particular, dibromodusol is alpha, omega-dibromohexitol, and dibromodusol has many in common with similar drugs such as dibromomannitol and mannitol myleran. Biochemical and biological properties. Dibromodusol is activated in vivo to form diglycol di-dehydrated galactitol, and the di-dehydrated galactitol can represent the predominant active form of the drug; this means that the dibromogalactitol has many prodrug properties. The absorption of dibromodusol by the oral route is rapid and quite complete. Dibromodusol is known to be active in melanoma, breast lymphoma (including Hodgkins and non-Hodgkin's), colorectal cancer, acute lymphoblastic leukemia, and has been shown to reduce the central nervous system. Nervous system leukemia, non-small cell lung cancer, cervical cancer, bladder cancer, and the occurrence of metastatic perivascular cell tumors.

Also included within the scope of the invention are derivatives of dibromodusol which are, for example, one or more hydrogens of a hydroxyl group are replaced by a lower alkyl group, or one or two bromo groups are replaced by another halo group (such as chlorine, Fluorine, or iodine) replacement.

In general, as derivatives of di-dehydrated galactitol, di-dehydrated galactitol, diethyl hydrazine di-dehydrated galactitol, diethylene hydrazine di-dehydrated galactitol, The optional substituent of the saturated carbon atom of a part of the structure of dibromodioyl alcohol and a derivative of dibromodusol may be the following substituent: a C ₆ -C ₁₀ aryl group, comprising a group selected from N, O, heteroaryl of 1-4 heteroatoms with S, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, cycloalkyl, F, amine (NR ¹ R ² ), nitro And -SR, -S(O)R, -S(O ₂ )R, -S(O ₂ )NR ¹ R ² , and -CONR ¹ R ² , which may be optionally substituted. Substituents which may be selected as appropriate are further illustrated below.

Substituents as described above which fall within the scope of the present invention do not substantially affect the activity of the derivative or the stability of the derivative, especially the stability of the derivative in aqueous solution.

The definitions of many commonly used groups which may be used as desired substituents are described below; however, any group missing under these definitions should not be considered as long as it meets the chemical and pharmacological requirements of the desired substituent. It is a group that cannot be used as a substituent as needed.

The term "alkyl" as used herein, is taken to mean unsubstituted, branched, or cyclic saturated hydrocarbon residue of 1 to 12 carbon atoms, or a combination thereof; when the alkyl residue is unsubstituted, only Contains C and H. Typically, the unbranched or branched saturated hydrocarbyl residue is from 1 to 6 carbon atoms, referred to herein as "lower alkyl." When the alkyl residue is cyclic and includes a ring, it is understood that the hydrocarbyl residue comprises at least three carbon atoms which form the minimum number of rings. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-g Base, and 1-octyl. The term "alkenyl" as used herein, refers to a non-branched, branched or cyclic hydrocarbon residue having one or more carbon-carbon double bonds. The term "alkynyl" as used herein, refers to a non-branched, branched, or cyclic hydrocarbyl residue having one or more carbon-carbon bonds; the residue may also include one or more double bonds. When "alkenyl" or "alkynyl" is employed, multiple double bonds appearing do not produce an aromatic ring. The terms "hydroxyalkyl", "hydroxyalkenyl", and "hydroxyalkynyl", as used herein, are meant to mean alkyl, alkenyl, or alkynyl, respectively, including one or more hydroxyl groups as substituents; as described in more detail below, Other substituents are included as needed. The term "aryl" as used herein refers to a monocyclic or fused bicyclic system having conventional aromatic character; examples of which include phenyl and naphthyl, which may optionally be substituted. The term "hydroxyaryl" as used herein, refers to an aryl group that includes one or more hydroxyl groups as a substituent; as further described in detail below, other substituents may be included as desired. The term "heteroaryl" as used herein, refers to a monocyclic or fused bicyclic system having conventional aromatic character and comprising one or more heteroatoms selected from the group consisting of O, S, and N. The aromaticity of the 5-membered ring and the 6-membered ring is allowed to contain heteroatoms. Typical heteroaromatic groups include monocyclic C ₅ -C ₆ heteroaromatic groups such as pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, An oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, and imidazolyl group, and a fused bicyclic moiety, which is one of the monocyclic heteroaromatic groups A phenyl ring or fused to any heteroaromatic monocyclic group to form a C ₈ -C ₁₀ bicyclic group, such as a fluorenyl group, a benzimidazolyl group, a carbazolyl group, a benzotriazole group, an isoquinoline Base, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quin A phenyl group, a porphyrin group, and other ring systems known in the art. Any monocyclic or fused ring bicyclic system having an aromatic character due to the distribution of the entire ring system by non-localized electrons is included in this definition. This definition also includes bicyclic group groups in which at least the ring directly attached to the remaining molecules has aromatic characteristics including a non-localized electron distribution which becomes an aromatic characteristic. Typically, the ring system comprises from 5 to 12 ring constituent atoms and up to 4 hetero atoms, wherein the hetero atom is selected from the group consisting of N, O, and S. Typically, the monocyclic heteroaryl comprises from 5 to 6 ring members and up to 3 heteroatoms selected from the group consisting of N, O, and S; typically, the bicyclic heteroaryl contains 8 to 10 rings A member and at most 4 heteroatoms selected from the group consisting of N, O, and S. The number and position of heteroatoms in the heteroaryl ring structure are based on conventional aroma and stability constraints, wherein the stability requirement is that the stability of the heteroaromatic group should be sufficient to expose to physiological temperature without Will degrade quickly. The term "hydroxyheteroaryl" as used herein, refers to a heteroaryl group that includes one or more hydroxyl groups as a substituent; as further described in detail below, other substituents are optionally included. The terms "haloaryl" and "haloaryl" as used herein mean aryl and heteroaryl, respectively, substituted by at least one halo group, wherein "halo" means selected from the group consisting of fluorine, chlorine, bromine, and iodine. Groups of halogens, typically the halogen is selected from the group consisting of chlorine, bromine, and iodine; other substituents may be included as desired, as described in more detail below. The terms "haloalkyl", "haloalkenyl", and "haloalkynyl" as used herein mean alkyl, alkenyl, and alkynyl, respectively, substituted with at least one halo group, wherein "halo" is selected Halogens from the group consisting of fluorine, chlorine, bromine, and iodine, typically the halogen is selected from the group consisting of chlorine, bromine, and iodine; as described in more detail below, other substituents may be included as desired. The term "heterocycloalkyl" refers to a monocyclic or bicyclic carbocyclic moiety containing from 3 to 10 ring members, wherein one or more of the same or different selected from oxygen, nitrogen or sulfur atoms are interspersed. a hetero atom; for example, morpholinyl, thiomorpholinyl, homocarbolyl, azacyclopropyl, azetidinyl, piperazinyl, piperidinyl, homocarbazinyl, pyrrolidinyl , imidazolidinyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyran, pendant oxazinyl, or oxetanyl moiety, all such groups Can be replaced as needed.

The term "optionally substituted" as used herein means that the particular group or group of groups referred to as desired may be free of non-hydrogen substituents, or the group or group of groups may have the chemistry of the resulting molecule. One or more non-hydrogen substituents of pharmacological activity. Unless otherwise expressly stated, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group; there may be a lower number than the substituents. If the optional substituent is attached by a double bond, such as carbonyl oxygen (C=O), the group occupies two available valences of the carbon atom to which the optionally substituted substituent is attached, and thus may be included The total number of substituents within the reduction will decrease with the available price. The term "substitution" as used herein, whether used as part of "optionally substituted" or otherwise stated, when used to modify a particular group, a moiety, Or a free radical means that one or more hydrogen atoms are each independently replaced by the same or a different substituent or group of substituents.

Substituents suitable for substituting a given group, a partial group, or a saturated carbon atom in a 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 ^- , -S(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 following are grouped together: alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Z ^{b is} independently hydrogen or Z ^a; and each Z ^c are each independently Z ^b, or Z ^c may be two The nitrogen atoms to which they are bonded together form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring structure, which may optionally include the same or different groups selected from the group consisting of N, O, and S. 1 to 4 heteroatoms. A clear example of -NZ ^c Z ^c is meant to include -NH ₂ , -NH-alkyl, -N-pyrrolidinyl, and -N-morpholinyl, but is not limited to such explicit options, and includes related art Other options are known. Similarly, in another specific example, substituted alkyl is meant to include -alkyl-O-alkyl, -alkyl-heteroaryl, -alkyl-cycloheteroaryl, -alkylene -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 their explicit options, and include Other options known in the art. The one or more substituents may form a ring together with the atoms to which they are bonded, including, but not limited to, cycloalkyl and cycloheteroalkyl.

Similarly, substituents suitable for substituting a given group, a moiety, or an unsaturated carbon atom in a 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 is as defined above.

Similarly, substituents suitable for substituting a nitrogen atom in a heteroalkyl group and a cycloheteroalkyl group 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 pairs of palmar centers and/or double bonds and thus may exhibit stereoisomers, such as double bond isomers (ie, geometric isomers such as E and Z), enantiomers Isomer or diastereomer. The present invention includes each of the isolated stereoisomers (eg, pure enantiomeric isomers, E and Z isomers, and other stereoisomers), and various pairs of palm purity or E and Z. A percentage of a mixture of stereoisomers, including racemic mixtures, mixtures of diastereomers, and mixtures of E and Z isomers. Thus, the chemical structures shown herein include all possible enantiomers and stereoisomers of the exemplified compounds, including stereoisomeric pure forms (eg, geometrically pure, enantiomerically pure or diastereomeric). Conformally pure) and a mixture of enantiomeric and stereoisomers. The enantiomeric and stereoisomeric mixtures can be resolved into their enantiomers or stereoisomers using separation techniques well known to those skilled in the art or by palm synthesis techniques. The present invention includes each stereoisomeric form and mixtures of stereoisomers of varying degrees to palm purity, including racemic mixtures. Also included are various diastereomers. Other structures indicating specific isomers may be present, but are provided for convenience only and are not intended to limit the invention to the isomers shown. When the chemical name of the isomeric form of the compound is not indicated, it means one of any possible isomeric forms of the compound or a mixture of such isomeric forms of the compound.

The compounds may also be in several tautomeric forms, and only one tautomer is shown herein for convenience, and it is understood that it includes the formula shown. He is a tautomer. Thus, the chemical structures shown herein include all possible tautomeric forms of the exemplified compounds. As used herein, the term "tautomer" refers to an isomer that is readily altered from one another, and thus may be in equilibrium; depending on the stability conditions, one of the tautomers may be strongly advantageous. For example, a ketone and an enol are two tautomeric forms of one compound.

The term "solvate" as used herein means a compound formed by solvation (combination of molecules or ions of a solvent molecule with a solute), or a solute ion or molecule (ie, a compound of the invention) and one or more solvents. Aggregate of molecular composition. When water is used as 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 materials. Those skilled in the art will appreciate that the pharmaceutically acceptable salts, and/or prodrugs of the present compounds may also be in the form of a solvate. The solvate is usually formed by hydration (which is part of the process for the 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, refers to any ester of the present compound wherein any -COOH functional group of the molecule is replaced by a -COOR functional group, wherein the R moiety of the ester is any of the groups forming the stability ester moiety. Carbon-containing groups, including but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted a derivative. The hydrolyzable esters of the present compounds are those in which the carboxyl group is in the form of a hydrolyzable ester group. That is, the esters are pharmaceutically acceptable and can be hydrolyzed in vivo to the corresponding carboxylic acid.

In addition to the above substituents, the alkyl, alkenyl and alkynyl groups may be modified or further substituted by C ₁ -C ₈ mercapto, C ₂ -C ₈ heterofluorenyl, C ₆ -C ₁₀ aryl, C ₃ -C ₈ A cycloalkyl group, a C ₃ -C ₈ heterocyclic group, or a C ₅ -C ₁₀ heteroaryl group, which may be optionally substituted as needed. Further, when two groups which can form a ring having 5 to 8 ring members are present in the same or adjacent atoms, the two groups may optionally have atoms or groups of atoms in the substituent to which they are attached. Together form these rings.

The definitions of "heteroalkyl", "heteroalkenyl", and "heteroalkynyl" and the like are analogous to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the term "hetero" refers to a backbone comprising from 1 to 3 O, S or N heteroatoms or a combination thereof; therefore, at least one carbon atom of the corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the designated heteroatoms to form a hetero Alkyl, heteroalkenyl, or heteroalkynyl. For reasons of chemical stability, it is also understood that unless otherwise stated, such groups may not include more than two adjacent heteroatoms unless there is a pendant oxy group, such as a nitro or sulfonyl group, at N or S.

Similarly, "heterocyclyl" can be used to indicate that at least one heteroatom (generally selected from N, O and S) is used as a ring member and that a ring atom is used to link the molecule (which can be C (carbon linkage) or N (nitrogen linkage). a non-aromatic cyclic group; and "heterocyclylalkyl" can be used to describe a group that is bonded to another molecule using a linker. The heterocyclic group may be fully saturated or partially saturated, but not aromatic. Suitable sizes and substituents for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for the alkyl groups described above. The heterocyclic group usually contains 1, 2 or 3 hetero atoms selected from N, O and S as a ring member; and N or S may be substituted by a group which is common in such a heterocyclic ring. The terms used herein also include rings containing one or two double bonds, as long as they are attached. The ring is not aroma. The substituted cycloalkyl and heterocyclic group also includes a cycloalkyl or heterocyclic ring fused to an aromatic ring or a heteroaromatic ring, but the attachment point of the group is attached to a cycloalkyl or heterocyclic group. Ring, not attached to the aromatic/heteroaromatic ring.

As used herein, "mercapto" encompasses a group comprising one of two available valence positions of an alkyl, alkenyl, alkynyl, aryl or arylalkyl attached carbonyl carbon atom, and a heterofluorenyl group. By a corresponding group, at least one carbon atom other than the carbonyl carbon is replaced by a hetero atom selected from N, O and S.

The sulfhydryl and heterocyclic groups are bonded to any group or molecule to which they are attached using any open valence of a carbonyl carbon atom. Usually, it is a C ₁ -C ₈ fluorenyl group, including a fluorenyl group, an ethyl fluorenyl group, a pentylene group, a benzhydryl group, and a C ₂ -C ₈ heterofluorenyl group, including a methoxyethyl fluorenyl group, Ethoxycarbonyl, and 4-pyridinecarbinyl.

Similarly, "arylalkyl" and "heteroarylalkyl" refer to a linking group such as a substituted alkyl group, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linking groups, The aromatic and heteroaromatic ring systems of the attachment points are bonded. Typically the linker is a C ₁ -C ₈ alkyl group. These linking groups may also include a carbonyl group, and thus they may provide a substituent as a mercapto or heteroindenyl moiety. The aryl or heteroaryl ring in the arylalkyl or heteroarylalkyl group may be substituted with the same substituent as illustrated by the above aryl group. Preferred arylalkyl groups include system optionally substituted by the group as defined in the above aryl group and the phenyl ring is unsubstituted or substituted with one or two C ₁ -C ₄ alkyl or heteroalkyl C ₁ of -C ₄ alkylene, wherein the alkyl or heteroalkyl group may optionally be cyclized to form a ring such as cyclopropane, dioxolane or oxolane. Similarly, a heteroarylalkyl group preferably includes a C ₅ -C ₆ monocyclic heteroaryl group which may be substituted with a group which is usually present at the substituent of the aryl group, and is unsubstituted or substituted by one or two C. ₁ -C ₄ alkyl or substituted heteroalkyl of C ₁ -C ₄ alkylene, optionally substituted or including the phenyl ring or a C ₅ -C ₆ monocyclic aryl group and the heteroaryl is unsubstituted or one or two C ₁ -C ₄ alkyl or substituted alkyl group of C ₁ -C ₄ heteroalkyl alkylene heteroalkyl, wherein the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxane Pentane, or oxolane.

If the arylalkyl or heteroarylalkyl group is meant to be substituted as desired, the substituent may be in the alkyl or heteroalkyl moiety, or in the aryl or heteroaryl portion of the group. Substituents which are optionally present in the alkyl or heteroalkyl moiety are the same as those generally described for the above alkyl groups; such substituents which may be present in the aryl or heteroaryl moiety and the above aryl are generally illustrated The substituents are the same.

As used herein, an "arylalkyl" group, if unsubstituted, is a hydrocarbyl group and is illustrated by the total number of carbon atoms in the ring and alkyl or similar linkage. Thus the benzyl group is a C7-arylalkyl group and the phenylethyl group is a C8-arylalkyl group.

The term "heteroarylalkyl" as used herein refers to a moiety comprising an aryl group attached by a linker, which differs from "arylalkyl" in that at least one ring of the aryl moiety is present. One of the atoms or the linking group is a hetero atom selected from N, O and S. The heteroarylalkyl group is illustrated by the total number of atoms in the ring and the combined linking group, and the like includes an aryl group attached via a heteroalkyl linker; a heteroaryl group attached via a hydrocarbyl linker, such as an alkylene group; And a heteroaryl group attached via a heteroalkyl linker. So, for example, C7-hybrid The alkyl group will include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.

As used herein, "alkylene" refers to a divalent hydrocarbon radical; since it is divalent, it can be joined to the other two groups. Usually means -(CH ₂ ) _n - wherein n is from 1 to 8, preferably n is from 1 to 4, but if specifically stated, alkylene may be substituted by other groups and may be of other lengths And the open price does not have to be at the opposite end of the chain.

In general, any alkyl, alkenyl, alkynyl, decyl, or aryl or arylalkyl group included in the substituent may itself be substituted with other substituents as desired. If the substituents are not otherwise stated, the nature of such substituents is similar to the nature of their original substitutions.

As used herein, "amino" refers to -NH ₂ , but if the amine group is "substituted" or "optionally substituted", the term includes NR ' R " , wherein each R ' and R ' Independently H, or an alkyl, alkenyl, alkynyl, fluorenyl, aryl, or arylalkyl group, and each alkyl, alkenyl, alkynyl, fluorenyl, aryl, or arylalkyl group is visible Substituted by a substituent suitable for the corresponding group as described herein; the R ' and R " groups and the nitrogen atom to which they are attached may optionally form a 3- to 8-membered ring which may be saturated, unsaturated or aromatic And comprising 1-3 heteroatoms each independently selected from N, O and S as a ring member, and which may optionally be substituted with a substituent suitable for the alkyl group as described herein, or if NR ' R " is an aromatic group It may optionally be substituted with a typical substituent as illustrated by the heteroaryl group.

The term "carbocyclic", "carbocyclyl" or "carbocyclic" as used herein means a ring containing only carbon atoms in the ring, and the term "heterocyclic" or "heterocyclic" means containing at least one hetero atom. Ring. Carbocyclic group can be completely saturated And or partially saturated, but not aromatic. For example, a carbocyclic group includes a cycloalkyl group. Carbocyclic and heterocyclic structures include compounds having a monocyclic, bicyclic or multiple ring system; and such systems can be mixed with aromatic, heterocyclic, and carbocyclic rings. The mixed ring system is illustrated by the ring attached to the remainder of the illustrated compound.

The term "heteroatom" as used herein refers to any atom other than carbon or hydrogen, such as nitrogen, oxygen or sulfur. When it is part of the backbone or backbone of a chain or ring, the heteroatom must be at least divalent and is typically selected from the group consisting of N, O, P, and S.

The term "alkyl fluorenyl" as used herein, refers to an alkyl group covalently bonded to a carbonyl group (C=O). The term "lower alkyl alkane" means that the alkyl moiety of the alkyl fluorenyl group is a C ₁ -C ₆ alkyl fluorenyl group. The alkyl moiety of the alkano group can be substituted as desired above. The term "alkylcarbonyl" can be used instead. 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; it can be considered that the alkyl group replaces the hydrogen atom of the hydroxyl group. The term "lower alkoxy" means alkoxy groups of the alkyl moiety is C ₁ -C ₆ alkoxy it. The alkyl moiety of the alkoxy group can be substituted as desired above. The term "haloalkoxy" as used herein means that the alkyl portion of the alkoxy group is substituted with one or more halo groups.

The term "sulfo" means a sulfonic acid (-SO ₃ H) substituents employed.

The term "amine sulfonyl" as used herein refers to a substituent of the structure -S(O ₂ )NH ₂ wherein the nitrogen of the NH ₂ moiety of the group can be substituted as desired above.

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

The term "amine-methylindenyl" as used herein refers to a group of the structure -C(O ₂ )NH ₂ wherein the nitrogen of the NH ₂ moiety of the group can be substituted as desired above.

The terms "monoalkylaminoalkyl" and "dialkylaminoalkyl" as used herein mean the radical -Alk ₁ -NH-Alk ₂ and -Alk ₁ -N(Alk ₂ )(Alk ₃ ). A group wherein Alk ₁ , Alk ₂ , and Alk _{3 are} as defined 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 defined above. The terms "alkenylsulfonyl" and "alkynylsulfonyl" refer to a sulfonyl group which is a covalently bonded alkenyl group and an alkynyl group, respectively. The term "arylsulfonyl" refers to a group of the structure -S(O) ₂ -Ar, wherein Ar means 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 an aryl group as described above. The term "arylalkylsulfonyl" refers to a group 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 "alkyloxycarbonyl" as used herein, refers to an ester substituent comprising an alkyl group, wherein the carbonyl carbon is the point of attachment to the molecule. An example of this is ethoxycarbonyl, which is CH ₃ CH ₂ OC(O)-. Similarly, the terms "alkenyloxycarbonyl", "alkynyloxycarbonyl", and "cycloalkylcarbonyl" are likewise meant to include ester substituents of alkenyl, alkenyl, or cycloalkyl, respectively. Similarly, the term "aryloxycarbonyl" refers to an ester substituent that includes an aryl group, wherein the carbonyl carbon is the point of attachment 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.

Other combinations of substituents are known in the art and are described, for example, in U.S. Patent No. 8,344,162 to Jung et al. For example, the term "thiocarbonyl" and a combination of substituents including "thiocarbonyl" include a carbonyl group in which a normally double bonded oxygen in a double-bonded sulfur-substituted group. The term "alkylene" and like terms refers to an alkyl, alkenyl, alkynyl, or cycloalkyl group as specifically indicated, wherein two hydrogen atoms are removed from a single carbon atom, such that the group is bonded by a double bond. structure.

For the medical use described below in relation to the improvement of substituted hexitol derivatives, the substituted hexitol derivatives are typically selected from the group consisting of: dehydrated galactitol, di-dehydrated a derivative of galactitol, a derivative of diethyl hydrazine galactitol, a derivative of diethyl hydration galactitol, a dibromodusol, and a derivative of dibromodusol, unless otherwise There are instructions. Preferably, the substituted hexitol derivative is dihydrated galactitol unless otherwise stated. In some instances, derivatives of dehydrated galactitol, such as compound analogs or prodrugs, are preferred as described below.

As used herein, the terms "treatment" and "treatment" refer to medical treatment and prophylactic or preventive measures, the purpose of which is to prevent or slow (reduce) undesired physiological changes or abnormalities, such as the growth, development or spread of cancer. For the purposes of the present invention, advantageous or desired clinical outcomes include, but are not limited to, alleviating symptoms, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, alleviating or reducing the disease state, and eliminating Except (whether partial or complete), whether detectable or undetectable. "Treatment" also means prolonging survival compared to the expected survival without treatment. Those who are in need of treatment include those who have suffered from the disease or disease and those who are prone to have the condition or disease or who need to prevent the condition or disease. The results of the treatment can be determined by methods known in the art, such as the degree of reduction in the amount of opiate or other pain medication required to determine the degree of pain reduction, the reduction in tumor load, and the improvement in the Karnofsky Performance Score. Recovery of the assay function, or other methods known in the art. The use of the terms "treatment" and "treatment" is not to be taken as implying the cure of any disease or condition.

As used herein, the term "potentiating" means that the efficacy of the medical combination is greater than the additive effect of the two or more single agents. Determination of synergistic interactions between: (i) di-dehydrated galactitol, diethylidene di-dehydrated galactitol, or derivatives or analogs thereof; and (ii) one or more other The chemotherapeutic agent can be analyzed by a known analytical method of the related art, and can be analyzed by the Chou and Talalay combination method and the Dose-Effect Analysis method using the CalcuSyn software. Combination Index (Chou and Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). When the combination index value is less than 0.8, it means that it has synergism, when the index is more than 1.2, it means that it has antagonisticity, and when the index is between 0.8 and 1.2, it means that it has additive effect. Combination therapy provides "potency" and confirms "synergism", that is, when the active ingredients are used together, the efficacy achieved is greater than the sum of the potencies of the compounds when used separately. To achieve synergistic effectiveness, Such active ingredients: (1) co-administered and combined unit dosage formulations for simultaneous administration or delivery; (2) alternate or parallel delivery of separate formulations; or (3) some other course of treatment. When delivered by alternation therapy, synergy can be achieved when the compounds are administered sequentially or delivered (e.g., using separate syringes for different injections or utilizing other routes of administration). Generally, during alternation therapy, the effective dose of each active ingredient is administered sequentially, i.e., sequentially, while in combination therapy, an effective dose of two or more active ingredients is co-administered. The combined efficacy can also be assessed using the BLISS independent model and the highest single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3: 80). The BLISS score quantifies the degree of enhancement of a single formulation, and a BLISS score > 0 indicates more than a simple addition. In some options, the combined efficacy can be assessed using both the BLISS independent model and the highest single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3: 80). The BLISS score quantifies the degree of enhancement of a single formulation, and a BLISS score > 0 indicates more than a simple addition. A HAS score > 0 indicates that the combined efficacy exceeds the maximum effect of the single formulation at the corresponding concentration. A HAS score > 0 indicates that the combined efficacy exceeds the maximum effect of the single formulation at the corresponding concentration.

Specific medical combinations according to the present invention include di-dehydrated galactitol and Dimensional; di-desogalactitol and Polo-like kinase inhibitors; di-dehydrated galactitol and preparations which reduce the activity or performance of YB-1 ; two dehydrated galactitol and Akt inhibitor; two dehydrated galactitol and RSK inhibitor; two dehydrated galactitol and PARP inhibitor olapaini; Lactitol and cisplatin or oxaliplatin; and di-dehydrated galactitol and topoisomerase II inhibitor etoposide. For the two dehydrated galactitol and Dimengite, when the two preparations are synergistically administered, it is usually administered for 3 days, then the second galactitol is administered for 3 days, but when administered simultaneously. There is no synergy. For other options, the formulations may be administered simultaneously or sequentially. Other medical combinations are described below.

As described in further detail below, treatment of pleomorphic glioblastoma (GBM) in pediatric patients includes, and specifically targets, the treatment of highly malignant gliomas (HGG) in such patients. The method of the present invention and the activity of the composition suppress the proliferation of cancer stem cells (CSC).

Therefore, one aspect of the present invention is a substituted hexitol derivative (such as di-galactose galactose) for treating a central nervous system malignant disease (such as glioblastoma multiforme or medulloblastoma) in a pediatric patient. Alcohol) A method for improving the efficacy of administration and/or reducing side effects, comprising the steps of: (1) discriminating with the treatment for pediatric patients with central nervous system malignancies (such as glioblastoma multiforme or medulloblastoma) At least one factor or parameter relating to the efficacy of the substituted hexitol derivative (eg, di-desaminogalactitol) and/or side effects; and (2) modulating the factor or parameter for use in treating a pediatric patient center Substituted hexitol derivatives of neurological malignancies (such as glioblastoma multiforme or medulloblastoma), such as di-dehydrated galactitol, improve drug delivery efficacy and/or reduce side effects.

Usually the factor or parameter is selected from the group consisting of: (1) dose adjustment; (2) route of administration; (3) dosing schedule; (4) disease stage selection; (5) patient selection; (6) patient/disease phenotype; (7) patient/disease genotype ( 8) preparation before/after treatment; (9) toxicity treatment; (10) pharmacokinetic/pharmacodynamic tracking; (11) drug combination; (12) chemotherapy sensitization; (13) chemotherapy synergy; 14) Patient treatment after treatment; (15) Alternative medical/medical support; (16) Improvement of API products; (17) Diluent system; (18) Solvent system; (19) Excipients; (20) Dosage form; (21) dose kit and packaging; (22) drug delivery system; (23) drug conjugate type; (24) compound analog; (25) prodrugs; (26) multi-drug systems; (27) biomedical agent strengthening methods; (28) biomedical agent resistance regulation; (29) enhanced radiation therapy; (30) novel action mechanisms; a selective target cell population medical method; (32) combined with free radiation; (33) combined with a preparation for enhancing its activity; (34) combined with a preparation for counteracting myelosuppressive effects; and (35) use to increase the substituted A preparation of the ability of hexitol to pass the blood-brain barrier.

As described in detail above, generally substituted hexitol derivatives suitable for use in the methods and compositions of the present invention include galactitol, substituted galactitol, dulcitol, and substituted dulcitol, including Dehydrated galactitol, diethylidene dihydrogalactitol, dibromodusol, its derivatives and the like. Typically, the substituted hexitol derivative is selected from the group consisting of: dehydrated galactitol, a derivative of di-dehydrated galactitol, diethyl hydrazine di-dehydrated galactitol, Derivatives of diacetyl hydrazine dehydrated galactitol, dibromodusol, and derivatives of dibromodusol. Preferably, the substituted hexitol derivative is dihydrated galactitol.

When improved by dose adjustment, the dose adjustment can be, but is not limited to, at least one dose adjustment selected from the group consisting of: (a) continuous iv infusion for hours to days; (b) each ( ² ) dose over 5 mg/m ² /day; (d) gradual increase from 1 mg/m ² /day depending on patient tolerance; (e) use of caffeine to regulate metabolism; (f) use Isoniazid regulates metabolism; (g) selective and intermittent additional dose; (h) single dose via bolus injection and multiple doses from 5 mg/m ² /day; (i) low oral dose At 30 mg/m ² ; (j) oral dose higher than 130 mg/m ² ; (k) oral dose up to 40 mg/m ² for 3 days, followed by a minimum/recovery period of 18-21 days; The lower dose of the drug is extended (for example: 21 days); (m) the higher dose is administered; (n) the lowest point of administration/recovery period is more than 21 days; (o) the degree of dose is cerebrospinal fluid (CSF) The concentration of the substituted hexitol derivative (such as di-dehydrated galactitol) is equal to or greater than 5 μM; (p) the dose level is such that the cytotoxic concentration is reached in the CSF; (q) is derived using the substituted hexitol Object (such as two water (galactitol) as a single cytotoxic agent; (r) a cumulative dose of about 9 mg/m ² in a 33-day cycle; (s) a cumulative dose of about 10 mg/m ² in a 33-day cycle; (t) a 33-day cycle The cumulative dose was about 20 mg/m ² ; (u) the cumulative dose was about 40 mg/m ² in a 33-day cycle; (v) the cumulative dose was about 80 mg/m ² in a 33-day cycle; (w) the cumulative dose was administered in a 33-day cycle. About 160 mg/m ² ; (x) a cumulative dose of about 240 mg/m ² administered in a 33-day cycle; (y) administration to a plasma half-life of about 1-2 hours; (z) administration such that C _max is <200 ng/ml; (aa) Administration results in a half-life of >20 hours in the cerebrospinal fluid of the substituted hexitol derivative.

When the improvement is made by the administration route, the administration route may be, but not limited to, at least one administration route selected from the group consisting of: (a) topical administration; (b) oral administration; (c) slow administration. Release oral delivery; (d) intrathecal administration via the spinal cord; (e) intra-arterial administration; (f) continuous infusion; (g) intermittent infusion; (h) intravenous administration, such as intravenous administration for 30 minutes (i) administration via a longer infusion; (j) administration via an IV bolus; and (k) administration to achieve a maximum concentration of the substituted hexitol derivative (eg, dehydrated galactitol) in the CSF .

When the improvement is made by the administration schedule, the administration schedule can be For example, but not limited to, at least one administration schedule selected from the group consisting of: (a) daily dosing; (b) weekly dosing; (c) weekly dosing for 3 consecutive weeks; (d) every two Weekly administration; (e) administration for 3 weeks every two weeks, with a withdrawal period of 1-2 weeks; (f) intermittent additional administration; (g) daily administration for one week for several weeks; and (h) for 33 days Dosing on days 1, 2, and 3 of the cycle.

When improved by disease stage selection, the stage selection may be, but is not limited to, at least one disease stage selected from the group consisting of: (a) for pediatric GBM (including highly malignant glioma (HGG) )) or the appropriate stage of disease in pediatric medulloblastoma; (b) use an angiogenesis inhibitor to prevent or limit metastatic spread; (c) for newly diagnosed diseases; (d) for recurring diseases; e) for resistant or recalcitrant diseases.

When improved by patient selection, the patient selection may be, but is not limited to, patient selection using criteria selected from the group consisting of: (a) selecting a subject selected from a high level selected from the group consisting of histones a diseased condition patient with a metabolic enzyme in the group consisting of acetamylase and ornithine decarboxylase; (b) selecting a low or high sensation for a group selected from the group consisting of hypoplateemia and neutrophilic hypoxia Patients with pathology; (c) patients who are unable to tolerate GI toxicity; (d) selection characterized by c-Jun, GPCR, signal transduction proteins, VEGF, prostate specific genes, and protein kinases Patients selected for the group to be over- or under-represented; (e) patients with an additional copy of the EGFR gene with pediatric GBM; (f) selection characterized by TP53, PDGFRA, IDH1, and selected from pediatric GBM a patient having a mutation in at least one gene in a group of NF1; (g) selecting a patient characterized by methylation or lack of methylation of a promoter of the MGMT gene; (h) selecting a patient characterized by an IDH1 mutation; i) selection is characterized by the presence of the IDH1 wild-type gene Persons; (j) selecting characterized by the presence 1p / 19q deletions of patients receiving combination; (K) is not selected wherein 1p / 19q deletions of patients receiving combination; (l) selecting wherein MGMT (O ⁶ - methyl guanine methyl conversion a patient with an unmethylated promoter region of the enzyme; (m) selecting a patient characterized by a methylated promoter region of MGMT; (n) selecting a patient characterized by a high degree of performance of the MGMT; (o) selecting a feature characterized by MGMT Patients with low performance; and (p) selection of patients characterized by mutations in EGFR, including but not limited to EGFR variant III.

The protein encoded by the cell proto-oncogene c-Jun is combined with c-Fos to form an AP-1 early response transcription factor. This proto-oncogene plays a key role in transcription and interacts with a variety of proteins that affect transcription and gene expression. It also involves the proliferation and apoptosis of cells that form part of many tissues, including endothelial cells and glandular epithelial cells. G-protein coupled receptors (GPCRs) are important signal transduction receptors. The superfamily of G protein coupled receptors includes a wide variety of receptors. These receptors are integral membrane proteins characterized by an amino acid sequence comprising seven hydrophobic domains predicted to represent the transmembrane region of the protein. It can be found in many organisms and involves the transmission of signals to the interior of the cell as a result of interaction with the heterotrimeric G protein. It responds to a wide variety of different formulations, including lipid analogs, amino acid derivatives, small molecules such as epinephrine and dopamine, and a variety of different sensory stimuli. The properties of many known GPCRs are outlined in "The G-Protein Linked Receptor Facts Book" by S. Watson & S. Arkinstall (Academic Press, London, 1994). GPCR receptors include, but are not limited to, acetylcholine receptors, β-adrenergic receptors, β ₃ -adrenergic receptors, serotonin (5-hydroxytryptamine) receptors, dopamine Receptors, adenosine receptors, type II angiotensin receptors, soothing peptide receptors, calcitonin receptors, calcitonin gene-related receptors, cannabinoid receptors, cholecystokinin receptors, chemical hormones Receptors, cytokine receptors, gastrin receptors, endothelin receptors, gamma-aminobutyric acid (GABA) receptors, galanin receptors, glucosamine receptors, glutamate receptors, yellow Body hormone receptor, chorionic gonadotropin receptor, follicle stimulating hormone receptor, thyroid stimulating hormone receptor, gonadotropin releasing hormone receptor, leukotriene receptor, neuropeptide Y receptor, opioid receptor, Parathyroid hormone receptor, platelet activating factor receptor, prostaglandin (prostaglandin) receptor, somatostatin receptor, thyrotropin releasing hormone receptor, angiotensin and oxytocin receptor.

EGFR mutations may be associated with sensitivity to medical agents such as gefitinib, as described in JGPaez et al., "EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib," Science 304: 1497-1500 (2004). One of the specific mutations of EGFR associated with resistance to tyrosine kinase inhibitors is known as EGFR variant III, which has been described in CALearn et al. "Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme, "Clin. Cancer Res. 10: 3216-3224 (2004). EGFR variant III is characterized by a deletion of 801 bp from the consensus and tumor specificity of the extracellular domain, which cleaves the codon and produces a novel glycine at the fusion junction. The protein encoded by this mutation has a constitutively active thymidine kinase that potentiates the tumorigenicity of cells bearing this mutation. The mutated protein sequence is expressed clonally in a significant proportion of glioblastoma, but no normal tissue is present.

When improved by patient or disease phenotypic analysis, the patient or disease phenotype analysis can be, but is not limited to, a patient or disease phenotype analysis performed by a method selected from the group consisting of: Method: (a) use diagnostic tools, diagnostic techniques, diagnostic kits, or diagnostics The analysis method confirms the specific phenotype of the patient; (b) the method of determining the marker selected from the group consisting of histone deacetylase, adenine decarboxylase, VEGF, and the gene of jun Product protein, protein kinase; (c) drug replacement compound; and (d) low dose preliminary test for enzymatic status.

When improved by patient or disease genotyping, the patient or disease genotyping assay can be, but is not limited to, a patient or disease genotype analysis using a method selected from the group consisting of: Method: (a) use diagnostic tools, diagnostic techniques, diagnostic kits, or diagnostic assays to identify a patient's specific genotype; (b) use a gene chip; (c) use gene expression analysis; (d) use a single core Polymorphism (SNP) assay; (e) determination of metabolite or metabolite content; (f) determination of PDGFRA gene mutation; (g) determination of IDH1 gene mutation; (h) determination of NF1 gene mutation; (i) determination The number of copies of the EGFR gene; (j) determining the methylation status of the promoter of the MGMT gene; (k) determining the presence of the IDH1 mutation; (1) determining the presence of the IDH1 wild type; (m) determining the presence of the 1p/19q combined deletion ; (n) determining the absence of a 1p/19q combined deletion; (o) determining the presence of an unmethylated promoter region of the MGMT gene; (p) determining the presence of a methylated promoter region of the MGMT gene; (q) determining Highly representative of the presence of MGMT; (r) Determination of the presence of low performance MGMT.

The use of gene chips is described in "DNA Microarrays in Biological Discovery and Patient Care" by AJ Lee & S. Ramaswamy, Essentials of Genomic and Personalized Medicine (GS Ginsburg & HF Willard, eds., Academic Press, Amsterdam, 2010), ch .7, pp. 73-88.

When the method is to use a single nucleotide polymorphism (SNP) assay, the SNP assay can be performed on a gene selected from the group consisting of histone deacetylase, adenine decarboxylation. Enzyme, VEGF, prostate specific gene, c-Jun, and protein kinase. The use of SNP analysis has been described in "DNA Sequencing for the Detection of Human Genome Variation" by S. Levy and Y.-H. Rogers, Essentials of Genomic and Personalized Medicine (GSGinsburg & HF Willard, eds., Academic Press, Amsterdam, 2010), ch. 3, pp. 27-37.

Other genomic techniques such as copy number variation analysis and DNA methylation analysis can also be used. The copy number variation analysis method has been described in "Copy Number Variation and Human Health" by C. Lee et al., Essentials of Genomic and Personalized Medicine (G.S. Ginsburg & H.F. Willard, eds., Academic Press, Amsterdam, 2010), ch. 5, pp. 46-59. This is particularly important for GBM because the increase in the number of copies of EGFR is associated with a particular subtype of GBM and may be applicable to other malignant diseases that may be treated using the compositions and methods of the present invention. DNA methylation assays are described in "DNA Methylation Analysis: Providing New Insight into Human Disease" by S. Cottrell et al., Essentials of Genomic and Personalized Medicine (GSGinsburg & HF Willard, eds., Academic Press, Amsterdam, 2010). ), ch. 6, pp. 60-72. The prognosis based on GBM will vary with the degree of methylation of the promoter of the MGMT gene, and this practice is particularly important for GBM and may be applicable to other malignant diseases that may be treated using the compositions and methods of the present invention.

When the improvement is made by preparation before/after treatment, the preparation before/after the treatment may be, but not limited to, a preparation method before/after treatment selected from the group consisting of: (a) using colchicum Or its analogues; (b) the use of diuretics; (c) the use of uric acid; (d) the use of uric acid oxidase; (e) the use of non-oral nicotine amide; (f) the use of sustained release nicotine 醯(g) using an inhibitor of poly-ADP ribose polymerase; (h) using caffeine; (i) using calcium leucovorin rescue; (j) controlling infection; and (k) using an antihypertensive agent.

Urinary acid drugs include, but are not limited to, probenecid, benzbromarone, and sulfinpyrazone. A particularly good uric acid drug is probenecid. Urinary acid drugs (including probenecid) may also have diuretic activity. Other diuretics are well known in the art and include, but are not limited to, hydrochlorothiazide, carbonic anhydrase inhibitors, furosemide, ethacrynic acid, amiloride And spironolactone (spironolactone).

Poly-ADP ribose polymerase inhibitors are described in GJ Southan & C. Szabó, "Poly (ADP-Ribose) Inhibitors," Curr. Med. Chem. 10:321-240 (2003), and includes nicotinamide, 3 -aminobenzamide, substituted 3,4-dihydroisoquinolin-1(2H)-one and isoquinolin-1(2H)-one, benzimidazoles, anthraquinones, pyridazines -1 (2H)-ketone, quinazolinone, isoindolinone, phenanthridine, and other compounds.

The leucovorin rescue consists of administering leucovorin to patients who have received methotrexate. Leucovorin is a reduced form of folic acid that bypasses dihydrofolate reductase and restores hematopoietic function. Leucovorin can be administered intravenously or orally.

In an alternative option, wherein the uric acid is administered before/after treatment, the uric acid is probenecid or an analog thereof.

When improved by toxic treatment, the toxic treatment may be, but is not limited to, a toxic treatment method selected from the group consisting of: (a) use of colchicine or its analogues; (b) use of diuretics; (c) use of uric acid; (d) use of urate oxidase; (e) use of non-oral nicotine amide; (f) use Sustained-release nicotine amide; (g) inhibitor of poly-ADP ribose polymerase; (h) use of caffeine; (i) rescue with calcium leucovorin; (j) use of sustained release allopurinol; k) use of non-oral allopurinol; (1) use of a bone marrow transplant; (m) use of a blood cell stimulating agent; (n) use of blood or platelet infusion; (o) administration of a preparation selected from the group consisting of: Filgrastim, G-CSF, and GM-CSF; (p) pain management techniques; (q) administration of anti-inflammatory agents; (r) administration of fluids; (s) administration of corticosteroids; (t) administration Insulin-regulating medicine; (u) antipyretic agent; (v) anti-nausea therapeutic agent; (w) anti-hypertensive therapeutic agent; (x) administering N-acetylcysteine; and (y) administering antihistamine.

Filgrastim is a particulate white blood cell colony stimulating factor (G-CSF) analog produced by recombinant DNA technology for stimulating the proliferation and differentiation of granular leukocytes and for the treatment of neutropenia; -CSF can be used in a similar manner. GM-CSF is a granulocyte white blood cell macrophage colony stimulating factor, and stimulates stem cells to produce granulocyte white blood cells (eosinophilic white blood cells, neutrophils, and basophilic white blood cells) and mononuclear blood cells; its administration is suitable for prevention or treatment. infection.

Anti-inflammatory agents are well known in the art and include corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs). Corticosteroids with anti-inflammatory activity include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone , prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone. Non-steroidal anti-inflammatory agents include, but are not limited to, ethoxylated salicylic acid (aspirin), sodium salicylate, choline magnesium salicylate, salsalate, difluorophenyl salicylic acid (diflunisal), sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac (diclofenac), ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen (fenoprofin), oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabendene Nabumetone, rofecoxib, celecoxib, etodolac, nimesulide, aceclofenac, aclofenac , amiloprofen, amfenac, ampiroxicam, apazone, araprofen, azapropazone, benzalic acid (bendazac), benoxaprofen, benzydamine, bermofolfen, benzpiperylon, bromfenac, bucloxic acid, cloth Bumadizone, butibufen, carprofen, cimicoxib, cinmetacin, cinnoxicam, chloralic acid Clidanac), clofezone, clonidine, clopirac, darbufelone, deracoxib, zhuoxikang Xicam), eltenac, enfenamic acid, epirizole, esflurbiprofen, ethenzamide, etofenamate , etoricoxib, felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozine, fenfluzine Fendosal), fentiazac, feprazone, filenadol, flobufen, Florifenine, flosulide, flubichin methanesulfonate, flufenamic acid, flufenisal, flunixin, fluoride Flunoxprofen, fluprofen, fluproquazone, furofenac, ibufenac, imrecoxib, 吲哚洛Indoprofen, isofazolac, isoxepac, isoxicam, licofelone, lobuprofen, lomoxicam , lonazolac, loxoprofen, lumiracoxib, mabuprofen, miroprofen, mofebutazone, moxazole Acid (mofezolac), morazone, nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaphthalene Nitronaproxen, orpanoxin, oxaceprol, oxindanac, oxpinac, hydroxypreservation (oxyphenbutazone), pamicogrel, parcetasal, parecoxib, parsalmide, pelubiprofen, pemedolac, Phenylbutazone, pirazolac, pirprofen, pranoprofen, salicin, salicylamide, salicylsalicylic acid, Satigrel, sudoxicam, suprofen, talmetacin, talniflumate, tazofelone, tert-butyl (tebufelone), tenidap, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, temacoxi ( Tammacoxib), tinoridine, tiopinac, tioxaprofen, tolfenamic acid, triflusal, tropesin, Ursolic acid, valdecoxib, ximoprofen, zaltoprofen, zidometacin, zomepirac, and its salts , solvates, analogs, congeners, bioelectronic isosteres, hydrolysates, metabolites, precursors, and prodrugs.

The clinical use of corticosteroids is described in "Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones" by BP Schimmer & KL Parker, described 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.

Anti-nausea therapeutics include, but are not limited to, ondansetron, metoclopramide, promethazine, cyclizine, hyoscine, tetrahydrocannabis Dronabinol, dimenhydrinate, diphenhydramine, hydroxyzine, medizine, dolasetron, granisetron, para Palone (trononose), Ramostron (ramosetron), domperidone, haloperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, betamethasone Betamethasone), dexamethasone, lorazepam, and thiethylperazine.

Anti- sputum therapeutics include, but are not limited to, diphenoxylate, difenoxine, loperamide, codeine, racecadotril, octreotide (octreoside), with berberine.

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

Poly-ADP ribose polymerase (PARP) inhibitors include, but are not limited to, (1) tetracycline derivatives as described in U.S. Patent No. 8,338,477 (issued to Duncan et al.); (2) 3,4-dihydro- 5-methyl-1( 2H )-isoquinoline, 3-aminobenzamide, 6-aminonicotinamide, and 8-hydroxy-2-methyl-4( 3H )-quin Oxazolinone, as described in U.S. Patent No. 8,324,282 to Gerson et al; (3) 6-( 5H )-phenanthridinedione and 1,5-isoquinolinediol, such as the US patent of Yuan et al. (4)(R)-3-[2-(2-Hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one, as described in Case No. 8,324,262; , as described in U.S. Patent No. 8,309,573 (issued to Fujio et al.); (5) 6-alkenyl-substituted 2-quinolinone, 6-phenylalkyl-substituted quinolinone, 6-ene Base-substituted 2-quine Linoleone, 6-phenylalkyl substituted 2-quinoline Chlorinone, substituted 6-cyclohexylalkyl substituted 2-quinolinone, 6-cyclohexylalkyl substituted 2-quinoline a ketone, a substituted pyridone, a quinazolinone derivative, a pyridazine derivative, a quinazolinedione derivative, and a substituted 2-alkylquinazolinone derivative, such as the U.S. Patent No. 8,299,256 (issued to Vialard et al.); (6) 5-bromoisoquinoline, as described in U.S. Patent No. 8,299,088 (issued to Mateucci et al.); (7) 5-bis-(2-chloroethyl) Amino]-1-methyl-2-benzimidazole butyric acid, 4-iodo-3-nitrobenzamide, 8-fluoro-5-(4-((methylamino)methyl) Phenyl)-3,4-dihydro-2H-azino[5,4,3-cd]indole-1(6H)-ketophosphoric acid, and N-[3-(3,4-dihydro) -4-Sideoxy-1-pyridazinyl)phenyl]-4-morpholinium decylamine methanesulfonate, as described in U.S. Patent No. 8,227,807 (issued to Gallagher et al.); (8) a oxazinone derivative as described in U.S. Patent No. 8,268,827 (issued to Branca et al.); (9) 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzoate -2H-pyridazin-1-one, as described in U.S. Patent No. 8,247,416, issued to Menear et al.; (10) tetraazaindole-3-one compound, such as U.S. Patent No. 8,236,802 ( issued to Xu et al.) described; (11) 2- substituted -1 H - benzo Oxazole-4-carboxyguanamine, as described in U.S. Patent No. 8,217,070 (issued to Zhu et al.); (12) Substituted 2-alkylquinazolinones, such as U.S. Patent No. 8,188,103 (issued) (13) 1 H -benzimidazole-4-carboxyguanamine, as described in U.S. Patent No. 8,183,250 (issued to Penning et al.); (14) anthraquinone isoquinoline Ketone analogs as described in U.S. Patent No. 8,119,654 (issued to Jagtap et al.); Carbazole carboxamide, as described in U.S. Patent No. 8,088,760 (issued to Chu et al.); (16) diazabenzo[de]indol-3-one compound, such as U.S. Patent No. 8,058,075 (17) Dihydropyridinopyridazinone, as described in U.S. Patent No. 8,012,976 (issued to Wang et al.); (18) Substituted azaindole, such as the U.S. Patent. No. 8,008,491 (issued to Jiang et al.); (19) fused tricyclic compounds as described in U.S. Patent No. 7,956,064 (issued to Chua et al.); (20) substituted 6a, 7,8 , 9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-6( 5H )-one, as described in U.S. Patent No. 7,928,105, issued to Gangloff et al. And (21) thieno[2,3-c]isoquinoline as described in U.S. Patent No. 7,825,129. Other PARP inhibitors are known in the art.

When improved by tracking pharmacokinetic/pharmacodynamics, the pharmacokinetic/pharmacodynamic trace can be, but is not limited to, a method selected from the group consisting of: (a) multiple determinations of plasma Concentration; and (b) multiple determinations of at least one metabolite in blood or urine.

Typically, immunoassay is used to determine plasma concentrations or to measure at least one metabolite in blood or urine. Methods for performing immunoassays are well known in the art and include radioimmunoassay, ELISA (enzyme-linked immunosorbent assay), competitive immunoassay, immunoassay using lateral flow test strips, and other assays.

When the improvement is made by a combination of drugs, the combination of drugs may be, but not limited to, a combination of drugs selected from the group consisting of: (a) using a pseudo-nucleoside in combination; (b) using a pseudo-nucleotide; And a thymidylate synthetase inhibitor; (d) combined with a signal transduction inhibitor; (e) in combination with cisplatin or a platinum analog; (f) in combination with an alkylating agent; (g) in combination with an anti-tubulin agent; (h) combined with antimetabolite; (i) combined with berberine; (j) combined with apigenin; (k) combined with colchicine or its analog; (l) combined with genistein; (m) And etoposide; (n) combined with cytarabine; (o) with camptothecin; (p) with vinca alkaloid; (q) with topoisomerase inhibitor; (r) combined with 5-fluorouracil (s) in combination with curcumin; (t) in combination with NF-κB inhibitor; (u) in combination with rosmarinic acid; (v) in combination with mitoguazone; (w) in combination with mesoindigo; x) use imatinib (y) with dasatinib (z) and nilotinib; (aa) with epigenetic modulator; (ab) And use a transcription factor inhibitor; (ac) use paclitaxel; (ad) and use high three tips Oral base (homoharringtonine); (ae) with pyridoxal (pyridoxal); (af) with snail (spirogermanium); (ag) with caffeine; (ah) with nicotine amide; (ai) with methyl Glyoxal bisindenyl hydrazine; (aj) combined with Rho kinase inhibitor; (ak) combined with 1,2,4-benzotriazine oxide; (al) combined with alkyl glycerol; (am) combined with Mer, Ax1 Or an inhibitor of Tyro-3 receptor kinase; (an) an inhibitor of ATR kinase; (ao) a combination of Fms kinase, Kit kinase, MAP4K4 kinase, TrkA kinase, or TrkB kinase; (ap) Endoxifen; (aq) combined with mTOR inhibitor; (ar) combined with Mnk1a kinase, Mkn1b kinase, Mnk2a kinase, or inhibitor of Mnk2b kinase; (as) combined with pyruvate kinase M2 modulator; (at) combined a modulator of phospholipid inositol 3-kinase; (au) in combination with a cysteine protease inhibitor; (av) in combination with phenformin; (aw) in combination with a vector based on Sindbis virus; And use a peptide mimetic that has a role as a mimetic of Smac and inhibits the action of IAP to initiate apoptosis; (ay) and a Raf kinase inhibitor; (az) and a nuclear transport regulator; And use an acidic neuroglutaminase inhibitor with a choline kinase inhibitor; (bb) with a tyrosine kinase inhibitor; (bc) with an anti-CS1 antibody; (bd) with an inhibitor of protein kinase CK2; (be) And use anti-guanylate cyclase C (GCC) antibody; (bf) combined with histone deacetylase inhibitor; (bg) with cannabinoid; (bh) with glucagon-like peptide-1 (GLP-1 a receptor agonist; (bi) in combination with an inhibitor of Bcl-2 or Bcl-xL; (bj) with a Stat3 pathway inhibitor; (bk) in combination with an inhibitor of Polo kinase 1 (P1k1); (bl) GBPAR1 activator; (bm) combined with serine-threonine protein kinase and poly(ADP-ribose) polymerase (PARP) activity modulator; (bn) combined with taxane; (bo) with dihydrofolate Inhibitor of the enzyme; (bp) combined with an inhibitor of aromatase; (bq) combined with an antitumor agent based on benzimidazole; (br) combined with O6-methylguanine-DNA-methyltransferase (MGMT) (bs) in combination with a CCR9 inhibitor; (bt) in combination with an acid sphingomyelinase inhibitor; (bu) in combination with a peptidomimetic macrocycle; (bv) in combination with guanyl cholinate; (bw) with a substituted oxygen Aza-heterophosphorus; (bx) combined with anti-TWEAK receptor (by) combined with ErbB3 protein; (bz) with glutathione S-convertase-activated anti-tumor compound; (ca) combined with substituted diamino phosphate; (cb) with inhibition of MEKK protein kinase (cd) combined with a COX-2 inhibitor; (ce) combined with cimetidine and a cysteine derivative; (cf) with an anti-IL-6 receptor antibody; (cg) with an antioxidant (ch) and the difference in the polymerization of tubulin An azole inhibitor; (ci) in combination with a PARP inhibitor; (cj) in combination with an Aurora protein kinase inhibitor; (ck) in combination with a peptide that binds to a prostate specific membrane antigen; (cl) in combination with a CD19 binding agent; (cm) in combination with benzene And diazonium; (cn) combined with Toll receptor (TLR) agonist; (co) combined with bicyclic sulfonamide; (cp) combined with inhibitor of epidermal growth factor receptor kinase; (cq) combined a T2 family ribonuclease with actin-binding activity; (cr) combined with myrsinoic acid A or its analog; (cs) with an inhibitor of cyclin-dependent kinase; (ct) with p53 An inhibitor of interaction with MDM2; (cu) an inhibitor of the receptor tyrosine kinase MET; (cv) with largazole or an analog of ergos; (cw) with AKT protein kinase Inhibitor; (cx) in combination with 2 ' -fluoro-5-methyl- β -L-arabinofuranosyluridine or L-deoxythymidine; (cy) with HSP90 modulator; (cz) with JAK kinase Inhibitor; (da) in combination with inhibitor of PDK1 protein kinase; (db) in combination with PDE4 inhibitor; (de) combined with inhibitor of the original oncogene c-Met tyrosine kinase; (df) with indoleamine 2,3 - inhibitor of dioxygenase; (dg) combined with a formulation that inhibits ATDC (TRIM29); (dh) a protein mimetic inhibitor that interacts with a nuclear receptor and a coactivator peptide; (di) uses the XIAP family Antagonist of protein; (dj) combined with superantigen targeting tumor; (dk) combined with inhibitor of Pim kinase; (dl) combined with inhibitor of CHK1 or CHK2 kinase; (dm) combined with inhibition of angiopoietin-4 protein (d) in combination with a Smo antagonist; (do) in combination with a nicotinic acetylcholine receptor antagonist; (dp) and a farnesyl protein invertase inhibitor; (dq) in combination with an adenosine A3 receptor antagonist; (dr) in combination with a cancer vaccine; (ds) with a JAK2 inhibitor; (dt) with a Src inhibitor; (du) with a preparation that inhibits the growth or replication of glioma or medulloblastoma stem cells; (dv) combined with lowering a formulation of the activity or performance of YB-1; (dw) an inhibitor of Akt; (dx) in combination with an inhibitor of RSK; and (dy) a combination of an inhibitor of Polo-like kinase.

Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, camptothecin, lamellarin D, amsacrine , etoposide, etoposide phosphate, teniposide, doxorubicin, and 4-[2-(3,5-di- oxy-1- Piperazinyl)-1-methylpropyl]piperazine-2,6-dione (ICRF-193).

Pseudonucleosides include, but are not limited to, cytosine arabinose, gem Gemcitabine, with fludarabine; other pseudonucleosides known in the art.

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

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

Signal transduction inhibitors are described in "New Mechanisms of Signal Transduction Inhibitor Action: Receptor Tyrosine Kinase Down-Regulation and Blockade of Signal Transactivation," by A. V. Lee et al., Clin. Cancer Res. 9: 516s (2003).

Alkylating agents include, but are not limited to, Shionogi 254-S, aldehyde-phosphonium analogs, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine ), bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, Cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) ₂ , diphenylspiromustine , diplatinum cytostatic, Erba distamycin derivative, Chugai DWA-2114R, ITI E09, ermustine, Erbamont FCE-24517, estramustine phosphate Estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin ), lomustine, mafosfamide, melphalan, dibromide Alcohol (mitolactol), Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, Semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, Teroxirone, tetraplatin, and trimelamol are described in U.S. Patent No. 7,446,122 to Chao et al.

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

Antimetabolites include, but are not limited to, methotrexate, pemetrexed, 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-hydrogen sulfide Basal, pentostatin, alanosine, AG2037 (Pfizer), 5-FU-fibrinogen, acanthifolic acid, aminyl thiadiazole, buquina sodium Brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine stearate, cytarabine conjugate, Lilly DATHF, Merrill-Dow DDFC , deazaguanine, dideoxycytidine, dideoxyguanosine, didox, yoshitomi DMDC, dexifluridine, Wellcome EHNA, Merck & Co. EX-015, Fazza Bin pull (fazarabine), fluoro deoxyuridine (floxuridine), fludarabine phosphate (fludarabine phosphate), N- (2 '- furan-alkyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine , Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norxine (no Rspermidine), NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitor, tyrosine protein kinase inhibitor, Taiho UFT and Yousheng (uricytin).

Berberine has antibiotic activity, and prevents and suppresses the expression of pro-inflammatory cytokines and E-selectin and increases adiponectin expression.

Apigenin is a flavonoid which can reverse the adverse effects of cyclosporine and has chemotherapeutic protective activity, which can be used alone or derivatized by sugar.

Colchicine is a tricyclic alkaloid whose activity is in association with protein tubulin. Analogs of colchicine include, but are not limited to, hydrolyzed colchiceinamide, N -deacetylated thiocolchicine, decarbonylated colchicine, N-acetyl iodine colchicine (N-acetyliodocolchinol), trimethyl colchicine acid (trimethylcolchicinic acid) (TMCA) methyl ether, N - acetyl alcohol colchicine yl (N-acetylcolchinol), TMCA ethyl ether, isopropyl colchicine, iso hydrolysis autumn Narcissus amide, iso-TMCA methyl ether, hydrolyzed colchicein, TMCA, N -benzylidene TMCA, colchicosamide, colchicoside, colchicol ( Colchinol) and colchinoic acid (MHZweig & CFChignell, "Interaction of Some Colchicine Analogs, Vinblastine and Podophyllotoxin with Rat Brain Microtubule Protein," Biochem. Pharmacol. 22: 2141-2150 (1973) and B. Yang et al. "Syntheses and Biological Evaluation of Ring C-Modified Colchicine Analogs," Bioorg. Med. Chem. Lett. 20: 3831-3833 (2010)).

Genistein is a isoflavone having the system name 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one. Genistein has many biological activities, including activation of PPAR, inhibition of several tyrosine kinases, inhibition of topoisomerase, antioxidant activity, activation of Nrf2 antioxidant effects, activation of estrogen receptor beta , and inhibition of mammals Hexose transporter GLUT2.

Etoposide is an anticancer agent whose main function is topoisomerase II inhibitor. Etoposide forms a ternary complex with DNA and topoisomerase II enzyme to prevent DNA strands from re-engaging, thus inducing DNA strand breakage and promoting apoptosis of cancer cells.

Cytarabine is a nucleoside analog that replaces ribose with arabinose. It can be incorporated into DNA, and it also inhibits DNA and RNA polymerase. Nucleotide reductase. It is especially suitable for the treatment of acute myeloid leukemia and acute lymphocytic leukemia, but can be used for other malignant diseases and for various drug combinations.

Camptothecin compounds include camptothecin, high-carb camptothecin, topotecan, irinotecan, DB 67, BNP 1350, extantan, and rituxan. (lurtotecan), ST 1481, and CKD 602. These compounds act as topoisomerase I inhibitors and block DNA synthesis in cancer cells.

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

Topoisomerase inhibitors include topoisomerase I inhibitors and topoisomerase II inhibitors. Topoisomerase I inhibitors include camptothecin and flavonoid D. In addition to amonafide and its derivatives and analogs, topoisomerase II inhibitors include etoposide, teniposide, doxorubicin, daunorubicin ), mitoxantrone, amsacrine, ellipticine, and aurintricarboxylic acid. There are many natural phenolic compounds derived from plants, such as genistein, quercetin, and resveratrol, for topoisomerase I and topoisomerase II. Both have inhibitory activity.

The 5-fluorouracil compound is a base analog that acts as a thymidine synthase inhibitor to inhibit DNA synthesis. When there is not enough supply of thymidine, the rapidly dividing cancer cells The process of thymineless death is dead.

Sacrificial curcumin has anti-tumor, anti-inflammatory, anti-oxidant, anti-ischemic, anti-arthritic, and anti-amyloid properties, and also has protective liver activity.

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

Rosmarinic acid is a natural phenolic antioxidant which also has anti-inflammatory activity.

Procarbazine is a polyamine biosynthesis inhibitor that competitively inhibits S -adenosylmethionine decarboxylase.

The activity of meisoindigo is transferred through several possible novel actions. It has a cell cycle-specific effect, including suppression of G(O)/G1 in AML cell lines, and suppression of G2/M in HT-29 colorectal cell lines. It also stimulates apoptosis through many mechanisms, including up-regulation of p21 and p27 in primary AML cells, down-regulation of Bcl-2, and up-regulation of Bak and Bax in AML cells (DKO that are not sensitive to chemotherapy), and in K562 cells. A novel caspase-dependent pathway. Isoniazid also affects the mitochondria, but does not alter the performance of Bcl-2, Bax, and Bid proteins. Isoniazid also stimulates pro-caspase 3, 8, 9 and PARP cleavage in HL-60 bone marrow cells. Isoniazid is also associated with multiple cell targets, which may be synergistic and complementary. For example, it promotes the differentiation of human myeloid leukemia cells with the down-regulation of c-myb gene expression. It also promotes DNA and RNA synthesis, microtubule assembly, glycogen synthase kinase-3β (GSK-3β) (at 5-50 nM), CDK1/cyclin B, and inhibition of W256 cells. With CDK5/p25 (tau microtubule protein phosphorylation). In addition, isoindole reduces β-catenin and c-myc (HL-60 cells, but not in K562), affecting the Wnt pathway by inhibiting GSK-3β and down-regulating the expression of β-catenin and c-myc proteins. . Isoniazid also promotes up-regulation of CD11b, promotes bone marrow differentiation, and up-regulates Ahi-1 (induced c-Myb phosphorylation) in Jurkat cells. In addition, isoindole has anti-angiogenic effects including reduction of VEGF protection, VCAM-1, microtubule formation in HUVEC, and apoptosis of ECV304 cells.

Imatinib is an inhibitor of the receptor tyrosine kinase ABL and is used to treat chronic myelogenous leukemia, gastrointestinal basal tumors, and other hyperproliferative lesions.

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

Nilotinib is another tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia; it inhibits the kinases BCR/ABL, KIT, LCK, EPHA3, and many other kinases. The use of nilotinib is described in U.S. Patent Application Publication No. 2011/0028422 to Aloyz et al.

Epigenetic modulators include epigenetic modulators based on polyamines, as described in SK Sharma et al., "Polyamine-Based Small Molecule Epigenetic Modulators," Med. Chem. Commun. 3: 14-21 (2012), and LGWang & JW Chiao, "Prostate Cancer Chemopreventive Activity of Phenethyl Isothiocyanate Through Epigenetic Regulation (Review), Int. J. Oncol. 37: Polyamine-based epigenetic modulator of 533-539 (2010).

Transcription factor inhibitors include 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 -pyrrole-2-benzoic acid (ER-50891), 7-vinyl-2-(3-fluoro-4-hydroxyphenyl)-5-benzo Oxazol (ERB 041), and 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).

Tetrandrine has a chemical structure of 6,6 ' ,7,12-tetramethoxy-2,2 ' -dimethyl-1 β- berbamine, and is blocked by calcium channels. The agent has anti-inflammatory, immune, anti-allergic effects and has an anti-rheumatic effect similar to quinidine. It has been separated from other Asian herbs by Stephania tetranda .

VEGF inhibitors include bevacizumab (Avastin, a monoclonal antibody against VEGF), itraconazole, suramin, and Bama He (batimastat) and marimastat (which is a matrix metalloproteinase inhibitor), and cannabinoids and their derivatives.

A cancer vaccine has been developed. Typically, cancer vaccines are based on an immune response to a protein or protein population that appears in cancer cells but does not appear in normal cells. Cancer vaccines include Provenge for metastatic hormone-resistant prostate cancer, Oncophage for kidney cancer, CimaVax-EGF for lung cancer, and cancer for Her2/neu (eg breast cancer, colon cancer, MOBILAN, Neuvenge, bladder cancer, and ovarian cancer, Stimuvax for breast cancer, and the like. Cancer vaccines have been described in "Cancer Vaccines: Acquisitions and Challenges," by S. Pejawar-Gaddy & O. Finn, Crit. Rev. Oncol. Hematol. 67: 93-102 (2008).

The use of methylglyoxalbiguanide in cancer therapy has been described in D. D. Von Hoff, "MGBG: Teaching an Old Drug New Tricks," Ann. Oncol. 5:487-493 (1994).

Rho kinase inhibitors (eg, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, ethacrynic acid, 4- [2(2,3,4,5,6-pentafluorophenyl)propenyl] cinnamic acid, (+)-trans-4-(1-aminoethyl)-1-(4-pyridyl Aminomethyl)cyclohexane, (+)-10 trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexane Alkylcarboxamide, and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide U.S. Patent No. 6,930,115 to Fujii et al.

1,2,4-benzotriazine oxide, such as 3-hydroxy-1,2,4-benzotriazine 1,4-dioxide, 3-amino-7-trifluoromethyl-1, 2,4-Benzotriazine 1-oxide, 3-amino-7-amine-mercapto-1,2,4-benzotriazine 1-oxide, 7-ethylindol-3-amine -1,2,4-benzotriazine 1-oxide oxime, 3-amino-6(7)decyl-1,2,4-benzotriazine 1,4-dioxide, 1,2 , 4-benzotriazine dioxide, 7-chloro-3-hydroxy-1,2,4-benzotriazine 1,4-dioxide, 7-nitro-3-amino-1,2 , 4-benzotriazine 1,4-dioxide, 3-(3-N,N-diethylaminopropylamino)-1,2,4-benzotriazine 1,4-two Oxide, 7-nitro-3-(2-N,N-diethylaminoethylamino)-1,2,4-benzotriazine 1,4-dioxide, 7-ene Propyloxy-1,2,4-benzotriazine 1,4-dioxide, 7-(3-N-ethylethylammonium-2-ethyloxypropoxy)1,2 , 4-benzotriazine 1,4-dioxide, 7-nitro-1,2,4-benzotriazine 1,4-dioxide, 3-propyl-1,2,4-benzene The use of triazine 1,4-dioxide and 3-(1-hydroxyethyl)-1,2,4-benzotriazine 1,4-dioxide is described in the US Patent No. of Brown. 6,277,835.

The use of alkyl glycerol is described in U.S. Patent No. 6,121,245 to Firshein.

The use of an inhibitor of Mer, Ax1, or Tyro-3 receptor tyrosine kinase is described in U.S. Patent Application Publication No. 2012/0230991 to Graham et al. Such inhibitors can be antibodies, including monoclonal antibodies, or fusion proteins.

The use of an inhibitor of ATR kinase is described in U.S. Patent Application Publication No. 2012/0177748, to the name of the. Inhibitors of such ATR kinases are substituted pyridine compounds such as 2-amino-N-phenyl-5-(3-pyridyl)pyridine-3-carboxamide, 5-(4-(methylsulfonate) Mercapto)phenyl-3-(5-phenyl-1,3,4- Diazol-2-yl)pyridin-2-amine, and 5-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-(5-phenyl-1 , 3,4- Diazol-2-yl)pyridin-2-amine.

The use of a compound that modulates one or more of the Fms kinase, Kit kinase, MAP4K4 kinase, TrkA kinase, or TrkB kinase activity is described in U.S. Patent Application Publication No. 2012/0165329 to Ibrahim et al. Such compounds include (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]pyrimidine-5- Methyl)-pyrimidin-2-yl]-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 (specifically, TrkA) are described in U.S. Patent Application Publication No. 2011/0301133 to Wu et al.

The use of endoxifen is described in U.S. Patent Application Publication No. 2012/0164075 to Ahmad et al.

The use of mTOR inhibitors is described in U.S. Patent Application Publication No. 2012/0129881 to Burke et al. Suitable mTOR inhibitors include, but are not limited to, 40-O-(2-hydroxyethyl)rapamycin. Such mTOR inhibitors can be used with Raf kinase inhibitors as described in US Patent Application Publication No. 2011/0301184 to Lane. Raf kinase inhibitors are also described in U.S. Patent Application Publication No. 2010/0286178 to Ibrahim et al.; such compounds include, but are not limited to, propane-1-sulfonic acid {2,4-difluoro-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]-decylamine, 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-phenyl]-3-fluoro-benzenesulfonamide, pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrole [2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-nonylamine, and N,N-dimethylamino-sulfonic acid [3-(5-cyano)- 1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-decylamine. Such mTOR inhibitors can also be used with compounds which increase the level of pAkt in malignant cells, as described in U.S. Patent Application Publication No. 2009/0274698 to Bhagwat et al. A number of compounds have been described which increase the level of pAkt, 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 issued to Jin et al.; Azinozein compound.

The use of an inhibitor of Mnk1a kinase, Mnk1b kinase, Mnk2a kinase, or Mnk2b kinase is described in U.S. Patent Application Publication No. 2012/0128686 to Austen et al. Such compounds include thienopyrimidines. The other thienopyrimidine inhibitors of one or more of these kinases are described in U.S. Patent Application Publication No. 2011/0212103 to Heckel et al. and U.S. Patent Application Publication No. 2011/0212102 to Lehmann-Lintz et al.

The use of a modulator of pyruvate kinase M2 is described in U.S. Patent Application Publication No. 2012/0122885 to Salituro et al. Suitable modulators of pyruvate kinase M2 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 phospholipid inositol 3-kinase is described in U.S. Patent Application Publication No. 2012/0122838 to Ren et al. Inhibitors of phospholipid inositol 3-kinase are also described in U.S. Patent Application Publication No. 2010/0209420 to Lamb et al. and U.S. Patent Application Publication No. 2009/0209340 to Buhr et al. Ketones. Inhibitors of phospholipid inositol 3-kinase are also described in U.S. Patent No. 8,242,104 to Blaquiere et al.; Nitrogen steroids. Inhibitors of phospholipid inositol 3-kinase are also described in U.S. Patent No. 8,193,182 to Ren et al.; such inhibitors include isoquinoline-1 (2H)-ketones. Inhibitors of phospholipid inositol 3-kinase are also described in U.S. Patent No. 7,928,428, issued to Do et al., which includes benzopyrans and benzo 呯 class.

The use of a cysteine protease inhibitor is described in U.S. Patent Application Publication No. 2012/0114765 to Cao et al. Suitable cysteine protease inhibitors include, but are not limited to, 1-[5-(2,4-dichlorophenylthio)-4-nitro-2-thienyl]ethanone, 1-[5- (2,4-difluorophenylthio)-4-nitro-2-thienyl]ethanone, and 1-{4-nitro-5-[2-(trifluoromethyl)phenylthio ]-2-thienyl} ethyl ketone.

The use of phenformin is described in U.S. Patent Application Publication No. 2012/0114676 to Thompson et al.

The use of a vector based on Sindbis virus is described in US Patent Application Publication No. 2011/0318430 to Meruelo et al. Such vectors can bind to solid tumors that exhibit a higher degree of high affinity laminin receptor.

U.S. Patent Application Publication No. 2011/0305777 to Condon et al., which is incorporated herein by reference.

Usage of nuclear transport regulators (especially inhibitors of Crm1) U.S. Patent Application Publication No. 2011/0275607 to Shacham et al. Such 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]-three Isoazol-1-yl]-isopropyl acrylate, (Z)-3-[3-(3-chlorophenyl)-[1,2,4]-triazol-1-yl]-acrylic acid tributyl Base ester, (Z)-3-[3-(3-chlorophenyl)-[1,2,4]-triazol-1-yl]-butyl 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-chlorobenzene) (1,2,4]-triazol-1-yl]-propenylamino}}-phenyl)-aminocarboxylic acid tert-butyl ester, (E)-3-[3-(3-chloro Phenyl)-[1,2,4]-triazol-1-yl]-N-(4-methoxyphenyl)-propenylamine, (E)-3-[3-(3-chlorobenzene -[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 epidermal growth factor receptor (EGFR) is present on the surface of mammalian cells and is activated by binding of the receptor to its specific ligand, including but not limited to, epidermal growth factor and transforming growth factor alpha. Upon activation by binding to its growth factor ligand, EGFR is converted from an inactive haplotype to an active homodimer, but it is possible to pre-form an active dimer prior to binding to the ligand. In addition to forming an active homodimer in combination with a ligand, EGFR may be paired with another member of the ErbB receptor family (eg, ErbB2/Her2/neu) to produce an activated heterodimer. There is also evidence to show that clustered activated EGFR forms, but it is still uncertain whether these clusters are important for activation itself or after activation of individual dimers. EGFR dimerization stimulates its intracellular endogenous protein-tyrosine kinase activity. As a result, several tyrosine residues at the carboxy terminal domain of EGFR undergo autophosphorylation. These residues include Y992, Y1045, Y1068, Y1148, and Y1171. Such autophosphorylation induces downstream activation and signaling through its own phosphotyrosine-binding SH2 domain by several other proteins associated with phosphorylated tyrosine residues. These proteins, in combination with phosphorylated tyrosine residues, are transmitted through their own phosphotyrosine-binding SH2 domain, which in turn initiates several signal transduction cascades and results in DNA synthesis and cell proliferation. The kinase domain of EGFR can also be cross-phosphorylated with other tyrosine residues of the cohesive receptor, which itself can be activated in this manner. The EGFR is encoded by the c-erbB1 proto-oncogene and has a molecular weight of 170 kDa. It is a transmembrane glycoprotein having a cysteine-rich extracellular domain, a functional domain comprising an uninterrupted tyrosine kinase site, and a multiplex autophosphorylation site clustered at the carboxy terminal tail as described above. . The extracellular fraction has been subdivided into four functional domains: functional domains I and III, which have 37% sequence identity, are less cysteic acid, and contain ligands (EGF and transforming growth factors) in conformation. α (TGFα)) binding site. The cysteine-rich functional domains II and IV comprise an N -linked glycosylation site and a disulfide bond, which determine the tertiary configuration of the outer domain of the protein molecule. In many human cell lines, the expression of TGFα is strongly correlated with the overexpression of EGFR, so TGFα is thought to act in an autocrine manner and is produced by EGFR activation when stimulating cell proliferation. The binding of stimulatory ligands to the extracellular domain of EGFR results in receptor dimerization and initiation of intracellular signal transduction, the first step of which is the activation of tyrosine kinase. The first result after kinase activation is phosphorylation (autophosphorylation) of its own tyrosine residue, as described above. This is followed by activation with the activation of the signal transducer, causing mitosis. Mutations that cause EGFR manifestations or overactivity have been associated with a variety of malignancies, including glioblastoma multiforme. EGFR-specific mutations known as EGFR variant III are frequently observed in glioblastoma (CT Kuan et al., "EGF Mutant Receptor VIII as a Molecular Target in Cancer Therapy," Endocr. Relat. Cancer 8: 83-96 (2001)). EGFR is considered an oncogene. Inhibitors of EGFR include, but are not limited to, erlotinib, gefitinib, lapatinib, lapatinib ditosylate, afati Afatinib, canertinib, neratinib, CP-724714, WHI-P154, TAK-285, AST-1306, ARRY-334543, ARRY-380, AG-1478, cheese Amino acid phosphorylation inhibitor (tyrphostin 9), dacomitinib (dcomitinib), desmethylerlotinib, OSI-420, AZD8931, AEE788, pelitinib, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035 HCl, BMS-599626, BIBW 2992, CI 1033, CP 724714, OSI 420, and vandetinib. Particularly preferred EGFR inhibitors include erlotinib, afatinib, and lapatinib.

The use of tyrosine kinase inhibitors is described in U.S. Patent Application Publication No. 2011/0206661 to Zhang et al., which is incorporated herein by reference. /0195066, which is a quinoline inhibitor of tyrosine kinase. The use of tyrosine kinase inhibitors is also described in U.S. Patent Application Publication No. 2011/053,968, to Zhang et al., which is incorporated herein by reference. The use of a tyrosine kinase inhibitor is also described in U.S. Patent Application Publication No. 2010/0291025 to Rao et al., which is incorporated herein by reference. The use of tyrosine kinase inhibitors is also described in US Patent Application Publication No. 2010/0190749 to Ren et al.; such tyrosine kinase inhibitors are benzo An azole compound; such compounds also inhibit mTOR and a lipid kinase (eg, phosphoinositide 3-kinase). The use of tyrosine kinase inhibitors is also described in U.S. Patent No. 8,242,270 to Lajeunesse et al.; such tyrosine kinase inhibitors are 2-aminothiazole-5-aromatic carboxamides.

The use of an acidic neuropterin inhibitor and a choline kinase inhibitor is described in U.S. Patent Application Publication No. 2011/0256241 to Ramirez de Molina et al.

The use of anti-CS1 antibodies is described in U.S. Patent Application Publication No. 2011/0165154 to Afar.

The use of a protein kinase CK2 inhibitor is described in U.S. Patent Application Publication No. 2011/0152240 to Haddach et al. Such protein kinase CK2 inhibitors include pyrazolopyrimidines. Other protein kinase CK2 inhibitors (including tricyclic compounds) are described in U.S. Patent Application Publication No. 2011/0071136 to Haddach et al.; such protein kinase CK2 inhibitors may also inhibit Pim kinase or other kinases. Other protein stimulation Enzyme CK2 inhibitors (including heterocyclic substituted mesalamines) are also described in U.S. Patent Application Publication No. 2011/0071115 to Haddach et al.; such protein kinase CK2 inhibitors may also inhibit Pim kinase or other kinases.

The use of anti-guanylate cyclase C (GCC) antibodies is described in U.S. Patent Application Publication No. 2011/0110936 to Nam et al.

The use of histone deacetylase inhibitors is described in U.S. Patent Application Publication No. 2011/0105474 to Thaler et al., which includes, but is 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-oxo-propenyl 1-phenyl}-propenylamine; (E)- N-hydroxy-3-{3-[(E)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propenyl]-phenyl}-propenylamine; (E )-3-[3-((E)-3-[1,4 ' ]bipiperidin-1 ' -yl-3-o-oxy-propenyl)-phenyl]-N-hydroxy-propenylamine (E)-N-hydroxy-3-{3-[(E)-3-o-oxo-3-(cis-3,4,5-trimethyl-piperazin-1-yl)-propene (E)-3-{3-[(E)-3-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2 .1]hept-2-yl)-3-oxo-propenyl]-phenyl}-N-hydroxy-propenylamine; (E)-N-hydroxy-3-{4-[(E)- 3-tertiaryoxy-3-(4-phenyl-piperazin-1-yl)-propenyl]-phenyl}-propenylamine; (E)-3-[4-((E)-3- [1,4 ' ]bipiperidin-1 ' -yl-3-o-oxy-propenyl)-phenyl]-N-hydroxy-propenylamine; (E)-N-hydroxy-3-{4- [( E)-3-Sideoxy-3-(cis-3,4,5-trimethyl-piperazin-1-yl)-propenyl]-phenyl}-propenylamine; (E)-N -hydroxy-3-{4-[(E)-3-o-oxo-3-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2 -yl)-propenyl]-phenyl}-propenylamine; (E)-N-hydroxy-3-{5-[(E)-3-oxo-3-(4-phenyl-piperazine) -1-yl)-propenyl]-pyridin-2-yl}-propenylamine; (E)-N-hydroxy-3-{5-[(E)-3-(4-methyl-piperazine- 1-yl)-3-oxo-propenyl]-pyridin-2-yl}-propenylamine; (E)-N-hydroxy-3-{6-[(E)-3-sideoxy- 3-(4-phenyl-piperazin-1-yl)-propenyl]-pyridin-2-yl}-propenylamine; (E)-N-hydroxy-3-{6-[(E)-3 -(4-methyl-piperazin-1-yl)-3-oxo-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-propenylamine; (E) -3-{6-[(E)-3-(4-Benzylmercapto-piperazin-1-yl)-3-oxo-propenyl]-pyridin-2-yl}-N-hydroxy- Acrylamide hydrochloride; (E)-3-(6-{(E)-3-[4-(2-chloro-phenyl)-piperazin-1-yl]-3-oxo-propene (-)-pyridin-2-yl)-N-hydroxy-propenylamine hydrochloride; (E)-N-hydroxy-3-{6-[(E)-3-oxooxy-3 -(4-phenyl-piperidin-1-yl)-propenyl]-pyridin-2-yl}-propenylamine hydrochloride; (E)-N-hydroxy-3-{6-[(E) 3-oxooxy-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propenyl]-pyridin-2-yl}-propenylamine hydrochloride; (E)-3- (6-{(E)-3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propenyl}-pyridin-2-yl)-N-hydroxyl - acrylamide hydrochloride; and (E)-3-{6-[(E)-3-(4-benzyl-piperazin-1-yl)-3-oxo-propenyl]- Pyridin-2-yl}-N-hydroxy-propenylamine hydrochloride. Other histone deacetylase inhibitors, including spirocyclic derivatives, are described in U.S. Patent Application Publication No. 2011/039840, to Varasi et al. The prodrug deacetylase inhibitor is described in U.S. Patent No. 8,227,636 to Miller et al. The histone deacetylase inhibitor is described in U.S. Patent No. 8,222,451 to Kozikowski et al. A histone deacetylase inhibitor, including a disubstituted aniline compound, is also described in U.S. Patent No. 8,119,685, issued to Heidebrecht et al. A histone deacetylase inhibitor, including a spirocyclic compound fused to an aryl group, is also described in U.S. Patent No. 8,119,852 to Hamblett et al.

The use of cannabinoids is disclosed in U.S. Patent Application Publication No. 2011/0086113 to Velasco Diez et al. Suitable cannabinoids include, but are not limited to, tetrahydrocannabinol and cannabidiol.

The use of a glucagon-like peptide-1 (GLP-1) receptor agonist is described in U.S. Patent Application Publication No. 2011/0046071 to Karasik et al. A suitable GLP-1 receptor agonist is exendin-4.

The use of an inhibitor of the anti-apoptotic protein Bcl-2 or Bcl-X1 is described in U.S. Patent Application Publication No. 2011/0021440 to Martin et al.

The use of the Stat3 pathway inhibitor is described in U.S. Patent Application Publication No. 2010/0310503 to Li et al. Such Stat3 pathway inhibitors include, but are not limited to, 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-dione, 2-ethylindolyl-7-chloro-naphthalene And [2,3-b]furan-4,9-dione, 2-ethylindolyl-7-fluoro-naphtho[2,3-b]furan-4,9-dione, 2-ethyl fluorenyl Naphtho[2,3-b]furan-4,9-dione, and 2-ethyl-naphtho[2,3-b]furan-4,9-dione.

The use of an inhibitor of a Polo-like kinase 1 (Plk1) is described in U.S. Patent Application Publication No. 2010/0278833 to Stengel et al. Such inhibitors include, but are not limited to, thiophene-imidazopyridines including, but not limited to, 5-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[ 2-(Trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, 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-amine A Mercapto-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-N-(2-methoxyethyl)-1H-imidazo[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-imidazole [4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide, 5-{6-[(cyclopropyl) Amino)methyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate Indoleamine, 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]pyridin-1-yl]- 3-{[2-(Trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide.

The use of the GBPAR1 activator is described in U.S. Patent Application Publication No. 2010/0261758 to Arista et al. Such GBPAR1 activators include, but are not limited to, heterocyclic guanamines. Such compounds include, but are not limited to, N-(3,5-dichlorophenyl)-3-methyl-N-naphthalen-2-ylmethyl-isonicotinamine, (3,5-dichlorobenzene) -N-(2-methoxybenzyl)-3-methyl-isonicotinamide, 3-methyl-N-phenyl-N-pyridin-3-ylmethyl-isonicotin Indoleamine, N-naphthalen-2-ylmethyl-1-oxy-N-phenyl-isonicotinamine, N-(3,5-dichlorophenyl)-3-methyl-N-( 2-Trifluoromethoxybenzyl)-isonicotinamide, 4-methyl- Oxazole-5-carboxylic acid benzyl-phenyl decylamine, N-benzyl-N-phenylisonicotin decylamine, N-benzyl-N-p-tolylisonicotinamide, N- Benzyl-2-fluoro-N-phenylisonicotinamide, N-benzyl-3,5-dichloro-N-phenyl-isonicotinamine, N-benzyl-2- Chloro-N-phenyl-isonicotinamide, N-benzyl-2-chloro-6-methyl-N-phenyl-isonicotinamine, N-benzyl-3-methyl- N-phenyl-isonicotinamide, N-benzyl-3-chloro-N-phenyl-isonicotinamine, N-benzyl-2,5-dichloro-N-phenyl- Isonicotinicinamide, N-benzyl-2-methyl-N-phenyl-isonicotinamine, N-benzyl-2-cyano-N-phenyl-isonicotinamine, N-Benzyl-N-phenethyl-isonicotinamide, N-benzyl-N-(2-fluoromethoxy-phenyl)-isonicotinamine, and N-benzyl -N-(4-chlorophenyl)-isonicotinamine decylamine. Other GBPAR1 activators are described in U.S. Patent Application Publication No. 2010/0048579 to Arista, which includes pyridazine, pyridine, and piperidine derivatives.

U.S. Patent Application Publication No. 2009/0105233 to Chua et al. and U.S. Patent to Drygin et al., the disclosure of which is incorporated herein by reference. Application for the public case number 2010/0173013. The serine-threonine protein kinase can be, but not limited to, CK2, CK2α2, 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 to Singh et al. The taxane can be, but is not limited to, paclitaxel or docetaxel.

The use of an inhibitor of dihydrofolate reductase is described in U.S. Patent Application Publication No. 2010/0150896 to Gant et al. Inhibitors of such dihydrofolate reductases include, but are not limited to, diaminoquinazolines.

The use of aromatase inhibitors is described in U.S. Patent Application Publication No. 2010/0111901 to Gant et al. These aromatase inhibitors These include, but are not limited to, triazoles.

The use of benzimidazole-based anti-tumor agents is described in U.S. Patent Application Publication No. 2010/0098691 to Goh et al. The benzimidazole-based antitumor agent can 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-methylthio-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-di Methylamino-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-Butyl-3-alken-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazole-5 -yl]-N-hydroxy-propenylamine, (E)-3-[2-but-3-enyl-1-(2-diethylamino-ethyl)-1H-benzimidazole-5 -yl]-N-hydroxy-propenylamine, (E)-3-[2-but-3-ynyl-1-(2-diethylamino-ethyl)-1H-benzimidazole-5 -yl]-N-hydroxy-propenylamine, (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-di-B Amino-ethyl)-2-ethoxymethyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-dimethyl Amino-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]- Acrylamide, (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-benzo Imidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(3-dimethylamino-2,2-dimethyl-propyl)-2-hex-3 -alkenyl-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-ene- 2-yl-1-(3-dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)- 3-[1-(2-Diethylamino-ethyl)-2-hex-3-enyl-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-isopropylamino-ethyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E) -3-[2-hex-3-enyl-1-(3-isopropylamino-propyl)-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E) -3-[1-(2-ethylamino-ethyl)-2-hex-3- Alkenyl-1H-benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-3-[1-(2-diethylamino-ethyl)-2-hexyl-1H- Benzimidazol-5-yl]-N-hydroxy-propenylamine, (E)-N-hydroxy-3-[1-(3-isopropylamino-propyl)-2-(2,4, 4-trimethyl-pentyl)-1H-benzimidazol-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]-acrylamide.

The use of O ⁶ -methylguanine-DNA-methyltransferase (MGMT) inhibitors is described in US Patent Application No. 2010/0093647 to Liu et al. Suitable MGMT inhibitors include, but are not limited to, O ⁶ -benzylguanine, O ⁶ --2-fluoropyridylmethylguanine, O ⁶ --3-iodobenzylguanine, O ⁶ --4-bromo Phenylguanine, O ⁶ -5-iodophenylguanine, O ⁶ -benzyl-8-oxyxanthine, O ⁶ -(p-chlorobenzyl)guanine, O ⁶ -(pair Benzoyl)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 -acetamidine --O ⁶ -benzylguanine, N ² -acetamido-O ⁶ -benzyl-8-oxyl-guanine, 2-amino-6-(p-methyl-benzyl- Thio)phosphonium, 2-amino-6-(benzyloxy)-9-[(ethoxycarbonyl)methyl]anthracene, 2-amino-6-(benzyloxy)-9 -(Pentylmethyloxymethyl) hydrazine, 2-amino-6-(benzyl-thio)indole, O ⁶ -benzyl-7,8-dihydro-8-hydroxy guanine , 2,4,5-triamino-6-benzyloxypyrimidine, O ⁶ -benzyl-9-[(3-o-oxy-5α-androstane-17 β -yloxycarbonyl) base Guanine, O ⁶ -benzylmethyl-9-[(3-o-oxy-4-androstene- 17β -yloxycarbonyl)methyl]guanine, 8-amino-O ⁶ -benzamide Bismuth (8-amino-BG), 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino-6-benzyloxy 5-5-nitropyrimidine and 2-amino-4-benzyloxy-5-nitropyrimidine.

The use of CCR9 inhibitors is described in U.S. Patent Application Publication No. 2010/0075963 to Lehr et al. Such CCR9 inhibitors include, but are not limited to, benzylsulfonyl hydrazines.

The use of an acid sphingomyelinase inhibitor is described in U.S. Patent Application Publication No. 2010/0022482 to Baumann et al. Typically, such compounds are biphenyl derivatives.

The use of peptidomimetic macrocycles is described in U.S. Patent Application Publication No. 2009/0275519 to Nash et al.

The use of guanamine cholamine is described in U.S. Patent Application Publication No. 2009/0258847 to Schreiner et al. Such phthalocyanine amines include, but are not limited to, substituted 4-(3-hydroxy-10,13-hydroxymethyl-hexadecahydro-cyclopenta(a)-phenanthrene-17-yl)pentanoate amine.

The use of substituted oxazaphosphines is described in U.S. Patent Application Publication No. 2009/0202540. The oxaza heterophosphazene can be, but is not limited to, ifosphamide and cyclophosphamide.

The use of anti-TWEAK receptor antibodies is described in U.S. Patent Application Publication No. 2009/0074762 to C. The TWEAK receptor is a member of the tumor necrosis receptor superfamily and is expressed in many solid tumors. Cell surface.

The use of the ErbB3 binding protein is described in U.S. Patent Application Publication No. 2008/0269133 to Zhang et al.

The use of glutathione S-convertase-activated (GST-activated) anti-tumor compounds is described in US Patent Application Publication No. 2008/0166428 to Brown et al. Preferably, the GST-activated anti-tumor compound is canfosfamide.

The use of a substituted diamino phosphate is described in U.S. Patent Application Publication No. 2008/0125398 to Ma et al., which is incorporated herein by reference to the specification of N, N, N ' , N ' - 肆 (2-chloroethyl)-diamine 2-{[2-(substituted amino)ethyl]sulfonyl}ethyl ester; and U.S. Patent Application Publication No. 2008/0125397 to Lui et al., which describes N, N, N ' , N ' -肆(2-chloroethyl)diaminophosphoric acid 2-({2-trioxy-2-[(pyridin-3-ylmethyl)amino]ethyl}sulfonyl)ethyl ester. The use of the substituted diamino phosphates is also described in U.S. Patent Application Publication No. 2008/0039429 to Allen et al., which is incorporated herein by reference.

The use of an inhibitor of the MEKK protein kinase is described in U.S. Patent Application Publication No. 2006/0100226, to Sikorski et al. Such inhibitors include, but are not limited to, 2-thiopyrimidinones such as 2-[3-(3,4-dichloro-benzylamino)-benzylsulfanyl]-4-(3- Methoxy-phenyl)-6-o-oxy-1,6-dihydro-pyrimidine-5-carbonitrile, 2-[3-(3,4-dichloro-benzylamino)-benzene Thiothio]-4-(3,4-dimethoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, with 2-[3-(3, 4-Dichloro-benzylamino)-benzylthio-4-(4-methoxy-3-thiophen-2-yl-phenyl)-6-oxo-1,6-di Hydrogen-pyrimidine-5-carbonitrile.

The use of a COX-2 inhibitor is described in US Patent Application Publication No. 2004/0072889 to Masferrer et al. Suitable COX-2 inhibitors include, but are not limited to, celecoxib, parecoxib, deracoxib, rofecoxib, etoricoxib, Valdecoxib, and meloxicam.

The use of cimetidine and N-ethinylcysteine is described in U.S. Patent Application Publication No. 2003/0158118 to Weidner. Derivatives of cimetidine or N-acetylcysteine can also be used.

The use of anti-IL-6 receptor antibodies is described in U.S. Patent Application Publication No. 2002/0131967 to Nakamura et al. The antibody can be a humanized antibody.

The use of antioxidants is described in US Patent Application Publication No. 2001/0049349 to Chinery et al. Suitable antioxidants include, but are not limited to, pyrrolidine dithiocarbamate, probucol (4,4 ' -(isopropylidene disulfide) bis (2,6-di-third) Phenol), vitamin C, vitamin E, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.

Differentiation of tubulin polymerization The use of azole inhibitors is described in U.S. Patent No. 8,269,017 to Sun et al. The appropriate polymerization of tubulin Azole inhibitors include, but are not limited to, 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-iso Zin-4-yl)-phenyl)acetamidine hydrochloride; 2-amino-3-hydroxy-N-(2-methoxy-5-[5-(3,4,5-trimethoxy) Phenyl) Zin-4-yl)-phenyl)propanamide hydrochloride; 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)iso) Zin-4-yl)-phenyl)propanamine; 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-iso Zin-4-yl)-phenyl)-4-(methylthio)butanamine hydrochloride; 2-amino-N-(2-methoxy-5-[5-(3,4, 5-trimethoxyphenyl)-iso Zin-4-yl)-phenyl)butanamine; 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)-iso Zin-4-yl)-phenyl)-3-phenylpropanamide hydrochloride; 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy) Base phenyl)-different Zin-4-yl)-phenyl)-4-methylpentanylamine hydrochloride; 2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy) Base-phenyl)-iso Zin-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide hydrochloride; 1-{2-methoxy-5-[5-(3,4,5- Trimethoxy-phenyl)-iso Zin-4-yl]-phenylamine-methylhydrazine}-2-methyl-propyl-ammonium chloride; 1-{2-methoxy-5-[5-(3,4,5-trimethoxy) Base phenyl)-different Zin-4-yl]-phenylamine-mercapto}-2-methyl-butyl-ammonium chloride; 2-hydroxy-1-{2-methoxy-5-[5-(3,4, 5-trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-mercapto}-propyl-ammonium chloride; 2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[5-(3, 4,5-trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride; C-{2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)- different Zin-4-yl]-phenylamine-methyl hydrazino}-C-phenyl-methyl-ammonium chloride; 2-(1H-indol-2-yl)-1-{2-methoxy-5 -[5-(3,4,5-trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride; 2-benzofuran-2-yl-1-{2-methoxy-5-[5-(3,4 ,5-trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride; 2-carboxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxy) Phenyl)-different Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride; 3-carboxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxy) Phenyl)-different Zin-4-yl]-phenylamine-mercapto}-propyl-ammonium chloride; 3-amine-methylmethyl-1-(2-methoxy-5-[5-(3,4,5-) Trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-mercapto}-propyl-ammonium chloride; 2-amine-mercapto-1-{2-methoxy-5-[5-(3,4,5- Trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride; and 2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[5-( 3,4,5-trimethoxyphenyl)-iso Zin-4-yl]-phenylamine-methylamino}-ethyl-ammonium chloride.

The use of pyridazinone PARP inhibitors is described in U.S. Patent No. 8,268,827 to Branca et al. Pyridazinone PARP inhibitors include, but are not limited to, 6-{4-fluoro-3-[(3-o-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5- Dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate; 6-{3-[(4-cyclohexyl-3-oxopiperazine-1-yl) )carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate; 6-{3-[( 4-cyclopentyl-3-yloxypiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one; 6-{4 -fluoro-3-[(3-o-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one hydrochloride 4-ethyl-6-{4-fluoro-3-[(3-o-oxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}pyridazine-3(2H)-one Fluoroacetate; 6-{3-[(4-cyclohexyl-3-p-oxypiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-ethylpyridazine-3 (2H) -ketotrifluoroacetate; 3-{4-fluoro-3-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl- 6-Sideoxy-1,6-dihydropyridazine-1-indole trifluoroacetate; 3-(4-fluoro-3-{[4-(4-fluorobenzyl)-3-oxooxy Piperazin-1-yl]carbonyl}benzyl)-4,5-dimethyl-6-oxirane-1,6-dihydropyridazine-1-indole trifluoroacetate; 6-(3- {[4-(2-Chlorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2 , 3-dihydropyridazine-1-indole trifluoroacetate; 6-(3-{[4-(3-chloro-4-fluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl 3-Benzyloxy-2,3-dihydropyridazine-1-indole trifluoroacetate; with 6-(3-{[4-(3,4-difluorophenyl)-3-oxooxy Piperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate. Other PARP inhibitors are described in U.S. Patent No. 8,143,447 to Moore et al.; these compounds include nitrobenzamide derivatives.

The use of Aurora protein kinase inhibitors is described in U.S. Patent No. 8,268,811 to Mortimore et al. 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 to Binch et al.; such Aurora protein kinase inhibitors include, but are not limited to, aminopyridines.

The use of a peptide that binds to a prostate specific membrane antigen (PSMA) is described in U.S. Patent No. 8,258,256 to Denmeade et al.

The use of the CD19 binding agent is described in U.S. Patent No. 8,242,252 issued to McDonagh et al. Such CD19 binding agents include, but are not limited to, anti-CD19 antibodies.

The use of benzodiazepines is described in U.S. Patent No. 8,242,109 issued to Glick.

The use of a Toll Receptor (TLR) agonist is described in U.S. Patent No. 8,242,106 to Howbert et al. Suitable TLR agonists include, but are not limited to, (1E,4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidin-1-carbonyl)phenyl)-3H-benzene And [b] azaindole-4-carboxyguanamine.

The use of bridged bicyclic sulfonamides is described in U.S. Patent No. 8,242,103 to Lewis et al.

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

The use of a T2 family ribonuclease having actin-binding activity is described in U.S. Patent No. 8,236,543, issued to thes. Typically, the ribonuclease binds to actin in its active or inactive ribonucleolytic cleavage form.

The use of myrsinoic acid A or its analogs is described in U.S. Patent No. 8,232,318 to Lee et al.

The use of inhibitors of cyclin-dependent kinases is described in U.S. Patent No. 8,227,605, issued to Shipps et al., which includes, but is not limited to, 2-aminothiazole-4-carboxamide. The use of inhibitors of cyclin-dependent kinases is also described in U.S. Patent No. 7,700,773 to Mallams et al.; such inhibitors include, but are not limited to, pyrazolo[1,5-a]pyridine, pyrazole [1,5-c]pyrimidine, 4-cyano, 4-amino, 4-aminomethyl derivative with 2H-carbazole compound, and imidazo[1,2-a]pyridine and imidazole [1,5-a] 5-cyano, 5-amino, and 5-aminomethyl derivatives of pyrazine compounds.

The use of an inhibitor of the interaction between p53 and MDM2 is described in U.S. Patent No. 8,222,288 issued toWang et al.

The use of the inhibitor of the receptor tyrosine kinase MET is described in U.S. Patent No. 8,222,269 to Dinsmore et al. Inhibitors of such receptors tyrosine kinase 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 to Jewell et al. Such compounds include, but are not limited to, benzocycloheptapyridines, including 5H-benzo[4,5]cyclohepta[1,2-b]pyridine derivatives.

The use of largazole or ergonomics is described in U.S. Patent No. 8,217,076 to Williams et al.

The use of inhibitors of the protein kinase AKT is described in U.S. Patent No. 8,207,169 to Furuyama et al.; such inhibitors include, but are not limited to, triazolopyridinopyridines, including substituted [1, 2, 4 Triazolo[4 ' ,3 ' :1,6]pyrido[2,3-b]pyrazine.

2 '- fluoro-5-methyl - β -L- arabinofuranosyl L- deoxy-thymidine or uridine group of instructions issued to Cheng in US Pat. No. Docket No. 8,207,143.

The use of a compound which modulates the activity of HSP90 is described in U.S. Patent No. 8,188,075, to the name of the disclosure. Such compounds include, but are not limited to, substituted triazoles, including 3-(2-hydroxyphenyl)-4-(naphthalen-1-yl)-5-hydrothiotriazole; 3-(2,4 -dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-hydrothiotriazole; 3-(2,4-dihydroxyphenyl) 4-(2-methyl-4-bromophenyl)-5-hydrothiotriazole; 3-(3,4-dihydroxyphenyl)-4-(6-methoxy-naphthalene-1- 5-)hydrothiotriazole; 3-(3,4-dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-hydrothiotriazole; 3- (3,4-dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-hydrothiotriazole; 3-(2,4-dihydroxy-5-ethyl- Phenyl)-4-(5-methoxy -naphthalen-1-yl)-5-hydrothiotriazole; 3-(3,4-dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-1-yl)-5-hydrogen Thiotriazole; 3-(2,4-dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-hydrothiotriazole; 3-(2,4-dihydroxybenzene 4-(2-methyl-6-ethylphenyl)-5-hydrothiotriazole; 3-(2,4-dihydroxyphenyl)-4-(2,6-diisopropyl Phenyl)-5-hydrothiotriazole; 3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-hydrothiotriazole; And 3-(2,4-dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-5-hydrothiotriazole .

The use of an inhibitor of JAK kinase or PDK kinase is described in U.S. Patent No. 8,183,245 to Guerin et al. JAK kinases include JAK1, JAK2, JAK3, and TYK2. Suitable inhibitors of such 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-yl]-1H-pyrrolo[2,3-b]pyridine; 3-[6-(cyclohexyloxy)pyrazin-2-yl]-5-(1-methyl-1H-pyrazole- 4-yl)-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]pyrazine-2- }--5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; and 3-{6-[(3S)-piperidin-3-yloxy]pyrene Pyrazin-2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine.

The use of an inhibitor of phosphodiesterase type IV (PDE4) is described in U.S. Patent No. 8,158,672, issued to Muller et al. Inhibitors of PDE4 include 1,3-dihydroisodecyl compounds substituted with fluoroalkoxy groups.

The use of the inhibitor of the c-Met proto-oncogene receptor tyrosine kinase is described in U.S. Patent No. 8,143,251, issued toJ. Such inhibitors include, but are not limited to, triazolotriazines, including [1,2,4]triazolo[4,3-b][1,2,4]triazines. Inhibitors of the c-Met proto-oncogene receptor tyrosine kinase are also described in U.S. Patent No. 8,106,197 issued to Cui et al.; these inhibitors include amine-based heteroaryl compounds.

The use of an inhibitor of indoleamine 2,3-dioxygenase is described in U.S. Patent No. 8,088,803, to the name of U.S. Patent No. 8,088, 803, including but not limited to 1,2,5- Diazole derivatives.

U.S. Patent No. 8,088,749 to Simeone et al., which is incorporated herein by reference. Such preparations include oligonucleotides that function through interfering RNA.

U.S. Patent No. 8,084,471 to Hamilton et al., which is incorporated herein by reference. Such inhibitors include, but are not limited to, 2,3 ' ,3 " -trisubstituted terphenyls.

The use of antagonists of the XIAP family of proteins is described in U.S. Patent No. 7,910,621, issued to Chen et al. Such antagonists include, but are not limited to, embelin.

U.S. Patent No. 7,763,253 to Hedlund et al.

The use of an inhibitor of Pim kinase is described in U.S. Patent No. 7,750,007 to Bearss et al. Such inhibitors include but are not limited to And imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine compound.

The use of inhibitors of CHK1 or CHK2 kinase is described in U.S. Patent No. 7,732,436 to Tepe. Such inhibitors include, but are not limited to, indenazozolines and their acid amine salts.

The use of an inhibitor of the angiopoietin 4 protein is described in U.S. Patent No. 7,740,846 to Gerber et al. Such inhibitors include, but are not limited to, antibodies, including monoclonal antibodies.

The use of Smo inhibitors is described in U.S. Patent No. 7,691,997 issued to Balkov et al. Smo or Smoothened is a dielectric conductor for the signal of the hedgehog protein transduction. 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- Diazole; 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- Diazole; 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- Diazole; 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- 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- Diazole; with 2-(1-fluoro-1-methylethyl)-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- Diazole.

The use of a nicotinic acetylcholine receptor antagonist is disclosed in U.S. Patent No. 7,652,038 to Cooke et al. Nicotinic acetylcholine receptor antagonists include, but are not limited to, mecamylamine, hexamethonium, dihydro- beta -erythroidine, d-tuberculosis ( Tubocurarine), pempidine, chlorisondamine, erysodine, trimethaphan camsylate, pentolinium, and silver snake venom protein Bungarotoxin), succinylcholine, tetraethylammonium, trimethaphan, chlorisondamine, and trimethidinium.

The use of a farnesyl protein invertase inhibitor is described in U.S. Patent No. 7,557,107 issued to Zhu et al. Such farnesyl protein convertase inhibitors include tricyclic compounds.

The use of adenosine A3 receptor antagonists is described in U.S. Patent No. 6,326,390 to Leung et al. Such adenosine A3 receptor antagonists include tricyclic non-xanthine antagonists and triazoloquinazolines.

Other pharmaceutical combinations may include a formulation such as the alkylated hexitol derivative described above and at least one glioma cancer stem cell grown or replicated. Such agents include, but are not limited to, tailless gene expression or an inhibitor of tailless gene activity, as described in U.S. Patent No. 8,992,923 to Liu et al.; inhibition of HDAC1, HDAC7, or phosphorylated HDAC7; For example, U.S. Patent No. 8,912,156 to Ince et al.; Stat3 inhibitors, such as naphthalene derivatives, as described in U.S. Patent No. 8,877,803, issued to Jiang et al.; Combination of a γ -secretase inhibitor, as described in U.S. Patent No. 8,853,274, issued to Wang; an inhibitor of an electron transport chain or a mitochondrial Krebs cycle, as described in the grant of Clement et al. U.S. Patent No. 8,815,844; Jak2/STAT3 pathway inhibitors, such as caffeic acid derivatives, such as U.S. Patent Application Publication No. 2015/0094343, to Priebe et al.; inhibitors of the glycine cleavage pathway, such as U.S. Patent Application Publication No. 2015/0011611, to Kim et al., and to glycosylated ether lipids, as described in U.S. Patent Application Publication No. 2015/0011486.

Y-box binding protein-1 (YB-1) is a nucleic acid binding protein encoded by the gene YBX1 . It was originally identified as a factor that binds to the Y-box of the class II MHC ( HLA-DRA ) promoter (inverted CCAAT (SEQ ID NO: 1) cassette) and suppresses transcription. It was later discovered that YB-1 is a multifunctional protein with many functions, including regulation of transcription and translation of several genes and proteins involved in tumor progression, cell survival, DNA replication and repair, drug resistance, and epithelial-mesenchymal transition.

YB-1 is a member of a highly retained family of nucleic acid binding polypeptides, termed the Y-box family of proteins. It has been described as a 42-50 kDa protein. Each member of the Y-box family of proteins contains a cold shock domain that has been identified as a 66 amino acid domain, which is a DNA-binding domain and is highly retained. YB-1 has been described as a transcription factor for many genes involved in cell death, growth, and survival of tumor cells, including the epidermal growth factor receptor (EGFR) gene, proliferating cell nuclear antigen (PCNA)/cyclin gene, and multiple antibodies. Multidrug resistant pump (mdr1) gene and CD-95. In addition, it has been shown to stimulate the transcription of long terminal repeats (LTRs) of human T-lymphocytic virus-1 (HTLV-1) and human immunodeficiency virus-1 (HIV-1) (US Patent Application Publication No. Watson et al. Case No. 2007/0004666). The Y-box is a promoter of many genes, such as DNA topoisomerase II α (Topo II α ), proliferating cell nuclear antigen (PCNA) and multidrug resistance 1 (MDR1). It has been reported that YB-1 (NSEP1/DBPB) is involved in the regulation of transcription and translation of gene expression, causing its effects to affect cell proliferation, genomic instability, multidrug resistance, RNA stabilization, and DNA repair. The expression of class II HLA genes is regulated by a series of cis-acting elements and trans-acting factors. The cis-acting element includes the Y-box, and studies have shown that YB-1 is a negative regulator of HLA-DR β- chain mRNA expression. The expression of class II HLA genes is regulated by a series of cis-acting elements and trans-acting factors. The cis-acting element includes the Y-box, and studies have shown that YB-1 is a negative regulator of HLA-DR β- chain mRNA expression. YB-1 has no particular effect on stable mRNA. YB-1 has been shown to be the major mRNA-binding protein, also known as p50, which is a potent mRNA stabilizer that is dependent on the capping structure (cap). Increase or excessive expression of YB-1 will significantly increase mRNA stability in vitro and in vivo, while elimination of YB-1 will accelerate mRNA decline. The cold shock domain of YB-1 is responsible for mRNA stabilizing activity, and YB-1 mediated stabilization requires blocking of the 5 ' end of the mRNA. YB-1 has been found to be required for stabilization of JNK-induced IL-2 mRNA by T-cell activation signals, which is particularly noteworthy because the DLBCL subpopulation with an activated phenotype has been associated with poor prognosis. YB-1 has also been identified as a protein that interacts with TGF- β response elements in the distal region of the collagen α 1 (I) gene. The YB-1 protein activates the collagen promoter and is translocated into the nucleus during the addition of TGF- β to the fibroblast, indicating that the role of this protein involves TGF- beta signal transduction. The YB-1 line is overexpressed in cell lines that are resistant to the cancer therapeutic drug cisplatin. Subsequent presentation of YB-1 binding to PCNA in vivo indicates that YB-1 may function as a protein that recognizes DNA damaged by cisplatin, which may be important for DNA repair or for responding to response of cells to DNA damage. YB-1 also binds directly to p53 tumor suppressor proteins (U.S. Patent Application Publication No. 2005/0158737 to Banham et al.). In contrast to normal mucosa, YB-1 is overexpressed in almost all cases of colorectal cancer (Pressman et al., U.S. Patent Application Publication No. 2003/0190602). Reducing the YB-1 expression, i.e., increasing the p53 tumor suppressor protein content, can then cause apoptosis of tumor cells (U.S. Patent Application Publication No. 2003/0074684 to Graham et al.). Therefore, when YB-1 is excessively expressed, apoptosis of a malignant cell induced by a preparation such as an antitumor drug can be reduced (U.S. Patent Application Publication No. 2002/0151063 to Latham et al.).

Many immunohistochemical studies have shown that the YB-1 protein content in malignant tissue is higher than in normal non-malignant tissues. In many malignant diseases, including breast cancer, lung cancer, colorectal cancer, prostate cancer, and ovarian cancer, the higher the YB-1 content, the higher the malignant grade of the tumor and the worse the prognosis of the patient. This indicates that YB-1 has a role as a proto-oncogene. It has been shown that when YB-1 is clamped by transfecting cells with an oligonucleotide comprising a YB-1 binding site, apoptosis of many tumor cells can be induced in vitro, indicating that YB-1 activity may be Play an important role in the survival of malignant cells.

The interaction of YB-1, which may have tumor growth, survival, or metastasis, is the interaction of epidermal growth factor receptor (EGFR) with human epidermal growth factor receptor-2 (HER-2). Specifically, it directly binds to its promoter to induce the expression of the human epidermal growth factor receptor ( her-2 ) gene and its dimerization target egfr gene. Increased performance of the gene encoding YB-1 has been shown to be associated with resistance to EGFR inhibitors (US Patent No. 8,148,076 to Baker et al.). An increase in the performance of the gene encoding YB-1 is also shown to be related to the resistance to doxorubicin (U.S. Patent No. 8,071,286 to Baker et al.). The promoter of the gene encoding the multidrug resistance protein MDR also binds to YB-1 (US Patent No. 7,105,656 to Colgan). The MDR1 gene is known to be a gene encoding a 170-kDa transmembrane protein P-gp located on the cytoplasmic surface of a cell, and its nucleotide sequence is also known. P-gp consists of two transmembrane domains and two nucleotide binding domains. Among the various molecular targets, P-gp expression is responsible for the resistance of cells to many anticancer drugs. When P-gp is overexpressed, it plays an important role in the resistance of various cancer cells. Enhancement of MDR1 gene expression in malignant cancer cells has produced a variety of different mechanisms, including nuclear translocation of YB-1, promoter recombination, and alteration of the methylation status of CpG sites on the MDR1 promoter (US Patent of Wada et al.) Application for the public case number 2006/0216738).

YB-1 is also over-expressed in a large proportion of brain tumors affecting adults and children, among which it is related to anti-tumor agents (such as Dimension). It has been shown that YB-1 is involved in the overexpression of the membrane-bound transport protein P-glycoprotein, which is a transporter of the ABC class. The nuclear localization of YB-1 directly affects the performance of P-glycoprotein. YB-1 can utilize a variety of different stresses Conditions (such as UV irradiation, administration of cytostatics, and heat therapy) are transported into the nucleus. It is also known that the nuclear localization of YB-1 affects other ABC transporters. This ABC transporter is referred to as MRP (Multiple Drug Resistance Related Protein) and is involved in the formation of a so-called atypical non-P-glycoprotein dependent multidrug resistance (U.S. Patent No. 8,951,772 to Holm).

Phosphosic acid/threonine kinase Akt phosphorylation has also been shown, and thus activates Ser ¹⁰² of YB-1, thereby inhibiting this phosphorylation reaction, i.e., inhibiting nuclear transport. In addition, the kinase p90 ribosomal S6 kinase RSK is the major kinase for phosphorylation of YB-1 at Ser ¹⁰² , and Akt and kinase pKCα also cause phosphorylation, but to a lesser extent (JHLaw et al., "Molecular Decoy to the Y- Box Binding Protein-1 Suppresses the Growth of Breast and Prostate Cancer Cells Staff Sparing Normal Cell Viability, "PLoS One 5: e12661 (2010)). Thus, as detailed below, the inhibitor of Akt can be used to reduce the activity of YB-1.

In particular, YB-1 appears to promote tumor growth by regulating the expression of E2Fas and E2F target genes. siRNA can be used to interfere with RNA to inhibit the expression of YB-1; the two siRNA molecules that can be used are 5'-GGUCCUCCACGCAAUUACCAGCAAA-3' (SEQ ID NO: 2) and 5'-GGUCCUCCACGCAAUUACCAGCAAA-3' (SEQ ID NO: 3) (A. Lasham et al., "YB-1, the E2F Pathway, and Regulation of Tumor Cell Growth," J. Natl. Cancer Inst. 104: 133-146 (2012)). Similarly, it has been shown in breast cancer cells overexpressing HER-2 in mice that targeting YB-1 using siRNAs SEQ ID NO: 2 and SEQ ID NO: 3 induces apoptosis via the mTOR/STAT3 pathway, and Decreased tumor cell growth (C. Lee et al., "Targeting YB-1 in HER-2 Overexpressing Breast Cancer Cells Induces Apoptosis via the mTOR/STAT3 Pathway and Suppresses Tumor Growth in Mice," Cancer Res. 68: 8661-8668 (2008) )). When reference is made herein to siRNA or other oligonucleotides or polynucleotides, the terms are generally referred to as nucleotides and/or polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). , an oligonucleotide, a fragment produced by polymerase chain reaction (PCR), and a fragment produced by any one of adhesion, cleavage, endonuclease action, and exonuclease action. A nucleic acid molecule can be composed of a monomer of a natural nucleotide (such as DNA and RNA), or an analog of a natural nucleotide (such as an enantiomeric form of a natural nucleotide), or a combination of both. The modified nucleotide may have a change in a sugar moiety group and/or a pyrimidine or purine base moiety. Sugar modification methods include, for example, the use of a halogen, an alkyl group, an amine, one or more hydroxyl groups with an azide group, or a sugar that can be functionalized as an ether or ester. In addition, the entire sugar moiety can be replaced by similar stereostructures and electronic structures, such as aza-saccharides and carbocyclic sugar analogs. Examples of modifications of the base moiety include alkylated purines and pyrimidines, mercaptophosphonium or pyrimidines, or other conventional heterocyclic substitution methods. Nucleic acid monomers can be linked using phosphodiester bonds or analogs of such linkers. Nucleic acids may be single or double stranded unless otherwise stated as single or double strands. Nucleic acids can include DNA-RNA hybrids unless specifically stated otherwise. When siRNA is employed, the siRNA can be modified by methods known in the art to increase its stability or reduce its sensitivity to nuclease hydrolysis activity.

YB-1 may also play other roles in tumor survival, growth, and metastasis. For example, YB-1 can be used for malignant diseases (such as polymorphic gummy mothers). Cell tumors) regulate uncoded RNA expression, such as miRNAs. In particular, YB-1 preferentially recognizes the UYAUC consensus motif and binds to most of the coding gene transcripts, including pre-mRNA and mature mRNA. YB-1 also actively binds to the terminal loop region of the primary (pri)-/precursor (pre)-miR-29b-2 and regulates miR-29b- by blocking the addition of a microprocessor and Dicer to its precursor. 2 birth synthesis. Down-regulation of miR-29b by YB-1, which is up-regulated in GBM, is important for cell proliferation (SLWu et al., "Genome-Wide Analysis of YB-1-RNA Interactions Reveals a Novel Role of YB-1 in miRNA Processing In Glioblastoma Multiforme," Nucleic Acids Res. 43:8516-8528 (2015)).

The inhibitor of Akt disclosed in US Patent No. 8,546,441 to Chen includes a compound of the formula (YI). Wherein: (1) X is selected from the group consisting of an alkyl group and a haloalkyl group; (2) Ar is an aryl group selected from the group consisting of phenyl, biphenyl, naphthyl, anthracene (3)Ar may be substituted by one or more groups selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ Haloalkyl, azido, C ₁ -C ₄ azidoalkyl, aryl, alkylaryl, haloaryl, haloalkylaryl, in combination therewith; and (4) R is selected from the group consisting of Groups of substances: nitrile, acetonitrile, ethyl nitrile, propyl nitrile, carboxamide, hydrazine, tetrazole, hydrazine, hydrazine, acetamidine, aminoacetamide, hydrazine, and urea.

U.S. Patent No. 8,319,899 to the name of U.S. Pat. In an alternative, the fusion construct comprises a peptide first domain comprising or consisting of 12, 13, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27 or 28 The L- or D-amino acid sequence of the residue comprising a peptide selected from the group consisting of KFAKFAKKFAKFAKK, KFAKFAKKFAKFAKKF, KFAKFAKKFAKFAKKFA, KFAKFAKKFAKFAKKFAK, KFAKFAKKFAKFAKKFAKF, KFAKFAKKFAKFAKKFAKFA and KFAKFAKKFAKFAKKFAKFAKKFAKFAK (SEQ ID NO. 4, 5, 6, 7, 8, 9) And 10) having one or more K residues substituted with a F or L residue, one or more F residues substituted with a K, A or L residue, or one or more A residues via K, Substitution of F or L residues. In another specific embodiment, the fusion construct comprises a peptide first domain consisting of an L- or D-amino acid sequence selected from the group consisting of KFAKFAKKFAKFAKK, KFAKFAKKFAKFAKKF, KFAKFAKKFAKFAKKFA, KFAKFAKKFAKFAKKFAK, KFAKFAKKFAKFAKKFAKF, KFAKFAKKFAKFAKKFAKFA and KFAKFAKKFAKFAKKFAKFAKKFAKFAK (SEQ ID NO. 4, 5, 6, 7, 8, 9, and 10) having one or more K residues substituted with F or L residues, one or more F residues via K, A or The L residue is substituted, or the one or more A residues are substituted with a K, F or L residue; and the second functional domain of the peptide, which comprises or consists of a binding moiety. In another specific embodiment, the fusion construct comprises or consists of a peptide first domain, It consists of an L- or D-amino acid sequence selected from the group consisting of KFAKFAKKFAKFAKK, KFAKFAKKFAKFAKKF, KFAKFAKKFAKFAKKFA, KFAKFAKKFAKFAKKFAK, KFAKFAKKFAKFAKKFAKF, KFAKFAKKFAKFAKKFAKFA and KFAKFAKKFAKFAKKFAKFAKKFAKFAK (SEQ ID NO. 4, 5, 6, 7, 8, 9, and 10) , having one or more K residues substituted with any F or L residue, one or more F residues substituted with any K, A or L residue, or one or more A residues via any K, F Or a L residue substitution; and a second functional domain of the peptide consisting of 1-25 L- or D-amino acid sequences (eg, binding moiety) different from the first functional domain.

U.S. Patent No. 8,163,507 to Mertens discloses the specific binding of antibodies to YB-1. Typically, the antibody is a monoclonal antibody. Typically, the antibody is a chimeric or humanized antibody.

US Patent Nos issued to Bennett et al 6,140,126 discloses the use of YB-1 targeting the 5 '-UTR of an antisense compound that hybridizes specific protein YB-1 expression and inhibition of protein YB-1. Typically, such antisense compounds are from 8 to 30 bases in length. The antisense compound may comprise a linker between at least one modified nucleoside, such as a phosphorothioate, a palmitic phosphorothioate, a dithiophosphate, a phosphate triester, an aminoalkyl phosphate triester. , methyl and other alkylphosphonates (including 3 ' -alkylene phosphonates and palmitic phosphonates), phosphonites, amino phosphates (including 3 ' -amino amino phosphates) And an aminoalkylamino phosphate, a thioketo amino phosphate, a thioketoalkylphosphonate, a thioketoalkyl phosphate, and a boron with a normal 3 ' -5 ' linker Phosphate esters, such 2 ' -5 ' linked analogs, and those of opposite polarity, wherein adjacent pairs of nucleoside units are linked to 3 ' -5 ' and 5 ' -3 ' or 2 ' -5 ' And 5 ' -2 ' ; these may be in the form of a salt, a mixed salt, or a free acid; or, the antisense compound may be in the form of a peptide nucleic acid. The antisense compound may comprise at least one modified sugar moiety such as a 2 ' -O-methoxyethyl sugar moiety or a 2 ' -dimethylaminooxyethoxy sugar moiety or 2 '- dimethylamino ethoxyethoxy sugar moiety. The antisense compound may comprise at least one modified nucleobase such as 5-methylcytosine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, adenine and guanine 6-methyl and other alkyl derivatives, adenine and guanine 2-propyl and other alkyl derivatives, 2-thiouracil, 2-thiothymidine and 2-thiocytosine, 5-halogen Pyrimidine and cytosine, 5-propynyl uracil and cytosine, 6-azauracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-Amino, 8-thiol, 8-sulfanyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (specifically 5-bromine), 5-trifluoromethyl And other 5-substituted uracil and cytosine, 7-methylguanine and 7-methyl adenine, 8-azaguanine and 8-azadenine, 7-deazaguanine 7-Deazadenine and 3-deazaguanine and 3-deazadenine. In another alternative, the oligonucleotide may be covalently linked to one or more portions or conjugates that enhance oligonucleotide activity, cellular distribution, or cellular uptake; such partial groups may be lipid moieties a group such as cholesterol, cholic acid, thioether (such as hexyl-S-trithiol), thiocholesterol, a fatty chain (such as a chain comprising a dodecanediol or undecane residue) , phospholipids, polyamines, polyethylene glycol chains, adamantane acetic acid, palmitoyl moiety, octyldecylamine moiety, or hexylamino-carbonyl-cholesterol moiety.

U.S. Patent Application Publication No. 2014/0088178 to Gleave et al. discloses the promoter of YB-1 binding clusterin to enhance cluster protein performance after endoplasmic reticulum (ER) stress response. Therefore, it is possible to block this expression using an anti-clustered antisense oligonucleotide such as custirsen.

U.S. Patent Application Publication No. 2013/0059292 to Kim et al. discloses that the Akt is associated with inactive mRNA and that activated Akt deactivates translational inhibition of YB-1 binding to mRNA. Therefore, Akt inhibitors may be suitable for the treatment of malignant diseases associated with excessive activity of YB-1. Inhibitors of Akt have been disclosed above; other Akt inhibitors are also described below.

U.S. Patent Application Publication No. 2012/0213801 to Gresko et al. discloses the interaction of YB-1 with Twist1, which utilizes Twist1 as a transcription factor to activate YB-1. Twist1 is activated by the phosphoric acid at Ser ⁴² . Therefore, inhibition of phosphorylation of Ser ⁴² by Twist1 is suitable for the treatment of malignant diseases associated with excessive activity of YB-1. The preparation for inhibiting phosphorylation of Ser ⁴² of Twist1 may be an anti-Twist1 antibody or a small molecule such as a peptide comprising an amino acid corresponding to Ser ⁴² which is phosphorylated by kinase PKB.

U.S. Patent Application Publication No. 2010/0029003 to Bartel et al. discloses the targeting of miRNAs to inhibit the performance of YB-1. In particular, the expression of YB-1 can be inhibited by targeting miR-216 (UAAUCUCGCUGGCAACUGUG (SEQ ID NO: 11).

Akt (protein kinase B; PKB) is a serine-threonine A kinase that occupies a central location in one of the major cellular signal transduction pathways (PI3K/Akt pathway). Akt is particularly involved in the growth, proliferation, and survival of tumor cells. Akt is activated in two steps: (1) phosphorylation of sulphonic acid 308 (P-T308) by PDK1, and (2) phosphorylation of serine 473 by mTORC2 (or mTOR-Rictor complex) (P-S473) ), resulting in complete activation. Akt in turn regulates a wide variety of proteins, including mTOR (mammalian target of rapamycin), BAD, GSK3, p21, p27, FOXO or FKHRL1. The activation of Akt promotes nutrient internalization, thereby initiating the assimilation metabolic process, which supports cell growth and proliferation. In particular, Akt controls the initiation of protein synthesis through a series of interactions, which use TSC1/2 (nodular sclerosis complex), Rheb, and TOR, thus creating two important targets for signal transduction pathways: p70S6K and 4EBP. Akt also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK313, which results in inhibition of apoptosis and cell cycle progression. Therefore, Akt becomes the target of anticancer therapy, and inhibition of Akt phosphorylation can inhibit its activation, and can induce apoptosis of malignant cells, thereby providing cancer treatment.

Akt inhibitors are described in the following patents and published patent applications: (1) U.S. Patent No. 9,156,853 (issued to Harrison et al.) (Substituted pyrimidinones, including 6-(4-((1s, 3s)-1-Amino-3-hydroxy-3-methylcyclobutyl)phenyl)-5-phenyl-3-(2,2,2-trifluoroethyl)furo[2,3- d]pyrimidin-4(3H)-one; 6-(4-((1r,3r)-1-amino-3-hydroxycyclobutyl)phenyl)-5-phenyl-3-(2,2 ,2-trifluoroethyl)furo[2,3,4-pyrimidin-4(3H)-one; 6-(4-((1s,3s)-1-amino-3-hydroxycyclobutyl) Phenyl)-5-phenyl-3-(2,2,2-trifluoroethyl)furo[2,3-d]pyrimidin-4(3H)-one; 6-(4-((1r, 3r)-1-Amino-3-hydroxy-3-methylcyclobutyl)phenyl)-5-phenyl-3-(2,2,2-trifluoroethyl)furo[2,3- d]pyrimidin-4(3H)-one; 6-(4-((1r,3r)-1-amino-3-hydroxy-3-methylcyclobutyl)phenyl)-5-phenyl-3 -(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one; 6-(4-((1r,3r)-1-amino-3- Hydroxy-3-methylcyclobutyl)phenyl)-7-methyl-5-phenyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d] Pyrimidine-4(7H)-one; 6-(4-((1s,3s)-1-amino-3-hydroxycyclobutyl)phenyl)-7-methyl-5-phenyl-3-( 2,2,2-trifluoroethyl)-3H-pyrrole [2,3-d]pyrimidine-4(7H)-one); (2) U.S. Patent No. 9,150,549 (issued to Nannini et al.) (ipatasertib); (3) US Patent Case No. 8,895,571 (issued to Huang et al.) (Isoindolinone and pyrrolopyridone derivatives, including 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]- 5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl ]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluoro Benzyl)ethyl]-5-(4-methyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino 1-(3-fluorobenzyl)ethyl]-5-(4-methoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; -[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-ethoxymethyl-1-methyl-1H-pyrazole-5-yl) Isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(2-propoxymethyl)- 1-methyl-1H-pyrazol-5-yl]isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5 -[4-(1-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one; 2-[(1S)-2-amino-1 -(3-fluorobenzyl)ethyl]- 5-(4-cyclobutoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-( 3-fluorobenzyl)ethyl]-5-(4-cyclopropylmethoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2- [(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[(methylthio)methyl-1-methyl-1H-pyrazol-5-yl] Isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-fluoro-1-methyl-1H-pyridyl Isoazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-bromo-1- Methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-( 4-cyano-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one; 2-[(1S)-2-amino-1-(3-fluorobenzyl) Ethyl]-5-(4-phenyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one); (4) 8,895,566 (Banka et al) (5) H - cyclopenta[d]pyrimidines, including (5R,7R)-4-(4-((S)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl) Piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (5R,7R)-4-(4-((R) -(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-ol; N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-A -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide; N-((S)-1-amino-3-(2,4- Dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl Thiophene-2-carboxamide; (5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-7-ol; N-((R)-2-(4-chlorophenyl)-2-(6((R)-5-methyl-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine; (R)-N-(2-(4- Chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine; (5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridyl Oxazide-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopentyl [d]pyrimidin-7-ol; (5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)-5,6-dihydro -[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine -7-alcohol); (5) U.S. Patent No. 8,853,216 (issued to Bencsik et al.) (hydroxylated pyrimidinylcyclopentane); (6) U.S. Patent No. 8,853,199 (issued to Mitchell et al.) And methoxylated pyrimidinylcyclopentane); (7) U.S. Patent No. 8,846,683 (issued to Bencsik et al.) (pyrimidinylcyclopentane); (8) U.S. Patent No. 8,846,681 (issued to Mitchell (i) (pyrimidinylcyclopentane); (9) U.S. Patent No. 8,835,450 (issued to Dumble et al.) (N-{(1S)-2-amino-1-[(3,4-difluoro) Phenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide; (10) US Patent Case No. 8,835,434 (issued to Bencsik et al.) (hydroxylated pyrimidinylcyclopentane); (11) U.S. Patent No. 8,828,451 (issued to Sebti et al.) (triciribine and trifluralin phosphate) Salt); (12) U.S. Patent No. 8,822,524 (issued to Sebti et al.) (non-peptide inhibitors that target binding sites for binding sites); Case No. 8,799,255 (available to Carry et al.) ((6-Phenoxy-1,6-dihydropyrimidin-2-yl)guanamine derivatives, including 2-[4-(morpholin-4-yl) -6-o-oxy-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide; N-(4-fluorophenyl)-2-[4-(morpholin-4-yl) 6-o-oxy-1,6-dihydropyrimidin-2-yl]acetamidamine; N-(3-chlorophenyl)-2-[4-(morpholin-4-yl)-6- Sideoxy-1,6-dihydropyrimidin-2-yl]acetamidamine; N-[3-(dimethylamino)phenyl]-2-[4-(morpholin-4-yl)- 6-Sideoxy-1,6-dihydropyrimidin-2-yl]acetamide; N-(2,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6 - pendant oxy-1,6-dihydropyrimidin-2-yl]acetamidamine; N-(3,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6- Sideoxy-1,6-dihydropyrimidin-2-yl]acetamidamine; 2-[4-(morpholin-4-yl)-6-oxooxy-1,6-dihydropyrimidin-2- [-]-N-(thiophen-3-yl)acetamide; N-(4-fluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-side oxygen -1,6-dihydropyrimidin-2-yl]acetamidamine; N-(2-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-oxyl-1, 6-dihydropyrimidin-2-yl]acetamide; N-(2-methylphenyl)-2-[4-(morpholin-4-yl)-6-o-oxy-1,6-di Hydropyrimidin-2-yl]acetamide; N-(2-methoxyphenyl)-2-[4-(morpholin-4- (6)-oxyl-1,6-dihydropyrimidin-2-yl]acetamidamine); (14) 8,691,825 (Chen et al.) (Substituted fused pyrimidine compounds, including 1-[ 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutylamine; 1-[4-(3,6-diphenylimidazo[1,2-a Pyrimidin-7-yl)phenyl]cyclobutylamine; 3-amino-3-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl] -1-methylcyclobutanol; 3-amino-1-methyl-3-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidine-7- Phenyl]cyclobutanol; 1-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutylamine; -[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]methanamine; 3-amino-1-cyclopropyl-3-[4-( 6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutanol; 1-[4-(6-phenyl-imidazo[1,2-a]pyrimidine -7-yl)-phenyl]-cyclobutylamine; 1-[4-(3-bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]- Cyclobutylamine; 1-[4-(6-phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine; 1-{4 -[3-(2-methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine; 7-[4- (1-amino-cyclobutyl)- Phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carbonitrile; 7-[4-(1-amino-cyclobutyl)-phenyl]-6-phenyl- Imidazo[1,2-a]pyrimidine-3-carboxylic acid decylamine; 1-[4-(3-chloro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzene ]-cyclobutylamine; 1-[4-(3-methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine; -{4-[3-(2-Cyclopropyl-vinyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine; [4-(2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine; 1-[4-(3-bromo-2,6 -diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine); (15) U.S. Patent No. 8,618,097 (issued to Bencsik et al.) (pyrimidinyl) Cyclopentane); (16) 8,614, 221 (issued to Fan et al.) (Substituted fused naphthyridine derivatives, including trans-3-amino-1-methyl-3-[4-(2-A) -7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutanol; cis-3-amino-1-methyl -3-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutanol; trans 3-amino-1-cyclopropyl-3-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-8- Phenyl]cyclobutanol; trans-3-amino-3-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e] Pyrimidin-8-yl)phenyl]cyclobutanol; trans-3-methoxy-1-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyridin[ 3,2-e]pyrimidin-8-yl)phenyl]cyclobutylamine; {1-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3, 2-e]pyrimidin-8-yl)phenyl]-3-oxocyclocyclobutyl}aminecarboxylic acid methyl ester; 1-[4-(2-methyl-7-phenylpyrazolo[1, 5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]methanamine; 2-methyl-7-phenyl-8-[4-(1H-pyrazole-1-yl-methyl) Phenyl]pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine; (1R)-1-[4-(2-methyl-7-phenylpyrazolo[1] , 5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]ethylamine; trans-3-amino-1-ethyl-3-[4-(2-methyl- 7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutanol; cis-3-amino-1-ethyl-3 -[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutanol; trans-3 -amino-1-vinyl-3-[4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)benzene Cyclobutanol; 3-methylene-1-[4-(2-methyl-7-phenylpyrazole) [1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutylamine; 3,3-difluoro-1-[4-(2-methyl-7-benzene Pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8-yl)phenyl]cyclobutylamine; 8-{4-[trans-1-amino-3-( 1,2-dihydroxyethyl)-3-hydroxycyclobutyl]phenyl}-2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine ;8-{4-[1-Amino-3-hydroxy-3-(hydroxymethyl)cyclobutyl]phenyl}-2-methyl-7-phenylpyrazolo[1,5-a] Pyrido[3,2-e]pyrimidine); (17) U.S. Patent No. 8,536,193 (issued to Furuyama et al.) (substituted [1,2,4]triazolo[4,3-a]- 1,5-naphthyridine compound, including trans-3-amino-3-{4-[1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3 -a]-1,5-naphthyridin-7-yl]phenyl}-1-methylcyclobutanol); (18) U.S. Patent No. 8,507,483 (issued to Certal et al) (1) H a pyrimidin-2-one derivative comprising 2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one ; 2-(1,3-benzoxazol-2-ylmethyl)-6-(morpholin-4-yl)pyrimidine-4(3H)-one; 2-[(6-bromo-1H-benzene And imidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidine-4(3H)-one; 2-[(6-methoxy-1H-benzimidazol-2-yl) Methyl]-6-(morpholin-4-yl)pyrimidine-4(3H)-one; 2-[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]-6- (morpholin-4-yl)pyrimidine-4(3H)-one; 2-[(6-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4- Pyrimidine-4(3H)-one; 2-[(5-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidine-4 ( 3H)-keto); (19) U.S. Patent No. 8,481,503 (issued to Layton et al.) (8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl[1,2, 4] Triazolo[3,4-f]-1,6-naphthyridin-3(2H)-one); (20) U.S. Patent No. 8,440,630 (issued to Noguchi et al.) (polypeptide inhibitor); (21) U.S. Patent No. 8,420,690 (issued to Seefeld et al.) (Heterocyclic Carboxamide Compounds, including N-(2-Amino-1-phenylethyl)-5-(1-methyl-1H) -pyrazol-5-yl)-3-thiophenecarboxamide; N[2-amino-1-(phenylmethyl)ethyl]-5-(1-methyl-1H-pyridyl N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5- (1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N-{(1S)-2-amino-1-[(2-fluorophenyl)methyl]ethyl }-5-(1-Methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N-{(1S)-2-amino-1-[(2-chlorophenyl)- Ethyl]ethyl}-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N[1-(aminomethyl)-2-methyl-2-benzene Propyl]-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N[2-amino-1-(1-naphthyl)ethyl]-5 -(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N[2-amino-1-(phenylmethyl)ethyl]-2-(3-furanyl) -5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide; N-((1S)-2-amino-1-{[2-(trifluoromethyl) Phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-furancarboxamide; N-((1S)-2-amino-1- {[2-(Trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylate Guanidine; N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-chloro-1-methyl-5-(1 -methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide; and N-((1S)-2-amino-1-{[2-(trifluoromethyl) Phenyl]methyl}ethyl)-2-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrole-3-carboxyindole Amine); (22) U.S. Patent No. 8,410,158 (issued to Seefeld et al.) (N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl ]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide; (23) US Patent No. 8,329,709 (issued to Banka et al) People) (5 H - cyclopenta[d]pyrimidine, including (5R,7R)-4-(4-((S)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl) Piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (5R,7R)-4-(4-((R)- (4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[ d]pyrimidin-7-ol; N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide; N-((S)-1-amino-3-(2,4-di) Chlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) Thiophene-2-carboxamide; (5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-7-ol; N-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine; (R)-N-(2-(4- Chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine; (5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridyl Oxazide-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-ol; (5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)-5,6-dihydro -[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-5-methyl-6,7-dihydro-5H-1-cyclopenta[d Pyrimidine-7-ol; (4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5 ,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methylamine; (5R,7R)-4-(3-(( R)-1-amino-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7 ( 8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (5R,7R)-4-(4-(1-(4-chloro) Phenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol hydrochloride (24) U.S. Patent No. 8,329,701 (issued to Mitchell et al.) (dihydrofuranpyrimidine); (25) U.S. Patent No. 8,324,221 (issued to Banka et al.) (pyrimidinylcyclopentane, including (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro-[porphyrin-3,4 ' - piperidine]; (R)-5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[porphyrin-3, 4 ' - piperidine]; 5-chloro-1-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5-1 ' -cyclopenta[d]pyrimidin-4-yl)spiro[porphyrin-3,4 ' - piperidine]; 5-chloro-1-(5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) snail [吲Porphyrin-3,4 ' - piperidine]; (5R,7R)-4-(5-chlorospiro[porphyrin-3,4 ' - piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (5R,7S)-4-(5-chlorospiro[ Porphyrin-3,4 ' - piperidinyl]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (R)-5-cyclopropyl-1-(5 -methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[porphyrin-3,4'-piperidine]; (R)-5-chloro-1- (5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[porphyrin-3,4 ' - piperidine]-4-carbonitrile; (R)-N-(3-chlorophenyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4 -yl)spiro[porphyrin-3,4'-piperidine]-5-amine; (R)-2-(1-(5-methyl-6,7-dihydro-5H-cyclopenta[ d]pyrimidin-4-yl)spiro[porphyrin-3,4'-piperidin]-5-yl)acetamidine; (R)-5-(3-fluorobenzyl)-1-(5) -methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[porphyrin-3,4 ' - piperidine]; 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) spiro[porphyrin-3,4 ' - piperidine]-5-yloxy)-2-phenylethylamine; (R)-(1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4 -Based)[Porphyrin-3,4'-piperidine]-5-yl)methylamine); (26) U.S. Patent No. 8,288,047 (issued to Kelly, III et al.) (Substituted naphthyridine) Classes, including 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine- 3-alcohol); (27) U.S. Patent No. 8,273,782 (issued to Seefeld et al.) (heterocyclic carboxamide, including N-{(1S)-2-amino-1-[(3-fluorophenyl) Methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide); (28) US Patent No. 8,168,652 (issued to Sanderson et al.) (Substituted naphthyridines, including 2,2-dimethyl-3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-) 1,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol; 3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-1 ,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol; {1-[({4-[3-phenyl-5-(1H-pyrazol-4-yl)-) 1,6-naphthyridin-2-yl]benzyl}amino)methyl]cyclobutyl}methanol; {1-[({4-[3-phenyl-5-(1H-pyrazole-4) -yl)-1,6-naphthyridin-2-yl]benzyl}amino)methyl]cyclopentyl}methanol; {1-[({4-[3-phenyl-5-(1H-) Pyrazol-4-yl)- 1,6-naphthyridin-2-yl]benzyl}amino)methyl]cyclohexyl}methanol; 4-({4-[3-phenyl-5-(1H-pyrazol-4-yl)) -1,6-naphthyridin-2-yl]benzyl}amino)butan-1-ol; 2,2-dimethyl-N-{4-[3-phenyl-5-(1H-pyridyl) Zyridin-4-yl)-1,6-naphthyridin-2-yl]benzyl}propan-1-amine; 2-({4-[3-phenyl-5-(1H-pyrazole-4- -1,6-naphthyridin-2-yl]benzyl}amino)ethanol; [(1R,2S)-2-({4-[3-phenyl-5-(1H-pyrazole- 4-yl)-1,6-naphthyridin-2-yl]-benzyl}amino)cyclohexyl]methanol; (2S)-1-methoxy-3-({4-[3-phenyl) -5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzyl}amino)propan-2-ol); (29) U.S. Patent No. 8,063,050 Mitchell et al. (Hydroxylated and methoxylated pyrimidinylcyclopentanes, including 2-(4-chlorophenyl)-1-(4((5R,7R)-7-hydroxy-5-methyl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2 -amino-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentyl And [d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl) -1((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3- Methyl piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R) ,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-propene- 1-ketone; (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydrol) -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-( (S)-4-((S)-7-Hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propane- 1-ketone; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4((S)-7-hydroxy-6,7-dihydrol -5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (2R)-2-amino-3-(4-chloro-3) -fluorophenyl)-1-((3S)-4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) -3-methylpiperazin-1-yl)propan-1-one); (30) U.S. Patent No. 8,008,317 (issued to Armstrong et al.) (Substituted naphthyridines, including 9-phenyl-8) -(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2, 4] Triazolo[3,4-f]-1,6-naphthyridin-3-amine; 9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1) , 2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[ 1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol; 9-phenyl-8-(4-{[4-(4-pyridin-2-yl) -1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine 9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}benzene [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-thiol; 3-methyl-9-phenyl-8-(4-{[4 -(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3 , 4-f]-1,6-naphthyridine; 9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl) Piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine; 3-(chloromethyl)-9-benzene 8-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazole And [3,4-f]-1,6-naphthyridine; 3-[(4-methylpiperazin-1-yl)methyl]-9-phenyl-8-(4-{[4-( 5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4 -f]-1,6-naphthyridine; 2-({[9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazole-) 3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl]methyl}amine Ethyl alcohol; 8-(4-aminomethyl-phenyl)-9 -phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-ol; 1-[4-(9-phenyl[1,2,4] Triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methylamine; 4-(3-methyl-9-phenyl-[1,2,4]triazole And [3,4-f][1,6]naphthyridin-8-yl)-benzylamine); (31) U.S. Patent No. 8,003,651 (issued to Mitchell et al.) (pyrimidinylcyclopentane, Including 2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d Pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride; (R)-2-amino-3-(4-chlorophenyl)-1-((S)- 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one Dihydrochloride; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-A 6,6-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride; 2-(aminomethyl)-3 -(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[ d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride; (R,S)-2-(2,4-dichlorophenyl)-3-(isopropyl Amino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1 -keto dihydrochloride; (R,S)-2-(4-chloro 3-(cyclopropylmethylamino)-1-(4((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl) Piperazine-1-yl)propan-1-one dihydrochloride); (32) U.S. Patent No. 8,003,643 (issued to Bilodeau et al.) (Substituted pyridazine and pyrimidine, including 5-phenyl- 2-pyridin-2-yl-4-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl Phenyl)pyrimidine; 1-{4-[5-phenyl-2-(pyridin-3-ylamino)pyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl- 4H-1,2,4-triazol-3-yl)piperidine; 1-{4-[2-(5-amino-1,3,4-thiadiazol-2-yl)-5-benzene Pyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine; 1-methyl-4-(2 -{[5-phenyl-4-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl Phenyl)pyrimidin-2-yl]amino}ethyl)piperazine; 1-[4-(2-amino-5-phenylpyrimidin-4-yl)benzyl]-4-(5- Pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine; 1-{4-[2-(methylthio)-5-phenylpyrimidin-4-yl]benzene Methyl}-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine; 1-{4-[2-(4-ethenylpiperazine- 1-yl)-5-phenylpyrimidin-4-yl]benzyl}-4-(5-pyridin-2-yl-4H-1,2,4-triazole-3 -yl)piperidine; 1-[4-(2-{[1-(ethoxycarbonyl)piperidin-4-yl]amino}-5-phenylpyrimidin-4-yl)benzyl]- 4-(5-Pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidine); (33) U.S. Patent No. 7,998,977 (issued to Joseph et al.) (4-[ 5-(2-Amino-ethanesulfonyl)-isoquinolin-7-yl]-phenol); (34) U.S. Patent No. 7,910,561 (issued to Arruda et al.) (Substituted naphthyridines, Including 3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}benzene -1,6-naphthyridin-5(6H)-one; 2-(4-{[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl) Piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one; 6-methyl-3-phenyl-2-(4-{[ 4-(5-Pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]-methyl}phenyl)-1,6-naphthyridin-5 ( 6H)-keto; 6-(2-hydroxyethyl)-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazole-3) -yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-(5-pyridine- 2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,7-naphthyridin-8(7H)-one; 2-( 4-{[4-(1,3-benzoxazol-2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H) -ketone 3-phenyl-2-(4-{[4-(5-pyridin-2-yl-2H-tetrazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6 -naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-1,2,3-triazol-1-yl)piperidin Pyridin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-(1-pyridin-2-yl-) 1H-pyrrol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4- (5-pyridin-2-yl-1,2,4- Diazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-( 5-pyridin-2-yl-1,3-thiazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl -2-(4-{[4-(3-pyridin-3-yl-1,2,4- Diazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-( 3-pyrimidin-4-yl-1,2,4- Diazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-(4-{[4-( 5-phenyl-1,3,4- Diazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; 2-(4-{[4-(1H-benzimidazole) -2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one; 2-(4-{[4-fluoro-4 -(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridine -5(6H)-keto); (35) U.S. Patent No. 7,750,151 (issued to Bilodeau et al.) (Substituted naphthyridines, including 3-[(3-hydroxyphenyl)amino]-3- oxo-N--[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]propane; [4-( 5-Phenoxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)phenyl]-N-{[5-(1H-pyrazol-1-yl)pyridine -2-yl]methyl}methane; (6-chloropyridin-3-yl)-N-[4-(5-oxo-oxy-3-phenyl-5,6-dihydro-1,6-naphthalene Pyridin-2-yl)benzyl]methane; [4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)phenyl]-N -(pyridin-3-ylmethyl)methane; (6-methoxypyridin-3-yl)-N-[4-(5-oxo-oxy-3-phenyl-5,6-dihydro-1 ,6-naphthyridin-2-yl)benzyl]methane; (6-o-oxy-1,6-dihydropyridin-3-yl)-N-[4-(5-sideoxy-3- Phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]methane; 3-[(2-hydroxyphenyl) Amino]-3-oxo-N-[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]propane 3-[(3-hydroxyphenyl)amino]-3-oxo-N--[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6- Naphthyridin-2-yl)benzyl]propane; 3-[(4-hydroxyphenyl)amino]-3-oxo-N-[4-(5-o-oxy-3-phenyl- 5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]propane; 3-[(2-methoxyphenyl)amino]-3-oxo-N-[4 -(5-oxo-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]propane; 3-[(2-methoxyphenyl)( Methyl)amino]-3-oxo-N-[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzene Propane; 3-[(3-hydroxypyridin-2-yl)amino]-3-oxo-N-[4-(5-oxo-oxy-3-phenyl-5,6-dihydro -1,6-naphthyridin-2-yl)benzyl]propane; 3-phenyl-2-[4-({[4-(1H-pyrazol-1-yl)benzyl]amino} Methyl)phenyl]-1,6-naphthyridin-5(6H)-one; 2,2,2-trifluoro-N-[4-(6-methyl-5-oxo-oxy-3-benzene (5), U.S. Patent No. 7,705,014 (issued to Chen et al.) (substituted) Naphthyridines, including 2-{4-[(3-hydroxy-4,7-dihydroiso) Zoxa[5,4-c]pyridine-6(5H)-yl)methyl]phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one; 3-phenyl-2 -(4-{[7-(Trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}phenyl)-1,6-naphthyridin-5(6H) -ketone; 2-[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-1,2,3,4 - tetrahydroisoquinoline-6-carboxylic acid methyl ester; 2-[4-(5-o-oxy-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl) Benzyl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methyl ester; 2-{4-[(6-amino-3,4-dihydroisoquinoline-2) (1H)-yl)methyl]phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one; 3-phenyl-2-[4-(1,4,6,7 -tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-ylmethyl)phenyl]-1,6-naphthyridin-5(6H)-one); (37) US Patent Case No. 7,655,649 (issued to Bilodeau et al.) (substituted azines and pyrimidines, including N,N-dimethyl-5-phenyl-6-(4-{[4-(5-pyridin-2-yl) -1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazin-3-amine; N-methyl-5-phenyl-6-(4-{[4-( 5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazin-3-amine; 4-[5-phenyl-6-(4- {[4-(5-Pyridin-2-yl-1H-1,2,4-triazol-3-yl)-piperidin-1-yl]methyl}phenyl)pyridazin-3-yl] Porphyrin 4-[5-Phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]- Tertyl}phenyl)pyridazin-3-yl]piperazine-1-carboxylic acid tert-butyl ester; 4-phenyl-6-piperazin-1-yl-3-(4-{[4-(5 -pyridin-2-yl-1H-1,2,4-triazol-3-yl)-piperidin-1-yl]methyl}phenyl)pyridazine; 4-[5-phenyl-6-( 4-{[4-(5-Pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazin-3-yl] Thiomorpholine); (38) U.S. Patent No. 7,638,530 (issued to Bilodeau et al.) (comprising a compound having a five-membered heterocyclic ring fused to a substituted pyridine moiety, including 1-{1-[4- (3-Amino-5-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H- Benzimidazol-2-one; 1-{1-[4-(3-amino-1-methyl-5-phenyl-1H-pyrazolo[3,4-b]pyridine-6-yl) Benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[3-amino-1-(2-morpholine) 4-ylethyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]benzyl}piperidin-4-yl)-1,3-dihydro- 2H-benzimidazol-2-one; 1-(1-{4-[3-amino-1-(2-hydroxyethyl)-5-phenyl-1H-pyrazolo[3,4-b Pyridine-6-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzene Imidazolyl-2-one; 1-[1-(4-{3-amino-1-[2-(1H-imidazol-4-yl)ethyl]-5-phenyl-1H-pyrazolo[3 ,4-b]pyridin-6-yl}benzyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; 1-methyl-6-(4- {[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenyl-1H-pyrazolo[3,4-b Pyridin-3-amine; 9-{1-[4-(3-amino-1-methyl-5-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzene Methyl]piperidin-4-yl}-9H-indol-6-amine); (39) U.S. Patent No. 7,625,890 (issued to Heerding et al.) (1) H -Imidazo[4,5-c]pyridin-2-yl compounds, including 4-(2-(4-amino-1,2,5-) Diazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl) -2-methyl-3-butyn-2-ol; 4-(2-(4-amino-1,2,5- Diazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl -2-methyl-3-butyn-2-ol; 4-(2-(4-amino-1,2,5-) Diazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl) -2-methyl-3-butyn-2-ol; with 4-[2-(4-amino-1,2,5- Diazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2-morpholinyl]methyl}oxy)-1H-imidazo[4,5-c Pyridin-4-yl]-2-methyl-3-butyn-2-ol); (40) U.S. Patent No. 7,625,890 (issued to Heerding et al.) (1) H -Imidazo[4,5-c]pyridin-2-yl compounds, including 4-(2-(4-amino-1,2,5-) Diazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl) -2-methyl-3-butyn-2-ol; 4-(2-(4-amino-1,2,5- Diazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl -2-methyl-3-butyn-2-ol; 4-(2-(4-amino-1,2,5-) Diazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl) -2-methyl-3-butyn-2-ol; with 4-[2-(4-amino-1,2,5- Diazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2-morpholinyl]methyl}oxy)-1H-imidazo[4,5-c Pyridin-4-yl]-2-methyl-3-butyn-2-ol); (41) U.S. Patent No. 7,589,068 (issued to Cosford et al.) (Substituted naphthyridines, including 5- Methoxy-2-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazole)piperidin-1-yl]methyl}phenyl)-3-( 2-thienyl)-1,6-naphthyridine; 2-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-4triazol-3-yl)piperidine- 1-yl]methyl}phenyl)-3-(2-thienyl)-1,6-naphthyridin-5(6H)-one; 1-{4-[4-(3-pyrimidin-5-yl) Quino 啉-2-yl)benzyl]cyclohexyl}-1,3-dihydro-2H-benzimidazol-2-one; 3-[3-(4-{[4-(2- oxy)- 2,3-Dihydro-1H-benzimidazol-1-yl)cyclohexyl]methyl}phenyl)quina 啉-2-yl]thiophene-2-carbaldehyde; 1-(4{4-[3(H-pyrazol-5-yl)quinaquine Oxa-2-yl]benzyl}cyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one; with 2-[4-(1-amino-1-methylethyl) Phenyl]-3-(2-thienyl)-1,6-naphthyridin-5(6H)-one); (42) U.S. Patent No. 7,579,355 (issued to Bilodeau et al.) (Substituted Pyridines) Including 1-(1-{4-[5-(5-amino-1,3,4-thiadiazol-2-yl)-3-phenylpyridin-2-yl]benzyl}piperidine 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(1-{4-[5-(1,2,4- Azoxa-3-yl)-3-phenylpyridin-2-yl]benzyl}piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (1-{4-[3-Phenyl-5-(1H-1,2,4-triazol-5-yl)pyridin-2-yl]benzyl}piperidin-4-yl)-1H- Pyrazolo[3,4-d]pyrimidin-4-amine; 1-{1-[4-(3-phenyl-5-pyrimidin-2-ylpyridin-2-yl)benzyl]piperidine- 4-yl}-1H-pyrazolo[3,4-d]pyrimidine-4-amine; 1-{1-[4-(5 ' -phenyl-2,3 ' -bipyridin-6 ' -yl)benzylidenepiperidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine); (43) U.S. Patent No. 7,576,209 (issued to Kelly, III, etc.) Human) (substituted naphthyridines, including 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f] -1,6-naphthyridin-3(2H)-one); (44) U.S. Patent No. 7,544,677 (issued to Bilodeau et al.) (Substituted 5-deazapteridines, including 2-(A) Ethylthio)-6-phenyl-7-(4-{[4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl] Methyl}phenyl)pyrido[2,3-d]pyrimidine; 2-(methylthio)-6-phenyl-7-(4-{[4-(3-pyridin-3-yl-1) , 2,4- Diazol-5-yl)piperidin-1-yl]methyl}phenyl)pyrido[2,3-d]pyrimidine; 2-(methylthio)-6-phenyl-7-(4- {[4-(5-Pyridin-4-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrido[2,3-d]pyrimidine; 5-(1 -{4-[2-(Methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzyl}piperidin-4-yl)-1,3,4 -thiadiazol-2-amine; 1-{4-[2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzyl}-N- Pyridyl-4-ylpiperidin-4-carboxyguanamine; 1-(1-{4-[2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7-yl Benzyl}piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 6-phenyl-7-(4-{[4-(5-pyridine- 2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyrido[2,3-d]pyrimidine-2-carboxamide; (45) U.S. Patent No. 7,524,850 (issued to Duggan et al.) (Substituted pyrazines, including 1-{1-[4-(5-hydroxy-6-isobutyl-3-phenylpyrazine) -2-yl)benzyl}piperidin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(6-hydroxy-5- Isobutyl-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1- [4-(5-Hydroxy-3-phenylpyrazin-2-yl)benzyl] Pyridin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(6-hydroxy-3-phenylpyrazin-2-yl)benzene Methyl]piperidin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(6-benzyl-5-hydroxy-3- Phenylpyrazin-2-yl)benzyl]piperidin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(5- Benzyl-6-hydroxy-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl-}-1,3-dihydro-2H-benzimidazol-2-one; -{1-[4-(6-Secondyl-5-hydroxy-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl-}-1,3-dihydro- 2H-benzimidazol-2-one; 1-{1-[4-(5-t-butyl-6-hydroxy-3-phenylpyrazin-2-yl)benzyl]piperidine-4- (M)-1,3-dihydro-2H-benzimidazol-2-one); (46) U.S. Patent No. 7,504,410 (issued to Bryant et al.) (pyrimidine derivatives, including N-[3-[[ 5-bromo-4-[[3-[[[1-(trifluoromethyl)cyclobutyl]carbonyl]amino]propyl]amino]-2-pyrimidinyl]amino]phenyl]-1 -pyrrolidinium carboxamide, N-[3-[[5-bromo-4-[[3-[[1-1-oxo-3-(phenylsulfonyl)propyl)]amino]propyl] Amino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide, N-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl))) Amino]phenyl]amino]]- 4-pyrimidinyl]amino]propyl]-2,2-dimethyl-propanediamine, N-[3-[[4-[[3-[[(1-aminocyclopentyl))carbonyl) Amino]propyl]amino]-5-bromo-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide, N-[3-[[4-[[3-[[ (1-Aminocyclobutyl)carbonyl]amino]propyl]amino]-5-iodo-2-pyrimidinyl]amino]phenyl]-1-pyrrolidine Carboxamide, N ¹ -[3-[[5-bromo-2-[[3-[(1-pyrrolidylcarbonyl)amino]phenyl]amino]-4-pyrimidinyl]amino]propyl]-1,1 -cyclopentane dicarboxy decylamine, (4R)-N-[3-[[5-bromo-2-[[3-(2,5-di- oxy-1-imidazolidinyl)phenyl]amine (4-pyrimidinyl)amino]propyl]-2-oxo-4-thiazolyl carboxamide, (4R)-N-[3-[[5-bromo-2-[[3- (3-methyl-2,5-di-oxy-1-imidazolidinyl)phenyl]amino]]-4-pyrimidinyl]amino]propyl]-2-oxo-4-thiazole Carboxylamidine, 3-[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimidinyl]amino]phenyl]- 2,4-imidazolidinone, 3-[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimidinyl]-amino- Phenyl]-1-methyl-2,4-imidazolidinone, N ' -[3-[[5-bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimidinyl]amino]phenyl]-N-ethyl-N 8-(1-piperidinyl)ethyl]-urea); (47) U.S. Patent No. 7,449,477 (issued to Barda et al.) (7-phenyl-isoquinoline-5-sulfonylamino) Derivatives, including 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-decylamine; 7-(3-difluoromethylphenyl)-isoquinolin-5-sulfonate Acid (2-amino-ethyl)-decylamine; 7-(4-aminophenyl)-isoquinoline-5-sulfonic acid (2-amino-ethyl)-decylamine; 7-(3 -aminophenyl)-isoquinoline-5-sulfonic acid (2-amino-ethyl)-decylamine; 7-(3-fluorophenyl)-isoquinoline-5-sulfonic acid (2-amine) -ethyl)-guanamine; 7-(4-methylsulfonylamino)-isoquinoline-5-sulfonic acid (2-amino-ethyl)-decylamine; 7-(3-hydroxybenzene ()-isoquinoline-5-sulfonic acid (2-amino-ethyl)-decylamine; 7-(4-hydroxyphenyl)-isoquinoline-5-sulfonic acid (2-amino-ethyl )-decylamine; 7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonic acid {2-[3-(4-nitro-phenyl)-propylamino]-ethyl}- Indoleamine dihydrochloride; and 7-phenyl-isoquinoline-5-sulfonic acid {2-[3-(4-nitro-phenyl)-propylamino]-ethyl}-decylamine Mesylate salt); (48) U.S. Patent No. 7,414,055 (issued to Duggan et al) Substituted pyridines, including 5-phenyl-6-[4-({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}methyl)phenyl] Alkaline carbonitrile; 5-phenyl-6-[4-({[(1S,2R)-2-phenylcyclopropyl]amino}methyl)phenyl]nicotinyl carbonitrile; 6-(4- {[(3,4-Difluorobenzyl)amino]methyl}phenyl)-5-phenylnicotinonitrile; 6-[4-({[2-(3-fluorophenyl)) Amino]methyl)phenyl]-5-phenylnicotinonitrile; 6-[4-({[2-(4-fluorophenyl)ethyl]amino}methyl)phenyl] -5-phenylnicotinophthalonitrile; 5-phenyl-6-[4-({[(4-phenylmorpholin-2-yl)methyl]amino)methyl)phenyl]nicotinate A Nitrile; with 6-[4-({[(4-phenylmethylmorpholin-2-yl)methyl)amino}methyl)phenyl]-5-phenylnicotinonitrile); (49) U.S. Patent No. 7,399,764 (issued to Duggan et al.) (a compound having a five-membered heterocyclic ring fused to a substituted pyrazine moiety, including 1-{1-[4-(3-phenylthiophene) [3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; N-ethyl-N ' -{(3R)-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}urea; N-{(3R )-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}-1,3-thiazole-5-carboxyindole Amine; 9-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-9H-indole-6-amine ; 2-(4-{[4-(3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenylthieno[3 , 4-b]pyrazine; 9-{(1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}- 9H-oxime; {1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]-1H-benzimidazol-2-yl}methanol); 50) U.S. Patent No. 7,396,832 (issued to Lindsley et al.) (Substituted 2,3-diphenylquinoline) Porphyrins, including N-[4-(3-phenylquinoline) (2) U.S. Patent No. 7,304,063 (issued to Bilodeau et al.) (Heterocyclic triazine derivatives, including 1-(1-) {4-[3-(1,3- Zin-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazole- 2-keto; 1-{1-[4-(6-phenyl-3-pyrimidin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl} -1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[3-(1H-imidazol-2-yl)-6-phenyl-1,2,4- Triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[3-(1- Methyl-1H-pyrazol-5-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro- 2H-benzimidazol-2-one; 1-(1-{4-[6-phenyl-3-(1H-pyrazol-5-yl)-1,2,4-triazin-5-yl] Benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[6-phenyl-3-(1H-pyrazole) -5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 1- (1-{4-[3-(1-Methyl-1H-pyrazol-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidine- 4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[3-(1-methyl-1H-imidazol-2-yl)-6- Phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one); (52) United States Patent Case No. 7,263,869 (issued to Lindsley et al.) Quinoline A morphyl derivative including 1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quina Phenyl-6-yl)benzyl}piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; N,N-dimethyl-1-[4-(6 -phenyl-1H-imidazo[4,5-g]quina Phenyl-7-yl)phenyl]methylamine; 1-{1-[4-(3-phenylbenzo[g]quina Benzyl-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one); (53) U.S. Patent No. 7,223,738 (issued to Bilodeau et al.) Human) (substituted 2,3-diphenylquinoline Porphyrins, including 1-{1-[4-(3-phenylquinoline) 啉-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 3-(4-{[4-(2-trioxy) -2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-2-phenylquinazoline-6-carboxylic acid; 2-(4- {[4-(2-Sideoxy-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-3-phenylquinazoline- 6-carboxylic acid; N-[3-(1H-imidazol-1-yl)propyl]-3-(4-{[4-(2-o-oxy-2,3-dihydro-1H-benzo) Imidazolyl-1-yl)piperidin-1-yl]methyl}phenyl)-2-phenylquinazoline-6-carboxamide; 1-{1-[4-(3-phenylpyridinium[ 3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4- (2-Phenylpyrido[3,4-b]pyrazin-3-yl)benzoyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; -{1-[4-(2-Phenylquinolin-3-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1- {1-[4-(6,7-diamino-3-phenylquinoline 啉-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 2-(4-{[3-(1H-吲哚- 3-yl)pyrrolidin-1-yl]methyl}phenyl)-3-phenylquin (54) U.S. Patent No. 7,098,208 (issued to Owens et al.) (Substituted triazolo[4,3-b]pyridazines, including N ' -(7-cyclobutyl-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2,N,N-tetramethyl- Propane-1,3-diamine; N ' -(7-cyclobutyl-3-(3,5-difluoro-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2 ,N,N-tetramethyl-propane-1,3-diamine; N ' -(7-cyclobutyl-3-(3,4-difluoro-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2 , N,N-tetramethyl-propane-1,3-diamine; N'-(7-cyclobutyl-3-(4-fluoro-phenyl)-[1,2,4]triazolo[ 4,3-b]pyridazin-6-yl)-2,2,N,N-tetramethyl-propane-1,3-diamine; with N ' -(7-cyclobutyl-3-(3-fluoro-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2,N, N-tetramethyl-propane-1,3-diamine); and U.S. Patent No. 6,958,334 (issued to Owens et al.) (substituted triazolo[4,3-b]pyridazines, including 2, 2,N,N-Tetramethyl-N-(3-phenyl-[1,2,4]triazolo[3,4-α]pyridazin-6-yl)-propane-1,3-di Amine, N ' -[3-(4-methoxy-phenyl)-[1,2,4]triazolo[4,3-α]pyridazin-6-yl)-2,2,N,N-tetramethyl Base-propane-1,3-diamine).

Other Akt inhibitors are described in U.S. Patent No. 9,133,168 to Brollo et al., including the compounds of formula (AI), (A-II), and (A-III). Formula (AI) is: Wherein: (1) Ra is hydrogen or alkyl; (2) R1a is hydrogen or methyl; (3) R2a is hydrogen or fluorine; (4) R3a is hydrogen or halogen; (5) R4a is hydrogen, halogen, hydroxyl Or an alkyl group, or an alkoxy group, wherein the alkyl group may be substituted by one or more groups, which may be the same or different, and which are halogen or hydroxy, and wherein the alkoxy group may be subjected to a or more halogens; (6) R5a and R5 'a are the same or different, is hydrogen or alkyl; (7) R6a is hydrogen or alkyl, which is optionally substituted with one or more groups, such groups The groups may be the same or different and are halogen or hydroxy; and (8) R7 is a halogen.

Formula (A-II) is: Wherein: (1) Rc is hydrogen or alkyl; (2) R1c is hydrogen or methyl; (3) R2c is hydrogen or fluorine; (4) R3c is hydrogen or halogen; (5) R4c is hydrogen, halogen, hydroxyl Or an alkyl group, or an alkoxy group, wherein the alkyl group may be substituted by one or more groups, which may be the same or different, and which are halogen or hydroxy, and wherein the alkoxy group may be subjected to a or more halo substituents; same (6) R5c and R5 'c or different and is hydrogen or alkyl; and (7) R6 is hydrogen or alkyl, wherein the alkyl group is optionally substituted with one or more halogen, hydroxy And substituted with an alkoxy group.

Formula (A-III) is: Wherein: (1) Xe and Ye may be the same or different, wherein Xe is O or S, and Ye is S; (2) Re is hydrogen or alkyl; (3) R1e is hydrogen or methyl; (4) R2e Is hydrogen or fluorine; (5) R3e is hydrogen or halogen; (6) R4e is hydrogen, halogen, hydroxy, alkyl, or alkoxy, wherein the alkyl group may be substituted by one or more groups, such groups may be the same or different and is a halogen or hydroxy, and wherein the alkoxy group optionally substituted with one or more halogen; are the same or different (7) R5e and R5 'e, is hydrogen or alkyl; ( 8) R6e is hydrogen or alkyl, wherein the alkyl group may be optionally substituted with one or more halogens, hydroxyl groups, and alkoxy groups; and (9) R7e is hydrogen or halogen.

Other Akt inhibitors are described in U.S. Patent No. 8,993,565 to the name of A. Formula (A-IV) is: Wherein: (1) R1 represents an aryl or heteroaryl group, which may optionally be substituted with one or more groups which may be the same or different selected from the group consisting of a halogen atom and a hydroxyl group, CN, a nitro group, -COOH, --COO alk, --NRxRy, --CONRxRy, --NRxCORy, --CORy, --NRxCO ₂ Rz, alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, ring Alkyl, O-cycloalkyl, heterocycloalkyl, aryl and heteroaryl; alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, aromatic The base and the heteroaryl group may be optionally substituted by one or more groups which may be the same or different selected from the group consisting of a halogen atom and a hydroxyl group, an alkoxy group, an NRvRw, a heterocycloalkyl group or a heteroaryl group; The heteroaryl group may be optionally substituted with one or more alkyl groups and alkoxy groups, which may itself be substituted with one or more halogen atoms as needed; the heterocycloalkyl group and the heteroaryl group may further comprise a side oxygen group. (2) R represents a hydrogen atom or forms a saturated or partially or fully unsaturated 5- or 6-membered ring together with R1, which may optionally contain one or more selected from the group consisting of: O, S, N, NH. Other miscellaneous with Nalk The aryl or heteroaryl residue is fused, and the bicyclic group may be substituted with one or more groups which may be the same or different selected from the group consisting of a halogen atom and CO--NH ₂ , a hydroxyl group. And an alkyl group and an alkoxy group; the alkyl group described later may be substituted by a hydroxyl group, an alkoxy group, an NH ₂ group, a NHalk group or an N (alk) ₂ group; (3) R 2 and R 3 may be the same or different and independently represent a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with one or more halogen atoms; (4) R4 represents a hydrogen atom; and R5 represents a hydrogen atom or an alkyl group which may optionally be substituted by one or more halogen atoms; And NRvRw such that Rv represents a hydrogen atom or an alkyl group, and Rw represents a hydrogen atom or a cycloalkyl group, CO ₂ alk, or an alkyl group which may optionally be substituted with one or more groups which may be the same or different selected from the group consisting of: a hydroxyl group, an alkoxy group, an NRvRw and a heterocycloalkyl group; or (6) Rx and Ry together with a nitrogen atom to which they are attached form a group comprising 3 to 10 ring members and optionally include one or more selected from the group consisting of: O, S a cyclic group of NH, and other heteroatoms of the N-alkyl group, which may be optionally substituted; NRvRw such that Rv represents a hydrogen atom or an alkane And Rw represents a hydrogen atom or a cycloalkyl or alkyl group which may be substituted with one or more groups which may be the same or different selected from the group consisting of: a hydroxyl group, an alkoxy group, and a heterocycloalkyl group; or (7) Rv and Rw together with the nitrogen atom to which they are attached form a cyclic group comprising from 3 to 10 ring members and optionally containing one or more other heteroatoms selected from the group consisting of: O, S, NH, and N-alkyl a cyclic group which may be substituted as desired; (8) a cyclic group wherein Rx and Ry or Rv and Rw, respectively, may form together with the nitrogen atom to which they are attached, optionally via one or more selected from the group consisting of Substituents which may be the same or different: halogen atom and alkyl group, hydroxyl group, pendant oxy group, alkoxy group, NH ₂ ; NH alk and N(alk) ₂ group; (9) Rz represents Ry in addition to hydrogen Definitions; - NRxCORy, - CORy and NRxCO ₂ Rz groups wherein Rx, Ry, and Rz are selected from the above definitions of Rx, Ry, and Rz; and (10) all of the above alkyl groups (alk), The alkoxy group and the alkylthio group are straight or branched and contain from 1 to 6 carbon atoms.

Other Akt inhibitors are disclosed in U.S. Patent No. 8,946,278, issued to Seefeld et al., which is incorporated herein by reference. The formula (AV) is: Wherein: (1) R ⁴¹ and R ⁴² are independently selected from the group consisting of: a subgroup (AV(a)) moiety Halogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, furan, substituted furan, thiophene And substituted thiophene; (2) wherein Q and Y are each independently selected from: nitrogen and -C(R ⁷⁰ )-; and (3) Z is selected from the group consisting of: nitrogen and -C(R ⁴⁸ )-, However, the limitation is that at least one of Q, Y, and Z and at most two are nitrogen, and R ³⁰ is selected from the group consisting of: C ₁ -C ₄ alkyl and C ₁ -C ₄ alkane substituted with one to three fluorine atoms (4) R ⁷⁰ is selected from the group consisting of: hydrogen and halogen; (5) R ⁴⁸ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted An aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, and halogen; (6) R ⁴³ is selected from Hydrogen, halogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, furan, and thiophene; (7) R ⁴⁴ is absent or is selected from: -(CR ⁶⁰ R ⁶¹ ) _m AR (wherein the AR system is unsubstituted), -(CR ⁶⁰ R ⁶¹ ) _m AR (wherein the AR system is substituted), and C ₁ -C ₆ alkyl; (8) where m is 0 to 3, AR is a cyclic or polycyclic aromatic or saturated or unsaturated non-aromatic ring containing from 3 to 16 carbon atoms and optionally containing from 1 to 3 heteroatoms, with the proviso that when the ring is aromatic When the number of carbon atoms is 3, the ring contains at least two hetero atoms, and when the ring is aromatic and the number of carbon atoms is 4, the ring contains at least one hetero atom, and R ⁶⁰ and R ⁶¹ are each independently selected from: Hydrogen and C ₁ -C ₄ alkyl, but with the proviso that when m is 3, no more than 4 R ⁶⁰ and R ^{61 are} added together to form a C ₁ -C ₄ alkyl group; (9) R ⁴⁵ is selected from Hydrogen and C ₁ -C ₄ alkyl; (10) R ²⁰ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, and alkoxy; (11) X is selected from the group consisting of: O, S, and R ⁴⁹ Wherein R ⁴⁹ is selected from the group consisting of: hydrogen and C ₁ -C ₄ alkyl; and (12) n is from 0 to 2, and if possible, such moiety may be substituted with a hydroxy C ₁ -C ₄ alkyl group as desired (13) but with the proviso that only one of R ⁴¹ and R ⁴² is derived from a moiety of the formula (AV(a)).

Other Akt inhibitors are described in U.S. Patent No. 8,592,475 to Rouse et al., which includes the compound of formula (A-VI). Formula (A-VI) is: Wherein: (1) R ¹ and R ² are each independently selected from the group consisting of: a subgroup (A-VI (a)) Halogen, and C ₁ -C ₄ alkyl, wherein R ⁶ is C ₁ -C ₄ alkyl, and R ⁷ is selected from: hydrogen, C ₁ -C ₄ alkyl, and halogen; (2) R ³ is selected From: hydrogen, C ₁ -C ₄ alkyl, and halogen; (3) R ⁴ is selected from the group consisting of: -(CH ₂ ) _m aryl and -(CH ₂ ) _m aryl, wherein the aryl group is substituted, wherein m is 0 to 2; (4) R ⁵ is selected from the group consisting of: hydrogen and C ₁ -C ₄ alkyl; (5) X is selected from: O and S; and (6) n is 0 to 2; (7) However, the restriction condition is that only one of R ¹ and R ² is a moiety of the formula (A-VI (a)); and (8) further limiting the condition that at least one of R ¹ , R ² and R ³ is hydrogen.

Other Akt inhibitors are described in U.S. Patent No. 8,436,002 to Beight et al., including the compound of formula (A-VII). Formula (A-VII) is: Wherein: (1) A is a subgroup (A-VII(a)) or (A-VII(b)) partial group (2) R ¹ is CH ₃ , CH ₂ CH ₃ or CF ₃ ; (3) R ² is H, CF ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ CF ₃ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, CN, Cl, Br, CH=CH ₂ , CH ₂ CH ₂ OCH ₃ , C(CH ₃ ) ₂ CH ₂ OCH ₃ or tetrahydropyran-4-yl, wherein C ₃ -C _{The 6} cycloalkyl group may be optionally substituted by a methyl group at the 1-position, and optionally substituted with a tetrahydropyran-4-yl group at the 4-position, and R ³ is H; or (4) both R ² and R ³ are Cl; and R ⁴ is H, and R ⁵ is CH ₃ , C(CH ₃ ) ₃ , CH(CH ₃ ) ₂ , cyclobutyl, cyclopentyl, CH ₂ -cyclopropyl, C(CH ₃ ) ₂ CH ₂ CH ₃ or tetrahydropyran-4-yl; or (5) R ⁴ and R ⁵ are both CH ₃ ; or R ⁴ and R ^{5 together} with the N to which they are attached form pyrrolidine (the 3-position is visible Requires substitution with a hydroxy group, or azetidine.

Other Akt inhibitors are described in U.S. Patent No. 8,377,937 to Bencsik et al., including the compound of formula (A-VIII). Formula (A-VIII) is: Wherein: (1) R ¹ and R ^1a are each independently selected from the group consisting of: hydrogen, methyl, ethyl, vinyl, trifluoromethyl, CHF ₂ , or CH ₂ F; (2) R ² is hydrogen, hydroxy, A Oxygen, or fluorine; (3) R ^2a is hydrogen, methyl, or fluorine; (4) R ³ is hydrogen, methyl, ethyl, or trifluoromethyl; (5) A is a sub-formula (A- Part VIII(a)) (6) G is a phenyl group (which may optionally be substituted with 1 to 4 R ^e groups) or a 5-6 membered heteroaryl group (which may optionally be substituted by halogen); (7) R ⁵ and R ⁶ are each independently H, OCH ₃ , C ₃ -C ₆ -cycloalkyl (which may optionally be substituted by F, OH, C ₁ -C ₃ alkyl or O(C ₁ -C ₃ alkyl)), 4-6 membered heterocyclic ring (which may optionally be substituted by F, OH, C ₁ -C ₃ alkyl, cyclopropylmethyl or C(=O)(C ₁ -C ₃ alkyl)), or C ₁ -C ₆ alkyl (which It may optionally be substituted by one or more groups independently selected from the group consisting of OH, pendant oxy, O(C ₁ -C ₆ alkyl), CN, F, NH ₂ , NH(C ₁ -C ₆ alkyl , N(C ₁ -C ₆ alkyl) ₂ , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, oxetanyl or tetrahydrogen pyran-yl); or (8) or R ⁵ and R ⁶ of which it is attached together form a 4-7 membered nitrogen heterocycle, which is optionally substituted with one or more groups each independently selected from the group of substituents: OH, Halogen, pendant oxy, trifluoromethyl, CH ₂ CF ₃ , CH ₂ CH ₂ OH, O(C ₁ -C ₃ alkyl), C(=O)CH ₃ , NH ₂ , NHMe, N(Me) _{2, S (O) 2 CH} 3, cyclopropylmethyl, and C ₁ -C ₃ alkyl; or (9) R ^c is , And R ⁶ and R ^D is attached thereto and so the atoms together form a 4-6 heterocycle having nitrogen atoms; (10) R ^a and R ^b is H; or (11) R ^a is H, and R ^b and R ⁶ together with the atoms attached thereto form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; (12) R ^c and R ^d are hydrogen or methyl; or (13) R ^c and R ^d and its attached atom together form a cyclopropyl ring; (14) each R ^{e is} independently halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ -cycloalkyl, O--(C ₁ -C ₆ alkyl), CF ₃ , OCF ₃ , S(C ₁ -C ₆ alkyl), CN, OCH ₂ -phenyl, NH ₂ , NO ₂ , N-(C ₁ -C ₆ alkyl) ₂ , piperidine, pyrrolidine, CH ₂ F, CHF ₂ , OCH ₂ F, OCHF ₂ , OH, SO ₂ (C ₁ -C ₆ alkyl), C(O)NH ₂ , C(O)NH (C ₁ -C ₆ alkyl), and C(O)N(C ₁ -C ₆ alkyl) ₂ ; (15) m and n are independently 0, 1, 2 or 3, respectively, but the constraint is (m + n) ) must be equal to 2, 3 or 4; and (16) p is 0 or 1.

Other Akt inhibitors are disclosed in U.S. Patent No. 8,338,434 to Seefeld et al., including the formula (A-IX) and the compound of formula (AX). Formula (A-IX) is: Wherein: (1) Q is selected from the group consisting of: phenyl, substituted phenyl, benzyl, and benzyl substituted with an aromatic ring; (2) R ¹ is selected from the group consisting of hydrogen, trifluoromethyl, a hydroxyl group, a C ₁ -C ₂ alkyl group, and a halogen; (3) L is selected from the group consisting of: nitrogen and --C(H)-; (4) P is selected from the group consisting of nitrogen and -C(R ⁴⁰ )- - wherein R ⁴⁰ is selected from the group consisting of: hydrogen, C ₁ -C ₄ alkyl, and halogen; (5) A is selected from: -C(O)-- and -N(H)--; B is selected from the group consisting of: -C(O)----N(H)--; and (7) X, Y, and Z systems are each independently selected from: nitrogen, --C(H)-- And --C(R ² )-, wherein R ² is selected from the group consisting of halogen, trifluoromethyl, hydroxy, and C ₁ -C ₄ alkyl; however, the limitation is: A and B are not the same; The restrictions are as follows: X, Y, and Z are not all nitrogen; and the restriction condition is that one of P and L must be nitrogen.

Formula (AX) is: Wherein: (1) Q is selected from the group consisting of phenyl, substituted phenyl, benzyl, and benzyl substituted with an aromatic ring; (2) R ¹ is selected from the group consisting of hydrogen and trifluoromethyl. a hydroxy group, a C ₁ -C ₂ alkyl group, and a halogen; (3) R ³ is selected from the group consisting of hydrogen, trifluoromethyl, hydroxy, C ₁ -C ₂ alkyl, and halogen; and (4) L is selected from the group consisting of: Nitrogen and --C(H)-;; (5) P is selected from the group consisting of: nitrogen and -C(R ⁴⁵ )-, wherein R ⁴⁵ is selected from the group consisting of: hydrogen, C ₁ -C ₄ alkyl, and halogen (6) A is selected from: - C (O) - and - N (H) -; (7) B is selected from: - C (O) - and - N (H) - and (8) X and Y are each independently selected from: nitrogen, -C(H)-, and -C(R ² )-, wherein R ² is selected from the group consisting of: halogen, trifluoromethyl a group, a hydroxyl group, and a C ₁ -C ₄ alkyl group; however, the limitation is that A and B are not the same; and the limitation is that one of P and L must be nitrogen.

Other Akt inhibitors are disclosed in U.S. Patent No. 8,148,387 to Shepherd et al., including the compound of formula (A-XI). Formula (A-XI) is: (A-XI), wherein: (1) X is F, Cl, CF ₃ , CN or H; (2) Y is F, H or Cl; R ¹ and R ² are independently H, C ₁ - C ₄ Alkyl or CH ₂ CH ₂ OH; or R ¹ and R ^{2 together} with the nitrogen atom to which they are attached form a pyrrolidine ring (which may be substituted at the 2-position with a hydroxymethyl group or at the 3-position via a hydroxy group) , or an azetidine ring (the 3-position of which is substituted by a hydroxy group); (3) R ³ is H or OH; (4) R ⁶ is H; or R ⁶ and R ² are attached to the nitrogen of R ² atom to form a piperidine ring; R ⁷ and R ⁸ are each independently H or CH ^3; or R ⁷ and R ¹ and attached to R a nitrogen atom of the ¹ form a pyrrolidine ring together; (5) W is CR ⁴ R ^5, NR ¹⁰ , C=O or C=CH--R ⁹ ; (6) R ⁴ and R ⁵ are each independently H, CH ₃ or CH ₂ CH ₃ ; R ⁴ and R ⁵ are attached to the carbon atom to which they are attached Together form a cyclopentane ring; or one of R ⁴ and R ⁵ is a benzyl group and the other is H; (7) R ⁹ is a 2-thiazolyl, 4-pyridyl, 2-methyl-4-thiazole a group, a 2-imidazolyl group, a 5-thiazolyl group, or a 4-imidazolyl group; and (8) R ¹⁰ is H or a C ₁ -C ₃ alkyl group.

Other Akt inhibitors are disclosed in U.S. Patent No. 7,414,063 to El-Awar et al., including the compound of formula (A-XII). Formula (A-XII) is: Wherein: (1) R ¹ is hydrogen, halo, amine or hydroxy; (2) R ² is hydrogen, C ₁ -C ₄ alkyl, or C ₂ -C ₄ alkenyl, wherein the C ₁ -C ₄ The alkyl group may be optionally substituted by a carboxy group, a trifluoro, a benzyl group, an acetamide, a C ₁ -C ₄ alkoxycarbonyl group, a substituted C ₁ -C ₄ alkoxycarbonyl group (wherein C ₁ -C ₄ alkyl substituted), or --NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are each independently hydrogen or C ₁ -C ₄ alkyl); (3) R ³ is hydrogen, or C ₁ -C ₄ alkyl; (4) R ⁴ is hydrogen, halo, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy; (5) R ⁵ is hydrogen, halo, C ₁ -C ₄ alkane a C ₁ -C ₄ alkoxy group, a trifluoromethyl group, or a nitro group, or R ⁴ and R ^{5 together} with the carbon atom to which they are attached form a benzofused ring; (6) R ⁶ is selected from The following groups are grouped together: hydrogen, halo, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, trifluoromethyl, nitro, cyano, C _3- C ₆ cycloalkyl, phenyl, phenoxy, phenethyl, benzyl, benzhydryl, iso An azole group, a furyl group, a thienyl group, and a methylsulfonyl group; wherein the C ₁ -C ₄ alkyl group may be substituted with N-morpholinyl, piperidine, pyrrolidine or NR ⁹ R ¹⁰ ; wherein the thienyl group Substituting halo or C ₁ -C ₄ alkyl; and wherein the phenyl, benzhydryl or benzyl group may be substituted with one to two substituents each independently selected from the group consisting of: halo , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, CF ₃ , amine, nitro, hydroxy, methylsulfonylamino, sulfonylamino, and C(O)R ¹¹ Wherein R ¹¹ is selected from the group consisting of N-morpholinyl, hydroxy or NR ⁹ R ¹⁰ ; (7) X is --O--, -S(O) _p --, Or --NR ⁸ --; (8) n is 2 or 3; (9) p is 0, 1, or 2; (10) R ⁷ is hydrogen, methyl, ethynyl, phenyl, thienyl or pyridyl An azole; wherein the phenyl, thienyl or pyrazole may be substituted with a hydroxy, halo or amine group; and (11) R ⁸ is hydrogen, C ₁ -C ₄ alkyl, benzyl or tert-butyl ester .

Other Akt inhibitors are disclosed in U.S. Patent No. 7,378,403 to Kozikowski et al., including the compound of formula (A-XIII). Formula (A-XIII) is: Wherein: (1) X and Y are each independently selected from the group consisting of: O, CF ₂ , CH ₂ , and CHF; (2) A is independently selected from the group consisting of the following: P (O) OH, CHCOOH, and C(COOH) ₂ ; (3) R ₂ is a group selected from the group consisting of H, OH, OH, and the C ₁ -C ₂₅ alkyloxy group. , C ₆ -C ₁₀ aryloxy, C ₃ -C ₈ cycloalkyloxy, C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkoxy, C ₂ -C ₂₂ alkenyloxy, C _3- C ₈ cycloalkenyloxy, C ₇ -C ₃₂ aralkyloxy, C ₇ -C ₃₂ alkylaryloxy, C ₉ -C ₃₂ arylalkenyloxy, and C ₉ -C ₃₂ Alkenyl aryloxy; (4) R _{3 -} R ₆ are each independently selected from the group consisting of H, OH, OH, and the same electronic arrangement; and (5) R ₁ and R ₇ are respectively Individually selected from the group consisting of C ₁ -C ₂₅ alkyl, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₂₂ alkenyl, C ₃ -C ₈ ring Alkenyl, C ₇ -C ₃₂ aralkyl, C ₇ -C ₃₂ alkylaryl, C ₈ -C ₃₂ aralkenyl, and C ₈ -C ₃₂ alkenylaryl; however, the limitation is (i) When X is O, Y is O or CH ₂ , and R ₃ is H, at least one of R ₂ and R _{4 -} R ₆ is not OH; (ii) when A is CH In the case of COOH or C(COOH) ₂ , X and Y may not be O at the same time; and (iii) all R _{2 -} R ₆ may not be H at the same time.

Other Akt inhibitors are disclosed in U.S. Patent No. 7,034,026 to Barnett et al., including the compound of formula (A-XIV). The formula (A-XIV) is: (A-XIV), wherein: (1) R ¹ independently represents an amine group, a C ₁ -C ₄ alkylamino group, a di-C ₁ -C ₆ -alkylamino group, an amine group -C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkylamino-(C ₁ -C ₆ )alkyl, di(C ₁ -C ₆ )amino-(C ₁ -C ₆ )alkyl, C ₃ -C ₇ ring alkylamino, di -C ₃ -C ₇ cycloalkyl group, - C ₃ -C ₇ cycloalkyl group, N- pyrrolidinyl -C ₁ -C ₆ alkyl, N- piperidinyl -C ₁ -C ₆ alkyl, piperidinyl or pyrrolidinyl; and (2) R ² independently represent hydrogen, amine, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ - Alkylamino, amino-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino-(C ₁ -C ₆ )alkyl or di(C ₁ -C ₆ alkyl)amino-( C ₁ -C ₆ )alkyl; (3)r is from 1 to 3; and (4)s is from 1 to 3.

Other Akt inhibitors are described in U.S. Patent No. 6,960,584 to Carling et al., including the formula (A-XV). The formula (A-XV) is: Wherein: (1) R ¹ is phenyl, furyl, thienyl or pyridyl, wherein any group may be substituted by 1, 2 or 3 substituents each independently selected from: (a) halogen; (b) C ₁ -C ₄ alkyl; (c) C ₁ -C ₄ alkoxy; (d) cyano; (e) di(C ₁ -C ₄ alkyl)amine; and (f) hydroxy; 2) R ² is an amino-C ₁ -C ₆ alkyl group, a C ₁ -C ₄ alkylamino group-(C ₁ -C ₄ )alkyl group, a di(C ₁ -C ₄ alkyl)amino group-( C ₁ -C ₆ )alkyl, hydroxy-(C ₁ -C ₆ )alkyl or C ₁ -C ₄ alkoxy-(C ₁ -C ₆ )alkyl, wherein any group may be substituted as desired; (3) R ³ is a C ₃ -C ₇ cycloalkyl or aryl group, wherein any group may be substituted as needed.

The kinase RSK (ribosomal S6 kinase) is also known as MAPK-activated protein kinase I (MAPKAP-K1) and functions as a signal transduction agent. Its receptors include glycogen synthase kinase 3 (GSK3) enzymes, which are also involved in the regulation of cell proliferation.

RSK inhibitors are disclosed in the following patents and patent publications: (1) U.S. Patent No. 9,150,577 (issued to Boyer et al.) (Substituted diazonium hydrazide, including N-(2- Methoxypyridin-4-yl)-1-yloxy-2,3,4,5-tetrahydro-1H-[1,4]diazepine[1,2-a]indole-8- Carboxylamidine; N-(1-ethyl-1H-benzimidazol-2-yl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazine [1,2-a]吲哚-7-carboxyguanamine; N-(1-ethyl-1H-benzimidazol-2-yl)-cis-3,4-dimethyl-1-oxo -1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide; (4R)--N-{1-[3-(dimethylamino) )propyl]-1H-benzimidazol-2-yl}-4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole- 7-Carboguanamine; N-(1-ethyl-1H-benzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[ 1,4]diazepine[1,2-a]indole-8-carboxamide; 5-methyl-1-oxo-N-[1-(propan-2-yl)-1H- Benzimidazol-2-yl]-2,3,4,5-tetrahydro-1H-[1,4]diazepine[1,2-a]indole-8-carboxyguanamine); (2 U.S. Patent No. 9,073,926 (issued to Boyer et al.) (Substituted pyrrolodiazepinecarboxamides, including 10-methyl-6-sideoxy-N) -[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-7,8,9,10-tetrahydro-6H-pyrido[3 ' ,2 ' :4,5] Pyrrolo[1,2-a][1,4]diazepine-2-carboxamide; N-(1-benzyl-1H-pyrazol-4-yl)-trans-8,9- Dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3 ' ,2 ' :4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide (9R)-N-(1-Benzyl-1H-pyrazol-4-yl)-9-methyl-6-oxirane-6,7,8,9-tetrahydropyrido[3 ' , 2 ' : 4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide; N-(1-benzyl-1H-pyrazol-4-yl)-10-methyl- 6-Sideoxy-7,8,9,10-tetrahydro-6H-pyrrolo[3 ' ,2 ' :4,5]pyrrolo[1,2-a][1,4]diazepine- 2-carboxyguanamine; (9S)-N-(1-benzyl-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydro Pyrido[3 ' ,2 ' :4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide; (9R)-9-methyl-N-(5-methyl-1, 2- Zyrid-3-yl)-6-tertiaryoxy-6,7,8,9-tetrahydropyrido[3 ' ,2 ' :4,5]pyrrolo[1,2-a]pyrazine-2- Carboxylamidine; (9R)-9-methyl-6-oxo-N-[1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl] -6,7,8,9-tetrahydropyrido[3 ' ,2 ' :4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide); (3) US Patent Case No. 8,829,185 (issued to Dixon et al.) (Substituted 4-amino-pyrrolotriazine derivative); (4) U.S. Patent No. 8,765,802 (issued to Shoemaker et al.) (5) U.S. Patent No. 8,748,601 (issued to Taunton et al.) (Substituted pyrrolopyrimidines having electrophilic substituents) (6) U.S. Patent No. 8,648,069 (issued to Akritopoulou-Zanze et al.) (triazolylcarbazole derivatives, including 5-(1-benzyl-1H-1,2,3- Triazol-4-yl)-1H-carbazole; 5-[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; -[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(4-methylbenzyl)- 1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(3-methoxybenzyl)-1H-1,2,3-triazole-4- -1H-carbazole; 5-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(3 -fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(4-fluorobenzyl)-1H-1,2,3- Triazol-4-yl]-1H-carbazole; 5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5- [1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(4-chlorobenzyl)-1H-1 , 2,3-triazol-4-yl]-1H-carbazole; 5-[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]-1H- Carbazole; 5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(3-nitrobenzene) Methyl)-1H-1,2,3-triazol-4-yl]-1H-carbazole; 5-[1-(4-nitrobenzyl)-1H-1,2,3-triazole 4-yl]-1H-carbazole; 2-{[4-(1H-吲) -5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile; 3-{[4-(1H-carbazol-5-yl)-1H-1,2 ,3-triazol-1-yl]methyl}benzonitrile; 4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]- Benzocarbonitrile; 5-{1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-carbazole; 5-{1 -[3-(Trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-carbazole); (7) U.S. Patent No. US Patent No. 8,426,404 (issued to Zhang et al.) (benzimidazole derivatives substituted with pyrimidine, including 3-[1-(6-amino-pyrimidin-4-yl)-1H-benzimidazol-2-ylamino) 4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide, N-{3-[1-(6 -amino-pyrimidin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-phenyl}-3-morpholin-4-yl-5-trifluoromethyl-benzene Formamide, N-(3-{1-[6-(4-diethylamino-butylamino)-pyrimidin-4-yl]-1H-benzimidazol-2-ylamino}- 4-methyl-phenyl)-3-trifluoromethyl-benzamide, N-(3-{1-[6-(4-diethylamino-butylamino)-pyrimidine-4 -yl]-1H-benzimidazol-2-ylamino}-4-methyl-phenyl)-4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-benzene Indoleamine, N-(3-{1-[6 -(4-Diethylamino-butylamino)-pyrimidin-4-yl]-1H-benzoimidazol-2-ylamino}-4-methyl-phenyl)-3-(4- Methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide, N-(3-{1-[6-(4-diethylamino-butylamino)-pyrimidine- 4-yl]-1H-benzimidazol-2-ylamino}-4-methyl-phenyl)-4-(4-ethyl-piperazin-1-yl-methyl)-3-trifluoro Methyl-benzamide, N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-phenyl} -3-trifluoromethyl-benzamide, N-{3-[1-(6-amino-pyrimidin-4-yl)-1H-benzimidazol-2-ylamino]-4-methyl Benzyl-phenyl}-4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-benzamide; (8) U.S. Patent No. 8,329,722 (issued to Siu et al) (Pyridinonaphthyridinone derivatives, including 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6 -naphthyridine-1(2H)-one; 6-{[1-(2,4-dichloro-5-fluorophenyl)ethyl]amino}pyrido[4,3-c]-1,6 -naphthyridine-1(2H)-one; 6-[(2,2,2-trifluoroethyl)amino]pyrido[4,3-c]-1,6-naphthyridine-1 (2H) -ketone; 6-[(3-thienylmethyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one; 6-[(1,3-thiazole) -2-ylmethyl)amino]pyridine [4,3-c]-1,6-naphthyridin-1(2H)-one; 6-[(pyridin-2-ylmethyl)amino]pyrido[4,3-c]-1,6 -naphthyridine-1(2H)-one; 6-{[(5-methyliso) Zyrid-3-yl)methyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one; (3S)-3-[(1-sideoxy- 1,2-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]piperidine-1-carboxylic acid tert-butyl ester; 6-(benzylamine) Pyridyl[4,3-c]-1,6-naphthyridin-1(2H)-one; 6-(methylamino)pyrido[4,3-c]-1,6-naphthyridine -1(2H)-one: 6-(dimethylamino)pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one; 6-(benzylamino) Pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one); (9) U.S. Patent No. 8,143,393 (issued to Dixon et al.) (Substituted 4-amino group - Pyrrolizine derivatives, including N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine- 5-yl]-2-fluorophenyl}-N ' -[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholine- 4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N ' -(3-tert-butyliso Zyrid-5-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine- 5-yl]phenyl}-N ' -[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl) Pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N -{4-[4-Amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N '-[3-(Trifluoromethyl)phenyl]urea; N-{4-[4-Amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1 , 2,4]triazin-5-yl]phenyl}-N ' -[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7- (morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N ' -[2- Fluor-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1, 2,4]triazin-5-yl]-2-fluorophenyl}-N ' -[4-(trifluoromethyl)pyridin-2-yl]urea; N-{5-[4-amino- 7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N ' -[2-fluoro- 5-(4-trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2, 4] triazin-5-yl] -2-fluorophenyl} -N '- [3- (trifluoromethyl) phenyl] ;N-{4-[4-Amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3- Fluorophenyl}-N ' -[4-(trifluoromethyl)pyridin-2-yl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrole [2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N ' -[4-(trifluoromethyl)pyridin-2-yl]urea); 10) U.S. Patent No. 8,133,995 (issued to Dixon et al.) (Substituted 4-amino-pyrrolotriazine derivatives, including 4-amino-5-{4-[({[2-fluoro-) 5-(Trifluoromethyl)phenyl]amino}carbonyl]-amino]-phenyl}-7-(morpholin-4-ylmethyl)-N-(2,2,2-trifluoroethyl -pyrrolo[2,1-f][1,2,4]-triazine-6-carboxamide; 4-amino-5-{4-[({[2-fluoro-5-( Trifluoromethyl)phenyl]amino}carbonyl)-amino]phenyl}-7-[(4-methylpiperazin-1-yl)methyl]-N-(2,2,2-tri Fluoroethyl)-pyrrolo[2,1-f][1,2,4]triazin-6-carboxamide; N-{4-[4-amino-6-(methoxymethyl) -7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N ' -[2-fluoro-5 -(Trifluoromethyl)phenyl]urea; N-(4-[4-amino-6-(methoxymethyl)-7-[(4-methylpiperazin-1-yl)methyl) ]-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl)-N ' -[2-fluoro-5-(trifluoromethyl)- Phenyl]urea; N-{4-[4-amino-7-{[(2-methoxyethyl)amino]methyl}-6-(methoxymethyl)-pyrrolo[2 , 1-f][1,2,4]triazin-5-yl]phenyl}-N ' -[2-fluoro-5-(trifluoromethyl)-phenyl]urea; N-{4- [4-Amino-7-[(2,6-dimethylmorpholin-4-yl)methyl]-6-(methoxymethyl)-pyrrolo[2,1-f][1, 2,4]triazin-5-yl]phenyl}-N ' -[2-fluoro-5-(trifluoromethyl)-phenyl]urea; N-(4-[4-amino-6- (Methoxymethyl)-7-[(3-Sideoxypiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl Phenyl)-N ' -[2-fluoro-5-(trifluoromethyl)-phenyl]urea; N-{4-[4-amino-7-{[(2-methoxyethyl) (methyl)amino]methyl}-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N ' -[2-Fluoro-5-(trifluoromethyl)phenyl]urea); (11) U.S. Patent No. 7,642,255 (Sim et al.) (pyridopyrimidinyl compound, including N-{3-[7- (3-Diethylamino-propylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl] 4-methyl-phenyl}-3-trifluoromethyl-benzamide; N-{4-methyl-3-[1-methyl-2-oxo-7-(pyridine-3) -ylamino)-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl]-phenyl}- 3-trifluoromethyl-benzamide; N-{4-methyl-3-[1-methyl-7-(6-methyl-pyridin-3-ylamino)-2-yloxy -1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl]-phenyl}-3-trifluoromethyl-benzamide; N-{3-[7- (2,5-Dimethyl-2H-pyrazol-3-ylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrido[4,3-d] Pyrimidin-3-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide; N-{4-methyl-3-[1-methyl-2-sidedoxy- 7-(Pyrazin-2-ylamino)-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl]-phenyl}-3-trifluoromethyl-benzene Methionamine; N-{4-methyl-3-[1-methyl-7-(3-morpholin-4-yl-propylamino)-2-oxo-1,4-dihydrogen -2H-pyrido[4,3-d]pyrimidin-3-yl]-phenyl}-3-trifluoromethyl-benzamide; N-{3-[7-(3-diethylamine) -propylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl]-4-methyl-benzene }}-3-trifluoromethyl-benzamide; N-{3-[7-(4-diethylamino-butylamino)-1-methyl-2-oxooxy-1 ,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide; (12) United States Patent Case No. 7,605,241 (to Hecht et al.) (Kaempferol) Glycoside (kaempferol glycoside) and its analogs; (13) U.S. Patent No. 7,521,446 (issued to Albers et al.) (4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[ (2,4,6-Trifluorophenyl)amino]-9H-indol-2-yl]amino]cyclohexanol); (14) U.S. Patent No. 7,470,709 (issued to Barsanti et al.) (Benzene) And imidazoquinolinones; (15) U.S. Patent No. 7,442,700 (issued to Mastalerz et al.) (pyrrolotriazine derivatives, including N-[4-({4-[(5-methyl-1H) -pyrazol-3-yl)amino]pyrrolo[2,1f][1,2,4]triazin-2-yl}thio)phenyl]cyclopropanecarboxamide; N-(3-ring propyl-1H-pyrazol-5-yl)-2-{[3-(methyloxy)phenyl]thio}pyrrolo[2,1-f][1,2,4]triazine-4 -amine; N-[4-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazine -2-yl}thio)phenyl]acetamidamine; 3-({4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f] [1,2,4]triazin-2-yl}thio)-N-methylbenzamide; N-(5-methyl-1H-pyrazol-3-yl)-2-(phenyl Thio)pyrrolo[2,1-f][1,2,4]triazin-4-amine; and N-(4-((4-((5-methyl-1H-pyrazole-3-) Amino)pyrrolo[2,1f][1,2,4]triazin-2-yl)thio)phenyl)benzamide (16) U.S. Patent No. 7,405,213 (issued to Chen et al.) (pyrolotriazine compound, including 3-chloro-4-fluoro-N-(5-{[6-({3-[4- (hydroxymethyl)piperidin-1-yl]propyl}oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}pyrimidine -2-yl)benzamide; 3-chloro-4-fluoro-N-(5-{[6-({3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl] Propyl}oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}pyrimidin-2-yl)-benzamide; -Chloro-4-fluoro-N-(5-{[6-({3-[(2S)-2-(hydroxymethyl)morpholin-4-yl)propyl}oxy)-5-methyl Pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}pyrimidin-2-yl)benzamide; 3-chloro-4-fluoro-N-(5- {[6-({3-[3-(Hydroxymethyl)morpholin-4-yl)propyl}oxy)-5-methylpyrrolo[2,1-f][1,2,4] Triazin-4-yl]amino}pyrimidin-2-yl)benzamide; N-(5-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl]-propyl氧基)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}pyrimidin-2-yl)benzamide; N-( 5-{[6-({3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propyl}oxy)-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-4-yl]amino}pyrimidin-2-yl)benzamide; (17) US Case No. 7,402,582 (Gavai et al.) (pyrrolotriazine compounds, including 2-(2-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl]propyl}) Oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}1,3-thiazol-5-yl)-N-(3- Methylphenyl)acetamide; N-(3-chlorophenyl)-2-(2-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl]propyl} Oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}-1,3-thiazol-5-yl)acetamidamine; N -(3-chloro-4-fluorophenyl)-2-(2-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl)propyl}oxy)-5- Methylpyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}-1,3-thiazol-5-yl)acetamidamine; N-(4-chlorobenzene 2-(2-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl)propyl}oxy)-5-methylpyrrolo[2,1-f ][1,2,4]triazin-4-yl]amino}-1,3-thiazol-5-yl)acetamidamine; N-(3-fluorophenyl)-2-(2-{[ 6-({3-[4-(Hydroxymethyl)piperidin-1-yl]propyl}oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine 4-yl]amino}-1,3-thiazol-5-yl)acetamidamine; N-(3-fluorophenyl)-2-(2-{[6-({3-[4-( Hydroxymethyl)piperidin-1-yl]propyl}oxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino}-1,3-thiazole- 5-yl)acetamide 2-(2-{[6-({3-[4-(hydroxymethyl)piperidin-1-yl]propyl}oxy)-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-4-yl]amino}-1,3-thiazol-5-yl)-N-phenylacetamide; N-(3-fluorophenyl)-2-(2- {[6-({3-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]propyl}oxy)-5-methylpyrrolo[2,1-f][1,2 , 4] triazin-4-yl]amino}-1,3-thiazol-5-yl)acetamidamine; N-(3-fluorophenyl)-2-(2-{[6-({3 -[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propyl}oxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amine And (18) US Patent No. 7,371,750 (issued to Sim et al.) (pyrimidopyrimidinyl compounds, including N-{3-[7 -(3-dimethylamino-phenylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl ]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide; N-{3-[7-(3-amine -Phenylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methyl-benzene }}-3-trifluoromethyl-benzamide; N-[4-methyl-3-(1-methyl-7-methylamino-2,4-di-oxy-1,4 -dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl -benzamide; N-[3-(7-benzylaminoamino-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidine -3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide; N-{4-methyl-3-[1-methyl-2-oxo-7 -(3-ureido-phenylamino)-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-phenyl}-3-trifluoromethyl-benzene Formamide; N-{3-[7-(3-hydroxymethyl-phenylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimidine[4, 5-d]pyrimidin-3-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide; N-(4-methyl-3-{1-methyl-7- [3-(4-Methyl-piperazin-1-ylmethyl)-phenylamino]-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidine -3-yl}-phenyl)-3-trifluoromethyl-benzamide; N-{4-methyl-3-[1-methyl-2-oxo-7-(3-amine Sulfomethyl-phenylamino)-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-phenyl}-3-trifluoromethyl-benzamide ).

Other RSK inhibitors are described in U.S. Patent No. 7,759,342 to Bennett et al., which includes a compound of formula (RI). The formula (RI) is: Wherein: (1) R ¹ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₁₀ heterocyclic ring or a substituted or unsubstituted C ₃ -C ₁₀ heteroaryl group; (2) R ² is H, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocyclic ring or substituted or unsubstituted a C ₃ -C ₁₀ heteroaryl group; and (3) R ³ is an aryl group substituted by one or more halogens or a C ₃ -C ₁₀ heteroaryl group substituted by one or more halogens, wherein the aryl group or The C ₃ -C ₁₀ heteroaryl group may be further subjected to one or more C ₁ -C ₆ alkyl groups, hydroxyl groups, hydroxyalkyl groups, alkoxy groups, alkoxyalkyl groups, amine groups, alkylamino groups, carboxyl groups, Aminocarbonyl, cyano, decylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl substituted.

Other RSK inhibitors are described in U.S. Patent Application Publication No. 2005/0233985 to Smith et al., which includes the compound of formula (R-II). Formula (R-II) is: Wherein: (1) R ₁ , R ₂ , and R ₃ are each independently selected from the group consisting of: hydroxy, --OCOR ₄ , --COR ₄ , C ₁ -C ₄ alkoxy, -- O-glucoside and -O-rhamnoside; (2) R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of H, hydroxy, --OCOR ₄ , -COR ₄ , C ₁ -C ₄ alkoxy, -O-glucoside and -O-rhamnoside; and (3) R ₄ is H or C ₁ -C ₄ alkyl; The restriction is that R ₁ , R ₂ and R _{3 are} not all hydroxyl groups.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that plays a key role in cell division and replication. PLK1 is a 66-kDa protein of 603 amino acid residues. In addition to the N-terminal kinase domain, there are two remaining polo-box regions of the 30 amino acids at the C-terminus. Kinase activity is at least partially regulated by the polo-box, which is functionally important in autoinhibition and subcellular localization. PLK1 is an early-on promoter of the G2/M transition in the cell cycle. It is often overexpressed in malignant cells and is considered a proto-oncogene (U. Holtrich et al., "Induction and Down-Regulation of PLK, a Human Serine/Threonine Kinase Expressed in Proliferating Cells and Tumors, "Proc. Natl. Acad. Sci. USA 91: 1736-1740 (1994).

PLK1 inhibitors include BI2536 ((R)-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridine-2- Amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide, volasertib (BI6727), rigosertib, GSK461364(5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-3-((R)-1-(2-) (trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxamide), HMN-214 (N-[(4-methoxyphenyl)sulfonyl]-N-[2-[( 1E)-2-(1-oxoyl-4-pyridyl)vinyl]phenyl]-acetamide, SBE 13 hydrochloride (N-(4-((6-chloropyridin-3-yl)) )methoxy)-3-methoxybenzyl)-2-(3,4-dimethoxyphenyl)ethylamine hydrochloride), NMS-P937 (4,5-dihydro-1- (2-hydroxyethyl)-8-[[5-(4-methyl-1-piperazinyl)-2-(trifluoromethoxy)phenyl]amino]-1H-pyrazolo[4 , 3-h] quinazolin-3-carboxyguanamine), and MLN0905 (2-[[5-[3-(dimethylamino)propyl]-2-methyl-3-pyridinyl]amine 5-]7-Dihydro-9-(trifluoromethyl)-6H-pyrimido[5,4-d][1]benzoazepine-6-thione). A particularly preferred PLK1 inhibitor is volasertib.

Other PKL1 inhibitors are known in the art. U.S. Patent No. 7,977,336 to Hashihayata et al. discloses aminopyrimidine PLK1 inhibitors, including 2-[((1S)-1-{4-[2-(t-butylamino)-1-hydroxyethyl) (phenyl)ethyl)amino]-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-pyrimidine-5-carbonitrile; (1R)-1-[4 -((1S)-1-{[5-bromo-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino}ethyl)phenyl ]-2-(t-butylamino)ethanol; 2-[((1S)-1-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}ethyl)amino]-4 -(8-Methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; 4-(8-ethylimidazo[1,2-a]pyridin-3-yl) -2-({(1S)-1-[4-(4-hydroxy-1-methylpiperidin-4-yl)phenyl]ethyl}amino)pyrimidine-5-carbonitrile; 4-(8 -ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylpiperidin-4-yl)methyl] Phenyl}ethyl)amino]pyrimidine-5-carbonitrile; 4-(8-cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1- {4-[Hydroxy(1-methylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; 4-(8-chloroimidazo[1,2-a Pyridin-3-yl)-2-[((1S)-1-{4-[(1-cyclopropylpiperidin-4-yl)(hydroxy)methyl]phenyl}ethyl)amino] Pyrimidine-5- Nitrile; 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methyl-piperidine-3) -yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; and 2-{[(1S)-1-(4-{hydroxy[1-methylpyrrolidin-2-yl] Methyl}phenyl)ethyl]amino}-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile). U.S. Patent No. 8,514,418 to Galemmo et al. discloses a dihydropterinone inhibitor of PLK1, including (7R)-7-ethyl-5-methyl-8-(tetrahydrofuran-3-yl)-2- (5-(thiazol-2-yl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one, (R)-7-ethyl-2-(2 -(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridine- 6(5H)-keto, (R)-7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-methyl -1H-pyrazol-3-yl)-7,8-dihydropteridin-6(5H)-one, (R)-7-ethyl-5-methyl-8-(1-methyl-1H -pyrazol-4-yl)-2-(2-phenyl-1H-imidazol-1-yl)-7,8-dihydropteridin-6(5H)-one, (R)-7-ethyl -5-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-4-yl )-7,8-dihydropteridin-6(5H)-one, (R)-2-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-7- Ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one, and (R)-7-B 5--5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(1-methyl-3-(thiazol-2-yl)-1H-pyrazole-4- Base)-7,8-dihydropteridin-6(5H)-one. U.S. Patent No. 8,445,503 to Galemmo et al., which is incorporated herein by reference in its entirety, the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of )-6a,7,9,10-tetrahydro-[1,4] Pyrazino[3,4-h]pteridin-6(5H)-one, (S)-6a-ethyl-5-methyl-2-(5-(thiazol-2-yl)-1H-pyrazole -4-yl)-6a,7,9,10-tetrahydro-[1,4] Pyrazino[3,4-h]pteridin-6(5H)-one, (S)-6a-ethyl-5,8-dimethyl-2-(2-phenyl-1H-imidazol-1- -7,8,9,10-tetrahydro-5H-pyrazino[2,1-h]pteridin-6(6aH)-one, (S)-2-(2-(2,4- Difluorophenyl)-1H-imidazol-1-yl)-6a-ethyl-5-methyl-6a,7,9,10-tetrahydro-[1,4] Pyrazino[3,4-h]pteridin-6(5H)-one, and (S)-6a-ethyl-2-(2-(5-fluoropyridin-2-yl)-1H-imidazole-1 -yl)-5-methyl-6a,7,9,10-tetrahydro-[1,4] Pyrazino[3,4-h]pteridin-6(5H)-one. U.S. Patent No. 8,318,727 to Cao et al. discloses inhibitors of PLK1, including 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-sideoxy-6,7, 8,9-Tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidine- 4-yl)benzamide. U.S. Patent No. 7,956,185 to Diebold et al. discloses a cyclobut-3-ene-1,2-dione inhibitor of PLK1.

The term "antibody" as used herein, unless otherwise defined or limited, includes both polyclonal and monoclonal antibodies, as well as genetically engineered antibodies, such as chimeric or humanized antibodies with appropriate binding specificity. The term "antibody" as used herein, unless otherwise defined or limited, also includes antibody fragments such as sFv, Fv, Fab, Fab ' , and F(ab) ' ₂ fragments. In many cases, monoclonal antibodies are preferred. This applies to antibodies or compositions comprising the above antibodies and other antibodies described herein.

In another alternative, when the pharmaceutical combination is an alkylating agent, the alkylating agent is selected from the group consisting of BCNU, BCNU implant (Gliadel), ACNU, CCNU. , bentamustine (Treanda), lomustine, and temozolimide (Temodar).

When the sensitization is improved by chemotherapy sensitization, the chemotherapeutic sensitization may include, but is not limited to, using a substituted hexitol derivative as a chemotherapeutic sensitizer in combination with a preparation selected from the group consisting of the following: : (a) topoisomerase inhibitor; (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) signal transduction inhibitor; (f) Cisplatin or platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; (l) naphthoquine (m) colchicine or the like; (n) genistein; (o) Etoposide; (p) cytarabine; (q) camptothecin; (r) vinca alkaloid; (s) topoisomerase inhibitor; (t) 5-fluorouracil; Curcumin; (v) NF-κB inhibitor; (w) rosmarinic acid; (x) acetaminophen; (y) tetrandrine; (z) tyrosine kinase inhibitor; (aa) EGFR Inhibitors; and (ab) inhibitors of PARP.

When the improvement is effected by chemotherapy synergy, the chemotherapy synergy may include, but is not limited to, using a substituted hexitol derivative as a chemotherapy synergist, in combination with a preparation selected from the group consisting of the following: : (a) topoisomerase inhibitor; (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) signal transduction inhibitor; (f) Cisplatin or platinum analog; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; (l) naphthophene; (m) colchicine or analog; (n) gold Isoflavone; (o) etoposide; (p) cytarabine; (q) camptothecin; (r) vinca alkaloid; (s) 5-fluorouracil; (t) curcumin; (u) NF-κB inhibitor; (v) rosmarinic acid; (w) acetaminophen; (x) tetrandrine; (y) tyrosine kinase inhibitor; (z) inhibitor of EGFR; ) inhibitor of PARP

In another alternative, when the chemotherapy synergy involves enhancing the chemotherapeutic efficacy of the alkylating agent by the di-desogalactitol activity, the alkylating agent can be in a group selected from the group consisting of: BCNU, BCNU implant (Geliadel), CCNU, bendamustine (Treanda), Luo Lomustine, ACNU, and temozolimide (Temodar).

When improved by post-treatment treatment, the post-treatment treatment may be, but is not limited to, a method selected from the group consisting of: (a) a treatment associated with pain management; (b) administering an antiemetic; (c) anti-nausea therapy; (d) administration of an anti-inflammatory agent; (e) administration of an antipyretic; and (f) administration of an immunostimulant.

When improved by an alternative medical/post-treatment support method, the alternative medical/post-treatment support method can be, but is not limited to, the use of herbs produced by synthesis or extraction.

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

When the herb produced by 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 herb produced by 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 herb produced by synthesis or extraction is an immunostimulant, the immunostimulant may be a product present in or isolated from Echinacea. When the herb produced by the synthesis or extraction is an antimicrobial agent, the antimicrobial agent may be berberine. When the herb produced by synthesis or extraction is a flavonoid or a flavonoid, the flavonoid, isoflavone, or flavonoid may be selected from the group consisting of apigenin, genistein, and genistein. , apigenenin, genistein, genistin, 6 " -O-propionyl soy isoflavone (genistin), 6 " -O-ethyl ketone soy isoflavone ( Genistin), daidzein, daidzin, 6 " -O-propanyl daidzin, 6 " -O-acetylglycosyl (genistin), daidzein ( Glycatein), glycyin, 6 " -O-propionyl glycyrrhizin (glycitin), and 6-O-ethyl decyl fulvin.

When the improvement is made by modifying the drug substance product, the improvement of the drug substance product may be, but not limited to, improvement of the drug substance product selected from the group consisting of: (a) salt formation; (b) homogeneity Crystalline structure; (c) pure isomer; (d) increased purity; (e) used to reduce residual solvent content; and (f) used to reduce heavy metal content.

When improved by the use of a diluent, the diluent may be, but is not limited to, a diluent selected from the group consisting of: (a) an emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF); (d) DMF; (e) ethanol; (f) benzyl alcohol; (g) water for injection containing dextrose; (h) castor oil polyoxyethylene ether ( Cremophor); (i) cyclodextrin; and (j) PEG.

When improved by the use of a solvent system, the solvent system can be, but is not limited to, a solvent system selected from the group consisting of: (a) an emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF); (d) DMF; (e) ethanol; (f) benzyl alcohol; (g) water for injection containing dextrose; (h) castor oil polyoxyethylene ether ( Cremophor); (i) cyclodextrin; and (j) PEG.

When modified by the use of excipients, the excipient can be, but is 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 (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; Perillyl alcohol 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 exenotelide B.

Suitable cytochrome P450 inhibitors include, but are not limited to, 1-aminobenzotriazole, N-hydroxy-N ' -(4-butyl-2-methylphenyl)formamidine, ketoconazole , methoxsalen, metyrapone, roquefortine C, proadifen, 2,3 ' , 4,5 ' -tetramethyl hydrazine, With tamarindmycin (troleandomycin).

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

Suitable organic resins include, but are not limited to, partially neutralized polyacrylic acid, as described in U.S. Patent No. 8,158,616 to Rodgers et al.

Suitable cleaning agents include, but are not limited to, nonionic detergents such as polysorbates or poloxamers, and are illustrated in Bj PCT Patent Application Publication No. WO/1997/039768 to rn et al.

The use of perillyl alcohol or an analogue thereof for improving the transport of anti-tumor agents is described in U.S. Patent Application Serial No. 2012/0219541 to Chen et al.

The use of an activator of a channel-forming receptor is described in U.S. Patent Application Publication No. 2010/0311678 to Bean et al. Activators of such channel-forming receptors include, but are not limited to, capsaicin, lidocaine, eugenol, arvanil (N-arachidonyl vanadium) Amine), anandamide, 2-aminoethoxydiphenylborate, resiniferatoxin, crotonyl 12-phenyl acetate 13-acetate 20-high carbon vanilla (phorbol 12-phenylacetate 13-acetate 20-homovanillate) (PPAHV), olvanil, N-oleyl dopamine, N-arachidontyl dopamine, 6 ' -iodophyllin toxin (resiniferatoxin) (6 ' -IRTX), C ₁₈ N-acetylethanolamine, lipoxygenase derivatives (such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (inhibitor cysteine knot) ICK) peptide (vanillotoxins), piperine, N-[2-(3,4-dimethylbenzyl)-3-(pentamyloxy)propyl]-2- [4-(2-Aminoethoxy)-3-methoxyphenyl]acetamide, N-[2-(3,4-dimethylbenzyl)-3-(pententyl) Oxy) propyl]-N'-(4-hydroxy-3-methoxybenzyl)thiourea, SU200 N-(4-t-butylbenzyl)-N ' -(4-hydroxy- 3-methoxybenzyl)thiourea), transacin, cinnamaldehyde, allyl-isothiocyanate, diallyl disulfide, icilin, cinnamon oil, holly Oil, clove oil, acrolein, mustard oil, ATP, 2-methylthio-ATP, 2 ' and 3' -O-(4-benzylidenebenzylidene)-ATP, ATP-5 ' - O-(3-thiotriphosphate), menthol, eucalyptol, linalool, geraniol, and hydroxycitronellal.

When modified by the use of 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) a capsule; (c) a topical gel; (d) Topical cream; (e) patch; (f) suppository; (g) lyophilized dose filler; (h) immediate release formulation; (i) sustained release formulation; (j) controlled release formulation; and (k) liquid contained in the capsule.

Formulations of pharmaceutical compositions in the form of lozenges, capsules, topical gels, topical creams or suppositories are known in the art and are disclosed, for example, in Griffin et al., U.S. Patent Application Publication No. 2004/ 0023290.

A method of dispensing a medical composition such as a patch, such as a leather patch, is known in the art and is disclosed, for example, in U.S. Patent No. 7,728,042 to E.

Lyophilized dose fillers are also well known in the art. A method commonly used in the preparation of such lyophilized dosage fillers, which is suitable for the preparation of such lyophilized dosage fillers, comprises the following steps:

(1) The drug is dissolved in water for injection which is pre-cooled to below 10 °C. Dilute to final volume with cold water for injection to give a 40 mg/mL solution.

(2) The bulk solution was filtered through a 0.2-μm filter paper into a receiving container under sterile conditions. The blending and filtration should be completed within 1 hour.

(3) Fill the nominal 1.0 mL filtration solution into a sterile glass vial under the control target under sterile conditions.

(4) After filling, all vials are covered with a rubber cap, inserted into the "freeze-drying position", and sent to a pre-cooled freeze dryer. Shed plate temperature of freeze dryer The degree was set at +5 ° C for 1 hour; then the shelf temperature was adjusted to -5 ° C for 1 hour, and the condenser was turned on and set at -60 ° C.

(5) The bottle is then frozen to 30 ° C or below and held for at least 3 hours, typically 4 hours.

(6) Then open the vacuum, adjust the shelf temperature to -5 ° C, the first drying for 8 hours; adjust the shelf temperature to -5 ° C again, and dry for at least 5 hours.

(7) Secondary drying was started after the condenser was turned on (setting -60 ° C) and vacuum. During secondary drying, the shelf temperature is controlled at +5 ° C for 1 to 3 hours, usually 1.5 hours, then at 25 ° C for 1 to 3 hours, usually 1.5 hours, and finally at 35-40 ° C, at least 5 hours, usually 9 hours, or until the product is completely dry.

(8) Break the vacuum using a filtered inert gas such as nitrogen. A stopper is added to the vacuum dryer.

(9) Remove the bottle from the freeze dryer and seal with an aluminum sealing cap. Visually inspect all bottles and label them with approval.

The immediate release formulation is described in U.S. Patent No. 8,148,393 to Van Dalen et al. The immediate release formulation can include, for example, a common film ingot.

The sustained release formulation is described in U.S. Patent No. 8,178,125, issued toWen et al. Sustained-release formulations can include, for example, microemulsions or liquid crystals.

Controlled release formulations are described in U.S. Patent No. 8,231,898 to Oshlack et al. Controlled release formulations may include For example, a parent material containing a controlled release material. Such controlled release materials may include hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, propylene resins, protein derived materials, waxes, shellac, and oils such as hydrogenated castor oil or hydrogenated vegetable oils. .

However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material which imparts controlled release to a nitrogen mustard-based alkylating agent can be used in accordance with the present invention. Preferred controlled release polymers include alkyl celluloses such as ethyl cellulose, acrylic and methacrylic polymers and copolymers, and cellulose ethers, especially hydroxyalkyl celluloses (eg, hydroxypropyl group). Base cellulose) with carboxyalkyl cellulose. Preferred acrylic acid and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, and methacrylic acid amine. Alkyl ester copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine copolymer methacrylate, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethyl Acrylate, polypropylene decylamine, poly(methacrylic anhydride), and glycidyl methacrylate copolymer.

When improved by the use of a dose kit and package, the dose kit and package may be, but is not limited to, a dose kit and package selected from the group consisting of: shading using a brown sample vial, and using The stopper of a specific coating improves shelf stability.

When improved 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) Oral dosage form; (b) Nanocrystals; (c) Nanoparticles; (d) Cosolvents; (e) Slurry; (f) Syrup; (g) Biodigestible polymer; (h) Liposomes (i) a sustained-release gel for injection; (j) a microsphere; 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.

U.S. Patent No. 8,258,132 to Bosch et al. Typically, such nanoparticles have an active ingredient having an average particle size of less than about 1000 nm, more preferably less than about 400 nm, and most preferably less than about 250 nm. Nanoparticles can be coated with surface stabilizers such as, but not limited to, gelatin, casein, lecithin (phospholipids), dextran, acacia, cholesterol, tragacanth, stearic acid, dimethylammonium chloride , calcium stearate, glyceryl monostearate, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ethers (eg : Polyglycol ethers such as: polyethylene glycol cetyl ether 1000 (cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (for example, available from commercial products) Tweens® such as Tween 20® and Tween 80® (ICI Speciality Chemicals); polyethylene glycols (eg Carbowaxes 3550® and 934® (Union Carbide)), polyoxyethylene stearate, colloidal Cerium oxide, phosphate, sodium lauryl sulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose , hydroxypropyl methylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, poly Enol (PVA), polyvinylpyrrolidone (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol and polymers of ethylene oxide and formaldehyde (also known as Tylo Tyloxapol, superione, and triton, poloxamer (for example, Pluronics F68® and F108®, which are embedded in ethylene oxide and propylene oxide). Segmental copolymer); poloxamine (eg, Tetronic 908®, also known as Poloxamine 908®, which is derived from an adduct of propylene oxide and ethylene oxide continuously added to ethylenediamine) Functional block copolymer (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), a dialkyl sulfosuccinate (eg, Aerosol OT®, which is a sulfonate) Sodium succinate (American Cyanamid), sodium dioctyl sulfosuccinate (DOSS), docusate sodium (Ashland Chem. Co., Columbus, Ohio); Duponol P® It is sodium lauryl sulfate (DuPont); Triton X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110®, which is sucrose stearate and sucrose Stearic acid Mixture (Croda Inc.); p-isodecylphenoxy-poly-(glycidol), also known as Olin-IOG® or Surfact 10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40 ® (Croda, Inc.); and SA9OHCO, which is C ₁₈ H ₃₇ CH ₂ (CON(CH ₃ )--0CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ (Eastman Kodak Co.); decane fluorenyl -N-methylglucamine; n-decyl β -D-glucopyranoside; n-decyl β -D-malemaltoside; n-dodecyl β -D-glucopyranoside; Alkyl β -D-maltoside; heptyl-N-methyl-glucosamine; n-heptyl- β -D-glucopyranoside; n-heptyl β -D-thioglucoside; n-hexyl β- D-glucopyranoside; mercapto-N-methylglucamine; n-decyl- β -D-glucopyranoside; octyl-N-methylglucamine; n-octyl β -D- Chloroglucoside; with octyl β -D-thioglucopyranoside. U.S. Patent Application Publication No. 2010/209479 to Carroll et al. These nanoparticles include carbon nanoparticles such as carbon nanotubes.

A pharmaceutically acceptable co-solvent is described in U.S. Patent No. 8,207,195, issued to Navratil et al., which is incorporated herein by reference. , tert-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, toluene, xylene (such as), ethylene glycol, dichloromethane, 1,2-dichloroethane, N-A Mercaptoamine, N,N-dimethylformamide, N-methylacetamide, pyridine, two Alkane, and ether.

A slurry for a pharmaceutical formulation is described in U.S. Patent Application Publication No. 2006/0229277 to Laxminarayan.

A syrup for use in a pharmaceutical formulation is described in U.S. Patent No. 8,252,930 to Stoit et al. Such syrups may include active ingredients and syrup forming components such as sugars or sugar alcohols, and ethanol, water, glycerin, propylene glycol, and polyethylene glycol. These liquid preparations may contain if necessary Colorants, flavors, preservatives, saccharin and carboxymethylcellulose or other thickeners.

A biodegradable polymer is described in U.S. Patent No. 7,318,931 to Okumu et al. When the bio-digestible polymer is placed in the living body, it decomposes, and the molecular weight of the polymer can be measured to decrease with time. The molecular weight of the polymer can be determined by a variety of different methods, including molecular size size exclusion chromatography (SEC), generally expressed as weight average or number average molecular weight. When the polymer was at pH 7.4 and phosphate buffered saline (PBS) at 37 ° C, its weight average molecular weight was reduced by at least 25% in 6 months as determined by SEC, ie, it was biodegradable. Suitable bio-digestible polymers include polyesters such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutyrate); polyanhydrides such as poly(adipate anhydride). And poly(maleic anhydride); polydioxanone; polyamine; polyamine; polyurethane; polyester decylamine; polyorthoester; polyacetal; polyketal; Polyester carbonate; polyphosphazene; poly(malic acid); poly(amino acid); polyvinylpyrrolidone; poly(methyl vinyl ether); poly(alkyl oxalate) Poly(alkyl succinate); polyhydroxy cellulose; chitin; chitosan; and copolymers and mixtures thereof.

Liposomes are conventional drug delivery vehicles. The lipid system method is described in European Patent Application Publication No. EP 1332755 to Weng et al. Liposomes can accommodate short oligopeptide sequences that can be targeted to the EGFR receptor, as described in U.S. Patent Application Publication No. 2012/0213844 to Huang et al. Alternatively, the liposome can comprise a nuclear localization signal/gene fusion peptide conjugate and form a target liposome complex, as described in the specification U.S. Patent Application Publication No. 2012/0183596 to Boulikas.

The sustained-release gel for injection is well known and described, for example, in "Drug Release from Biodegradable Injectable Thermosensitive Hydrogel of PEG-PLGA-PEG Triblock Copolymers," by J. Controlled Release 63: 155-. 163 (2000).

The use of microspheres to deliver drugs is known in the art and has been disclosed, for example, in "Biodegradable Microspheres in Drug Delivery," by H. Okada & H. Taguchi, Crit. Rev. Ther. Drug Carrier Sys. 12: 1-99 (1995) ).

The use of a targeting composition comprising an epidermal growth factor receptor-binding peptide is described in U.S. Patent Application Publication No. 2010/0151003 to Trikha et al.

When the improvement is made by using a drug conjugate type, the drug conjugate type may be, but not limited to, a drug conjugate type selected from the group consisting of: (a) a polymer system; (b) a polylactic acid; (c) polyglycolide; (d) amino acid; (e) peptide; (f) multivalent linker; (g) immunoglobulin; (h) cyclodextrin polymer; (i) modified Transferrin; (j) a hydrophobic or hydrophobic-hydrophilic polymer; (k) a conjugate with a phosphonic acid partial ester; (1) a conjugate with a cell binding agent incorporating a charged valent crosslinker; (m) a conjugate of a linker with β -glucuronide.

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

Polyglycolide conjugates are also known in the art and are described, for example, in PCT Patent Application Publication No. WO 2003/070823 to Elmaleh et al.

Multivalent linkages are known in the art and are described, for example, in U.S. Patent Application Publication No. 2007/0207952 to Silva et al. For example, a multivalent linker can comprise a thiol group reactive with reactive cysteine, and a multiple nucleophilic group (such as NH or a group that can attach a plurality of biologically active moiety groups to the linker) OH) or an electrophilic group (such as an activated ester).

The conjugate of the immunoglobulin is disclosed in U.S. Patent No. 4,925,662 to Oguchi et al. The conjugate is prepared using a crosslinking agent such as carbodiimide, glutaraldehyde, or diethyl propylenediamine.

The cyclodextrin polymer, its conjugate with a medically active agent, and its co-administration with particles are described in U.S. Patent Application Publication Serial No. 2012/0213854 to Fetzer.

The conjugate with the modified transferrin is described in U.S. Patent Application Publication No. 2011/0288023 to Kamei et al.

The conjugate with a hydrophobic or hydrophobic-hydrophilic polymer is described in U.S. Patent Application Publication No. 2011/0268658 to Crawford et al. Such polymers may include single peptides, dipeptides or tripeptides. These polymers may also include polylactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide) acid (PLGA), polycaprolactone (PCL), polydioxane. Ketone (PDO), polyanhydride, polyorthoester, or chitosan.

The conjugate with the phosphonic acid partial ester is described in U.S. Patent Application Publication No. 2010/227,831 to Saha et al.

The conjugate of a cell-binding agent incorporating a charged cross-linking agent is described in U.S. Patent No. 8,236,319 to Chari et al.

The conjugate of a linker with a beta -glucuronide is described in U.S. Patent No. 8,039,273 to Jeffrey.

Reagents suitable for crosslinking a plurality of functional group combinations are well known in the art. For example, an electrophilic group can react with a number of functional groups, including those found in proteins or polypeptides. Combinations of various reactive amino acids with electrophiles are well known in the art and can be used. For example, an N-terminal cysteine containing a thiol group can be reacted with a halogen or maleimide. Thiol groups are known for many coupling agents (eg, alkyl halides, haloacetyl derivatives, maleimine, aziridine, propylene fluorenyl derivatives), aromatizing agents (eg, aromatic The base halide) and the like are reactive. These are described in "Bioconjugate Techniques" by G.T. Hermanson (Academic Press, San Diego, 1996), pp. 146-150. The reactivity of cysteine residues can be borrowed Optimized by appropriate selection of adjacent amino acid residues. For example, a histidine acid residue adjacent to a cysteine residue increases the reactivity of the cysteine residue. Other combinations of reactive amino acids and electrophilic reagents are known in the art. For example, maleimide can be reacted with an amine group such as an epsilon-amino group from an amine acid side chain, particularly at a higher pH range. Aryl halides also react with such amine groups. The haloacetyl derivative reacts with the imidazolyl side chain nitrogen of histidine, the side chain thioether group of methionine, and the epsilon-amine group of the amine acid side chain. Many of the electrophilic reagents that are reactive with the epsilon-amine groups of the amine acid side chain are known in the art, including, but not limited to, isothiocyanates, isocyanates, decyl azides, N-hydroxy amber. Terpene imide, sulfonyl chloride, epoxide, ethylene oxide, carbonates, imido esters, carbodiimides, and anhydrides. These are described in "Bioconjugate Techniques" by G.T. Hermanson (Academic Press, San Diego, 1996), pp. 137-146. Further, an electrophilic reagent which is known to react with a side chain of a carboxylic acid ester (such as aspartate and glutamate) is, for example, a diazo alkane and a diazoethyl fluorenyl compound, carbonyl diimidazole, and Carbodiimides. These are described in "Bioconjugate Techniques" by G.T. Hermanson (Academic Press, San Diego, 1996), pp. 152-154. Furthermore, electrophilic agents which are known to react with hydroxyl groups (e.g., the hydroxyl groups on the side chains of their serines and threonine) include reactive halocarbon derivatives. These are described in "Bioconjugate Techniques" by G.T. Hermanson (Academic Press, San Diego, 1996), pp. 154-158. In another alternative embodiment, the relative position of the electrophile and the nucleophile (i.e., the molecule that will react with the electrophile) is reversed, so that the amino acid residue of the protein has a reaction with the nucleophile. An electrophilic group and can target a molecule in which a nucleophilic group is included. These include, for example, the reaction of the above aldehyde (electrophile) with hydroxylamine (nucleophile), but are not limited by such reactions; other groups may be used as the electrophile and nucleophile. Suitable groups are conventionally known in the art of organic chemistry and do not require further elaboration.

Other reactive group combinations for crosslinking are known in the art. For example, the amine group can be combined with isothiocyanates, isocyanates, decyl azides, N-hydroxysuccinimide (NHS) esters, sulfonyl chlorides, aldehydes, glyoxal, epoxides, rings Oxygenethane, carbonates, alkylating agents, imidoesters, carbodiimides, and anhydrides are reacted. The thiol group can be reacted with a haloethenyl or alkyl halide derivative, a maleimide, an aziridine, an acrylonitrile derivative, a hydrazine, or the like by oxidation and formation. a thiol group of a sulfide. The carboxyl group can be reacted with a diazo alkane, a diazoacetinyl compound, a carbonyl diimidazole, or a carbodiimide. Hydroxyl groups can be used with epoxides, ethylene oxide, carbonyl diimidazole, N,N ' -disuccinimide carbonate, N-hydroxysuccinimide chloroformate, periodate (for oxidation) Reaction), alkyl halogen, or isocyanate reaction. The aldehyde and ketone groups can be reacted with hydrazines, Schiff base forming reagents, and other groups for reductive amination reactions or Mannich condensation reactions. Still other groups suitable for crosslinking reactions are known to those skilled in the art. Such cross-linking reagents and reactions are described in GTHermanson, "Bioconjugate Techniques" (Academic Press, San Diego, 1996).

When improved by using a compound analog, the compound analog may be, but not limited to, a compound selected from the group consisting of the following: Analogs: (a) altering the side chain to increase or decrease lipophilicity; (b) adding additional chemical functional groups to alter the properties of the group selected from the group consisting of: reactivity, electron affinity, and binding ability; And (c) changing the salt type.

When improved by the use of a prodrug system, the prodrug system can be, but is not limited to, a prior art 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; and (f) using a drug that releases nitric oxide; (g) using a fibroblast Activating the protein alpha cleavable oligopeptide prodrug; (h) using a drug that is a reaction product with an ethylating agent or an amine carbinylating agent; (i) using a drug (j) prior to use as a hexanoate conjugate To be a polymer-formulation conjugate prodrug; and (k) to use a drug that can be subjected to a redox activation reaction.

The term "prodrug" as used herein refers to a compound that can be converted in vivo to the disclosed compound or a pharmaceutically acceptable form of the compound. In some embodiments, the prodrug is a compound that can be converted under physiological conditions or solvosolved to a biologically active compound as described herein. Therefore The term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. Prodrugs may be inactive when administered to an individual, but may be converted to the active compound in vivo, for example, via hydrolysis (eg, hydrolysis in blood or tissue). In some instances, the prodrug has improved physical and/or delivery properties over the parent compound from which the prodrug is derived. Prodrugs often provide solubility, tissue compatibility, or delayed release advantages in mammalian organisms (H. Bundgard, Design of Drugs (Elsevier, Amsterdam, 1988), pp. 7-9, 21-24). A discussion of prodrugs is provided in T. Higuchi et al., "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14 and EB Roche, Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987). . Examples of advantages of prodrugs include, but are not limited to, their physical properties, such as enhancing the solubility at physiological pH in parenteral administration, enhancing the absorption of the digestive tract, or enhancing the stability of long-term storage compared to the parent compound. Sex.

The term "prodrug" also includes any covalently bonded carrier which, when administered to an individual, releases the active compound in vivo. The prodrugs of the medically active compounds described herein are modified to modify one or more functional groups of the medically active compound in a manner which will be cleavable by routine manipulation or in vivo to produce a medically active parent compound. Prodrugs include compounds in which a hydroxyl group, an amine group, or a thiol group are covalently bonded to any group such that when the active compound is administered to an individual, it can be cleaved separately to form a free hydroxyl group, a free amine group, or a free thiol group. . Examples of prodrugs include, but are not limited to, alcohol formate or benzoate derivatives, or amines available for reaction A functionally active medically active agent of acetamide, formamide or benzamide derivative.

For example, if the pharmaceutically active agent or health of the medical type comprising a pharmaceutically active agent of the carboxylic acid functional group, a prodrug can comprise the replacement of a hydrogen atom from the carboxylic acid group of the group formed by the esters: such as C _{1- 8-} alkyl, C _2-12 alkyl fluorenyloxymethyl, 1-(alkyl fluorenyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1- having 5 to 10 carbon atoms (alkylnonyloxy)ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, having 5 to 1-methyl-1-(alkoxycarbonyloxy)ethyl group of 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl group having 3 to 9 carbon atoms, having 4 to 10 carbons 1-(N-(alkoxycarbonyl)amino)ethyl, 3-indenyl, 4-crotonyl lactone, γ -butyrolactone-4-yl, di-N,N (C ₁ -C ₂ )alkylamino (C ₂ -C ₃ )alkyl (such as (3-dimethylaminoethyl), amine indenyl-(C ₁ -C ₂ )alkyl, N,N- Di(C ₁ -C ₂ )alkylaminemethanyl-(C ₁ -C ₂ )alkyl and piperidinyl-, pyrrolidinyl-, or N-morpholinyl(C ₂ -C ₃ )alkyl .

Similarly, if the disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, the hydrogen atom of the alcohol group can be replaced by the following group to form a prodrug: such as (C ₁ -C ₆ )alkylmercaptooxymethyl , 1-((C ₁ -C ₆ ))alkylnonyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkylenyloxy)ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N(C ₁ -C ₆ ) alkoxycarbonylaminomethyl, amber fluorenyl, (C ₁ -C ₆ )alkyl fluorenyl, α-amino group (C ₁ - C ₄ ) an alkyl fluorenyl group, an aryl fluorenyl group and an α-amino fluorenyl group, or an α-amino fluorenyl-α-amino fluorenyl group, wherein each α-amino fluorenyl group is independently selected from the group consisting of: natural L- Amino acid, P(O)(OH) ₂ , P(O)(O(C ₁ -C ₆ )alkyl) ₂ or a glycosyl group (a group formed by removing a hydroxyl group from a hemiacetal type carbohydrate) ).

If the disclosed compound or a pharmaceutically acceptable form of the compound comprises an amine functional group, the hydrogen atom of the amine group may be replaced by a group such as: R-carbonyl, RO-carbonyl, NRR ' -carbonyl (where R And R ' are independently (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ )cycloalkyl, benzyl, or R-carbonyl are natural α-aminoindenyl or natural α-aminoindole Base-natural α-aminoindenyl), 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 )alkylaminoalkyl), 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, N-morpholinyl, piperidin-1-yl or pyrrolidin-1-yl).

The use of prodrug systems is described in "Design and Pharmaceutical Applications of Prodrugs" by T. Järvinen et al., Drug Discovery Handbook (SCGad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 17, pp. 733. -796. This publication uses an enzyme-sensitive ester as a prodrug. The use of dimers as prodrugs is described in U.S. Patent No. 7,879,896 to Allegretti et al. The use of peptides in prodrugs has been described in "Delivering Multiple Anticancer Peptides as a Single Prodrug Using Lysyl-Lysine as a Facile Linker," J. Peptide Sci. 13:458-467 (2007) by S. Prasad et al. The use of Schiff base as a prodrug is described in U.S. Patent No. 7,619,005 to Epstein et al. The use of a caffeine complex as a prodrug is described in U.S. Patent No. 6,443,898 to Unger et al. The use of a nitric oxide-releasing prodrug is described in N. Nath et al., "JS-K, a Nitric Oxide-Releasing Prodrug, Modulates β -Catenin/TCF Signaling in Leukemic Jurkat Cells: Evidence of an S-Nitrosylated Mechanism," Biochem . Pharmacol. 80: 1641-1649 (2010). U.S. Patent Application Publication No. 2002/0155565 to Garin-Chesa et al. The use of a reaction product with an acetamidine or an amine formazon as a prodrug is described in JHLin & JYHLu, "Role of Pharmacokinetics and Metabolism in Drug Discovery and Development," Pharmacol. Rev. 4: 403-449 (1997). ). The use of hexanoate conjugates is described in U.S. Patent No. 8,101,661 issued to Mickle. The use of a polymerization agent-formulation conjugate is described in R. Satchi et al., "PDEPT: Polymer-Directed Enzyme Prodrug Therapy," Br. J. Cancer 85: 1070-1076 (2001). The use of a drug prior to reductive oxygen activation is described in SH Van Rijt & PJ Sadler, "Current Applications and Future Potential for Bioinorganic Chemistry in the Development of Anticancer Drugs," Drug Discov. Today 14: 1089-1097 (2009).

When improved by the use of 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) multiple drug resistance inhibitors; (b) specific drug resistance Inhibitor; (c) a specific inhibitor of a selective enzyme; (d) signal transduction inhibitor; (e) mesoindigo; (f) imatinib; (g) hydroxyurea; (h) dasatinib; (i) card Capecitabine; (j) nilotinib; (k) repair inhibitor; and (l) topoisomerase inhibitors without overlapping side effects.

Multi-drug resistance inhibitors are described in U.S. Patent No. 6,011,069 issued to Inomata et al.

Specific anti-drug inhibitors are described in T. Hideshima et al., "The Proteasome Inhibitor PS-341 Inhibits Growth, Induces Apoptosis, and Overcomes Drug Resistance in Human Multiple Myeloma Cells," Cancer Res. 61:3071-3076 (2001).

Selective inhibitors of specific enzymes are described in D. Leung et al., "Discovering Potent and Selective Reversible Inhibitors of Enzymes in Complex Proteomes," Nature Biotechnol. 21: 687-691 (2003).

Repair inhibition has been described by N.M. Martin, "DNA Repair Inhibition and Cancer Therapy," J. Photochem. Photobiol. B 63: 162-170 (2001).

When improved by the biomedical agent strengthening method, it can be used For the sensitizer/potentiator, a medical agent or technique is used in combination for the biomedical agent strengthening method, which may be, but not limited to, a medical agent or technology selected from the group consisting of: (a) cytokines; (b) lymphokines; (c) medical antibodies; (d) antisense therapy; (e) gene therapy; (f) ribozyme; (g) RNA interference; and (h) vaccine.

Antisense therapies are described, for example, in "Antisense RNA Gene Therapy for Studying and Modulating Biological Processes," by Cell. Mol. Life Sci. 55: 334-358 (1999) by B. Weiss et al.

Ribozymes are described, for example, in "RNA-Based Therapies" by S. Pascolo, in Drug Discovery Handbook (S. C. Gad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 27, pp. 1273-1278.

RNA interference is described, for example, in "RNA-Based Therapies" by S. Pascolo, in the Drug Discovery Handbook (S. C. Gad, ed., Wiley-Interscience, Hoboken, NJ, 2005), ch. 27, pp. 1278-1283.

As mentioned above, usually cancer vaccines are based on the presence of cancer The cells do not have an immune response to the protein or protein group of normal cells. Cancer vaccines include Provenge for metastatic hormone-resistant prostate cancer, Oncophage for kidney cancer, CimaVax-EGF for lung cancer, and cancer for Her2/neu (eg breast cancer, colon cancer, bladder cancer, and Ovarian cancer) MOBILAN, Neuvenge, Stimuvax for breast cancer, etc. Cancer vaccines have been described in the above document, S. Pejawar-Gaddy & O. Finn (2008).

When a biomedical agent boosting method is used as a sensitizer/potentiator, when used in combination with a medical antibody, the medical antibody may be, but not limited to, a medical antibody selected from the group consisting of: Bevac Monoclonal antibody (bevacizumab) (Avastin), rituximab (Rituxan), trastuzumab (Herceptin), and west Cetuximab (Erbitux).

When improved by using a biomedical agent resistance control method, the biomedical agent resistance control method may be, but not limited to, used to combat resistance to medical agents or techniques that have been grouped from the following: Polymorphic glioblastoma: (a) a biological response modifier; (b) cytokines; (c) lymphokines; (d) medical antibodies; (e) antisense therapy; (f) gene therapy; (g) ribozyme; (h) RNA interference; and (i) vaccine.

When biomedical agent resistance regulation is used to combat tumor resistance to medical antibodies, the medical antibody can be, but is not limited to, a medical antibody selected from the group consisting of bevacizumab (bevacizumab) ) (Avastin), rituximab (Rituxan), trastuzumab (Herceptin), and cetuximab (cetuximab) (Erbitux).

When enhanced by enhanced radiation therapy, the booster radiation therapy can be, but is not limited to, a radiation therapy booster or technique selected from the group consisting of: (a) an anoxic cell sensitizer; (b) radiation. a sensitizer/protective agent; (c) a photosensitizer; (d) a radiation repair inhibitor; (e) a thiol consumer; (f) a vascular targeting agent; (g) a DNA repair inhibitor; Radioactive particles; (i) radionuclides; (j) radiolabeled antibodies; and (k) in vivo radiation therapy (brachytherapy).

Substituted hexitol derivatives (eg, dehydrated galactitol) Radiotherapy can be used in combination for the treatment of glioblastoma multiforme or other malignant diseases as described herein.

Hypoxic cell sensitizers have been described by C. C. Ling et al., "The Effect of Hypoxic Cell Sensitizers at Different Irradiation Dose Rates," Radiation Res. 109:396-406 (1987). Radiosensitizers are described in "Radiation Sensitizers and Targeted Therapies," Oncology 17 (Suppl. 13) 23-28 (2003) by T. S. Lawrence. Radioprotectants have been described in "Evaluation of D-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis," by S. B. Vuyyuri et al., Clin. Cancer Res. 14:2161-2170 (2008). Photosensitizers have been described in "Oncologic Photodynamic Therapy Photosensitizers: A Clinical Review," Photo Diagnosis Photodynamic Ther. 7: 61-75 (2010) by R. R. Allison & C. H. Sibata. Radiation repair inhibitors and DNA repair inhibitors have been described in "Evaluation of Repair of Radiation-Induced DNA Damage Enhances Expression from Replication-Defective Adenoviral Vectors," by M. Hingorani et al., Cancer Res. 68: 9771-9778 (2008). Thiol consuming agents have been described in "Postirradiation Sensitization of Mammalian Cells by the Thiol-Depleting Agent Dimethyl Fumarate," Radiation Res. 127: 75-80 (1991) by K. D. Held et al. The vascular targeting agent has been described in "Tumor Necrosis Factor α Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response," A.L. Seynhaeve et al., Cancer Res. 67: 9455-9462 (2007). As mentioned above, radiation therapy is often used to treat GBM, so enhanced radiation therapy is of importance for this malignant disease.

When the novel action is used for improvement, the novel action can be, but is not limited to, a novel interaction with a target or a machine that is selected from the group consisting of: (a) Inhibitors of poly-ADP ribose polymerase; (b) preparations that affect vascular structure or vasodilation; (c) agents that target carcinogenicity; (d) signal transduction inhibitors; (e) EGFR inhibition; f) protein kinase C inhibition; (g) phospholipase C downregulation; (h) Jun downregulation; (i) histone genes; (j) VEGF; (k) avian acid decarboxylase; (l) pan (C) Jun D; (n) v-Jun; (o) GPCR; (p) protein kinase A; (q) protein kinase other than protein kinase A; (r) prostate specific gene; (s) telomerase; (t) histone deacetylase; and (u) tyrosine kinase inhibitor.

EGFR inhibition has been described in G. Giaccon & JA Rodriguez, "EGFR Inhibitors: What Have We Learned from the Treatment of Lung Cancer," Nat. Clin. Pract. Oncol. 11: 554-561 (2005). Protein kinase C inhibition has been described by HCS Wannie & SB Kaye, "Protein Kinase C Inhibitors," Curr. Oncol. Rep. 4: 37-46 (2002). Phospholipase C downregulation has been described in "Marostelli et al., "Phosphoinositide Signaling in Nuclei of Friend Cells: Phospholipase C beta Downregulation Is Related to Cell Differentiation," Cancer Res. 54: 2536-2540 (1994). The down-regulation of Jun (clearly c-Jun) has been described in AAPZada et al., "D Downregulation of c-Jun Expression and Cell Cycle Regulatory Molecules in Acute Myeloid Leukemia Cells Upon CD44 Ligation," Oncogene 22: 2296-2308 ( 2003). The role of histone genes as a medical intervention has been described in B. Calabretta et al., "Altered Expression of G1-Specific Genes in Human Malignant Myeloid Cells," Proc. Natl. Acad. Sci. USA 83: 1495-1498 (1986) ). The role of VEGF as a target for medical intervention has been described in "VEGF-Mediated Angiogenesis of Human Pheochromocytomas Is Associated to Malignancy and Inhibited by anti-VEGF Antibodies in Experimental Tumors," A. Zielke et al., Surgery 132: 1056-1063 (2002). ). The role of alginate decarboxylase as a target for medical intervention has been described in "Targeting Ornithine Decarboxylase in Myc-Induced Lymphomagenesis Prevents Tumor Formation," by Canonsson et al., Cancer Cell 7: 433-444 (2005). The role of ubiquitin C as a target for medical intervention has been described in C. Aghajanian et al., "A Phase I Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies," Clin. Cancer Res. 8:2505-2511 (2002) ). The role of Jun D as a target for medical intervention has been described in "JunD Is Involved in the Antiproliferative Effect of △ ^{9 -} Tetrahydrocannibinol on Human Breast Cancer Cells," Oncogene 27: 5033-5044 (2008) by MMCaffarel et al. The role of v-Jun as a target for medical intervention has been described in M. Gao et al., "Differential and Antagonistic Effects of v-Jun and c-Jun," Cancer Res. 56: 4229-4235 (1996). The role of protein kinase A as a target for medical intervention has been described in PC Gordge et al., "Elevation of Protein Kinase A and Protein Kinase C in Malignant as Compared With Normal Breast Tissue," Eur. J. Cancer 12: 2120-2126 (1996). ). The role of telomerase as a target for medical intervention has been described in EK Parkinson et al., "Telomerase as a Novel and Potentially Selective Target for Cancer Chemotherapy," Ann. Med. 35: 466-475 (2003). The role of histone deacetylase as a target for medical intervention has been described in "Histone Deacetylases as Therapeutic Targets in Hematologic Malignancies," Curr. Opin. Hematol. 9:322-332 (2002) by A. Melnick & JDLicht.

When using a selective target cell population medical approach When improved, the use of the selective target cell population medical method can be, but is not limited to, the use of a group selected from the group consisting of: (a) for anti-radiosensitive cells; (b) for anti-radiation resistance Cells; and (c) for combating energy-consuming cells.

It can also be used in combination by using dehydrated galactitol, diethyl hydrazine galactitol, or di-dehydrated galactitol or a derivative or analog of diethyl hydrazine galactitol. Free radiation is improved.

When the improvement is carried out by enhancing the activity of an alkylated hexitol derivative such as di-dehydrated galactitol or diethyl hydrazine galactitol, the enhanced alkylated hexitol derivatives are The active preparation may be, but not limited to, a preparation selected from the group consisting of: (a) nicotinamide; (b) caffeine; (c) tetandrine; and (d) berberine. .

When the improvement is made by using a preparation for counteracting myelosuppressive action, the preparation for counter-myelosuppressive action may be, but not limited to, a dithiocarbamate.

US Patent No. 5,035,878 to Borch et al. discloses the use of dithiocarbamate for the treatment of myelosuppression; the dithiocarbamate is of the formula R ¹ R ² NCS(S)M or R ¹ A compound of R ² NCSS-SC(S)NR ³ R ⁴ wherein R ¹ , R ² , R ^{3 are the} same as or different from R ⁴ , and R ¹ , R ² , R ³ and R ⁴ are aliphatic, a cycloaliphatic or heterocyclic aliphatic group which is unsubstituted or substituted with a hydroxy group; or wherein one of R ¹ and R ² and one of R ³ and R ⁴ may be hydrogen; or wherein R ¹ , R ² , R ³ , and R ⁴ may form a 5-membered or 6-membered N-heterocyclic ring together with a nitrogen atom substituted with a pair of R groups, which is a lipid or interpenetrated with an epoxy or a second ring nitrogen. The lipid system, and M is hydrogen or one equivalent of a pharmaceutically acceptable cation, in which case the remaining molecules are negatively charged.

U.S. Patent No. 5,294,430 to Borch et al. discloses other dithiocarbamates for the treatment of myelosuppressive properties. In general, these are compounds of the formula (DI): Wherein: (i) R ¹ and R ² are the same or different C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₅ -C ₆ heterocycloalkyl; or (ii) R ¹ And one of R ² (but not simultaneously) may be H; or (iii) R ¹ and R ² may form a 5-membered or 6-membered N-heterocyclic ring with a nitrogen atom, which is a lipid or interspersed with a ring Oxygen or a second ring nitrogen lipid; and (iv) M is hydrogen or one equivalent of a pharmaceutically acceptable cation, in which case the remaining molecules are negatively charged; or (v) M is as in formula (D-II) Part of the group: Wherein R ³ and R ⁴ are the same as defined for R ¹ and R ² . Wherein the group defined by the formula (DI) is an anion, the cation may be an ammonium cation or may be derived from a monovalent or divalent metal such as an alkali metal or an alkaline earth metal such as Na ⁺ , K ⁺ , or Zn ⁺² . Taking dithiocarbamic acid as an example, a group as defined by formula (DI) is attached to an ionizable hydrogen atom; typically the hydrogen atom will dissociate at a pH above about 5.0. The dithiocarbamate which can be used is: N-methyl, N-ethyldithiocarbamate, hexamethylenedithiocarbamate, bis(β-hydroxyethyl)dithio Different kinds of dipropyl, dibutyl and dipentyl esters of sodium carbamide and dithiocarbamate, N-methyl, sodium N-cyclobutylmethyldithiocarbamate, N-allyl-N-cyclopropane Sodium methyldithiocarbamate, cyclohexylpentyl dithiocarbamate, diphenylmethyl-dithiocarbamate, dimethylene-dithiocarbamate, various different Dithiocarbamate, pyrrolidine-N-dithioformate, piperidine-N-dithiocarbamate, morpholine-N-dithiocarbamate, α-mercaptodithiocarbamate And imidazoline dithiocarbamate. Another option is one in which R ^{1 of} formula (DI) is substituted with a hydroxy group, or preferably a lower alkyl group having up to 6 carbon atoms substituted by a (two to five) polyhydroxy group. For example: R ¹ can be HO-CH ₂ -CHOH-CHOH-CHOH-CHOH-CH ₂ -. In such compounds, R ² can be H or a lower alkyl group (unsubstituted or substituted with one or more hydroxyl groups). When R ² is H, methyl, or ethyl, stereoscopic problems can be minimized. Therefore, such a particularly preferred compound is N-methyl-glucosamine dithiocarbamate, and the most preferred cation of these salts is sodium or potassium. Other preferred dithiocarbamate salts include alkali metal or alkaline earth metal salts wherein the anion is di-n-butyldithiocarbamate, di-n-propyldithiocarbamate, penta-methylene Dithiocarbamate, or tetramethylene dithiocarbamate.

When the preparation is improved by using a preparation for increasing the ability of the substituted hexitol to pass through the blood-brain barrier, the preparation for improving the ability of the substituted hexitol to pass the blood-brain barrier may be a group selected from the following Formulations of the group: (a) a chimeric peptide of the structure of formula (D-III): Wherein: (A) A is somatostatin, thyroid stimulating hormone releasing hormone (TRH), angiotensin, alpha interferon, endorphin, cell wall dipeptide or ACTH 4-9 analogue; (B) B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of formula (D-III), wherein the A The disulfide-bonded bridge chain between B is replaced by a small molecule (D-III(a)) bridge: A-NH(CH ₂ ) ₂ SSB (cleavable linker) (D-III(a)), Wherein the bridge chain forms a bridge chain using cysteamine and EDAC as a bridging agent; or a chimeric peptide of the structure of formula (D-III), wherein the disulfide bridge between the A and B is as small as Molecular Formula (D-III(b)) Bridge Chain Replacement: A-NH=CH(CH ₂ ) ₃ CH=NH-B (non-cleavable linker) (D-III(b)), wherein the bridge is used Glutaraldehyde is formed as a bridging agent; (b) a substituted hexitol derivative comprising avidin or avidin fusion protein-bonded biotinylated to form avidin-biotin-formulation complex a composition of matter comprising a protein selected from the group consisting of: pancreas , transferrin, anti-receptor monoclonal antibody, cationized protein, and lectin; (c) neutral liposome, which is glycosylated and incorporated into the substituted hexitol And wherein the polyethylene glycol strand is conjugated to at least one transportable peptide or targeting agent; (d) a humanized murine antibody that is linked to the trans-avidin-biotin linkage a human insulin receptor binding of a hexitol derivative; and (e) a fusion protein comprising a first segment and a second segment: the first segment comprises a variable region of an antibody that recognizes an antigen on a cell surface Performing antibody-receptor-mediated endocytosis after binding to the variable region of the antibody, and further comprising at least one functional domain of the constant region of the antibody, if desired; and the second segment comprises a material selected from the group consisting of Group of protein domains: avidin, avidin mutein, chemically modified avidin derivative, streptavidin, streptavidin mutein, and chemically modified Streptavidin derivative The fusion protein of the link connected to the substituted hexitol covalent biotin.

A formulation for improving the ability to penetrate blood-brain barriers is disclosed in "The Blood-Brain Barrier: Botleneck in Brain Drug Development," Neuro Rx 2: 3-14 (2005) by W. M. Pardridge.

One such preparation is disclosed in U.S. Patent No. 4,801,575 issued to Pardridge, which discloses a chimeric peptide for delivering a formulation through the blood-brain barrier. Such chimeric peptides include peptides of the structure of formula (D-IV): Wherein: (i) A is a somatostatin, a thyroid stimulating hormone releasing hormone (TRH), an angiotensin, an alpha interferon, a endorphin, a cell wall dipeptide or an ACTH 4-9 analogue; and (ii) B is insulin, IGF-I, IGF-II, transferrin, cationized (alkaline) albumin or prolactin. In still another alternative, the disulfide-bonded bridge between A and B is replaced by a small molecule (D-IV(a)) bridge: A-NH(CH ₂ ) ₂ SSB (cleavable linker) ) (D-IV (a) ); small as the formula (D-III (a)) of a bridge formed when tethered cysteamine and EDAC as a bridging chain. In still another alternative, the disulfide bridge between A and B is replaced by a bridge of the small formula (D-IV(b)): A-NH=CH(CH ₂ ) ₃ CH=NH-B (non-cleavable linker) (D-IV (b)); the bridge chain of the small formula (D-III (b)) is formed when glutaraldehyde is used as a bridge agent.

US Patent No. 6,287,792 to Pardridge et al. discloses a method and composition for delivering a formulation through the blood-brain barrier comprising a biotinylated or avidin fusion protein-bound biotinylated formulation, An avidin-biotin-formulation complex is formed. The avidin fusion protein may comprise an amino acid sequence of a protein such as insulin or transferrin, an anti-receptor monoclonal antibody, a cationized protein, or a lectin.

U.S. Patent No. 6,372,250 to Pardridge discloses a method and composition for the passage of a liposome delivery formulation through the blood-brain barrier. The liposome is a neutral liposome. The surface of the neutral liposome is polyethylene glycolated. The polyethylene glycol strands are joined to a transportable peptide or other targeting agent. Suitable targeting agents include insulin, transferrin, insulin-like growth factors, or lectins. Alternatively, the surface of the liposome can be joined to two different transportable peptides, one of which targets the endogenous BBB receptor and the other that targets the endogenous BCM (brain cell serosa) peptide. The latter is specific to specific cells in the brain, such as neurons, glial cells, pericytes, smooth muscle cells, or microglia. The targeted peptide may be an endogenous peptide ligand of the receptor, an analog of the endogenous ligand, or a peptide mimetic MAb that will bind to the same receptor as the endogenous ligand. A monoclonal antibody of a transferrin receptor-specific peptide mimetic can be used as a transportable peptide. A monoclonal antibody against the human insulin receptor can be used as a transportable peptide. The bonding agent that can be used to join the blood barrier targeting agent to the surface of the liposome can be any of the conventional polymeric bonding agents such as sphingomyelin, polyethylene glycol (PEG) or other organic polymers, preferably PEG. The liposomes preferably have a diameter of less than 200 nanometers. Liposomes having a diameter between 50 and 150 nm are preferred. Particularly preferred liposomes or other nanocontainers have a diameter of about 80 nm. Suitable types of lipid system made neutral phospholipid, such as 1-acyl-2-palm oil acyl - sn - glycero-3-phosphocholine (POPC), di-acyl phosphatidyl choline phosphate, distearyl XI Phospholipid thioglycolamine (DSPE), or cholesterol. The transportable peptide is linked to the liposome by thiolation with a transportable peptide (such as insulin or HIRMAb) and conjugated to a small portion of the maleic imine group at the top of the PEG strand; or The surface carboxyl group of the transit peptide (such as transferrin or TfRMAb) is bonded to have a carboxyl activating group (such as N-methyl-N ' -3 (dimethylaminopropyl) carbodiimide hydrochloride (EDAC) a 醯肼 (Hz) partial group at the top of the PEG strand; thiolated from the transportable peptide and bonded to the N-succinimide 3-(2-pyridyl) by a disulfide linkage a liposome that reacts with a thio)propionate (SPDP); or is joined to a liposome surface by a transportable peptide using avidin-biotin technology, eg, by a biotinylation of a transportable peptide, and Avidin or streptavidin (SA) binding on the surface of the PEG strand.

U.S. Patent No. 7,388,079 to Pardridge et al. discloses the use of a humanized murine antibody that binds to the human insulin receptor; the humanized murine antibody can be linked to the preparation to be delivered via an avidin-biotin linkage.

U.S. Patent No. 8,124,095 to Pardridge et al. discloses a monoclonal antibody that binds to a transport system mediated by an intrinsic blood-brain barrier receptor and is therefore a carrier for transport of BBB. Individual antibodies can be, for example, specifically binding to human pancreas on human BBB An antibody to an island receptor.

US Patent Application Publication No. 2005/0085419 to Morrison et al. discloses the use of antibody-receptor-mediated endocytosis to deliver fusion proteins of various formulations to cells comprising a first segment and a second segment: first The segment comprises a variable region of an antibody that recognizes an antigen on the surface of the cell, performs antibody-receptor-mediated endocytosis upon binding to the variable region of the antibody, and further comprises at least an antibody constant region as needed a functional domain; and the second segment comprises a protein domain selected from the group consisting of avidin, avidin mutein, chemically modified avidin derivative, streptavidin Biotin protein, streptavidin mutein, and chemically modified streptavidin derivatives. Usually the antigen is a protein. Usually the protein antigen on the surface of the cell is a receptor, such as a transferrin receptor or an insulin receptor. The invention also encompasses antibody constructs incorporating a fusion protein that is a heavy or light chain that, together with a complementary light or heavy chain, forms an intact antibody molecule. The medical agent can be a non-protein molecule and can be covalently linked to biotin.

Inhibitors of poly-ADP ribose polymerase (PARP) enzymes have been developed for a variety of indications, especially for the treatment of malignant diseases. Several cancer types are more dependent on PARP activity than non-malignant cells.

PARP enzyme catalyzes the polymerization of poly-ADP ribose chains, usually attached to a single strand of cellular DNA. The coenzyme NAD ^{+ is required} as a substrate to produce an ADP-ribose monomer which can be used for polymerization; nicotine decylamine is a detachment group during polymerization, whereas, during normal DNA or RNA synthesis, pyrophosphate is used as a detachment group, the former The pyrophosphate is left as a linker between adjacent ribose in the chain, unlike the phosphate present in normal DNA or RNA. The PARP enzyme contains four functional domains: a DNA-binding domain, a caspase-cleavage domain, an auto-modifying domain, and a catalytic domain. The DNA-binding domain contains two zinc finger motifs. When a damaged DNA is present, the DNA-binding domain will bind to the DNA and induce a conformational change. PARP can be inactivated by cleavage of caspase-3, which occurs in the course of planning for cell death (apoptosis).

Several PARP enzymes are known, including PARP1 and PARP2. Of these two enzymes, PARP1 is responsible for most cellular PARP activities. PARP1 binds to the single-strand break in the DNA through the zinc-terminal motif at the amino terminus, and recruits XRCC1, DNA-binding enzyme III, DNA polymerase β, and kinase to the nick. This process is called base excision repair (BER). PARP2 has been shown to oligomerize with PARP1 and this oligomerization stimulates this catalytic activity. PARP2 therefore also relates to BER.

PARP1 inhibitors inhibit PARP1 activity and thus inhibit the repair of single-strand breaks in DNA. When these breaches are not repaired, subsequent DNA replication induces a double-strand break. The proteins BRCA1, BRCA2, and PALB2 repair DNA double-strand breaks by an error-free homologous recombinational repair (HRR) pathway. In tumors with mutations in the genes BRCA1 , BRCA2 , or PALB1 , these double-stranded fissures cannot be effectively repaired, resulting in cell death. Normal cells do not replicate their DNA as frequently as tumor cells, and normal cells without mutated BRCA1 or BRCA2 proteins can still repair these double-strand breaks through homologous repair. Thus normal cells are less sensitive to PARP inhibitor activity than tumor cells.

Some tumor cells lacking the tumor preparation PTEN may be sensitive to PARP inhibitors due to the downregulation of related homologous recombination components. Tumor cells under hypoxia are also sensitive to PARP inhibitors.

PARP inhibitors are also considered to be useful for the treatment of other life-threatening diseases, including stroke and myocardial infarction, and long-term neurodegenerative diseases (G. Graziani & C. Szabó, "Clinical Perspectives of PARP Inhibitors," Pharmacol. Res .52:109-118 (2005)).

A wide variety of PARP inhibitors are known in the art. PARP inhibitors include, but are not limited to, iniparib, talazoparib, olaparib, rucaparib, veliparib, CEP- 9722 (CEP-8983 (11-methoxy-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)- Diketone prodrug), MK 4827 ((S)-2-(4-(piperidin-3-yl)phenyl)-2H-carbazole-7-carboxamide), and BGB-290.

U.S. Patent No. 9,073,893 to Papeo et al. discloses 3-oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP inhibitors, including: 3-sided oxy groups -2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclopentylpiperidin-4-yl)-3-sideoxy Benzyl-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclohexylpiperidin-4-yl)-3-yloxy-2,3-dihydro-1H- Oxazole-4-carboxyguanamine; 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-yloxy-2,3-dihydro-1H-indazole- 4-carboxyguanamine; 2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1-H-indazole-4- Carboxylamidine; 2-(1-cyclopentylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 2 -(1-methylpiperidin-4-yl)-3-oxooxy-2,3-dihydro-1H-indazole-4-carboxamide; 1-methyl-3-oxo-2 -(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 1-methyl-2-(1-methylpiperidin-4-yl)-3- Sideoxy-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-ethylpiperidin-4-yl)-3-oxo-2,3-dihydro- 1H-carbazole-4-carboxamide; 3-oxo-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-ethylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 1-methyl-3 -Sideoxy-2-[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide; 3-sided oxy-2 -[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidine-4- 3-yloxy-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-3- side Oxy-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidin-4-yl)-1-methyl-3-oxo- 2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2 , 3-dihydro-1H-indazole-4-carboxamide; 6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-carbazole- 4-carboxyguanamine; 6-fluoro-1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 2- (1-cyclohexylpiperidin-4-yl)-6-fluoro-3-indolyl-2,3-dihydro-1H-indazole-4-carboxamide; 2-[1-(4,4 -difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; [1-(4,4-Dichlorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxylate Guanamine.

U.S. Patent No. 9,062,061 to Honda et al. discloses a PARP inhibitor of formula (PI): Wherein: (1) R ¹ represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amine group, a nitro group or a cyano group; (2) R ² and R ³ may be the same or different, respectively Represents a hydrogen atom, a halogen atom, or a lower alkyl group; (3) R ⁴ and R ⁵ may be the same or different and each represent a hydrogen atom, a halogen atom or a lower alkyl group, or R ⁴ and R ⁵ may form a pendant oxy group; R ^a and R ^b may be the same or different and each represent a hydrogen atom, a lower alkyl group (which may optionally have a substituent), or an aryl group (which may optionally have a substituent); R ^a and R ^b may be bonded to each other to form a nitrogen-containing heterocyclic ring which may be substituted by one or more R ^c ; (4) R ^c represents a lower alkyl group (which may optionally have one substituent), a lower carbon cycloalkyl group (which a substituent may be optionally included), an aryl group (which may optionally have a substituent), a heterocyclic group (which may optionally have a substituent), a hydroxyl group, a lower alkoxy group (which may optionally have a substituent), a low carbon number An alkylcarbonyl group (which may optionally have a substituent), a lower carbon cycloalkylcarbonyl group (which may optionally have a substituent), a lower alkylalkylaminocarbonyl group (which may optionally have a substituent), and a low a cycloalkylaminocarbonyl group (which may optionally have a substituent), a lower alkoxycarbonyl group (which may optionally have a substituent), an amine group, a lower alkylamino group or a carboxyl group; (5) an A ring Represents a benzene ring or an unsaturated heteromonocyclic ring; and (6) m represents 0, 1, or 2.

U.S. Patent No. 9,062,043 to Chua et al. discloses a fused tricyclic PARP inhibitor comprising a compound of formula (P-II):

U.S. Patent No. 9,018,201 to Chu et al. discloses a dihydropyridinopyridazinone inhibitor of PARP.

U.S. Patent No. 8,993,594 to Pape et al. discloses a substituted isoquinoline-1(2H)-one derivative as a PARP inhibitor.

U.S. Patent No. 8,980,902 to Brown et al. discloses substituted benzamide PARP inhibitors, including: N-ethyl-4-(4-((6-o-oxy-5,6-dihydro) Pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N-methyl-4-(4-( (6-Sideoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzimidazole Amine; N-cyclopropyl-4-(4-((6-o-oxy-5,6-dihydropyridyl) [2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-chloro-N-methyl-4-(4 -((6-Phenoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzene Methionamine; 3-chloro-N-ethyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]] Pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N,3-dimethyl-4-(4-((6-o-oxy-5,6-dihydropyridine) [2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N-ethyl-3-methyl-4-( 4-((6-Phenoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl) Benzylamine; 3-fluoro-N-methyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c] Pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; and N-ethyl-3-fluoro-4-(4-((6-o-oxy-5,6-di) Hydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide.

U.S. Patent No. 8,946,221 to Mevellec et al. discloses a pyridazine derivative as a PARP inhibitor.

U.S. Patent No. 8,894,989 to Xu et al. discloses a tetraazaphenalen-3-one derivative as a PARP inhibitor.

U.S. Patent No. 8,889,866 to Angibaud et al. discloses tetrahydrophenanthone and tetrahydrocyclopentaquinolinone as PARP inhibitors.

U.S. Patent No. 8,883,787 to Xu et al. discloses diazabenzo[de]indol-3-one derivatives as PARP inhibitors.

U.S. Patent No. 8,877,944 to Pape et al., the disclosure of which is incorporated herein by reference. As a PARP inhibitor, including 2-[1-(cis-4-methoxycyclohexyl)piperidin-4-yl]-3-yloxy-2,3-dihydro-1H-isoindole -4-carboxyguanamine; 2-[1-(trans-4-methoxycyclohexyl)piperidin-4-yl]-3-yloxy-2,3-dihydro-1H-isoindole -4-carboxyguanamine; 2-{1-[cis-4-(hydroxymethyl)cyclohexyl]piperidin-4-yl}-3-yloxy-2,3-dihydro-1H-iso吲哚-4-carboxyguanamine; 2-{1-[trans-4-(hydroxymethyl)cyclohexyl]piperidin-4-yl}-3-yloxy-2,3-dihydro-1H -isoindole-4-carboxyguanamine; 2-{1-[cis-4-(methoxymethyl)cyclohexyl]piperidin-4-yl}-3-yloxy-2,3- Dihydro-1H-isoindole-4-carboxamide; 2-{1-[trans-4-(methoxymethyl)cyclohexyl]piperidin-4-yl}-3-yloxy- 2,3-dihydro-1H-isoindole-4-carboxamide; 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-indolyl-2, 3-dihydro-1H-isoindole-4-carboxamide; 2-[1-(1,4-dioxaspiro[4.5]dec-8-yl)piperidin-4-yl]-3- Sideoxy-2,3-dihydro-1H-isoindole-4-carboxamide; 2-{1-[4-(dimethylamino)benzyl]piperidin-4-yl}- 3-sided oxy-2,3-dihydro-1H-isoindole-4-carboxamide; 2-[1-(4-fluorobenzyl)piperidin-4-yl]-3-sideoxy Base-2,3-dihydro-1H-iso哚-4-carboxyguanamine; 2-[1-(2-fluorobenzyl)piperidin-4-yl]-3-yloxy-2,3-dihydro-1H-isoindole-4- Carboxylamidine; 2-[1-(3-fluorobenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; 2-{1-[(1-methyl-1H-pyrrol-2-yl)methyl]piperidin-4-yl}-3-yloxy-2,3-dihydro-1H-isoindole- 4-carboxyguanamine; 3-oxo-2-{1-[4-(trifluoromethylbenzyl)piperidin-4-yl}-2,3-dihydro-1H-isoindole- 4-carboxyguanamine; 3-oxo-2-[1-(quinolin-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-isoindole-4- Carboxylamidine; 2-[1-(2,4-difluorobenzyl)piperidin-4-yl]-3-yloxy-2,3-dihydro-1H-isoindole-4-carboxylate Indoleamine; 2-[1-(3,4-dimethylbenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4- Carboxylamidine; 2-[1-(2-methylbenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide ;2-[1-(2-bromobenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; 2-[ 1-(3-bromobenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; 2-[1-(4 -bromobenzyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; with 3-sided oxy-2-{1 -[3-(Trifluoromethyl)benzyl]piperidin-4-yl}-2,3-dihydro-1H-isoindole-4-carboxamide.

U.S. Patent No. 8,778,966 to the name of U.S. Pat.

U.S. Patent No. 8,697,736 to Penning et al. discloses 1H-benzimidazole-4-carboxamide as a PARP inhibitor.

The PARP inhibitors disclosed in U.S. Patent No. 8,669,249 to Brown et al. include: 2-methyl-6-((4-phenylpiperidin-1-yl)methyl)-2H-benzo[b] [1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-phenylpiperazin-1-yl)methyl)-2H-benzo[b][1,4] Pyrazine-3(4H)-one; 6-((4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-yl)methyl)-2-methyl-2H-benzene And [b][1,4] Pyridin-3(4H)-one; 6-((4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-yl)methyl)-2-methyl-2H-benzene And [b][1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-p-tolylpiperidin-1-yl)methyl)-2H-benzo[b][1,4] Pyridin-3(4H)-one; 6-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Azin-3(4H)-one; 6-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazin-1-yl)methyl) -2H-benzo[b][1,4] Pyridin-3(4H)-one; 6-((4-cyclopentylpiperazin-1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Pyrazin-3-(4H)-one; 6-((4-(1-benzo[d]imidazol-2-yl)piperazin-1-yl)methyl)-2-methyl-2H-benzo [b][1,4] (S)-2-methyl-6-((4-phenylpiperidin-1-yl)methyl)-2H-benzo[b][1,4] (R)-2-methyl-6-((4-phenylpiperidin-1-yl)methyl)-2H-benzo[b][1,4] Pyridin-3(4H)-one; 6-((4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)-2-methyl-2H-benzo[ b][1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-2H-benzo[b][1,4 ] Pyridin-3(4H)-one; 4-(4-((2-methyl-3-yloxy-3,4-dihydro-2H-benzo[b][1,4]] 6-((4-cycloheptylpiperazin-1-yl)methyl)-2-methyl-2H-benzo[b] ][1,4] Pyrazin-3-(4H)-one; 1,3,7-trimethyl-8-(4-((2-methyl-3-yloxy-3,4-dihydro-2H-benzo[ b][1,4] Pyrida-6-yl)methyl)piperazin-1-yl)-1H-indole-2,6(3H,7H)-dione; 6-((4-(4-aminophenyl)piperazine- 1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Pyridin-3(4H)-one; 6-((4-(6-fluorobenzo[d]) Zyrid-3-yl)piperidin-1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Pyridin-3(4H)-one; 6-((4-(2-hydroxyphenyl)piperazin-1-yl)methyl)-2-methyl-2H-benzo[b][1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-phenyl-5,6-dihydropyridine-1(2H)-yl)methyl)-2H-benzo[b][ 1,4] Pyridin-3(4H)-one; 2-methyl-6-((4-phenyl-5,6-dihydropyridine-1(2H)-yl)methyl)-2H-benzo[b][ 1,4] Azin-3(4H)-one; 6-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)-2-methyl-2H-benzo[b][1, 4] Ethyl-3(4H)-one; 6-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)-2-methyl-2H-benzo[b][1 , 4] (S)-6-((4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-yl)methyl)-2-methyl -2H-benzo[b][1,4] (R)-6-((4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-yl)methyl)-2-methyl -2H-benzo[b][1,4] Pyridin-3(4H)-one; with 2-methyl-6-((3-oxo-4-phenylpiperazin-1-yl)methyl)-2H-benzo[b][1, 4] Pyrazin-3(4H)-one.

U.S. Patent No. 8,663,884 to Kennis et al. discloses quinazolinedione derivatives as PARP inhibitors.

U.S. Patent No. 8,623,872 to Guillemont et al. discloses quinazolinone derivatives as PARP inhibitors.

U.S. Patent No. 8,546,368 to Penning et al. discloses pyrazoloquinolones as PARP inhibitors, including 7,9-dimethyl-1,2,3,4,6,7-hexahydro-5H-pyridin. Zoxao[3,4-h]-1,6-naphthyridin-5-one.

U.S. Patent No. 8,541,417 to Brown et al. discloses PARP inhibitors, including: 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6 (5H) -ketone; N-ethyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl) Methyl) piperazin-1-yl)benzamide; N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrole) And [1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N-cyclopropyl-4-(4-((6- oxo-5), 6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-chloro-N-A 4-(4-((6-Phenoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazine -1-yl)benzamide; 3-chloro-N-ethyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[ 1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N,3-dimethyl-4-(4-((6- oxo-5), 6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N-ethyl 3-methyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)) Piperazine-1-yl)benzamide; 3-fluoro-N-methyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e] Pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N-ethyl-3-fluoro-4-(4-((6-side) Oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N- Isopropyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl) Piperazine-1-yl)benzamide; N-isopropyl-3-methyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e] Pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-fluoro-N-isopropyl-4-(4-((6-) Sideoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide;3 -Chloro-N-isopropyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3- Methyl)piperazin-1-yl)benzamide; 3-bromo-N-isopropyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2] , 3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; N -isopropyl-3-methoxy-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine- 3-yl)methyl)piperazin-1-yl)benzamide; N-isopropyl-3-(methylamino)-4-(4-((6- oxo-5,6) -dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-ethyl-N-iso Propyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperidin Nazin-1-yl)benzamide; N-isopropyl-3-(methylsulfanyl)-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3] -e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-bromo-N-methyl-4-(4-((6) - alkoxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide; 3-methoxy -N-methyl-4-(4-((6-o-oxy-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)) Peptazin-1-yl)benzamide; and N-methyl-3-(methylamino)-4-(4-((6-o-oxy-5,6-dihydropyridine) [2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide.

U.S. Patent No. 8,541,403 to Chu et al. discloses dihydropyridinopyridazinone derivatives as PARP inhibitors, including: 8,9-diphenyl-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one; 8,9-bis(4-methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one; 8,9-bis(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]酞Azin-3(7H)-one; 8,9-bis(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)- Ketone; 8,9-bis(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-isopropyl -8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(4-((methylamino)methyl) Phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(4-((dimethyl) Amino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(3- ((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; -(4((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2Hpyrido[4,3,2-de]pyridazine-3(7H)-one , 8,9-bis(3-((methylamino)methyl)phenyl)-8,9-di Hydrogen)-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3(7H)-one; 8,9-bis(3-(4-(isobutyrylpiperazine-1-carbonyl) Phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine -3(7H)-one; 9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]酞Pyrazin-3(7H)-one; 9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de] Pyridazine-3(7H)-one; 8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one; 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8(4-((methylamino)methyl) Phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; with 9-(4-(4-(cyclopropanecarbonyl)piperidin Pyrazin-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de] Pyridazine-3(7H)-one.

U.S. Patent No. 8,513,433 to Panicker et al. discloses inhibitors of PARP, including 2-(4-aminoformamido-1H-benzo[d]imidazol-2-yl)porphyrin-1-carboxylic acid Benzyl ester; 2-(porphyrin-2-yl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-aminocarbamimido-1H-benzo[d]imidazole 2-yl)-3,4-dihydroquinolin-1(2H)-carboxylic acid tert-butyl ester; 2-(1,2,3,4-tetrahydroquinolin-2-yl)-1H -benzo[d]imidazole-4-carboxamide; 1-(4-aminocarbamimido-1H-benzo[d]imidazol-2-yl)isoindoline-2-carboxylic acid benzyl ester ; 2-(isoindoline-1-yl)-1H-benzo[d]imidazole-4-carboxamide; 1-(4-aminocarbamimido-1H-benzo[d]imidazole-2- -3,4-dihydroisoquinoline-2(1H)-carboxylic acid benzyl ester; 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-1H-benzene And [d]imidazole-4-carboxamide; 3-(4-aminocarbamimido-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2 (1H) - benzyl carboxylic acid ester; 2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide; 3-(4- Aminomethyl-1H-benzo[d]imidazol-2-yl)-3-methyl-3,4-dihydroisoquinolin-2(1H)-carboxylic acid benzyl ester; 2-(3 -methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxylate Indoleamine; 7-((t-butoxycarbonyl)amino)-3-(4-aminocarbazinyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquine Tert-butyl-2(1H)-carboxylic acid tert-butyl ester; 7-amino-3-(4-aminocarbazinyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydro Isoquinoline-2(1H)-carboxylic acid tert-butyl ester; (3-(4-aminocarbamimido-1H-benzo[d]imidazol-2-yl)-1,2,3,4- Tert-butyl tetrahydroisoquinolin-7-yl)aminecarboxylate; with 2-(7-amino-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzoate [d] Imidazole-4-carboxyguanamine.

U.S. Patent No. 8,470,825 to Xu et al. discloses a substituted diazabenzo[de]indol-3-one compound as a PARP inhibitor.

U.S. Patent No. 8,420,650, issued toWang et al., discloses a dihydropyridinopyridazinone inhibitor of PARP comprising: 8,9-bis(pyridin-4-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one; 8,9-bis(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one; 8,9-bis(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H)-keto; 5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2- De]pyridazine-3(7H)-one; 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl -1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(1-isopropyl-1H -imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(4-methyl -1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 8-phenyl- 9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(1- Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 8,9 - bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-( 1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9-(1-B -1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 8-phenyl -9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 9- (1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one; 8-(4-Fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine- 3(7H)-one; 9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one; with 8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2 , 4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one.

U.S. Patent No. 8,362,030 to Ingenito et al. discloses a tricyclic PARP inhibitor comprising: N-methyl[4-(6-o-oxy-3,4,5,6-tetrahydro-2H-nitrogen) Indolo[5,4,3-cd]oxazol-2-yl)phenyl]methylammonium trifluoroacetate; N,N-dimethyl[4-(6-sideoxy-3,4,5 ,6-tetrahydro-2H-azino[5,4,3-cd]oxazol-2-yl)phenyl]methylammonium trifluoroacetate; N ² ,N ² -dimethyl-N-[ 4-(1-o-oxy-1,2,3,4-tetrahydroazino[3,4,5-hi]pyridazin-5-yl)phenyl]glycidylamine; 3-[ 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-2H-azino[5,4,3-cd]oxazol-2-yl)phenyl]piperidine鎓Trifluoroacetate; 8-fluoro-2-{4-[(3R)-piperidin-3-yl]phenyl}-2,3,4,5-tetrahydro-6H-azaindole [5, 4,3-cd]carbazole-6-one; 8-fluoro-2-{4-(3S)-piperidin-3-yl]phenyl}-2,3,4,5-tetrahydro-6H- Nitroindolo[5,4,3-cd]oxazol-6-one; 2-[4-(6-o-oxy-3,4,5,6-tetrahydro-2H-azaindole[5, 4,3-cd]oxazol-2-yl)benzyl]-2,7-diaza cation spiro[4.5]decane bis(trifluoroacetate); [4-(8-fluoro-6-side Oxy-3,4,5,6-tetrahydro-2H-azino[5,4,3-cd]oxazol-2-yl)phenyl]-N,N-dimethylmethylammonium trifluoride Acetate; 5-phenyl-3,4-dihydroindolo[3,4,5-hi]吲哚Pyridin-1(2H)-one; 4-(1-o-oxy-1,2,3,4-tetrahydroindolo[3,4,5-hi]pyridazin-5-yl)benzoic acid Ethyl ester; 5-(4-nitrophenyl)-3,4-dihydroindolo[3,4,5-hi]pyridazine-1(2H)-one; 5-[4-( Hydroxymethyl)phenyl]-3,4-dihydroindolo[3,4,5-hi]pyridazine-1(2H)-one; N-[4-(1-trioxy-1 , 2,3,4-tetrahydroindolo[3,4,5-hi]pyridazin-5-yl)phenyl]nicotinium amide; N-[4-(1-sideoxy-1 , 2,3,4-tetrahydroindolo[3,4,5-hi]pyridazin-5-yl)phenyl]pyridine-2-carboxamide; and N-[4-(1- side Oxyl-1,2,3,4-tetrahydroindolo[3,4,5-hi]pyridazin-5-yl)phenyl]-2-pyrrolidin-1-ylacetamide.

U.S. Patent No. 8,354,413 to Jones et al. discloses quinolin-4-one and 4-sided oxydihydroporphyrin derivatives as PARP inhibitors, including: 1-[3-(8-aza-1) -Nitrogen snail [4.5] 癸-8-ylcarbonyl)-4-fluorobenzyl]-4- oxo-1,4-dihydroquinolinium bis(trifluoroacetate); 1-[4 -fluoro-3-({4-[2-(4-fluorobenzyl) amidoximeyl]piperazin-1-yl}carbonyl)benzyl]quinoline-4(1H)-one; 1- [3-(8-Aza-1-nitrogen snail [4.5] fluoren-8-ylcarbonyl)-4-fluorobenzyl]-4- oxo-1,4-dihydroporphyrin-1- Bis(trifluoroacetate); 1-[3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl]quinoline-4(1H)-one; -{4-Fluoro-3-[(4-propynylpiperazin-1-yl)carbonyl]benzyl}quinoline-4(1H)-one; 1-(4-fluoro-3-{[3 -(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]carbonyl}benzyl}quinoline- 4(1H)-ketone; 1-[3-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-4-fluorobenzyl]quinoline-4(1H)-one; 1-[4-fluoro-3 -(piperazin-1-ylcarbonyl)benzyl]quinoline-4(1H)-one; 1-[3-(2,6-diazaspiro[3.5]indol-2-ylcarbonyl)-4 -fluorobenzyl]quinoline-4(1H)-one; 1-[3-(2,5-diazabicyclo[2.2.2]oct-2-ylcarbonyl)-4-fluorobenzyl] Quinoline-4(1H)-one; 1-(4-fluoro-3-{[4-(2-methylindenyl)piperazin-1-yl]carbonyl}benzyl}quinoline-4 (1H)-keto; 1-(4-fluoro-3-{[4-(3,3,3-trifluoro-N,N-dimethylpropylaminoindolyl)piperazin-1-yl]carbonyl}benzene Methyl)quinoline-4(1H)-one; (2R)-2-[(4-{2-fluoro-5-[(4-side oxyquinolin-1(4H)-yl)methyl] Benzamethylene}piperazin-1-yl)carbonyl]-2-methylazetidiniumtrifluoroacetate; 1-{4-fluoro-3-[(4-propynylpiperazine-1 -yl)carbonyl]benzyl}-4- oxo-1,4-dihydroporphyrin-1-indole trifluoroacetate; 1-{3-[(3-ethyl-5,6-di Hydrogen [1,2,4]triazolo[4,3-a]pyrazine-2-indole-7(8H)-yl)carbonyl]-4-fluorobenzyl}-4- oxo-1 , 4-dihydroporphyrin-1-indole bis(trifluoroacetate); 1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2, 4] Triazolo[4,3-a]pyrazine-7(8H)-yl]carbonyl}benzyl}-4-oxo-1,4- Hydroquinone-1-indole trifluoroacetate; and 8-fluoro-1-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4] Triazolo[4,3-a]pyrazine-7(8H)-yl]carbonyl}benzyl)-4-oxo-1,4-dihydroporphyrin-1-indole trifluoroacetate.

U.S. Patent No. 8,268,827 to Branca et al. discloses pyridazinone derivatives as PARP inhibitors, including: 6-{4-fluoro-3-[(3-oxo-4-phenylpiperazine-1 -yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate; 6-{3-[(4- Cyclohexyl-3-yloxypiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1 -鎓Trifluoroacetate; 6-{3-[(4-cyclopentyl-3-oxyloxypiperazine) -1-yl)carbonyl]-4-fluorobenzyl}-4,5-dimethylpyridazin-3(2H)-one; 6-{4-fluoro-3-[(3-sideoxy-) 4-phenylpiperazin-1-yl)carbonyl]benzyl}-4,5-dimethylpyridazin-3(2H)-one hydrochloride; 4-ethyl-6-{4-fluoro- 3-[(3-Sideoxy-4-phenylpiperazin-1-yl)carbonyl]benzyl}pyridazine-3(2H)-one trifluoroacetate; 6-{3-[(4- Cyclohexyl-3-yloxypiperazin-1-yl)carbonyl]-4-fluorobenzyl}-4-ethylpyridazine-3(2H)-one trifluoroacetate; 3-{4-fluoro -3-[(4-Methyl-3-oxopoxypiperazin-1-yl)carbonyl]benzyl}-4,5-dimethyl-6-oxo-1,6-dihydroanthracene Azin-1-indole trifluoroacetate; 3-(4-fluoro-3-{[4-(4-fluorobenzyl)-3-oxopiperazin-1-yl]carbonyl}benzyl) -4,5-dimethyl-6-o-oxy-1,6-dihydropyridazine-1-indole trifluoroacetate; 6-(3-{[4-(2-chlorophenyl)-3 -Sideoxypiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1-fluorene Acetate; 6-(3-{[4-(3-chloro-4-fluorophenyl)-3-oxoxypiperazin-1-yl]carbonyl}-4-fluoro-benzyl)-4, 5-dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate; 6-(3-{[4-(3,4-difluorophenyl)-3 -Sideoxypiperazin-1-yl]carbonyl}-4-fluoro Methyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridazine-1-indole trifluoroacetate; and 6-(3-{[4-(3,5-) Difluorophenyl)-3-oxopiperazin-1-yl]carbonyl}-4-fluorobenzyl)-4,5-dimethyl-3-oxo-2,3-dihydroanthracene Pyrazine-1-indole trifluoroacetate.

U.S. Patent No. 8,217,070 to Zhu et al. discloses 2-substituted-1H-benzimidazole-4-carboxamide as a PARP inhibitor, including: 2-(1-aminocyclopropyl)-1H -benzimidazole-4-carboxyguanamine; 2-[1-(isopropylamino)cyclopropyl]-1H-benzimidazole-4-carboxyguanamine; 2-[1-(cyclobutylamine) Cyclopropyl]-1H-benzimidazole-4-carboxyguanamine; 2-{1-[(3,5-dimethylbenzyl)amino]cyclopropyl}-1H-benzimidazole -4-carboxyguanamine; 2-{1-[(pyridyl) Pyridin-4-ylmethyl)amino]cyclopropyl}-1H-benzimidazole-4-carboxamide; 2-[1-(dipropylamino)cyclopropyl]-1H-benzimidazole -4-carboxyguanamine; 2-{1-[bis(cyclopropylmethyl)amino]cyclopropyl}-1H-benzimidazole-4-carboxyguanamine; 2-(1-aminocyclobutane -1H-benzimidazole-4-carboxyguanamine; 2-[1-(propylamino)cyclobutyl]-1H-benzimidazole-4-carboxyguanamine; 2-{1-[( Cyclopropylmethyl)amino]cyclobutyl}-1H-benzimidazole-4-carboxamide; 2-[1-(isopropylamino)cyclobutyl]-1H-benzimidazole-4 Carboxylamidine; 2-[1-(dipropylamino)cyclobutyl]-1H-benzimidazole-4-carboxamide; 2-[1-(dibutylamino)cyclobutyl] -1H-benzimidazole-4-carboxamide; 2-(1-aminocyclohexyl)-1H-benzimidazole-4-carboxyguanamine; 4-[4-(aminocarbonyl)-1H-benzene And imidazol-2-yl]piperidin-4-ylaminecarboxylic acid 9H-fluoren-9-ylmethyl ester; 4-amino-4-[4-(aminocarbonyl)-1H-benzimidazole-2- Benzylpyridine-1-carboxylic acid benzyl ester; [2-(4-amino-piperidin-4-yl]-1H-benzimidazole-4-carboxylic acid decylamine; 2-(2-amine -1,2,3,4-tetrahydronaphthalen-2-yl)-1H-benzimidazole-4-carboxamide; and 2-(2-amino-2,3-dihydro-1H-indole -2-yl)-1H-benzimidazole-4-carboxyguanamine.

U.S. Patent No. 8,188,103 to Van der Aa et al. discloses a substituted 2-alkylquinazolinone derivative as a PARP inhibitor.

U.S. Patent No. 8,173,682 to Weintraub et al. discloses 2,3,5-substituted pyridone derivatives as PARP inhibitors, including: 5-(5-ethyl-2-methyl-6-side oxygen -1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(3-hydroxy-pyrrolidin-1-yl)-propyl]-nonylamine hydrochloride; 5- (5-ethyl-2-methyl-6-o-oxy-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic acid [2-(1-methylpyrrolidin-2-yl) Ethyl] decylamine hydrochloride; 5-(5-ethyl-2- Methyl-6-o-oxy-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(3,3-difluoro-pyrrolidin-1-yl)-propyl ]-guanamine hydrochloride; 5-[5-ethyl-2-methyl-6-o-oxy-1,6-dihydropyridin-3-yl]thiophene-2-sulfonic acid [3-(2 -Sideoxypyrrolidin-1-yl)propyl]decylamine; 5-[5-ethyl-2-methyl-6-o-oxy-1,6-dihydropyridin-3-yl]thiophene- 2-sulfonic acid methyl (1-methylpyrrolidin-3-yl) decylamine hydrochloride; 3-ethyl-5-[5-(3-hydroxypyrrolidin-1-sulfonyl)thiophene-2 -yl]-6-methyl-1H-pyridin-2-one; 5-(5-ethyl-2-methyl-6-o-oxy-1,6-dihydropyridin-3-yl)thiophene- 2-sulfonic acid (2-pyrrolidin-1-yl)ethylguanamine hydrochloride; 5-(5-ethyl-2-methyl-6-o-oxy-1,6-dihydropyridine-3 -yl)-thiophene-2-sulfonic acid (1-ethyl-pyrrolidin-2-ylmethyl)decylamine hydrochloride; 3-ethyl-6-methyl-5-[5-((S) -2-phenylaminomethylpyrrolidin-1-sulfonyl)-thiophen-2-yl]-1H-pyridin-2-one hydrochloride; 5-(5-ethyl-2-methyl- 6-Sideoxy-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [3-(2R-hydroxymethyl-pyrrolidin-1-yl)-propyl]-decylamine Hydrochloride; 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonic acid [2 -(2R-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-nonylamine hydrochloride; 5-(5-ethyl-2-methyl-6-oxo-oxy-1,6-di Hydrogen-pyridin-3-yl)-thiophene-2-sulfonic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-ethyl]-decylamine; and 1-{2-[5- (5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-sulfonylamino]-ethyl}-pyrrolidine-2 -carboxylic acid.

US Patent No. 8,129,382 to Kalish et al. discloses a PARP inhibitor of formula (P-III) Wherein: (1) R1 is H, halogen, alkoxy, or lower alkyl; (2) R2 is H, halogen, alkoxy, or lower alkyl; (3) R3 is independently H , an amine group, a hydroxyl group, --NN, a halogen-substituted amine group, an -O-alkyl group, an -O-aryl group, or an optionally substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, Heterocycloalkyl, aryl, heteroaryl, --COR8, wherein R8 is H, --OH, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl Or a heteroaryl group, or --OR6 or -NR6R7, wherein R6 and R7 are each independently hydrogen or may be substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or hetero Aryl; (4) R4 is independently H, amine, hydroxy, -N--N, -CO--NN, halogen-substituted amine group, -O-alkyl group, -O-aryl group Or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR8 group optionally substituted, wherein R8 is H, -OH, optionally substituted An alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, or --OR6 or --NR6R7, wherein R6 and R7 are independently Hydrogen may be optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and (5) R5 are independently H, amine, hydroxy, -N -N, -CO--NN, halogen-substituted amine group, -O-alkyl group, -O-aryl group, or alkyl, alkenyl group, alkynyl group, cycloalkyl group which may be optionally substituted , heterocycloalkyl, aryl, heteroaryl, --COR8, wherein R8 is H, --OH, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl Or heteroaryl, or --OR6 or --NR6R7, wherein R6 and R7 are each independently hydrogen or may be substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl.

U.S. Patent No. 8,088,760 to Chu et al. discloses the benzene of PARP. Carbazole carbamide inhibitors, including: 2-(4-((methylamino)methyl)phenyl)benzo[d] Oxazole-4-carboxyguanamine; 2-(2-methylpyrrolidin-2-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(4-((methylamino)methyl)phenyl)benzo[d] Zylo-7-carboxyguanamine; 2-(2-methylpyrrolidin-2-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(pyrrolidin-2-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(pyrrolidin-2-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(7-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(7-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(2-methyl-7-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(2-methyl-7-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(2-azabicyclo[2.1.1]hexane-1-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(2-azabicyclo[2.1.1]hexane-1-yl)benzo[d] Azole-7-carboxyguanamine; 2-(6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Zylo-7-carboxyguanamine; 2-((1S,5R)-6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-((1S,5R)-6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Zylo-7-carboxyguanamine; 2-((1R,5S)-6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-((1R,5S)-6-azabicyclo[3.2.1]octane-5-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(2-benzyl-2-azabicyclo[2.2.2]octane-1-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(2-benzyl-2-azabicyclo[2.2.2]octane-1-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(2-azabicyclo[2.2.2]octane-1-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(2-azabicyclo[2.2.2]octane-1-yl)benzo[d] Zylo-7-carboxyguanamine; 2-(4-azaspiro[2.4]heptane-5-yl)benzo[d] Oxazole-4-carboxyguanamine; 2-(4-azaspiro[2.4]heptane-5-yl)benzo[d] Zylo-7-carboxyguanamine; 2-((1R,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Oxazol-4-carboxyguanamine; with 2-((1R,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d] Azole-7-carboxyguanamine.

U.S. Patent No. 8,071,623 to Jones et al., the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the in the in the in the in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in Carboxylamidine; 2-{4-[(3R)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; 2-{4-[(3S)-piperidine-3 -yl]phenyl}-2H-carbazole-7-carboxamide; 5-fluoro-2-(4-piperidin-3-ylphenyl)-2H-carbazole-7-carboxamide; 5- Fluor-2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; 5-fluoro-2-{4-[(3R)-piperidine -3-yl]phenyl}-2H-carbazole-7-carboxyguanamine; 5-fluoro-2-(3-fluoro-4-piperidin-3-ylphenyl)-2H-carbazole-7- Carboxylamidine; 5-fluoro-2-{3-fluoro-4-[(3R)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; with 5-fluoro-2 -{3-Fluoro-4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

U.S. Patent No. 8,058,275 to Xu et al. discloses a diazabenzo[de]indol-3-one compound as a PARP inhibitor.

U.S. Patent No. 8,012,976 to Wang et al. discloses dihydropyridinopyridazinone compounds as PARP inhibitors, including 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H -1,2,4-Triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one.

U.S. Patent No. 8,008,491 to Jiang et al. discloses substituted azaindole derivatives as PARP inhibitors, including: 1-phenyl-2-(piperazin-1-yl)-1,3-di Hydropyrrolo[2,3-b]pyridine-3-carbaldehyde, 1-phenyl-2-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde, 2 -[1,4]diazepan-1-yl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-formaldehyde trifluoroacetate, with 2-piperazine-1 -yl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde bis-trifluoroacetate.

U.S. Patent No. 7,999,117 to Giranda et al. discloses 1H-benzimidazole-4-carboxamide as a PARP inhibitor, including: 6-fluoro-2-[4-((S)-2-hydroxymethyl) Pyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 6-fluoro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl) Phenyl]-1H-benzimidazole-4-carboxamide; 6-fluoro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H- Benzimidazole-4-carboxyguanamine; 2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxyguanamine; 2-[4-(2-Trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxyguanamine; 2-[4-((R)-2-hydroxyl Methyl pyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide; 6-chloro-2-[4-(2-trifluoromethylpyrrolidin-1-yl) Phenyl]-1H-benzimidazole-4-carboxamide; 6-chloro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]- 1H-benzimidazole-4-carboxyguanamine; 6-chloro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)benzene -1H-benzimidazole-4-carboxyguanamine; 2-[2-fluoro-4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzene Imidazole-4-carboxyguanamine; 2-{4-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxyguanamine; and 2-( 4-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-carboxyguanamine.

U.S. Patent No. 7,994,182 to Sumegi et al. discloses quinazolinone derivatives as PARP inhibitors of formula (P-IV): Wherein: (1) R ¹ is hydrogen or a small molecule (P-IV (a)) part of the group: (2) k is 1, 2, 3, or 4; (3) n is 0 or 1; (4) Q is an oxy group or hydrogen; (5) R _a and R _b are each independently hydrogen or C ₁ -C ₆ alkyl; (6) R _b and R _d are independently C ₁ -C ₆ alkyl; (7) in the six-membered rings optionally selected the dotted line covalent bond (the bond is a single or double bond); (8) R ² is: (8a) if R ^{1 is} not hydrogen, it is hydrogen or C ₁ -C ₆ alkyl; (8b) if R ¹ is hydrogen, it is a small formula (P-IV(b) )), small formula (P-IV (c)), or small formula (P-IV (d)) group: Wherein: (9) in the small molecular formula (P-IV(b)), k, n, R _a , R _b , R _c , R _d , and the dotted line are as described above in (2), (3), (5), (6), and (7); (10) In the small formula (P-IV(c)), k is 1, 2, or 3, and R ³ and R ⁴ are independently C ₁ -C ₆ An alkyl group; (11) or together with the attached nitrogen to form a small formula (P-IV(e)) group, wherein p is 0 or 1, and R _{a '} , R _{b '} , R _{c '} , and R _{d 'is} independently hydrogen or C ₁ -C ₆ alkyl; And (11) a small molecular formula (in P-IV(d), n, R _a , R _b , R _c , R _d , and a dotted line are as described above in (3), (5), (6), and (7). The definition in ).

U.S. Patent No. 7,834,015 to Jones et al. discloses pyrrolo[1,2-a]pyrazine-1(2H)-one and pyrrolo[1,2-d][1,2,4]triazine A -1(2H)-one derivative is used as a PARP inhibitor.

U.S. Patent No. 7,825,129 to Pellicciari et al. discloses thieno[2,3-c]quinolone as a PARP inhibitor, including a compound of formula (PV): Wherein: (1) Y is selected from the group consisting of sulfur, nitrogen, and oxygen; (2) R ₁ , R ₂ , R ₃ , R ₄ , and R _{5 are the} same or different from R ₆ and represent hydrogen, hydroxyl, OR ₇ , respectively. COOR ₇ , carboxyl, amine, NHR ₇ or halogen, or R ₅ and R ₆ together form a fused non-aromatic 5- or 6-membered carbocyclic ring; and (3) R ₇ is a C ₁ -C ₆ alkyl group a C ₂ -C ₆ alkenyl group or a C ₃ -C ₇ cycloalkyl group which may optionally be substituted with one or more groups selected from the group consisting of a hydroxyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, a C ₁ - C ₆ alkoxycarbonyl, amine, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino and halogen.

U.S. Patent No. 7,820,668 to Xu et al. discloses a diazabenzo[de]indole-3-one compound as a PARP inhibitor.

U.S. Patent No. 7,732,491 to Sherman et al. discloses 4-iodo-3-nitrobenzamide as a PARP inhibitor.

U.S. Patent No. 7,728,026 to Zhu et al. discloses 2-substituted 1H-benzimidazole-4-carboxamide as a PARP inhibitor, including 2-(1-amino-1-methylethyl). -1H-benzimidazole-4-carboxyguanamine; 2-[1-methyl-1-(propylamino)ethyl]-1H-benzimidazole-4-carboxyguanamine; 2-[1- (butylamino)-1-methylethyl]-1H-benzimidazole-4-carboxamide; 2-{1-methyl-1-[(2-phenylethyl)amino]B }}-1H-benzimidazole-4-carboxyguanamine; 2-[1-(Isopropylamino)-1-methylethyl]-1H-benzimidazole-4-carboxyguanamine; 2-{1-[(cyclopropylmethyl)amino]- 1-methylethyl}-1H-benzimidazole-4-carboxamide; 2-[1-(cyclobutylamino)-1-methylethyl]-1H-benzimidazole-4-carboxylate Indoleamine; 2-[1-(cyclopentylamino)-1-methylethyl]-1H-benzimidazole-4-carboxyguanamine; 2-(1-{[(cyclopentylamino)) Carbonyl]amino}-1-methylethyl)-1H-benzimidazole-4-carboxyguanamine; 2-(1-{[(ethylamino)carbonyl]amino}-1-methylethyl -1H-benzimidazole-4-carboxyguanamine; 2-(1-{[(dimethylamino)sulfonyl]amino}-1-methylethyl)-1H-benzimidazole -4-carboxyguanamine; 2-(3-amino-1-methylpropyl)-1H-benzimidazole-4-carboxyguanamine; 2-[3-(cyclopentylamino)-1- Methylpropyl]-1H-benzimidazole-4-carboxamide; 2-[3-(cyclohexylamino)-1-methylpropyl]-1H-benzimidazole-4-carboxamide; 2-(1-Aminoethyl)-1H-benzimidazole-4-carboxamide; 2-[1-(propylamino)ethyl]-1H-benzimidazole-4-carboxyguanamine; 2-[1-(butylamino)ethyl]-1H-benzimidazole-4-carboxyguanamine; 2-{1-[(cyclopropylmethyl)amino]ethyl}-1H-benzene Imidazole-4-carboxyguanamine; 2-[1-(isobutylamino)ethyl]-1H- Imidazole-4-carboxyguanamine; 2-[1-(isopropylamino)ethyl]-1H-benzimidazole-4-carboxyguanamine; 2-[1-(cyclopentylamino)ethyl -1H-benzimidazole-4-carboxamide; 2-[1-(cyclohexylamino)ethyl]-1H-benzimidazole-4-carboxyguanamine; 2-{1-[(2 -phenylethyl)amino]ethyl}-1H-benzimidazole-4-carboxamide; 2-[1-(dipropylamino)ethyl]-1H-benzimidazole-4-carboxylate Indoleamine; 2-{1-[butyl(pentyl)amino]ethyl}-1H-benzimidazole-4-carboxamide; 2-{1-[bis(cyclopropylmethyl)amine Ethyl}-1H-benzimidazole-4-carboxamide; 2-(1-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-benzimidazole-4- Carboxylamidine; 2-(1-aminopropyl)-1H-benzimidazole-4-carboxamide; 2-[(1R)-1-(dimethylamino)-2-phenylethyl ]-1H-benzimidazole-4-carboxyindole An amine; with 2-(1-amino-1-methylethyl)-5-chloro-1H-benzimidazole-7-carboxamide.

U.S. Patent No. 7,595,406 to Penning et al. discloses substituted 1H-benzimidazole-4-carboxamide as a PARP inhibitor, including 2-{4-[1-(cyclohexylmethylamino)B. Phenyl]phenyl}-1H-benzimidazole-4-carboxamide; 2-[4-(1-cyclobutylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide; 2-[3-(2-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxyguanamine; 2-(4-cyclopropylaminomethylphenyl)-1H- Benzimidazole-4-carboxyguanamine; 2-(4-cyclobutylaminomethylphenyl)-1H-benzimidazole-4-carboxyguanamine; 2-(4-cyclopentylaminomethyl) Phenyl)-1H-benzimidazole-4-carboxamide; 6-chloro-2-{4-[(1,2,3,4-tetrahydronaphthalen-1-ylamino)methyl]phenyl }-1H-benzimidazole-4-carboxyguanamine; 2-(4-cyclopropylaminomethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxyguanamine; 2-(4 -cyclobutylaminomethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxamide; 2-(4-cyclopentylaminomethylphenyl)-6-fluoro-1H- Benzimidazole-4-carboxyguanamine; 2-[4-(2-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxyguanamine; 2-[4-(2- Cyclobutylaminoethyl)phenyl]-1H-benzimidazole-4-carboxamide; 2-(4-cyclopropylaminomethyl-2-fluorobenzene -1H-benzimidazole-4-carboxamide; 2-[4-(1-cyclopropylaminoethyl)phenyl]-1H-benzimidazole-4-carboxyguanamine; 2-(4 -cyclobutylaminomethyl-2-fluorophenyl]-1H-benzimidazole-4-carboxamide; 2-(4-cyclohexylaminomethyl-2-fluorophenyl)-1H-benzene And imidazole-4-carboxyguanamine; and 2-(4-cyclopentylaminomethyl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide.

U.S. Patent No. 7,550,603 issued to Zhu et al. discloses the disclosure of 2-H-benzimidazole-4-carboxamide which is substituted with a quaternary carbon as a PARP inhibitor, including 2-(2-methylpyrrolidine-2 -yl)-1H-benzimidazole-4- Carboxylamidine; 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide; 2-[(2S)-2-methylpyrrolidine-2 -yl]-1H-benzimidazole-4-carboxamide; 2-(1,2-dimethylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide; 2-(1 -ethyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxyguanamine; 2-(2-methyl-1-propylpyrrolidin-2-yl)-1H- Benzimidazole-4-carboxyguanamine; 2-(1-isopropyl-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxyguanamine; 2-(1-cyclobutene 2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide; 2-(3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxylate Indoleamine; 2-(3-methyl-1-propylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide; 2-[1-(cyclopropylmethyl)-3- Methyl pyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide; 2-(1-isobutyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4 Carboxylamidine; 2-(1-isopropyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxamide; 2-(1-cyclobutyl-3-methyl Pyryryryl-3-yl)-1H-benzimidazole-4-carboxamide; 2-(1-cyclopentyl-3-methylpyrrolidin-3-yl)-1H-benzimidazole-4- Carboxylamidine; 2-(1-cyclohexyl-3-methylpyrrolidin-3-yl)-1H -benzimidazole-4-carboxyguanamine; 2-(3-methyl-1-tetrahydro-2H-piperidin-4-ylpyrrolidin-3-yl)-1H-benzimidazole-4-carboxyindole Amine; 2-[3-methyl-1-(pyridin-4-ylmethyl)pyrrolidin-3-yl]-1H-benzimidazole-4-carboxyguanamine; 2-[3-methyl-1 -(2-phenylethyl)pyrrolidin-3-yl]-1H-benzimidazole-4-carboxyguanamine; 2-[3-methyl-1-(1-methyl-3-phenylpropane) Pyrrolidin-3-yl]-1H-benzimidazole-4-carboxamide; 2-(2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxyindole Amine; 2-(1-isopropyl-2-methylazetidin-2-yl)-1H-benzimidazole-4-carboxyguanamine; 2-(1-cyclobutyl-2-methyl Azetidin-2-yl)-1H-benzimidazole-4-carboxamide; 2-(1-cyclopentyl-2-methylazetidin-2-yl)-1H- Benzimidazole-4-carboxyguanamine; 2-(1-cyclohexyl-2- Methylazetidin-2-yl)-1H-benzimidazole-4-carboxamide; 2-(3-methylazetidin-3-yl)-1H-benzimidazole-4 Carboxylamidine; 2-(3-methyl-1-propylazetidin-3-yl)-1H-benzimidazole-4-carboxamide; 2-[1-(cyclopropylmethyl) 3-methylazetidin-3-yl]-1H-benzimidazole-4-carboxamide; 2-(1-isobutyl-3-methylazetidine-3 -yl)-1H-benzimidazole-4-carboxamide; 2-(1-cyclobutyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxyindole Amine; 2-(1-cyclopentyl-3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxyguanamine; 2-(1-cyclohexyl-3-methyl Azetidin-3-yl)-1H-benzimidazole-4-carboxamide; 2-(3-methyl-1-tetrahydro-2H-piperidin-4-ylazetidine- 3-yl)-1H-benzimidazole-4-carboxyguanamine; 2-{1-[(dimethylamino)sulfonyl]-3-methylazetidin-3-yl}- 1H-benzimidazole-4-carboxamide; and 2-(2-methylpiperidin-2-yl)-1H-benzimidazole-4-carboxamide.

U.S. Patent No. 7,405,300 to Jiang et al., the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in in哚-3-carbaldehyde; 2-(piperazin-1-yl)-1-(4-methoxyphenyl)-1H-indole-3-carbaldehyde; 2-(piperazin-1-yl)-1 -(4-t-butylphenyl)-1H-indole-3-carbaldehyde; 2-(piperazin-1-yl)-1-(4-bromophenyl)-1H-indole-3-carbaldehyde ; 2-(piperazin-1-yl)-1-(4-chlorophenyl)-1H-indole-3-carbaldehyde; 2-(piperazin-1-yl)-1-(3-chloro-4 -fluorophenyl)-1H-indole-3-carbaldehyde, 2-(piperazin-1-yl)-1-(3-methoxyphenyl)-1H-indole-3-carbaldehyde; 2-( Piperazin-1-yl)-1-(4-thiomethylphenyl)-1H-indole-3-carbaldehyde; 2-(piperazin-1-yl)-1-(3-fluorophenyl)- 1H-indole-3-carbaldehyde; 2-(piperazin-1-yl)-1-(3-methylphenyl)-1H-indole-3-carbaldehyde; 1-(4-t-butylbenzene 2-piperazin-1-yl-1H-indole-3-carbaldehyde; 1-(4-t-butylphenyl)-2-piperidin-1-yl-1H-indole-3- Formaldehyde; 1-(3-methylnonylphenyl)-2-(piperazin-2-yl)-1H-indole-3-carbaldehyde; 1-(biphenyl-4-yl)-2-(piperazine) -1-yl)-1H-indole-3-carbaldehyde hydrochloride; 1-(4-ethylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carbaldehyde hydrochloride a salt; and 1-(3-bromophenyl)-2-piperazin-1-yl-1H-indole-3-carbaldehyde.

U.S. Patent No. 7,087,637 to Grandel et al., 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 the吲哚-4-carboxyguanamine; 2-(4-piperazin-1-yl-phenyl)-1H-indole-4-carboxamide; 2-(4-(4-isopropyl-piperazine) -1-yl)-phenyl)-1H-indole-4-carboxamide; 2-(4-(4-benzyl-piperazin-1-yl)-phenyl)-1H-indole- 4-carboxyguanamine; 2-(4-(4-n-butyl-piperazin-1-yl)-phenyl)-1H-indole-4-carboxamide; 2-(4-(4-B 2-piperazin-1-yl)-phenyl)-1H-indole-4-carboxamide; 2-(4-(2-N,N-dimethylamino-eth-1-yloxy) -phenyl)-1H-indole-4-carboxamide; 2-(4-(2-pyrrolidinyl-1-yl-ethenyloxy)-phenyl)-1H-indole-4-carboxylate Indoleamine; 2-(4-(2-piperidinyl-eth-1-yloxy)-phenyl)-1H-indole-4-carboxamide; 2-(4-(2-piperazine-1) -yl-eth-1-yloxy)-phenyl)-1H-indole-4-carboxamide; 2-(4-(2-(4-methyl-piperazin-1-yl)-ethyl- 1-yloxy)-phenyl)-1H-indole-4-carboxamide; 2-(4-(2-(4-propyl-piperazin-1-yl)-eth-1-yloxy) -phenyl)-1H-indole-4-carboxamide; 2-(4-(2-(4-ethyl-piperazin-1-yl)-eth-1-yloxy)-phenyl)- 1H-indole-4-carboxamide; and 2-(4-(2-(4-phenyl) - piperazin-1-yl) - ethyl-1-yloxy) - phenyl) lH-indol-4-2carboxamide.

U.S. Patent No. 7,041,675 issued to Lubisch et al. discloses the substituted pyridine carboxamide as a PARP inhibitor, including 2-phenylimidazo[1,2-a]pyridin-8-carboxamide; 2-( 4-nitrophenyl)imidazole And [1,2-a]pyridine-8-carboxamide; 2-(4-aminophenyl)imidazo[1,2-a]pyridine-8-carboxamide; 2-(2-benzo Thienyl)imidazo[1,2-a]pyridin-8-carboxamide; 2-(4-bromophenyl)-imidazo[1,2-a]pyridine-8-carboxamide; (4-Imidazol-1-ylphenyl)imidazo[1,2-a]pyridine-8-carboxamide.

U.S. Patent No. 6,924,284 to Beaton et al. discloses substituted bicyclic aryl PARP inhibitors, including: N-[3-(4-trioxy-3,4-dihydro-pyridazine-1 -ylamino)-propyl]-3-[3-(1H-pyrrol-2-yl)-[1,2,4] Oxazol-5-yl]propanoxime; N-[3-(4-o-oxy-3,4-dihydro-pyridazin-1-ylamino)-propyl]-3-(3-thiophene -3-yl-[1,2,4] Diazol-5-yl)propanamine; 3-(3-furan-2-yl-[1,2,4] Oxazol-5-yl)-N-[3-(4-o-oxy-3,4-dihydro-pyridazin-1-ylamino)-propyl]-propanamine; N-[3- (4-Sideoxy-3,4-dihydro-phthalazin-1-ylamino)-propyl]-3-(3-thiophen-2-yl-[1,2,4] Diazol-5-yl)-propanamine; 3-[3-(2-methyl-thiophen-3-yl)-[1,2,4] Oxazol-5-yl]-N-[3-(4-trioxy-3,4-dihydro-pyridazin-1-ylamino)-propyl]-propanamide; 3-[3- (3,5-dihydroxy-phenyl)-[1,2,4] Oxazol-5-yl]-N-[3-(4-trioxy-3,4-dihydro-pyridazin-1-ylamino)-propyl]-propanamide; 3-[3- (3-hydroxy-phenyl)-[1,2,4] Diazol-5-yl]-N-[3-(4-o-oxy-3,4-dihydro-pyridazin-1-ylamino)-propyl]-propanamide; with 3-[3 -(5-Amino-3H-imidazol-4-yl)-[1,2,4] Diazol-5-yl]-N-[3-(4-o-oxy-3,4-dihydro-phthalazin-1-ylamino)-propyl]-propanamide.

U.S. Patent No. 6,635,642 to Jackson et al. discloses a pyridazinone derivative as a PARP inhibitor, including 4-(3-nitro-4-(piperidin-1-yl)phenyl-pyridazine-1 ( 2H)-keto; 4-(4-(dimethylamino)-3-nitrophenyl)-pyridazine-1(2H)-one; 4-(3-amino-4-(dimethyl) Amine Phenyl)-pyridazine-1(2H)-one; 4-(4-phenylpiperazin-1-yl)-pyridazine-1(2H)-one; with 4-(4-(4-chlorobenzene) Base)-piperazin-1-yl)-pyridazine-1(2H)-one.

U.S. Patent No. 6,448,271 to Lubsch et al. discloses substituted benzimidazoles as PARP inhibitors, including 2-(piperidin-4-yl)benzimidazole-4-carboxyguanamine dihydrochloride; 2-(N-Ethylpiperidin-4-yl)benzimidazole-4-carboxamide; 2-(N-propylpiperidin-4-yl)benzimidazole-4-carboxyguanamine; -piperidin-3-ylbenzimidazole-4-carboxyguanamine dihydrochloride; 2-(N-(O-t-butoxycarbonyl)piperidin-3-yl)benzimidazole-4-carboxylate Indoleamine; 2-(N-benzylpiperidin-3-yl)benzimidazole-4-carboxamide; 2-(N-methylpiperidin-3-yl)benzimidazole-4-carboxyindole Amine dihydrochloride; 2-piperazin-4-yl-benzimidazole-4-carboxamide; 2-(N-propylpiperidin-3-yl)benzimidazole-4-carboxyguanamine dihalide 2-(N-(3-phenylprop-1-yl)-piperidin-3-yl)benzimidazole-4-carboxyguanamine dihydrochloride; 2-(N-benzylidene) Piperidin-3-yl)benzimidazole-4-carboxamide; 2-(N-benzylpiperidin-4-yl)benzimidazole-4-carboxyguanamine dihydrochloride; 2-(1 -(1-methylpiperidin-4-yl)piperidin-4-yl)benzimidazole-4-carboxyguanamine trihydrochloride; 2-(N-n-pentylpiperidin-4-yl)benzene Imidazole-4-carboxyguanamine; 2-(N-isobut-1-yl-piperidin-4-yl)benzimidazole-4-carboxylate Indoleamine; 2-(N-n-butylpiperidin-4-yl)benzimidazole-4-carboxamide hydrochloride; 2-(N-(3-methyl-butan-1-yl)piperidine 4-yl)benzimidazole-4-carboxamide hydrochloride; 2-(1,4-dimethylpiperazin-2-yl)benzimidazole-4-carboxyguanamine dihydrochloride; - piperazin-2-yl-benzimidazole-4-carboxyguanamine dihydrochloride; 2-(N-isopropylpiperidin-4-yl)benzimidazole-4-carboxamide hydrochloride; 2-(4-(2-ethyl-propan-1-yl)piperidin-4-yl)benzimidazole-4-carboxamide; 2-(1,4-Diphenylmethylpiperazine-2- Benzimidazole-4-carboxyguanamine dihydrochloride; with 2-(N-benzylpiperidin-4-yl)-1-(1-phenylmethylpiperidin-4-ylcarbonyl Benzimidazole-4-carboxyguanamine.

U.S. Patent No. 6,426,415 to Jackson et al. discloses a PARP inhibitor substituted with an alkoxy group, including 1-(benzyloxy)-5-methylpyridazine; 1-(methoxy)-5- Methyl-pyridazine; 1-(ethoxy)-5-methylpyridazine; 1-(propoxy)-5-methylpyridazine; 1-(butoxy)-5-methyl-oxime 1-(methoxy)-5-hydroxypyridazine; 1-(ethoxy)-5-hydroxypyridazine; 1-(propoxyoxy)-5-hydroxy-pyridazine; 1-(butyl) Oxy)-5-hydroxypyridazine; 1-(benzyloxy)-5-methylisoquinoline; 1-(methoxy)-5-methyl-isoquinoline; 1-(ethoxyl) -5-methylisoquinoline; 1-(propoxy)-5-methylisoquinoline; 1-(butoxy)-5-methylisoquinoline; 1-(ethoxy)- 5-hydroxyisoquinoline; 1-(propoxy)-5-hydroxyisoquinoline; and 1-(butoxy)-5-hydroxy-isoquinoline.

U.S. Patent No. 6,395,749 to Li et al. discloses substituted carboxamide as a PARP inhibitor, including 5-aminoformylquinoline-4-carboxylic acid.

U.S. Patent No. 6,387,902 to Zhang et al. discloses the substituted phenazines as PARP inhibitors, including compounds of formula (P-VI): Wherein: (1) R ₁ -R ₉ and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, cyano, nitro, amine, imido, alkylamino, amin a group, a thiol group, a thioalkyl group, an alkylthio group, a sulfonyl group, an alkylsulfonyl group, a C ₁ -C ₉ straight or branched alkyl group, a C ₂ -C ₉ straight or branched alkenyl group, C ₂ -C ₉ straight or branched alkynyl, C ₁ -C ₆ straight or branched alkoxy, C ₂ -C ₆ straight or branched alkenyloxy, C ₂ -C ₆ straight or branched Alkenyloxy, aryl, carbocyclic, heterocyclic, aralkyl, alkylaryl, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyl, aralkylamino , an arylamine group, an arylazo group, an arylthio group, or an aralkylthio group; or (2) Z is a small group (P-VI(a)) partial group Wherein U is C or N; R ₇ and R ₈ are as defined in (1); and X and Y are each independently an aryl group, a carbocyclic ring, or a heterocyclic ring.

U.S. Patent No. 6,380,211 to Jackson et al. discloses a PARP inhibitor substituted with an alkoxy group, including 1-(methoxy)-5-methylisoquinoline, 1-(ethoxy)-5- Methyl-isoquinoline, 1-(propoxy)-5-methylisoquinoline, 1-(butoxy)-5-methylisoquinoline, 1-(ethoxy)-5-hydroxyl -isoquinoline, 1-(propoxy)-5-hydroxyisoquinoline, 1-(butoxy)-5-hydroxyisoquinoline, 1-(benzyloxy)-5-methylpyridazine With 1-(benzyloxy)-5-methylisoquinoline.

U.S. Patent No. 6,358,975 to Eliasson et al. discloses PARP inhibitors, including 6(5H)-phenanthridine, 2-nitro-6(5H)-phenanthridine, 4-hydroxyquinazoline, 2- Methyl-4(3H)-quinazoline, 2-hydrothio-4(3H)-quinazoline, benzamidine, 6-amino-1,2-benzopipenone, trp -P-1 (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole), juglone, luminol, 1 (2H) -pyridazinone, phthalic acid, and chlorophene Chlorothenoxazine.

U.S. Patent No. 6,235,748 to Li et al. discloses a compound which is substituted with a pendant oxy group of at least one ring nitrogen as a PARP inhibitor.

U.S. Patent No. 6,201,020 to Zhang et al. discloses an o-diphenol compound as a PARP inhibitor, including a compound of formula (P-VII): Wherein: (1) A is O or S; (2) R is a C ₁ -C ₁₀ linear or branched alkyl group, a C ₂ -C ₁₀ straight or branched alkenyl group, a C ₂ -C ₁₀ straight chain or Branched alkynyl, aryl, heteroaryl, carbocyclic, or heterocyclic; (3) D is a bond, or a C ₁ -C ₃ straight or branched alkyl group, a C ₂ -C ₃ straight or branched chain An alkenyl group, a C ₂ -C ₃ linear or branched alkynyl group, wherein any carbon atom of the alkyl, alkenyl or alkynyl group of D may be replaced by oxygen, nitrogen, or sulfur as desired; and (4) X is Aryl, heteroaryl, carbocyclic, or heterocyclic.

U.S. Patent No. 5,756,510 to Griffin et al. discloses a benzin analog as a PARP inhibitor, including: 3-benzyloxybenzamide; 3-(4-methoxybenzyloxy) Benzobenzamide; 3-(4-nitrobenzyloxy)benzamide; 3-(4-azidobenzyloxy)benzamide; 3-(4-bromo) Benzyloxy)benzamide; 3-(4-fluorobenzyloxy)benzamide; 3-(4-aminobenzyloxy)benzamide; 3-(3 -nitrobenzyloxy)benzamide; 3-(3,4-methylenedioxyphenylmethyloxy)benzamide; 3-(piperidinyloxy)benzamide 3-(N-Ethyl-4-aminobenzyloxy)benzamide; 3-(4-trifluoromethylbenzyloxy)benzamide; 3-(4- Cyanobenzyloxy)benzamide; 3-(4-carboxymethylbenzyloxy)benzamide; 3-(2-nitrobenzyloxy)benzamide; 3-(4-carboxybenzyloxy)benzamide; 3-(8-adenos-9-yloctyloxy)benzamide; 3-[5-(6-chloroindole-9 -yl)pentyloxy]benzamide; 3-(5-adenos-9-ylpentyloxy)benzamide; 3-[8-(6-chloroin-9-yl)octyl Benzyloxy]benzamide; 3-[12-(6- Purin-9-yl) dodecyloxy] benzoyl amine; with 3- (12-adenosyl-9-dodecyloxy) benzoyl amine.

U.S. Patent Application Publication No. 2015/0175617 to Zhou et al. discloses the condensed tetra- or pentacyclic dihydrodiazepine-oxazolone as a PARP inhibitor comprising: 2,3,5,10-tetrahydro- [1,2] diazepine [3,4:5,6-def]carbazole-6(1H)-one; 5,6,7,8-tetrahydro-4H-4,9,10-triazaindole[2,1, 7-kla]heptene-11(10H)-one; 2-methyl-2,3,5,10-tetrahydro-[1,2]diazepine[3,4:5,6-def ]carbazole-6(1H)-one; 3,3-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine[3,4:5,6-def] Oxazol-6(1H)-one; 2-phenyl-2,3,5,10-tetrahydro-[1,2]diazepine[3,4:5,6-def]indazole-6 (1H)-keto; with 2-isopropyl-2,3,5,10-tetrahydro-[1,2]diazepine[3,4:5,6-def]indazole-6 (1H )-ketone.

U.S. Patent Application Publication No. 2015/0152118 to Jana et al. discloses a tetrahydroquinazolinone derivative as a PARP inhibitor comprising: 2 ' -(3-(4-(4-fluorophenyl)piperazine-1 - yl) propyl) -6 ', 7' - dihydro -3 'H- spiro [cyclopropane-1,8' - quinazolin] -4 '(5' H) - one; 2 '- (3 - (4- (4-chlorophenyl) piperazin-1-yl) propyl) -6 ', 7'-dihydro -3' H- spiro [cyclopropane-1,8 '- quinazolin] - 4 ' (5 ' H)-keto; 2 ' -(3-(4-phenyl-5,6-dihydropyridine-1(2H)-yl)propyl)-6 ' , 7' -dihydro- 3 ' H-spiro[cyclopropane-1,8 ' -quinazoline]-4 ' (5 ' H)-one; 2 ' -(3-(3-(4-fluorophenyl)-3,8- Diazabicyclo[3.2.1]octane-8-yl)propyl)-4a ' ,5 ' ,6 ' ,7 ' -tetrahydro-3 ' H-spiro [cyclopropane-1,8 ' -quinoline Oxazoline]-4 ' (8a ' H)-one; 2 ' -(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-7 ' , 8' -dihydro- 3 ' H-spiro[cyclopropane-1,6 ' -quinazoline]-4 ' (5 ' H)-one; 2 ' -(3-(4-(4-chlorophenyl)piperazin-1- yl) propyl) -7 ', 8' - dihydro -3 'H- spiro [cyclopropane-1,6' - quinazolin] -4 '(5' H) - one; 2 '- (3- (3-(4-Fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)propyl)-7 ' , 8' -dihydro-3 ' H-spiro [ Cyclopropane-1,6 ' -quinazoline]-4 ' (5 ' H)-keto; 2 ' -(3-(8-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)propyl)- 7 ' ,8 ' -dihydro-3 ' H-spiro[cyclopropane-1,6 ' -quinazoline]-4 ' (5 ' H)-one; 2 ' -(3-(4-(4- fluorophenyl) -5,6-dihydropyridin -1 (2H) - yl) propyl) -7 ', 8' - dihydro -3 'H- spiro [cyclopropane-1,6' - quinazoline ]-4 ' (5 ' H)-one; with 2 ' -(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)propyl)-7 ' , 8' -di Hydrogen-3 ' H-spiro [cyclopropane-1,6 ' -quinazoline]-4 ' (5 ' H).

US Patent Application Publication No. 2015/0031652 to Gangloff et al. discloses substituted 1,2,3,4-tetrahydropyrido[2,3-b]pyrazine as a PARP inhibitor, including (S)-3 -((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a Pyrazin-6(5H)-one; (S)-3-((4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-yl)methyl)-6a, 7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-6(5H)-one; (S)-3-((4-(4-chloro) Phenyl)piperidin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-6(5H)- Ketone; (S)-4-(4-((6-o-oxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a Pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile; (S)-6-(4-((6-a-oxy-5,6,6a,7,8,9) -hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile; (S)-N-A -6-(4-((6-Sideoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine- 3-yl)methyl)piperazin-1-yl)nicotinium amide; (S)-6-(4-((6-o-oxy-5,6,6a,7,8,9-hexahydro) Pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid ethyl ester; (S)-6-(4- ((6- Oxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazine-1- Nicotinic acid; (S)-N-ethyl-6-(4-((6-o-oxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]] Pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinium amide; (S)-N-cyclopropyl-6-(4-((6-) Sideoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazine-1 -based nicotine amide; (S)-N-isopropyl -6-(4-((6-Sideoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3 -yl)methyl)piperazin-1-yl)nicotinium amide; (S)-N-ethyl-4-(4-((6- oxo-5,6,6a,7,8, 9-Hexidopyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide; (S)-4- (4-((6-Phenoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl) Ethyl methyl)piperazin-1-yl)benzoate; (S)-4-(4-((6-o-oxy-5,6,6a,7,8,9-hexahydropyridin[ 3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid; (S)-N-methyl-4-(4-( (6-Sideoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)per (S)--N-isopropyl-4-(4-((6-o-oxy-5,6,6a,7,8,9-hexahydropyridine) And [3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide; (S)-N-cyclopropyl-4 -(4-((6-Sideoxy-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl) )methyl)piperazin-1-yl)benzamide; (S)-3-fluoro-4-(4-((6-olyl-5,6,6a,7,8,9-six) Hydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)perazine And (S)-3-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9- Tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-6(5H)-one.

U.S. Patent Application Publication No. 2015/0025071 to Buchstaller et al. discloses a tetrahydroquinazolinone derivative as a PARP inhibitor comprising: 2-[4-(4-methoxy-phenyl)-piperazine-1 -yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(3-fluorophenyl)piperazin-1-yl]-5,6,7 , 8-tetrahydro-3H-quinazolin-4-one; 2-[4-(4-fluorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quin Oxazolin-4-one; 2-[4-(3-methoxyphenyl)piperazin-1-yl]-5,6,7,8- Tetrahydro-3H-quinazolin-4-one; 2-[4-(4-chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazoline- 4-keto; 2-[4-(2-chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-(4- Trifluoromethylpiperidin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(3-chlorophenyl)piperazine-1- 5-]6,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(2-methoxyphenyl)piperazin-1-yl]-5,6, 7,8-tetrahydro-3H-quinazolin-4-one; 2-(4-t-butylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazoline 4-ketone; 2-[4-(4-methoxyphenyl)-3-oxopiperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazoline- 4-keto; 2-[4-(piperidin-1-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4 -(6-hydroxypyridin-2-yl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-(4-benzoguanidinopiperine Pyrazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one; N-pyridin-2-yl-2-[4-(4-trioxy-3, 4,5,6,7,8-hexahydroquinazolin-2-yl)piperazin-1-yl]acetamide; 2-(4-ethylhydrazinopiperazin-1-yl)-5,6 ,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(morpholine-4-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro- 3H-quinazolin-4-one; 2-[4-(3-aminopropionyl)piperazine -1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(4-trioxy-5,6,7,8-tetrahydro- 3H-quinazolin-2-yl) piperazin-1-yl]pyridine-3-carboxamide; 2-[4-(4-trioxy-3,4,5,6,7,8-six Hydroquinazolin-2-yl) piperazin-1-yl]-N-pyridin-3-ylacetamide; 2-[4-(2,2-dimethylpropenyl)piperazine-1- 5-[6,7,8-tetrahydro-3H-quinazolin-4-one; 2-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7, 8-tetrahydro-3H-quinazolin-4-one; 2-[4-[2-(2-pyridyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydro -3H-quinazolin-4-one; 2-[4-(piperidin-2-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazoline-4 -ketone; 4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazine-2-carboxamide; 2-[3-(hydroxyl) Piperazine -1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one; (2R)-1-(4-sided oxy-5,6,7,8-tetrahydro -3H-quinazolin-2-yl)piperazine-2-carboxamide; and 2-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-5,6,7,8 - tetrahydro-3H-quinazolin-4-one.

U.S. Patent Application Publication No. 2015/0018356 to Zhou et al. discloses fused tetra or pentacyclic pyridoindazinones as PARP inhibitors.

U.S. Patent Application Publication No. 2014/0336192 to Pape et al. discloses a substituted 3-phenyl-isoquinolin-1(2H)-one derivative as a PARP inhibitor, including: 4-(2-amine -ethoxy)-3-(4-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro-3 -(3-trifluoromethyl-phenyl)-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro-3-(4-morpholin-4- -phenyl)-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-3-(3-bromo-4-morpholin-4-yl-phenyl)-7 -fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-3-(3-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one 4-[4-(2-Amino-ethoxy)-7-fluoro-1-o-oxy-1,2-dihydro-isoquinolin-3-yl]-benzonitrile; 4-( 2-aminoethoxy)-7-fluoro-3-(4-pyrrolidin-1-yl-phenyl)-2H-isoquinolin-1-one; 4-(2-amino-ethoxyl) --3-(4-chloro-phenyl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro-3-(4-methane Sulfomethyl-phenyl)-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro-3-(4-fluoro-phenyl)-2H-isoquine啉-1-one; 3-[4-(2-amino-ethoxy)-7-fluoro-1-o-oxy-1,2-dihydro-isoquinolin-3-yl]-benzene Nitrile; 4-(2-amino-ethoxy) 3-(4-bromo-phenyl)-7,8-difluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-3-(4-chloro-3 -methyl-phenyl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino- Ethoxy)-3-(3,4-dichloro-phenyl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-3-(3 ,4-difluoro-phenyl)-7-fluoro-2H-isoquinolin-1-one; 5-[4-(2-amino-ethoxy)-7-fluoro-1-yloxy- 1,2-dihydro-isoquinolin-3-yl]-2-morpholin-4-yl-benzonitrile; 5-[4-(2-amino-ethoxy)-7-fluoro-1 - pendant oxy-1,2-dihydro-isoquinolin-3-yl]-2-pyrrolidin-1-yl-benzonitrile; 4-(2-amino-ethoxy)-3-( 3-bromo-4-pyrrolidin-1-yl-phenyl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-3-(2,3 -dihydro-benzo[1,4]dioxine-6-yl)-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)- 3-benzo[1,3]dioxol-5-yl-7-fluoro-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro -3-(3-fluoro-4-methoxy-phenyl)-2H-isoquinolin-1-one; 4-(2-amino-ethoxy)-7-fluoro-3-(4- Trifluoromethoxy-phenyl)-2H-isoquinolin-1-one; and 4-(2-amino-ethoxy)-3-(3,4-dihydro-2H-benzo[b] ][1,4]dioxo-7-yl)-7-fluoro-2H-isoquinolin-1-one.

US Patent Application Publication No. 2014/0235675 to Papeo et al. discloses 3-oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP inhibitors, including: 3-side Oxy-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclopentylpiperidin-4-yl)-3- 2-oxy-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro- 1H-carbazole-4-carboxamide; 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indole Oxazole-4-carboxyguanamine; 2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxyindole Amine; 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxoyl-2,3-dihydro-1H-indazole-4- Carboxylamidine; 2-(1-cyclopentylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 2 -(1-methylpiperidin-4- 3-yloxy-2,3-dihydro-1H-indazole-4-carboxamide; 1-methyl-3-oxo-2-(piperidin-4-yl)-2 , 3-dihydro-1H-indazole-4-carboxamide; 1-methyl-2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydro- 1H-carbazole-4-carboxamide; 2-(1-ethylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 3-Phenoxy-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-ethylpiperidine-4 -yl)-1-methyl-3-indolyl-2,3-dihydro-1H-indazole-4-carboxamide; 1-methyl-3-oxo-2-[1-( Prop-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide; 3-sided oxy-2-[1-(propan-2-yl) Piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidin-4-yl)-3-oxo-2, 3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-3-o-oxo-2,3-dihydro-1H -carbazole-4-carboxyguanamine; 2-(1-cyclobutylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4 Carboxylamidine; 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4- Carboxylamidine; 6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 6-fluoro- 1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclohexylpiperidine- 4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide; 2-(1-cyclohexylpiperidine-4- -6-fluoro-3-indolyl-2,3-dihydro-1H-indazole-4-carboxamide; and 2-[1-(4,4-difluorocyclohexyl)piperidine- 4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide.

US Patent Application Publication No. 2014/0023642 to Cai et al. discloses 1-(arylmethyl)quinazoline-2,4(1H,3H)-dione as a PARP inhibitor, including: 1-(3- Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-di Ketone; 1-(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-( 4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-cyclohexylpiperazine-1 -carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-([1,2,4]triazolo[4,3-b]哒Pyridin-6-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-ethylpiperazine-1-carbonyl) Benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-benzylmercaptopiperazine-1-carbonyl)benzyl)quinazoline-2,4 (1H,3H)-dione; 1-(3-(4-(4-fluorobenzylidyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)- Diketone; 1-(3-(4-(4-chlorobenzylidyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-( 3-(4-(4-bromobenzylidene)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-( 4-methoxybenzimidyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-(tetrahydro-2H) -piperazin-4-yl)carbonylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-(cyclopentylcarbonyl)) Piperazine-1-carbonyl)benzyl)quinazoline-2,4-(1H,3H)-dione; 1-(3 -(4-(cyclopropylcarbonyl)piperazine-1-carbonyl)benzyl)quinazoline-2,4-(1H,3H)-dione; 1-(3-(4-(ethyl) Mercapto) piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; 1-(3-(4-ethinylpiperazine-1-carbonyl)benzene Quinazoline-2,4(1H,3H)-dione; 1-(3-(4-phenylpiperidin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H )-dione; 1-(3-(4-phenylpiperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione; and 1-(3-(4) -(Pyrazin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.

U.S. Patent Application Publication No. 2013/0225647 to Donawho et al. discloses a PARP inhibitor of formula (P-VIII): Wherein: (1) R ₁ , R ₂ , and R ₃ are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, halo Alkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR _A R _B , and (NR _A R _B )carbonyl; (2) A contains 1 or 2 nitrogen atoms, and optionally a non-aromatic 4, 5, 6, 7, or 8-membered ring of a sulfur or oxygen atom, wherein the non-aromatic ring may be substituted with 1, 2, or 3 substituents selected from the group consisting of: Substituted: alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl , cyano, haloalkoxy, haloalkyl, halogen, heterocyclic, heterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NR _C R _D , (NR _C R _D )alkyl, (NR _C R _D )carbonyl, (NR _C R _D )carbonylalkyl, and (NR _C R _D )sulfonyl; and (3)R _A , R _B , R _C , and R _{D is} independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl.

The PARP inhibitor disclosed in U.S. Patent Application Publication No. 2013/0129841 to Ciavolella et al. includes 2-[1-(4,4-difluorocyclohexane). Piperidin-4-yl]-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; 2-[1-(4,4-difluorocyclohexyl) Piperidin-4-yl]-6-fluoro-3-o-oxo-2,3-dihydro-1H-isoindole-4-carboxamide; 6-fluoro-3-indolyl-2-[ 1-(4-Sideoxycyclohexyl)piperidin-4-yl]-2,3-dihydro-1H-isoindole-4-carboxamide, with 2-[1-(4,4-di Chlorocyclohexyl)piperidin-4-yl]-6-fluoro-3-o-oxo-2,3-dihydro-1-H-isoindole-4carboxamide.

The gene PTEN encodes the protein PTEN, which acts as a tumor suppressor. The protein encoded by PTEN is phospholipid creatinine-3,4,5-triphosphate 3-phosphatase. It comprises a tensin-like domain and a catalytic domain similar to the catalytic domain of the bispecific protein tyrosine phosphatase. Unlike most protein tyrosine phosphatases, this protein preferentially dephosphorylates phospholipid inositol. It negatively regulates the content of phospholipid inositol-3,4,5-triphosphate in cells and has the function of tumor suppressor by negatively regulating the Akt/PKB signal transduction pathway. The PTEN gene often mutates, deletes, or downregulates its performance in cancer. Therefore, the absence or inactivation of PTEN function is increasingly recognized as a goal of medical intervention (LMDillon & TW Miller, "Therapeutic Targeting of Cancers with Loss of PTEN Function," Curr. Drug Targets 15: 65-79 (2014)). PTEN deficiency can be caused by genetic germ cell mutations, somatic mutations, gene and transcriptional silences, post-translational modifications, and protein-protein interactions.

Germ cell mutations can include, but are not limited to, an Exon 5 mutation that encodes a PTEN phosphatase domain. Other mutations have been shown to present the PTEN promoter or to the donor and acceptor sites.

Missense, nonsense, embedding, and deletion mutations occur throughout the PTEN and result in the absence of PTEN expression and/or function. Although the distribution of these mutations usually occurs occasionally, and these mutations can occur throughout the genome, there are still many mutation hotspots, including Arg ¹³⁰ , Arg ¹⁷³ , and Arg ²³³ .

Attachment of genes and transcriptional silence can also result in loss of PTEN function. Several studies show, PTEN promoter of "CpG island" (CpG island) will be hypermethylated in cancer, caused by PTEN transcription silent. PTEN transcription can be suppressed by the gene-containing press complex Mi-2/NuRD containing Achromidase and histone deacetylase (HDAC) containing chromatin (Chromatin). This repression occurs when the transcription factor Sal protein 4 (SALL4) binds to the PTEN promoter and recruits Mi-2/NuRD. PTEN transcription is also inhibited by the transcription factors NF-Kb, c-JUN, and BM1.

The tumor suppressor gene p53 acts as a transcription factor and initiates PTEN expression; therefore, the p53 deletion function reduces PTEN expression. The ubiquitous transcription factor specific protein 1 (Sp1) also inhibits PTEN expression: acetylated Sp1 binds to the PTEN promoter and recruits HDAC1 to suppress PTEN transcription. Thus, overexpression of Sp1 up-regulates PI3K pathway activation (analyzed by AKT phosphorylation) and promotes metastasis and invasion of human salivary adenoid cystic carcinoma cells. MicroRNAs (miRNAs) have been shown to suppress PTEN mRNA translation by interacting with the 3 ' untranslated region. In particular, miRNA miR-21 suppresses PTEN expression in many cancer subtypes and metabolic diseases; this miRNA can also suppress PTEN expression by enhancing the performance of other miRNAs known to suppress PTEN expression. In some models, the transcription factor transforming growth factor beta (TGF- β ), which inhibits PTEN expression, up-regulates miR-21 expression. Post-translational modifications including phosphorylation, acetylation, oxidation, and ubiquitination have been shown to cause loss of PTEN function. Phosphorylation of several serine and threonine residues at the C-terminus of PTEN inhibits its phosphatase activity. This phosphorylation can be driven by the activity of kinase CK2. Although these phosphorylations stabilize PTEN, they reduce PTEN localization on the plasma membrane, thereby limiting its interaction with PIP ₃ . PTEN can also be inhibited by oxidation and acetylation. PTEN contains a residue unique to protein tyrosine phosphatase, called a catalytic cysteine nucleophile, which is easily oxidized at Cys124; Cys124 forms a disulfide bond with Cys71 and inhibits the catalytic activity of PTEN. In addition, the residue of PTEN, Lys125-128, undergoes an ethylene group-based action, which also inhibits the catalytic activity of PTEN. Monoubiquitination of PTEN in Lys13 and Lys289 promotes nuclear localization and suppresses its phosphatase activity.

Several proteins have been shown to interact with PTEN to suppress their tumor suppressor function. Parkinson Protein 7 (PARK7, DJ-1) binds to PTEN under oxidative stress conditions, and this interaction is associated with increased AKT activation and poor clinical outcomes in different cancer subtypes. PIP ₃ -dependent Rac Exchange Factor 2a (P-REX2a), Shank-Interacting Protein-like 1 (SIPL1) and α -mannosidase 2C1 (MAN2C1) It has been shown to bind PTEN and inhibit its phosphatase activity, resulting in increased AKT activation. Other proteins can stabilize PTEN, but mutations in these proteins will therefore reduce the activity of PTEN and promote tumorigenesis. Protein-epithelial cadherin (E-cadherin) and MAGI-2 (which are missing in some cancers) localized in the membrane promote PTEN stability. The p85 subunit of PI3K combines with PTEN to promote stability. Genes encoding the p85 isoform ( PIK3R1 , PIK3R2 ) are frequently mutated in endometrial cancer, and some mutations destabilize PTEN and promote activation of the PI3K pathway.

There is also an interaction between PTEN and p53, which may suppress or promote tumorigenesis. Nuclear PTEN binds to p53 in a phosphatase-dependent manner, promoting p53 stabilization, thus promoting PTEN transcription. PTEN complexes with p300/CBP acetylated invertase due to DNA damage, promoting p53 acetylation, and p53 acetylation enhances PTEN-p53 interaction. Thus, in cells expressing wild-type p53, PTEN inhibits cell proliferation and increases apoptosis. Conversely, PTEN promotes proliferation and inhibits apoptosis in cells expressing mutant p53.

Formulations that may be suitable for counteracting PTEN loss are temsirolimus, everolimus, and other inhibitors of the AKT/mTOR pathway, including AZD6482 ((R)-2-(1- (7-methyl-2-morpholin-4-oxo -4H- pyrido [1,2-a] pyrimidin-9-yl) ethyl) benzoic acid) (which is a PI3K / p110 β Inhibitor), MK-2206(8-(4-(1-aminocyclobutyl)phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1 , 6] naphthyridine-3(2H)-one) (which is an ectopic AKT inhibitor), and 17-AAG ([(3 S , 5 S , 6 R , 7 S , 8 E , 10 R , 11 S) , 12 E , 14 E )-21-(allylamino)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-three Sideoxy-17-azabicyclo[16.3.1]docosa-8,12,14,18,21-penten-10-yl]carbamate) (Hsp90 fold protein (chaperonin) Inhibitors) induce the degradation of many proteins, including HER2 and AKT.

Deletion or inhibition of PTEN can drive resistance to many anti-tumor therapies.

A variety of drugs have been proposed for the treatment of PTEN-deficient malignancies. These drugs include: (1) buparlisib; (2) XL-147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinaquine Phenyl-2-yl]-4-methylbenzenesulfonamide); (3) PX-866 ((1E, 4S, 4aR, 5R, 6aS, 9aR)-5-(ethenyloxy)-1-[ (di-2-propen-1-ylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl) -4a,6a-dimethyl-cyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione); (4)picilsi Dimethanesulfonate; (5) Copanlisib; (6) CH5132799 (5-(7-(methylsulfonyl)-2-morpholinyl-6,7-dihydro-5H) -pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidine-2-amine); (7) GDC-0084; (8) SZTK474 (2-(difluoromethyl)-1-(4,6) -N-N-morpholinyl-1,3,5-triazin-2-yl)-1H-benzo[d]imidazole); (9) GDC-0032 (2-methyl-2-[4-[ 2-(5-Methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4] Benzooxazin-9-yl]pyrazol-1-yl]propanamine); (10) apelisib; (11) MLN1117 (6-(2-aminobenzo[ d ] Zyrid-5-yl (1,2-a)pyridin-3-yl (N-morpholinyl ketone); (12) GSK2636771 (2-methyl-1-[[2-methyl-3-(three) Fluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid; (13) rigosertib; (14) CUDC-097 ( N-hydroxy-2-(((2-(6-methoxypyridin-3-yl)-4-N-morpholinylthieno[3,2-d]pyrimidin-6-yl)methyl)) Methyl)amino)pyrimidine-5-carboxamide; (15) gedatolisib; (16) dactolisib; (17) BGT226 (8-(6-methoxy) Pyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quina Porphyrin-2(3H)-keto maleic acid); (18) apitolisib; (19) vortalis (voxtalisib); (20) SF1126 ((8S, 14S, 17S)-14- (carboxymethyl)-8-(3-mercaptopropyl)-17-(hydroxymethyl)-3,6,9,12,15-penta-oxy-1-(4-(4-side oxygen) -8-phenyl-4H-chromen-2-yl)morpholinyl-4-indole-2-oxo-7,10,13,16-tetraazaoctadecane-18-acid (21) LY3023414; (22) everolimus; (23) temsirolimus; (24) ridaforolimus; (25) MLN0128 (3-(2- Aminobenzo[d] Zyrid-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine); (26) AZD-2014 (3-(2,4-bis((S) )-3-methyl-N-morpholinyl)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzimidamide); (27) CC-223; (28) AZD -5313(5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxylate (29) LY2780301; (30) ipatasertib; (31) afuresertib; (32) MK-2206 (8-(4-(1-amino) cycline Phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one); (33) Orapa (olaparib); (34) veliparib (veliparib); (35) iniparib (36) rucaparib; (37) CEP-9722 (11-methoxy -4,5,6,7-tetrahydro-1 H -cyclopenta[ a ]pyrrolo[3,4- c ]carbazole-1,3( 2H )dione; (38)E7016(10- ((4-Hydroxypiperidin-1-yl)methyl)chromen[4,3,2-de]pyridazin-3(2H)-one); and (39)E7449 (9-isoporphyrin) -2-ylmethyl-1,2-dihydro- 3H -pyridazino[3,4,5- de ]quinazolin-3-one). Other medical agents are known in the art.

U.S. Patent No. 8,933,070 to Pan et al. discloses the treatment of a malignant disease characterized by a mutation in the PTEN gene by administering a PLK4 antagonist.

U.S. Patent Application Publication No. 2015/0159161 to Krieg et al. discloses a single-stranded oligonucleotide for enhancing or activating PTEN expression, such as an oligonucleotide having the sequence 5 ' -XYZ, wherein X is any nucleotide , Y is a nucleotide sequence of 6 nucleotides in length, which is not a seed sequence of human microRNA, and Z is a nucleotide sequence of 1-23 nucleotides in length, wherein a single strand oligonucleotide is At least 8 contiguous nucleotides in the PRC2-binding region of the PTEN gene are complementary.

U.S. Patent Application Publication No. 2014/0378525 to Ashworth et al. discloses the use of an inhibitor of mitotic kinase for the treatment of a cancer characterized by a PTEN mutation or defect. The mitotic kinases include AURKA, TTK, CDK4, PLK4, BUB1B, PLK1, CDC2, PLK3, and AURKB. The inhibitor can be a small molecule inhibitor. Such as: TTK small molecule inhibitors, such as: AZ3146 (9-cyclopentyl-2-(2-methoxy-4-(1-methylpiperidin-4-yloxy)phenylamino)-7 -Methyl-7H-indole-8(9H)-one) or CCT132774. Antibodies, peptide fragments, antisense nucleic acids, or interfering RNA molecules can also be used.

US Patent Application Publication No. 2014/0112917 to Yu et al. discloses the use of ErbB2-targeting agents when PTEN is reduced in transcription or when at least one dual gene of PTEN is deleted, such as trastuzumab, LY294002, 渥Wortmannin, demethoxy viridin, Perifosine, SAR245408 (XL147), BKM120, BEZ235, GS-1101 (CAL-101), PX-866, IPI -145, and BAY 80-6946.

U.S. Patent Application Publication No. 2012/0165340 to Furnari et al. discloses that phosphorylation of the Y240 residue in PTEN is associated with poor prognosis and increased resistance to anti-tumor agents. The resistance may be caused by the src home Driven by phosphorylation of Y240 mediated by a family of kinases.

U.S. Patent Application Publication No. 2012/0107299 to Morishita et al. discloses a protein NDRG2 which inhibits phosphorylation of residues T382, T383, and S380 of PTEN or induces dephosphorylation of such amino acid residues of PTEN; The activity of this protein can be utilized to inhibit the activation of the PI3K/Akt pathway.

U.S. Patent Application Publication No. 2011/0189169 to Abounader et al. discloses the co-administration of an agonist of PTEN with an inhibitor of hepatocyte growth factor (HGF). The agonist of PTEN can be an mTOR inhibitor (see WO 00/00388), which can be rapamycin, sirolimus, temsirolimus, evmus. (everolimus), monoclonal antibody, zinc finger, or other agonist.

U.S. Patent Application Publication No. 2010/0286141 to Durden is related to the specification of the following PTEN proteins. The PTEN crystal structure, which was unraveled in 1999, shows a protein of 403 amino acids containing three functional domains of known function. These are the N-terminal catalytic domain (residues 1-185), the C2 domain (residues 186-349) (which are involved in membrane binding and catalysis), and the C-terminal tail (residues 350-403). . Each of these functional domains becomes a suitable target for a medical agent that is rationally designed to modulate PTEN activity. Particularly preferred are regions such as the N-terminus and the C2 domain, and specifically include regions of the P-ring, the WPD ring, and certain unique residues within and adjacent to the TI ring. These residues are involved in the identification of specific PIP3 receptors and their catalysis. Another suitable region includes the C-terminal tail region, which is involved in PTEN regulation and is degraded in vivo. Small peptide molecules corresponding to these regions are beneficial for use in design A therapeutic agent that effectively modulates the PTEN, PI-3 kinase cascade, AKT cascade activity, and p53-mediated transcription and cell death. PTEN is phosphorylated on tyrosine, serine, and threonine residues. Also, as small molecules that affect PTEN phosphorylation, formulations that affect the phosphorylation status of the protein should also modulate the interaction of PTEN with other proteins. The last N-terminal DDLLTIIYP motif of PTEN (residues 22-30; SEQ ID NO: 12) contains the YXXP motif (SEQ ID NO: 13), the possibility of an adaptor protein (eg, crk and crkl) interacting via SH2 A docking site. Another motif, YFSPN (SEQ ID NO: 14), has been identified at the C-terminus as the binding site for crk and crkl. The last C-terminal YLVLTL motif (SEQ ID NO: 15) is the interaction site of SH2 with Shc or SHP-1. The YSYL motif (SEQ ID NO: 16) contains tyrosine at position 178, which is 100% retained from Drosophila to humans. Other tyrosine phosphorylation motifs include: YRNNIDD (SEQ ID NO: 17), Y at position 46, a sequence that appears in the catalytic domain, which has been identified as the binding site for Grb2 via its SH2 domain.

Song et al., U.S. Patent Application Publication No. 2009/0019558, discloses a formulation that modulates the activity of PGD to restore PTEN function.

a substituted hexitol derivative as described above, which comprises di-dehydrated galactitol, diethyl hydrazine galactitol, di-dehydrated galactitol or diethyl hydrazine galactitol A derivative or analog that can be co-administered with other DNA nociceptive antitumor agents, which is administered as a medically effective amount of another DNA-nociceptive antitumor agent. DNA-nociceptive anti-tumor agents are disclosed in K. Cheung-Ong et al., "DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology," Chem. Biol. 20:648-659 (2013). The DNA-injury anti-tumor agent is also disclosed in the following patents or published patent applications, which are hereby incorporated herein by reference in its entirety in U.S. US Patent No. 9,096,602; U.S. Patent No. 8,840,898 to Goldmakher; U.S. Patent No. 8,735,590 to Adejare et al; U.S. Patent No. 8,415,357 to Kawabe et al; US Patent No. 7, 902, 165 to Kim, U.S. Patent No. 7, 875, 586 to Kovbasnjuk et al., U.S. Patent No. 7,652,04, issued to Kawabe et al., and US Patent to Chu et al. U.S. Patent No. 7, 070, 968 to Kufe et al.; U.S. Patent Application Serial No. 2011/0028422 to Aloyz et al.; and U.S. Patent Application Publication No. 2007 to Mallazs et al. /0032502. DNA-nociceptive anti-tumor agents can act through a variety of different mechanisms, including modifying DNA bases (such as alkylation), embedding in DNA structures, forming crosslinks in DNA, preventing DNA release or replication to induce double strands. Break, enter the DNA to replace normal nucleosides, and other machines. DNA-nociceptive anti-tumor agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, picoplatin, nedaplatin, satraplatin, tetraplatin, a Doxorubicin, daunorubicin, methotrexate, 5-fluorouracil, gemcitabine, podophyllotoxin, etoposide, teniposide, Cyclophosphamide, chlorambucil, melphalan, carmustine, lomustine, estramustine, simustine Semustine), bendamustine, prednamustine, uramustine, chlornaphazine, dacarbazine, altretamine, Dimension, mitomycin C, streptozotocin, chlorozotocin, capecitabine, floxuridine, 6-hydrogen Thioguanidine, 8-azaguanine, azathiopurine, 5-ethynyl uracil, thioguanine, fluda Fludarabine, cytarabine, cladribine, 2-fluoro-arabityl-adenine, aminopterin, pemetrexed, ralitrexed, camptothecin , epirubicin, idarubicin, methylnitronitroguanidine, topotecan, irinotecan, mechlorethamine ), ifosfamide, trofosfamide, busulfan, procarbazine, mitoxantrone, actinomycin , calicheamicin, Tegafur (R, S-1-(tetrahydro-2-furanyl)-5-fluorouracil), 2 ' , 2 ' -difluoro-2 ' -deoxycytidine, double Chloroethyl sulfide, thiotepa, aziridine benzoquinone, BCNU, CCNU, 4-methyl CCNU, ACNU, rebeccamycin, bleomycin, Pello Pepleomycin, ethyl methanesulfonate, methyl methanesulfonate, dimethyl nitrosamine, dimethyl sulfate, and N'-[2-[2-(4-methoxyphenyl)ethylene 4--4-oxazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride

a substituted hexitol derivative as described above, which comprises di-dehydrated galactitol, diethyl hydrazine galactitol, di-dehydrated galactitol or diethyl hydrazine galactitol a derivative or analog that can be administered together with a preparation that modulates at least one of the following: γH2AX, p-RPA32 (S4/8, S33), ATR, ATM, Rad51, CtIP, BRCA1, and LEDGF, which are administered in a medically effective amount. A formulation that modulates at least one of these routes. Formulations that modulate one or more of these routes can be used to prevent or reduce resistance to anti-tumor agents, including, but not limited to, substituted hexitol derivatives.

When more than one formulation is administered in accordance with the methods of the invention, the formulations may be administered simultaneously or substantially simultaneously. In another alternative, the formulations can be administered sequentially. When the preparations are sequentially administered, if the preparations can be combined into a composition which does not have an adverse interaction between the preparations, and if the preparations can be administered by a route suitable for administration of the single pharmaceutical composition, A single pharmaceutical composition is administered. Alternatively, the preparations may be administered as separate pharmaceutical compositions, depending on the appropriate route to which they are administered, or by the same route of administration or by different routes of administration.

Another aspect of the present invention is a composition for treating a central nervous system malignant disease (such as glioblastoma multiforme or medulloblastoma) in a pediatric patient using a substituted hexitol as described above, at a low level Improving efficacy and/or reducing side effects in optimal administration therapy, comprising an option selected from the group consisting of: (i) a medically effective amount of a modified hexitol derivative, or hexitol a derivative, analog, or prodrug of a derivative or modified hexitol derivative, wherein the modified hexitol derivative or a derivative, analog, or derivative of the modified hexitol derivative Prodrugs have improved medical efficacy or reduced side effects compared to unmodified hexitol derivatives when treating central nervous system malignancies (such as glioblastoma multiforme or medulloblastoma) in pediatric patients (ii) a composition comprising: (a) a therapeutically effective amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative And (b) at least one other medical agent, a medical agent that is sensitized by chemotherapy, a medical agent that is synergized with chemotherapy, a diluent, an excipient, a solvent system, a drug delivery system a preparation for counteracting myelosuppressive action, or a derivative, analog, or a modification of the hexitol derivative, the modified hexitol derivative, or the hexitol derivative or the modified hexitol derivative, Or a preparation of a prodrug that passes the blood-brain barrier, The composition has improved medical efficacy or reduced side effects compared to unmodified hexitol derivatives when treating a central nervous system malignant disease (such as glioblastoma multiforme or medulloblastoma) in a pediatric patient. (iii) a pharmaceutically acceptable amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative, analog, or prodrug that has been included in the dosage form. a derivative, analog, or prodrug of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative in the dosage form for treating a child Suffer In patients with central nervous system malignancies (such as glioblastoma multiforme or medulloblastoma), it has improved medical efficacy or reduced side effects compared to unmodified hexitol derivatives; (iv) has been included A medically effective amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative derivative, analog, or pre-packaged in a dosage kit. a drug, wherein the hexitol derivative, the modified hexitol derivative, or the hexitol derivative or the modified hexitol derivative derivative, analog, or the like, which has been packaged in the dosage kit, Or a prodrug for the treatment of pediatric patients with central nervous system malignancies (such as glioblastoma multiforme or medulloblastoma), with improved medical efficacy or reduced compared to unmodified hexitol derivatives a side effect; and (v) a pharmaceutically acceptable amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative derivative that has been modified by a drug substance product , analog, or prodrug, wherein the raw material A modified hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a derivative, analog, or prodrug of a modified hexitol derivative for treating a central nervous system in a pediatric patient Malignant diseases (such as glioblastoma multiforme or medulloblastoma) have improved medical efficacy or reduced side effects compared to unmodified alkylated hexitol derivatives.

As described above, the alkylated hexitol derivative may be, but not limited to, di-desaled galactitol, a derivative or analog of deglycolal galactitol, diethyl hydrazine galactitol, or A derivative or analog of diethylaminosodium galactitol.

In another alternative, the pharmaceutical composition is formulated to have a cytotoxic effect against cancer stem cells.

In another alternative, the composition comprises a pharmaceutical combination comprising: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug of a modified alkylated hexitol derivative; and (ii) other medical agent selected from the group consisting of: (a) a topoisomerase inhibitor (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) signal transduction inhibitor; (f) cisplatin or platinum analogue; (g) alkane Base agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; (l) naphthophene; (m) vinca alkaloid; 5-fluorouracil; (o) curcumin; (p) NF-κB inhibitor; (q) rosmarinic acid; (r) acetamiprid; and (s) Tetrandrine.

In these options, when the other medical agent is an alkylating agent, the alkylating agent may be, but not limited to, an alkylating agent selected from the group consisting of BCNU, BCNU implants, CCNU, bendastatin, and Temodar. In another alternative, the pharmaceutical composition comprises one or more other formulations as described above in connection with the method of using a pharmaceutical combination according to the invention. According to the pharmaceutical combination of the present invention, the alkylated hexitol derivative and other preparations are present in a medically effective amount. More than one other formulation may be present in a pharmaceutical combination according to the invention, provided that the at least one other formulation does not adversely interact with one or more other formulations of the alkylated hexitol derivative or composition in the composition. .

In another alternative, the composition comprises: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkyl group. a derivative, analog, or prodrug of a hexitol derivative; and (ii) a medical agent that is sensitized by chemotherapy in a group selected from the group consisting of: (a) a topoisomerase inhibitor (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) signal transduction inhibitor; (f) cisplatin or a platinum analogue; (g) an alkylating agent; (h) an anti-tubulin agent; (i) an antimetabolite; (j) berberine; (k) apigenin; Colchicine or colchicine analogue; (m) genistein; (n) etoposide; (o) cytarabine; (p) camptothecin; (q) vinca alkaloid; r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; and (v) propylene bromide; wherein the alkylated hexitol derivative, modified The alkylated hexitol derivative, or the alkylated hexitol derivative or the modified alkylated hexitol derivative derivative, analog, or prodrug acts as a chemotherapeutic sensitizer.

In another alternative, the composition comprises: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkyl group. a derivative, analog, or prodrug of a hexitol derivative; (ii) a medical agent that is selected from the group consisting of: (a) a pseudonucleotide; (b) a pseudonucleotide; (c) a thymidylate synthase inhibitor; a signal transduction inhibitor; (e) cisplatin or a platinum analog; (f) an alkylating agent; (g) an anti-tubulin agent; (h) an antimetabolite; (i) berberine; j) apigenin; (k) colchicine or colchicine analogue; (l) genistein; (m) etoposide; (n) cytarabine; (o) camptothecin; Vinca alkaloid; (q) topoisomerase inhibitor; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; (v) Promethazine; and (w) a biotherapeutic agent; wherein the alkylated hexitol derivative, modified alkylated hexitol derivative, or alkylated hexitol derivative or modified alkylated hexitol is derived The action of a derivative, analog, or prodrug is used as a chemotherapy potentiator.

Among these options, the other medical agent is a biomedical agent, which may be, but not limited to, a biomedical agent selected from the group consisting of Avastin and Hepatic ( Herceptin), Rituxan, and Erbitux.

In another alternative, the alkylated hexitol derivative of the composition, the modified alkylated hexitol derivative, or the alkylated hexitol derivative or the modified alkylated hexitol is derived When the derivative, analog, or prodrug of the substance is modified by the drug substance product, the improvement of the drug substance product is selected from the group consisting of: (a) forming a salt; and (b) forming a homogeneous crystalline structure. (c) making a pure isomer; (d) increasing the purity; (e) using a method for reducing the residual solvent content; and (f) using a method for reducing the heavy metal content.

In another alternative, the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkylated hexitol a derivative, an analog, or a prodrug and a diluent of the derivative, wherein the diluent is selected from the following Group: (a) emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF); (d) dimethylformamide (DMF); (e) Methylacetamide (DMA); (f) ethanol; (g) benzyl alcohol; (h) water for injection containing dextrose; (i) castor oil polyoxyethylene ether (Cremophor); (j) ring Dextrin; and (k) PEG.

In still another alternative, the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkylated hexose a derivative, analog, or prodrug and solvent system of an alcohol derivative, 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 for injection containing dextrose; (i) castor oil polyoxyethylene ether (Cremophor); (j) PEG; and (k) salt system.

In still another alternative, the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkylated hexose a derivative, analog, or prodrug and an excipient of an alcohol derivative, wherein the excipient is 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; (1) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibitor; (o) organic resin; (p) a detergent; (q) perillyl alcohol or an analogue thereof; and (r) an activator of a channel-forming receptor.

In still another alternative, the alkylated hexitol derivative, the modified alkylated hexitol derivative, or the alkylated hexitol derivative or modified alkylated hexitol is derived Derivatives, analogs, or prodrugs are included in a dosage form selected from the group consisting of: (a) lozenges; (b) capsules; (c) topical gels; (d) topical (e) patch; (f) suppository; (g) lyophilized dose filler (h) immediate release formulation; (i) sustained release formulation; (j) controlled release formulation; (k) a liquid contained in a capsule.

In still another alternative, the alkylated hexitol derivative, modified alkylated hexitol derivative, or alkylated hexitol derivative or modified alkylated hexitol derivative The derivative, analog, or prodrug is included in a dose set and package selected from the group consisting of a shaded brown sample vial and a specially coated cap to improve shelf stability.

In still another alternative, the composition comprises: (i) an alkane a derivative, analog, or former derivative of a hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkylated hexitol 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) nanocrystals; (c) nanoparticle; (d) a cosolvent (e) syrup; (f) syrup; (g) bio-digestible polymer; (h) liposome; (i) sustained-release gel for injection; (j) microspheres; and (k) with epidermis A targeting component of a growth factor receptor binding peptide.

In still another alternative to the composition of the present invention, the medical agent is a modified alkylated hexitol derivative, and the modification is selected from the group consisting of: (a) changing the side chain To increase or decrease lipophilicity; (b) to add additional chemical functional groups to modify the properties of the group selected from the group consisting of: reactivity, electron affinity, and binding ability; and (c) changing the salt form.

According to still another alternative of the composition of the present invention, the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or modified a derivative or analog of an alkylated hexitol derivative, and the medical agent is contained in the composition in a drug conjugate form, wherein the drug conjugate type is selected from the group consisting of the following Drug conjugate type: (a) polymer system; (b) polylactic acid; (c) polyglycolide; (d) amino acid; (e) peptide; (f) multivalent linker; (g) immunization a globulin; (h) a cyclodextrin polymer; (i) a modified transferrin; (j) a hydrophobic or hydrophobic-hydrophilic polymer; (k) a conjugate with a phosphonic acid partial ester; l) a conjugate with a cell binding agent incorporating a charged crosslinker; and (m) a conjugate of a linker with β -glucuronide.

According to still another alternative of the composition of the present invention, the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or modified A derivative or analog of an alkylated hexitol derivative, and the medical agent is in the form of a prodrug system, wherein the prodrug 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) prodrug-releasing drug; (g) fibroblast-activated protein α cleavable oligopeptide prior to the drug; (H) the reaction product of acyl acyl or carbamoyl of the agent; (I) acetate in hexanes conjugate; (j) polymer - formulation conjugate; and ( k) A drug that can be subjected to a redox activation reaction.

According to still another alternative of the composition of the present invention, the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or modified a derivative, analog, or prodrug of an alkylated hexitol derivative, and the composition further comprises at least one additional medical agent to form a multi-drug system, wherein the at least one additional medical agent is selected from the group consisting of The following groups are grouped together: (a) inhibitors of multidrug resistance; (b) inhibitors of specific resistance; (c) specific inhibitors of selective enzymes; (d) signal transduction inhibitors; (e) an inhibitor of repairing enzymes; and (f) a topoisomerase inhibitor having no overlapping side effects.

According to still another alternative of the composition of the present invention, the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or modified A derivative, analog, or prodrug of an alkylated hexitol derivative, and the composition further comprises a preparation for counteracting myelosuppressive action. Typically, the anti-myelosuppressive formulation is a dithiocarbamate.

According to still another alternative of the composition of the present invention, the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or modified a derivative, analog, or prodrug of an alkylated hexitol derivative, and the composition further comprises a formulation for increasing the ability of the substituted hexitol to cross the blood brain barrier, wherein the substitution may be increased The preparation of hexitol through the blood-brain barrier ability is selected from the group consisting of: (a) a chimeric peptide of the formula (D-III): Wherein: (A) A is somatostatin, thyroid stimulating hormone releasing hormone (TRH), angiotensin, alpha interferon, endorphin, cell wall dipeptide or ACTH 4-9 analogue; (B) B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of formula (D-III), wherein the A The disulfide-bonded bridge chain between B is replaced by a small molecule (D-III(a)) bridge: A-NH(CH ₂ ) ₂ SSB (cleavable linker) (D-III(a)), Wherein the bridge chain forms a bridge chain using cysteamine and EDAC as a bridging agent; or a chimeric peptide of the structure of formula (D-III), wherein the disulfide bridge between the A and B is as small as Molecular Formula (D-III(b)) Bridge Chain Replacement: A-NH=CH(CH ₂ ) ₃ CH=NH-B (non-cleavable linker) (D-III(b)), wherein the bridge is used Glutaraldehyde is formed as a bridging agent; (b) a substituted hexitol derivative comprising avidin or avidin fusion protein-bonded biotinylated to form avidin-biotin-formulation complex a composition of matter comprising a protein selected from the group consisting of: pancreas , transferrin, anti-receptor monoclonal antibody, cationized protein, and lectin; (c) neutral liposome, which is glycosylated and incorporated into the substituted hexitol And wherein the polyethylene glycol strand is conjugated to at least one transportable peptide or targeting agent; (d) a humanized murine antibody that is linked to the trans-avidin-biotin linkage a human insulin receptor binding of a hexitol derivative; and (e) a fusion protein comprising a first segment and a second segment: the first segment comprises a variable region of an antibody that recognizes an antigen on a cell surface Performing antibody-receptor-mediated endocytosis after binding to the variable region of the antibody, and further comprising at least one functional domain of the constant region of the antibody, if desired; and the second segment comprises a material selected from the group consisting of Group of protein domains: avidin, avidin mutein, chemically modified avidin derivative, streptavidin, streptavidin mutein, and chemically modified Streptavidin derivative, wherein The fusion protein utilizes a covalent linkage to link the substituted hexitol to biotin.

In another alternative, when the alkylated hexitol derivative is dihydrated galactitol, it is formulated into a composition for administration of dehydrated galactitol, which is continuous for three consecutive days every 21 days. Do it once.

When the pharmaceutical composition according to the present invention comprises a prodrug, the compound prodrug and active metabolite can be discriminated by routine 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); Bvan's Advances in Drug Res., 13, 224-331 (1984); Bundgaard's Design of Prodrugs (Elsevier Press 1985); Larsen's Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al. Edited 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 pharmacologically active compound in the pharmaceutical composition according to the present invention has a sufficiently acidic, sufficiently basic functional group, or a functional group which is both sufficiently acidic and sufficiently basic, such groups or groups of groups may It is reacted with any of a wide variety of inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include those formed by the reaction of a pharmacologically active compound with a mineral or organic or inorganic base, such as: sulfates, pyrosulfates, hydrogen sulfate, sulfites, sulfurous acid. Hydrogen salt, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octoate, acrylate , 220rabic220, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, horse Acid salt, butyne-1,4-diacid salt, hexyne-1,6-diacid salt, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoic acid Salt, hydroxybenzoate, methoxybenzoate, decanoate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate , lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate Class. If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, for example, by treating the free base with a mineral acid, such as hydrochloric acid. Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or treatment of free bases with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid , salicylic acid, glucuronide (such as glucuronic acid or galacturonic acid), α -hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic An acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), or the like. If the pharmacologically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, for example, by treating the free acid with an inorganic or organic base, such as A secondary, tertiary or tertiary amine, an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include those derived from amino acids (such as glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine). Organic salts, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

If the formulation is a solid, those skilled in the art will appreciate that the compounds and salts of the present invention may be in different crystalline or polymorphic forms, and are included within the scope of the invention and the formulae indicated.

The specified pharmacologically active agent, such as the above-mentioned analog or derivative of dehydrated galactitol or didehydrated galactitol, in the unit dose of the pharmaceutical composition according to the present invention, varies depending on the following factors, such as a specific compound, The symptoms of the disease and its severity, characteristics of the individual in need of treatment (e.g., body weight), are still conventionally determined by those skilled in the art. Generally, such pharmaceutical compositions include a pharmaceutically effective amount of a pharmaceutically active agent and an inert pharmaceutically acceptable carrier or diluent. Typically, such compositions are formulated in unit dosage forms suitable for the chosen route of administration, such as oral administration or parenteral administration. For example, the above pharmacologically active agent can be administered in a conventional dosage form, which is prepared by combining a medically effective amount of such a pharmacologically active agent as an active ingredient with a suitable pharmaceutical carrier or diluent according to a conventional process. These processes may involve mixing, granulation and The ingredients are dissolved or dissolved as appropriate to form the desired formulation. The pharmaceutical carrier used may be solid or liquid. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent may include a delayed release or timed release material known in the art, such as glyceryl monostearate or glyceryl distearate, either alone or in combination with wax, ethylcellulose, hydroxyl Propyl methylcellulose, methyl methacrylate and the like.

A variety of different medical types are available. Thus, if a solid carrier is employed, the preparation may be compressed into tablets, placed in powder or pellet form in hard gelatin capsules, or in tablet or tablet form. The amount of solid carrier used may vary, but will generally range from about 25 mg to about 1 g. When a liquid carrier is employed, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution or suspension in an ampule or vial, or a nonaqueous liquid suspension.

In order to obtain a stable water-soluble dosage form, the pharmaceutically acceptable salt of the above pharmacologically active agent is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M succinic acid or citric acid solution. If a soluble salt form is not available, the formulation can be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, in concentrations ranging from 0 to 60% of the total volume. In a specific embodiment, the compound of formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution in the form of a salt of the active ingredient in a suitable aqueous vehicle such as water or isotonic physiological saline or dextrose solution.

It is understood that the actual dosage of the preparation to be used in the compositions of the present invention will depend on the particular compound employed, the particular composition being formulated, the mode of administration, and the particular site being treated, the host, and the condition and/or condition being treated. . The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied so that the amount of active ingredient obtained can be effective to achieve the desired medical response to a particular individual, composition, and mode of administration without toxic to the individual. The selected dosage level will vary with various pharmacokinetic factors, including the activity of the particular medical agent, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the severity of the condition, other health considerations affecting the individual, and The condition of the individual's liver and kidney function. It also depends on the duration of treatment, other drugs, the compounds and/or materials used in combination with the particular medical agent employed, and the age, weight, condition, general health and past medical history of the individual being treated, and similar factors. Methods for determining the optimal dosage are described in the related art, for example: Remington: The Science and Practice of Pharmacy , Mack Publishing Co., 20th ed., 2000. Those skilled in the art will be able to determine the optimal dosage for a particular group of conditions, based on experimental data from the formulation, using commonly used dose-determining tests. When administered orally, a typical daily dosage example is from about 0.001 to about 3000 mg/kg body weight, which can be repeated at appropriate intervals during the course of treatment. In some embodiments, the daily dose is from about 1 to 3000 mg/kg body weight.

A typical daily dose for a patient can be any dose between about 500 mg to about 3000 mg administered once or twice daily, for example, 3000 mg can be administered twice a day for a total dose of 6000 mg. a specific In embodiments, the dosage is between about 1000 and about 3000 mg. In another specific embodiment, the dosage is between about 1500 and about 2800 mg. In other specific embodiments, the dosage is between about 2000 and about 3000 mg.

The plasma concentration of the individual can be between about 100 [mu]M and about 1000 [mu]M. In some embodiments, the plasma concentration can range from about 200 [mu]M to about 800 [mu]M. In other specific embodiments, the concentration is from about 300 [mu]M to about 600 [mu]M. In still other embodiments, the plasma concentration can range from about 400 to about 800 [mu]M. Usually, the amount of the pre-dosing agent is based on the body weight of the fully active weight.

The compositions of the present invention may be prepared by conventional techniques known for use in the preparation of pharmaceutical compositions, for example, conventional techniques such as mixing, dissolving, granulating, dragee, suspension, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries which facilitate the processing of the active compound into preparations and which may be used in pharmaceuticals.

Appropriate formulations will depend on the route of administration chosen. At the time of injection, the preparation of the present invention can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer. When the mucosa is administered, a penetrant suitable for penetrating the barrier can be used in the formulation. Such penetrants are well known in the art.

When administered orally, the compound is readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions, and the like. The substance is taken orally by the patient being treated. A solid excipient may be mixed with the active ingredient (agent), the resulting mixture may be ground as needed, and the granular mixture may be processed after the addition of a suitable adjuvant, and if necessary, a lozenge or a sugar-coated core may be obtained to prepare a pharmaceutical for oral administration. preparation. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, nail Cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If necessary, a disintegrating agent such as cross-linked polyvinylpyrrolidone, acacia, or alginic acid or a salt thereof such as sodium alginate may be added.

The dragee core can have a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, a varnish solution, and a suitable organic solvent or solvent mixture. . Dyestuffs or pigments may be added to the lozenge or dragee coating to discriminate or resolve different combinations of active agents.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain a mixture of the active ingredient with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active agent can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer can be added. All oral administration formulations should be in dosages suitable for such administration. Composition when administered intravaginally The lozenge or lozenge form can be formed in a conventional manner.

Pharmaceutical formulations for parenteral administration may include aqueous solutions or suspensions. 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 substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension may also contain suitable stabilizers or modulators which increase the solubility or dispersion of the composition, as desired, to form a highly concentrated solution, or may comprise a suspending or dispersing agent. The pharmacologically active agent may be combined with a solid excipient, the resulting mixture may be ground as needed, and the granular mixture may be processed after the addition of a suitable adjuvant, and if necessary, a lozenge or a sugar-coated core may be obtained to prepare a pharmaceutical preparation for oral administration. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin , tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If necessary, a disintegration regulator such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

Other ingredients may be used, such as stabilizers, for example, antioxidants such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium hydrogen sulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl-α-naphthylamine, or lecithin. Chelating agents such as EDTA can also be used. Other ingredients commonly used in the pharmaceutical compositions and formulations may be used, such as lubricants, colorants, or flavoring agents for tablets or pills. In addition, you can use the common medical form Agent or carrier. Pharmaceutical excipients can include, but are not limited to, calcium carbonate, calcium phosphate, various sugar or starch types, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art. Examples of pharmaceutically acceptable carriers include, but are not limited to, any and/or all solvents, including aqueous and non-aqueous solvents, dispersing media, coatings, antibacterial and/or antifungal agents, isotonic and/or delayed Absorbents, and/or the like. The use of such media and/or formulations on pharmaceutically active substances is well known in the art. Unless any conventional medium, carrier, or formulation is not compatible with the active ingredient or ingredient group, its use is included in the compositions according to the invention. Supplementary active ingredients may also be included in the compositions, as specified above. When administering any of the compounds used in the present invention, the formulation should meet the sterility, pyrogenicity, general safety, and purity standards required by the FDA's Office of Biologics Standards or other regulatory agency.

For intranasal or inhalation administration, the compounds used according to the invention are preferably in the form of aerosol sprays, from the use of suitable propellants, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Transfer from a pressurized tank or sprayer of carbon dioxide or other suitable gas. Taking a pressurized aerosol as an example, a metering device can be used to determine the dosage unit. Gelatin capsules and cartridges for inhalers or insufflators and the like can be formulated using a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, for example, by rapid injection or continuous infusion. Formulations for injection may be presented in unit dosage form, such as ampoules or multi-dose containers. Composition can be presented For example, it is contained in the form of a suspension, solution or emulsion of an oily or aqueous vehicle, and may contain a formulation such as a suspending agent, a stabilizer, and/or a dispersing agent.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active agents can be formulated into suitable oily injection suspensions. 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. The suspension may also contain suitable stabilizers or formulations which increase the solubility of the compound, as desired, in order to prepare a highly concentrated solution.

Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle (for example, sterile pyrogen free water) prior to use. The compounds may also be formulated in rectal compositions such as suppositories or enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the above formulations, the compounds may also be formulated as a depot preparation. 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 formulated with an ion exchange resin, or a poorly soluble derivative, for example, a poorly soluble salt.

Examples of pharmaceutical carriers for hydrophobic compounds are cosolvent systems comprising benzyl alcohol, a nonpolar surfactant, a water miscible organic polymer, and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is 3% w/v benzyl alcohol, 8% w/v non-polar surfactant polysorbate Ester 80, with 65% w/v polyethylene glycol 300, a volumetric solution of anhydrous ethanol. The VPD cosolvent system (VPD: 5W) contained a 1:1 dilution of VPD using a 5% aqueous solution of dextrose. This cosolvent system also dissolves hydrophobic compounds, which are inherently less toxic when administered systemically. The proportion of the cosolvent system can of course also vary greatly without destroying its solubility and toxicity characteristics. In addition, the composition of the cosolvent may vary: for example, a low toxicity aprotic surfactant may be used instead of polysorbate 80; the proportion of polyethylene glycol may vary; other biocompatible polymers may be used instead. Instead of polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides can be used instead of dextrose.

Alternatively, other delivery systems can be used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are examples of delivery vehicles or carriers known for use in hydrophobic drugs. Certain organic solvents, such as dimethyl hydrazine, may also be used, but usually at the expense of higher toxicity. In addition, the compounds can be delivered using a sustained release system such as a semipermeable matrix comprising a solid hydrophobic polymer of a medical agent. A variety of different sustained release materials have been established and are known to those skilled in the relevant art. Sustained-release capsules may vary depending on their chemical nature, and the compound is continuously released for several weeks up to more than 100 days. Depending on the chemical nature of the medical reagent and the biosafety, other strategies for stabilizing the protein may be used.

The pharmaceutical compositions may also contain suitable solid phase or gel phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

The pharmaceutical compositions can be administered by a variety of different methods known in the art. The route and/or mode of administration can vary depending on the desired result. Depending on the route of administration, the pharmacologically active agent can be coated with a material to protect the targeted composition or other medical agent from the action of the acid and other compounds which may deactivate the formulation. Conventional pharmaceutical procedures can be employed to provide formulations or compositions suitable for administering such pharmaceutical compositions to an individual. Any suitable route of administration may be employed, such as, but not limited to, intravenous, parenteral, intraperitoneal, intravenous, transdermal, subcutaneous, intramuscular, intraurethral, or oral administration. Depending on the severity of the malignant disease or other disease, condition, or condition being treated, and other conditions affecting the individual being treated, the pharmaceutical composition may be delivered systemically or locally during the course of treatment. The pharmaceutical composition as described above may be administered in combination with other medical agents for treating a particular disease or condition, which may be the same disease or condition for which the pharmaceutical composition is planned to be treated, which may be a related disease or condition, or even possible Is an unrelated disease or condition.

A pharmaceutical composition comprising di-dehydrated galactitol, diethylidene di-dehydrated galactitol, and comprising di-dehydrated galactitol or diethylamino-dehydrated galactitol is usually administered orally or intravenously.

The pharmaceutical compositions according to the present invention can be prepared according to methods known in the art and routinely employed. See, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20 th ed, 2000; and Sustained and Controlled Release Drug Delivery Systems, JRRobinson, ed, Marcel Dekker, Inc., New York, 1978... The pharmaceutical composition is preferably manufactured under GMP conditions. Parenteral formulations may include, for example, excipients, sterile water, or physiological saline, polyalkylene glycols (e.g., polyethylene glycol), vegetable derived oils, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactate/glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other parenteral delivery systems that may be suitable for use in the molecules of the invention include exfoliating ethyl-vinyl acetate copolymer particles, osmotic pumps, and implantable infusion systems. Formulations for inhalation may comprise an excipient, for example, lactose, or may be an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be administered An oily solution, or a gel.

Pharmaceutical compositions according to the invention are typically administered to a subject multiple times. The interval between single doses can be one week, one month, or one year. Irregular intervals may also be used depending on medical response or other parameters known in the art. Alternatively, the pharmaceutical composition can be administered in a sustained release formulation where a lower frequency of administration is required. The dosage and frequency will vary with the half-life of the pharmacologically active agent included in the pharmaceutical composition in the individual. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or medical. In prophylactic applications, relatively low doses are administered chronically at relatively infrequent intervals. Some individuals may continue to receive treatment for the rest of their lives. In medical applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is reduced or terminated, preferably until partial or complete relief of the disease symptoms of the individual. After that, the individual can be administered a preventive treatment.

For the purposes of this application, clinical parameters can be improved by observing one or more of the symptoms, conditions, or conditions associated with the condition being treated, or by observing one or more of the diseases, conditions, or conditions being treated. Tracking.

Sustained release formulations or modified release formulations are known to those skilled in the art. For example, a sustained release or modified release formulation may be (1) a sustained release or controlled release formulation for oral administration; (2) a multi-layer sustained release or modified release tablet formulation for oral administration; Oral multi-particulate sustained release or regulatory release formulation; (4) oral osmotic sustained release or regulatory release formulation; (5) oral chewable sustained release or regulatory release formulation Or (6) a skin sustained release or modified release patch formulation.

The pharmacokinetic principles governing drug delivery are described, for example, in "Pharmacokinetic/Pharmacodynamic Basis of Controlled Drug Delivery" by BMSilber et al., in Controlled Drug Delivery: Fundamentals and Applications (JR Robinson & VHLLee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 5, pp. 213-251.

Those skilled in the art will readily be able to prepare formulations for controlled release or sustained release comprising a pharmacologically active agent according to the present invention by modifying the above formulations, as per VHKLi et al., "Influence of Drug Properties and Routes of Drug Administration". On the Design of Sustained and Controlled Release Systems", Controlled Drug Delivery: Fundamentals and Applications (JR Robinson & VHLLee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94 Reveal the principle. This process usually takes into account the physiochemical properties of the pharmacologically active agent, such as water solubility, partition coefficient, molecular size, safety Qualitative, its non-specific combination of protein and other biological macromolecules. This process also takes into account the biological factors of the pharmacologically active agent, such as absorption, distribution, metabolism, duration of action, possible side effects, and safety margins. Thus, those skilled in the art can modify the formulation to a formulation having the desired properties described above for a particular use.

The use of various pharmacologically active agents and pharmaceutical compositions is disclosed in U.S. Patent No. 6,573,292 to Nardell, U.S. Patent No. 6,921,722 to Nardella, U.S. Patent No. 7,314,886 to Chao, et al. Methods of treating a wide variety of diseases and conditions, including cancer, and methods of determining the medical effectiveness of such pharmacologically active agents and pharmaceutical compositions are herein incorporated by reference.

Typically, a therapeutically effective amount of water to two-galactitol is from about 40mg / m ^2. The medically effective amount of acetaminophen dehydrated galactitol should also take into account molecular weight differences. Other acceptable dosages include di-galactositol at a maximum of 50 mg/m ² . Higher doses can also be employed, especially when preventing myelosuppression.

Another aspect of the invention is a method of treating a central nervous system malignancy in a pediatric patient, comprising the step of administering a therapeutically effective amount of a substituted hexitol derivative to a patient suffering from a malignant disease. As described in detail above, the substituted hexitol derivative is a group selected from the group consisting of: dehydrated galactitol, derivative of didehydrated galactitol, and diethyl hydrazine deionized water. a derivative of galactitol, diethylstilbene di-dehydrated galactitol, dibromodusol, and a derivative of dibromodusol. Preferred substituted hexose The alcohol derivative is di-dehydrated galactitol.

Typically, when the substituted derivatives of hexitol two galactose water to an alcohol, the therapeutically effective amount of water to two galactose alcohol is from about 1mg / m ² to about 40mg / m ² of a dose. Preferably the two lines to the medical water-galactitol effective amount is about 5mg / m ² to about 25mg / m ² of a dose. The medically effective amount of diacetyl hydrazine dehydrated galactitol should also take into account molecular weight differences. Other acceptable dosages include di-galactositol at a maximum of 50 mg/m ² . Higher doses can also be employed, especially when preventing myelosuppression.

Typically, the substituted hexitol derivative (e.g., di-dehydrated galactitol) is administered by a route selected from the group consisting of intravenous and oral. A route similar to that used for the administration of diacetyl hydrazine galactitol can be employed. Other feasible routes of administration are as explained above.

The method can further comprise the step of administering a therapeutically effective dose of free radiation. The method can further comprise administering a therapeutically effective amount of Dimension, Bevacizumab, or a corticosteroid.

The method can further comprise administering a medically effective amount of a tyrosine kinase inhibitor as described above.

The method can further comprise administering a medically effective amount of an epidermal growth factor receptor (EGFR) inhibitor as described above. The EGFR inhibitor can affect a wild type binding site or a mutated binding site, including variant III as described above.

Another aspect of the invention is a kit comprising a hexitol derivative as described above for the treatment of a malignant disease in a pediatric patient, in particular, a central nervous system malignant disease, separately packaged in two or more different doses. Typically, the hexitol derivative is di-dehydrated galactitol or diethyl hydrazine galactitol. When the alkylated hexitol derivative is dihydrated galactitol, the kit includes, but is not limited to, the following dosage combinations: (i) 1.5 mg/m ² and 3.0 mg/m ² ; (ii) 1.5 mg /m ² , 3.0 mg/m ² , and 5.0 mg/m ² ; (iii) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 mg/m ² , and 10 mg/m ² ; (iv) 1.5 mg/ m ² , 3.0 mg/m ² , 5.0 mg/m ² , 10 mg/m ² , and 15 mg/m ² ; (v) 10 mg/m ² ; (iv) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 Mg/m ² , 10 mg/m ² , 15 mg/m ² , and 20 mg/m ² ; (vi) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 mg/m ² , 10 mg/m ² , 15 mg/m ² , 20 mg/m ² , and 25 mg/m ² ; (vii) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 mg/m ² , 10 mg/m ² , 15 mg/m ² , 20 mg/m ² , 25 mg /m ² , and 30 mg/m ² ; (viii) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 mg/m ² , 10 mg/m ² , 15 mg/m ² , 20 mg/m ² , 25 mg/m ² , 30 mg/m ² , and 40 mg/m ² ; and (ix) 1.5 mg/m ² , 3.0 mg/m ² , 5.0 mg/m ² , 10 mg/m ² , 15 mg/m ² , 20 mg/m ² , 25 mg /m ² , 30 mg/m ² , 40 mg/m ² , and 50 mg/m ² . Other dosage combinations may also include dosages of two or more such alternatives. The hexitol derivative can be in the form of a pharmaceutical composition. These doses can be assembled in a blister pack that is commonly used to package pharmaceutical doses. The kit may further include instructions for use.

Thus, one aspect of the present invention is a method for treating a central nervous system malignant disease (such as glioblastoma multiforme or medullary cell) in a pediatric patient by administering a medically effective amount of a substituted hexitol derivative according to the present invention as described above. Method of tumor).

The method for treating a central nervous system malignant disease (such as glioblastoma multiforme or medulloblastoma) in a pediatric patient can adopt the above method A method for improving the efficacy of administration of a substituted hexitol and/or reducing side effects.

The method for treating a central nervous system malignant disease (e.g., glioblastoma multiforme or medulloblastoma) in a pediatric patient can employ the composition according to the present invention as described above.

The method of treating a central nervous system malignancy (such as glioblastoma multiforme or medulloblastoma) in a pediatric patient can further comprise administering a medically effective amount of a PARP inhibitor.

The method of treating a central nervous system malignant disease (e.g., glioblastoma multiforme or medulloblastoma) in a pediatric patient can further comprise administering a therapeutically effective amount of a formulation having a counterproductive PTEN deficiency as described above.

The following examples illustrate the invention. The examples are included for illustrative purposes only and are not intended to limit the invention. In some examples, as described below, these examples provide results from cell lines other than cells of the central nervous system malignant disease; in these examples, as detailed in the clear examples, the results are related to the treatment of central nervous system malignancies, Because the mechanism described is also related to the resistance in the central nervous system malignant cells.

Example 1

Activity of two dehydrated galactitol against medulloblastoma and pediatric high-grade glioma cell lines

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 15-30% of all children with intraorbital tumors. Highly malignant glioma (HGG) is more common in children than in adults, accounting for only 5%-10% of childhood brain tumors. Although various subject treatments have significantly improved 5-year survival in children, the prognosis for MB and HGG recurrence is still poor, with a median overall survival <1 year. Dimension (TMZ) is often used to treat MB and pediatric HGG; however, there is still no clinical evidence and due to the repair protein O ⁶ -methylguanine-DNA methyltransferase (MGMT) (which is associated with TMZ resistance) The high performance has been reported to have poor consequences. Di-dehydrated galactitol (VAL-083) is a bifunctional alkylating agent with a unique structure that causes DNA cross-linking at the guanine N ⁷ position. VAL-083 is easily passed through the blood-brain barrier and has been shown to accumulate in brain tumor tissue. In addition, the clinical activity of VAL-083 against MB and HGG has been demonstrated in historical NCI-sponsored clinical studies. We have recently shown that VAL-083 has demonstrated cytotoxic activity in GBM-dependent MGMT expression in vitro and in vivo. We further showed that VAL-083 is highly potent against GBM cancer stem cells (CSC) and non-CSC, and its role in the in vitro GBM cell line is a radiosensitizer. VAL-083 is currently undergoing phase II clinical trials in adult relapsed GBM. In the current adult GBM clinical trial, VAL-083 showed an advantageous safety profile, and a preliminary analysis of the survival benefit at the selected dose supported further studies. Based on these recent studies and data supporting the clinical activity of VAL-083 in historical MB and HGG studies, we sought to explore cells with VAL-083 by studying drugs that can fight MB and pediatric HGG cell lines in vitro. Toxic activity is a possible medical option for pediatric brain tumors.

Materials and Methods

Cell line and culture conditions

All cells except BT74 were in DMEM (Dulbecco's Modified Eagle's Medium medium; Invitrogen/Gibco) (containing 10% FBS) (fetal calf serum; Invitrogen/Gibco) during the experiment, 37 ° C Incubate with 5% CO ₂ and subculture twice a week. BT74 cells were non-adherently grown using Neurocult supplements containing growth factors: EGF (20 ng/ml), FGF (20 ng/mL) and heparin (2 mg/mL) in NeuralBasal medium. SF188 (pediatric) and U251 (adult) GBM cell lines were obtained from ATCC.

drug:

TMZ was purchased from Sigma-Aldrich and dissolved in DMSO (dimethyl hydrazine; Sigma-Aldrich). The 100 mM mother liquor before use was stored at -20 °C. The second dehydrated galactitol (also referred to herein as "VAL-083") is a lyophilized powder which is dissolved in sterile PBS (phosphate buffered saline) in a vial to make a 100 mM mother liquor, which is stored before use. -20 ° C.

Growth analysis method:

Each cell strain was seeded at 3,000 cells/well in 100 μL of a 96-well plate (BD Falcon) and cultured overnight. The cells were then treated with TMZ or VAL083 in fresh medium for a period of 72 h at a concentration of 0.1-100 μM. The cells were fixed in 2% paraformaldehyde (Sigma-Aldrich) containing the nuclear stain 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 prior to HCS (high content screening; ThermoFisher Scientific) analysis. 20 fields were scanned per well and analyzed. Growth inhibition was calculated as a reference group with respect to a solvent-free and drug-free control group and a sample treated with only a solvent. There were three replicates for each treatment and each experiment was repeated.

Neuronal spheroid analysis

When nerve cells spheroid assay, take about 10 ⁴ cells / well coated using human recombinant FGF (20ng / ml) and heparin (2 μ g / ml) of recombinant human nerve cells containing EGF (20ng / ml) The medium has a low adhesion in a 6-well plate. The nerve cell spheres are grown for 5-6 days after coating. Cell spheres >30 μm were calculated and photographed using an Aniovert 40CFL microscope and an AxioCam MRc camera. The NeuroCult Chemical Dissociation Kit (Stem Cell Technologies, cat. #05707) was used to subculture the cells, and single cell coating was calculated and taken. All drug treatments were performed at the time of coating and were repeated during successive passages.

Human cell lines MB take DAOY, UW228, ONS-76 and UW426 HGG cell line SF188 and pediatric use VAL-083, a concentration of 0.1-100 μ M treatment 72h. Growth inhibition was measured using a high throughput screening assay. Neuronal spheroid formation of DAOY and SF188 cells was determined by neuronal spheroidal community analysis.

result

VAL-083 can inhibit the growth of all cell lines (DAOY, UW228, ONS-76 UW426 and SF188) in the low micromolar concentrations IC _50. DAOY, UW228 and SF188 cells are most sensitive to VAL-083. DAOY cells cultured neurons beginning spheroid formation at 5 μ M VAL-083 completely inhibited, and VAL-083 formed in the spheroid cultured neurons against SF-188 cells at the beginning than TMZ; observed in combination with TMZ of VAL-083 To completely inhibit SF-188 neuronal cells.

Example 2

Other applications of the treatment of central nervous system malignant diseases with di-dehydrated galactitol

Additional results for the treatment of central nervous system malignancies, including glioblastoma multiforme, using di-dehydrated galactitol are described below.

Figure 1 is a comprehensive list showing the glioblastoma multiforme (GBM) pattern and its response to di-dehydrated galactitol (VAL-083).

Figure 2 shows three cell lines: SF188, U251, and T98G (TMZ) resistance and MGMT status. SF188 is a highly malignant glioma cell line in children. In Fig. 2, protein actin was used as a control group. Show the Western dot map.

Figure 3 shows SF188 (top), U251 (middle), and T98G (bottom) using 0.1, 1, 2.5, 5, 10, 25, 50, and 100 μM Dimension (TMZ) and two de-water half The survival result of lactitol (VAL). Two tests were presented for each cell line.

Figure 4 shows that dehydrated galactitol provides over 95% repressivity in a community formation assay of SF188 at 5 [mu]M.

Figure 5 shows that the effect of di-dehydrated galactitol (VAL) in inhibiting SF188 growth in secondary cell spheroid formation is higher than that of Dimension (TMZ). Two dehydrated galactitols were used at 5 μM, and Dimensions were used at 10 μM.

Figure 6 shows that dehydrated galactitol (VAL083) completely inhibits neuronal spheroid formation in the primary neuronal spheroids and secondary neuronal spheroids of BT74 cancer stem cells. The second dehydrated galactitol was used at 5 μM.

Figure 7 shows the dehydrated galactitol (VAL083) at When SF188 and DAOY cell lines (DAOY is a medulloblastoma cell line) inhibit the formation of primary neuronal spheroids, they are more effective than Dimension (TMZ). Two dehydrated galactitols were used at 5 μM, and Dimensions were used at 10 μM.

Figure 8 shows that dehydrated galactitol at 100 μM provides 100% repression of colony formation of DAOY medulloblastoma cells and >80% repression of colony formation of SF188 glioblastoma cells.

The materials and methods for the results shown in Figs. 1 to 8 are as follows. Cell lines and culture conditions: All cells were cultured in DMEM (Dure's modified Ig's medium; Invitrogen/Gibco) (containing 10% FBS) (fetal calf serum; Invitrogen/Gibco) at 37 ° C and 5% CO ₂ during the experiment. And subcultured twice a week. Dimensions were purchased from Sigma-Aldrich and dissolved in DMSO (dimethyl hydrazine; Sigma-Aldrich). The 100 mM mother liquor before use was stored at -20 °C. The second dehydrated galactitol was a lyophilized powder, which was dissolved in sterile phosphate buffered saline (PBS) in a vial to prepare a 100 mM mother liquor, which was stored at -20 ° C until use. Each cell line was seeded at 3,000 cells/well in 100 μL of a 96-well plate (BD Falcon) and cultured overnight. The cells were then treated with Dimensions or di-dehydrated galactitol in fresh medium for 72 h at the indicated concentrations of 0.1-100 [mu]M. The cells were fixed in paraformaldehyde (Sigma-Aldrich) containing the nuclear stain 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 prior to HCS (high content screening; ThermoFisher Scientific) analysis. 20 fields were scanned per well and analyzed. Growth inhibition was calculated as a reference group with respect to a solvent-free and drug-free control group and a sample treated with only a solvent. There were three replicates for each treatment and each experiment was repeated.

Figure 9 shows a method for calculating the number of spheroids of glioblastoma multiforme cells (GBM4) including the control group and the two-dehydrated galactitol-treated group (VAL).

Figure 10 shows the inhibition of 10 μM di-dehydrated galactitol (VAL) on first and second generation GBM4 cells.

Figure 11 shows the inhibition of cell spheroids when GBM4 and GBM8 cells were treated with 10 μM of dehydrated galactitol (VAL) for 1 week.

Figure 12 is a diagram showing the effect of various concentrations of dihydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) in a single layer of hNSC for 72 hours. .

Figure 13 is a graph showing the efficacy of various concentrations of di-dehydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) in a single layer of aBT001 for 72 hours. .

Figure 14 is a diagram showing the other experiments in which different concentrations of dihydrated galactitol (VAL083) (0.1 μM, 1 μM, 2.5 μM, 5 μM, 10 μM, 25 μM, 50 μM, and 100 μM) were treated in a single layer of hNSC 72 The pattern of the effectiveness of the hour.

Figure 15 is a series of graphs showing the general dose-response curves and S-type dose-response curves of U251, T98G, and SF188 cell lines treated with various concentrations of di-dehydrated galactitol and Dimensional multi-treatment.

Figure 16 shows the S-type dose effect curve from Figure 15. A list of IC50 for line calculations.

Figure 17 is a graphical representation showing the efficacy of sequential administration of di-dehydrated galactitol (VAL-083) and Dimensional Polysaccharide (TMZ) on pediatric high-grade glioma cell line SF188; treated with TMZ for 3 days, It was then washed and treated with two dehydrated galactitol for 3 days. This combination completely inhibits neuronal spheroid formation.

18 photo shows two to produce water of galactitol induced DNA alkylating N ⁷ figures of the activity.

Figure 19 is a graph showing the efficacy of simultaneous administration of DM188 cells in combination with the combination of Dimensions and di-dehydrated galactitol.

Figure 20 is a graph showing the efficacy of reducing the formation of colonies when SF188 cells were treated with Simeral and Dihydrogalactitol.

Figure 21 is a graph showing the efficacy of sequential administration of dehydrated galactitol (VAL-083) and Dimension (TMZ) on pediatric high-grade glioma cell line SF188; treated with TMZ for 3 days, then Washed and treated with two dehydrated galactitol for 3 days; two dehydrated galactitol used two concentrations: 10 μM and 25 μM.

Figure 22 is a graphical representation of the progression of malignant disease recurrence caused by cancer stem cell survival.

Figure 23 is a graph showing the efficacy of the combination of di-dehydrated galactitol and Dimension on the first and second passage SF188 cells.

Figure 24 is a graph showing that BT74 cancer stem cells did not show significant sensitivity to Dimension.

Figure 25 is a graph showing the efficacy of di-dehydrated galactitol on primary freshly isolated GBM cultures.

Figure 26 is a graph showing that dihydrated galactitol is active against tumors exhibiting YB-1 because the DNA repair enzyme is unable to repair the N ⁷ -adduct produced by the treatment with dihydrated galactitol.

Figure 27 is a graph showing inhibition of YB-1 in adult glioblastoma, which may increase sensitivity to Dimension.

Figure 28 shows that YB-1 stays in the nucleus in the presence of the Dimension; the Dimensional multi-system uses 10 μM; the left picture shows the control group; the right picture shows the DMC multi-treatment group; the magnification is 200×.

Figure 29 is a diagram showing the efficacy of administration of Dimensions and di-dehydrated galactitol to reduce the formation of neuronal spheroids in SF188 cells; 10 μM for Dimensional multi-line; 5 μM for di-dehydrated galactitol .

Figure 30 is a graphical representation of inhibition of YB-1 and its interaction with the MGMT pathway in MGMT-positive adult glioblastoma cells.

Figure 31 is a diagram showing the efficacy of the combination of di-dehydrated galactitol and Dimensions to reduce the effect of SF188 cell line on neuronal spheroid formation compared to the use of di-dehydrated galactitol alone; Alcohol was used at 5 μM, and Dimensions was used at 10 μM.

Figure 32 shows Western blots of U251 and SF188 cells using p-RSK, PLK1, P-YB-1, and actin (as a control). Glioblastoma cell lines were treated with 5 μM of dehydrated galactitol, PBS, or untreated for 72 h, collected, and subjected to Western blot analysis.

Figure 33 shows the pre-treatment effect of di-dehydrated galactitol prior to administration of the Polo kinase inhibitor BI6727 to the SF188 and U251 cell lines. After 72 hours of treatment with 5 [mu]M didesaminogalactitol, cells were seeded into 96-well plates, treated with a range of BI6727 for 72 hours, and an untreated control group was used.

Figure 34 is a graph showing the inhibitory effect of di-despartate galactitol on the growth of medulloblastoma cell lines DAOY, ONS76, UW228, and UW426. The medulloblastoma cell line was inoculated into a 96-well plate and treated with a gradually increasing concentration of the second dehydrated galactitol for 72 hours.

Figure 35 is a graph showing the effect of pre-treatment of di-dehydrated galactitol prior to administration of Polo kinase inhibitor BI6727 in medulloblastoma cell lines DAOY, ONS76, UW228, and UW426. After 72 hours of treatment with 5 [mu]M didesaminogalactitol, cells were seeded into 96-well plates, treated with a range of BI6727 for 72 hours, and an untreated control group was used.

Conclusion Dihydrogalactitol will inhibit the growth of brain tumor cells, independent of MGMT status, and can be used to overcome TMZ resistance. Dihydrogalactitol is active against TMZ-resistant glioblastoma multiforme cell lines and against BTIC (brain tumor-initiating cells with stem cell-like properties). The second dehydrated galactitol is synergistic when combined with the Dimension in sequence. The second dehydrated galactitol is also active against tumors that also exhibit YB-1 because this DNA repair enzyme cannot repair the N ⁷ adduct. Both Dimensional (TMZ) and didehydrated galactitol are alkylating agents. TMZ (Dimensional) undergoes rapid chemical conversion at physiological pH to form the active compound: monomethyltriazepidinecarboxamide (MTIC). Cytotoxicity of MTIC is thought mainly based on the methylation of DNA guanine ^6-position of the O. The content or activity of the DNA repair protein O ⁶ -methylguanine-DNA methyltransferase (MGMT) is primarily responsible for the development of TMZ resistance. However, di-dehydrated galactitol is believed to form inter-strand crosslinks in guanine N ⁷ and act on N ^{7 of} guanine. Crosslinking induced by nitrogen mustard does not break/repair by MGMT. Therefore, the activity of di-dehydrated galactitol should not be dependent on MGMT.

Example 3

The activity of the second dehydrated galactitol does not depend on MMR

The activity of the second dehydrated galactitol is independent of MMR and independent of the p53 state. The results of this example are from experiments using ovarian cancer cell lines; however, because MMR is a DNA repair machine, it develops resistance to chemotherapy in central nervous system malignancies, including juvenile glioblastoma and medulloblastoma. Regarding, the development of MMR-free therapies is important for the use of such anti-drug-resistant therapies.

method:

The cell lines used were confirmed by molecular analysis to confirm the tissue type and were free of mycoplasma infection. The p53 status is established by the sequencing of the DNA. The drug used was obtained from Sigma (cisplatin and oxaliplatin) or by Del Mar Pharmaceuticals (dihydrogalactitol).

The cytotoxicity assay (expressed as IC50 (concentration at 50% inhibition of cell growth) or at the indicated drug concentration (Fa)) is based on the MTT growth inhibition assay after the 5-day drug exposure period. data. Substituting Fa values from the drug concentration range into four-parameter logic (logistic) dose-effect S-curve equation, using the Graphpad Prism v.6 software to generate IC50 values. The resistance factor (for the ovarian group) was calculated as the ratio of the IC50 in a particular tumor pattern to the IC50 in A2780.

result

Cisplatin-sensitive A2780 and cisplatin-resistant 2780CP-16, OVCAR-10, Hey and OVCA-433 tumor models (A2780: p53 wild type, in different state p53 and mismatch repair (MMR) DNA repair systems, MMR is defect-free; 2780CP-16: heterogeneous p53wt/V172Fmut, MMR deficiency; OVCAR-10: p53 V172F mutant, MMR non-defective; HEY: p53 P72R mutant, MMR non-defective; OVCA-433: p53 P72R mutant, The cytotoxicity against them was determined in MMR without defects. The dose-response curve of di-dehydrated galactitol in the ovarian tumor cell group is shown in Figure 36. The corresponding IC50 values for the dehydrated galactitol are shown in Figure 37. The aqueous two-galactitol in A2780 cells in the IC50 is from about 0.5 μ M, and cisplatin - the resistance patterns is within 2-4 μ M range. The activity of di-dehydrated galactitol relative to cisplatin and oxaliplatin (expressed as IC50) is shown in Figure 38 as a bar graph. In the A2780 model, all three drugs have demonstrated similar activity (IC50,0.2-0.5 μ M), but other modes having a higher apparent IC50 values of resistance to cisplatin, about 3-8 μ M. Conversely, oxaliplatin against cisplatin _- sensitive (0.2 μ M) and cisplatin - resistant (0.2-0.6 μ M) Both cell have good potency. The activity of the dehydrated galactitol against the resistance pattern is between cisplatin and oxaliplatin, but the activity relative to A2780 is measured (in terms of resistance factor (RF), after RF for A2780 is 1 Correction) showed that di-dehydrated galactitol effectively evaded cisplatin resistance in HEY mode, but slightly decreased in 2780CP-16, OVCAR-10 and OVCA-433 cell lines (Fig. 39). This indicates that VAL-083 can evade cisplatin resistance in ovarian cancer cell lines, independent of its p53 status and MMR status.

The Mismatch Repair System (MMR) is a DNA repair system that involves repairing mismatched Watson Crick base pairing. MMR defects can cause viable cells and often accumulate mutations in many cancer cells, including GBM and medulloblastoma. As mentioned above, the MMR system involves repairing DNA lesions caused by several alkylated chemotherapeutic agents, including TMZ and cisplatin. MMR-deficient cells are less sensitive or completely resistant to these drugs. Since the water to the two unique mechanism of action of galactitol, which is deficient cell lines in MMR- 2780CP-16 (group of MLH1 MMR deficiency component) in the cytotoxic activity of an IC50 value of 2.2 μ M does not seem to depend MMR. Thus, these results are associated with the treatment of glioblastoma and medulloblastoma in juvenile patients, as the development of resistance to chemotherapeutic agents in these malignancies is often associated with MMR DNA repair activity.

Summary of all possible combinations of deglytriol, dimethoate, cisplatin, and nitrosourea in MGMT-positive or MGMT-negative or MMR-deficiency or MMR-deficiency (MGMT-positive/MMR-no defect The activity in cells of MGMT-positive/MMR-deficiency; MGMT-negative/MMR-deficient; or MGMT-negative/MMR-deficient) is shown in Table 1.

The references in Table 1 are as follows: ¹ M. Sanada et al., Carcinogenesis 12: 2657-2663 (2007); ² M. Kartalou et al., Mutat. Res. 478: 23-43 (2001); ³ Y. Sedletska et al. J. Mol. Biol. 369: 27-40 (2007); ⁴ B. Cui et al., Mol. Pharmacol. 75: 1356-1363 (2009).

Table 1 shows that dehydrated galactitol can exhibit its anti-tumor properties in any combination of MGMT-positive or -negative and MMR-deficient or defective environments, while Dimensions, cisplatin, and nitrosourea The opposite is true.

Example 4

Synergistic effect of dihydrogalactitol and olapa

Di-dehydrated galactitol has more than additive activity when administered with olaparibin A2780 ovarian cancer cell line. Although these are ovarian cancer cell lines, they are associated with the treatment of juvenile glioblastoma and medulloblastoma, as it is expected to produce the same synergy or excess of the addition activity in the cells of their malignant diseases. The A2780 ovarian cancer cell line received either dehydrated galactitol or olaparib alone or simultaneously, and cytotoxicity was analyzed after 5 days.

The proportion of affected cells (Fa) was determined and shown in Figure 40. At the indicated concentrations, the Fa at the time of separate use of the drug was about 15-25%, but when combined, it caused a Fa of 56%, which was shown by the Bliss mode, and the cytotoxicity of the combination exceeded the additivity. Therefore, PARP inhibitors including olaparib have the potential to provide synergistic interactions with di-dehydrated galactitol.

Example 5

Synergistic effect of dihydrogalactitol with cisplatin and oxaliplatin

Di-dehydrated galactitol has been shown to have an activity exceeding the addition when combined with a platinum-containing antitumor agent: cisplatin and oxaliplatin. Although it is a result of NSCLC cell lines, it is associated with the treatment of juvenile glioblastoma and medulloblastoma, because cisplatin is often used to treat such malignancies, and a more effective combination of drugs is highly desirable. The cytotoxicity assay is expressed as the combination of A drug alone, B drug alone, or A drug + B drug at the indicated concentration of IC ₅₀ or the proportion of affected cells (Fa), which is a 5-day drug treatment MTT growth inhibition. data. The IC ₅₀ value was obtained by substituting the Fa value from the drug concentration range into a four-parameter logistic dose-effect S-curve equation. The predictive additive effect assay for the [Drug A + Drug B] combination is defined by the following formula by Tallarida (RJ Tallarida, "Drug Synergism: Its Detection and Application," J. Pharm. Exp. Ther. 298: 265-272 (2001) )): [Drug A + Drug B] = Addition Effect of FaA+( 1 -FaA)FaB

The results of NSCLC cell lines H460 (wild type p53 and wild type EGFR), A549 (wild type p53 and wild type EGFR), and H1975 (mutated p53 and mutant EGFR with T790M mutation) are shown in Fig. 41, 42, and 43. The data available in Figures 41, 42, and 43 are expressed as mean +/- SE, N = 4. Fa: The proportion of cells affected. The CI values for the indicated Fa are provided in the table and are achieved at the indicated drug concentration (i.e., ED75: effective dose at which 75% of the cells are killed).

Advantages of the invention

The present invention provides an effective method and composition for treating a wide variety of central nervous system malignancies affecting pediatric patients including, but not limited to, glioblastoma multiforme (including highly malignant glioma) and medulloblastoma. These methods are well tolerated with the composition and do not cause significant side effects. They can be used with radiation therapy, surgery, or other chemotherapeutic agents.

The method according to the invention has industrial use for the preparation of a medicament for the treatment of a wide variety of diseases and conditions, including malignant diseases of the central nervous system of pediatric patients as described above. The composition according to the invention has industrial use as a pharmaceutical composition.

The method claimed by the present invention provides specific method steps that go beyond the general application of natural law and which require a specific use in addition to the natural laws stated or implied by the scope of the patent application. The use of other steps than is known in the art is intended to define the scope of the patent application for the particular use set forth herein. In some cases, the scope of such patent applications is a novel way of using existing drugs.

The invention described herein can be operated in the absence of any element or group of elements, limitations or multiple limitations not expressly disclosed herein. Therefore, for example, the terms "including", "including", "containing" and the like should be interpreted broadly and without limitation. In addition, the terms and expressions used herein are for illustrative purposes and are not limiting, and are not intended to be used to exclude any equivalents or any parts thereof that are subsequently shown and described. The scope of the patent is subject to various modifications. Therefore, it is to be understood that the invention may be modified and varied within the scope of the invention as disclosed herein, and such modifications and variations are apparent to those skilled in the art. It is within the scope of the invention as disclosed herein. The invention has been described broadly and generically herein. The narrower species and sub-attribute classifications within the general disclosure also form part of these inventions. It includes a general description of each invention, but its limitations or negative limitations are those that exclude the subject matter of any genus, regardless of whether or not the material being removed is present.

In addition, if the features or aspects of the present invention have been described using the Markush group, the present invention may also utilize the group description of any individual member or group member of the Markusi group. It is also understood that the above description is illustrative and not limiting. Many specific embodiments are familiar to those skilled in the art from the foregoing description. Therefore, the scope of the invention should not be determined by the above description, but should be The scope of the patent application is determined by the full scope of the equivalents claimed in the scope of the claims. All documents and references, including patent publications, are hereby incorporated by reference.

Claims (132)

A method for treating a central nervous system malignant disease in a pediatric patient, which is administered as a therapeutically effective amount of a substituted hexitol derivative selected from the group consisting of: dehydrated galactitol, quaternary galactose A derivative or analog of an alcohol, a derivative or the like of diethylaminodihydrogalactitol, and diethylaminosodium galactitol to treat a malignant disease. The method of claim 1, wherein the malignant disease is a glioblastoma multiforme. The method of claim 2, wherein the glioblastoma multiforme is a highly malignant glioma. The method of claim 1, wherein the malignant disease is medulloblastoma. The method of claim 4, wherein the medulloblastoma is a Sonic Hedgehog type or a Type 3 medulloblastoma. The method of claim 1, wherein the substituted hexitol derivative is selected from the group consisting of derivatives or analogs of didehydrated galactitol and didehydrated galactitol. The method of claim 6, wherein the substituted hexitol derivative selected from the group consisting of derivatives or analogs of didehydrated galactitol and didehydrated galactitol is Dehydrated galactitol. The method of claim 6, wherein the substituted hexitol derivative selected from the group consisting of derivatives or analogs of didehydrated galactitol and didehydrated galactitol is A derivative or analog of dehydrated galactitol. The method of claim 8, wherein the derivative or analog of the dehydrated galactitol is a derivative of dihydrated galactitol selected from the group consisting of: (i) a derivative of two dehydrated galactitols in which one or two hydrogens of two dehydroxylated galactitols are replaced by a lower alkyl group; (ii) one of two epoxide rings is attached thereto or a derivative of two dehydrated galactitols in which a plurality of hydrogens are replaced by a lower alkyl group; (iii) one or two methyl groups attached to the same carbon having a hydroxyl group in the dehydrated galactitol _a derivative of _2- C ₆ lower alkyl substituted galactitol; and (iv) one of the same carbons having a halo-substituted hydroxy group attached to the di-dehydrated galactitol A derivative of two dehydrated galactitols in which two methyl groups are replaced by a halogen group (the hydrogen of which is a methyl group is replaced by a halogen group). The method of claim 1, wherein the hexitol derivative is a derivative or the like selected from the group consisting of diethyl decyl galactitol and diethyl hydrazine galactitol. In groups. The method of claim 10, wherein the hexose selected from the group consisting of derivatives or analogs of diethyl hydrazine galactitol and diethyl hydrazine galactitol The alcohol derivative is diethylaminodihydrogalactitol. The method of claim 10, wherein the hexose selected from the group consisting of derivatives or analogs of diethyl hydrazine galactitol and diethyl hydrazine galactitol The alcohol derivative is a derivative or the like of diethylaminodihydrogalactitol. The method of claim 12, wherein the derivative or analog of diethyldithiogalactositol is diacetyl hydrazine galactose selected from the group consisting of the following: a derivative of an alcohol: (i) a diacetyl hydrazine galactose in which one or two methyl groups as a part of the ethyl thiol moiety are replaced by a C ₂ -C ₆ lower alkyl group a derivative of an alcohol; (ii) a derivative of diethylaminobisdehydrogalactitol in which one or two hydrogens of the epoxide ring are replaced by a lower alkyl group; (iii) an attachment band a derivative of diethylhydrazine didehydrogalactitol having one or two methyl groups of the same carbon of the same group substituted by a C ₂ -C ₆ lower alkyl group; and (iv) attached thereto A derivative of diethylhydrazine didehydrated galactitol which is substituted with a halo group (which is a hydrogen of a methyl group is replaced by a halo group) by a halogen group-substituted hydroxy group. The method of claim 1, wherein the method comprises the steps of: (a) discriminating the efficacy and/or occurrence of the administration of the substituted hexitol derivative for treating a central nervous system malignant disease in a pediatric patient; At least one factor or parameter related to side effects; and (b) modulating the factor or parameter to improve administration efficacy and/or reduce side effects for substituted hexitol derivatives for use in the treatment of GBM, NSCLC, or ovarian cancer. The method of claim 14, wherein the factor or parameter is selected from the group consisting of: (a) dose adjustment; (b) administration route; (c) administration schedule; (d) disease stage selection; (e) patient selection; (f) patient/disease phenotype; (g) patient/disease genotype (h) preparation before/after treatment; (i) toxicity management; (j) drug Kinetic/pharmacodynamic tracking; (k) drug combination; (1) chemotherapy sensitization; (m) chemotherapy synergy; (n) patient treatment after treatment; (o) alternative medical/medical support; o) improvement of APIs; (q) diluent systems; (r) solvent systems; (s) excipients; (t) dosage forms; (u) dose kits and packaging; (v) drug delivery systems; w) drug conjugate type; (x) compound analog; (y) prodrug; (z) multiple drug system; (aa) biomedical agent boosting method; (ab) biomedical agent resistance regulation; (ac) enhanced radiation therapy; (ad) novel action machine; (ae) selective target cell population medical method; (af) combined with free radiation; (ag) combined with reinforcement a preparation thereof; (ah) a preparation for counteracting myelosuppressive action; and (ai) a preparation for improving the ability of the substituted hexitol to pass through the blood-brain barrier. The method of claim 15, wherein the factor or parameter is dose adjustment, and wherein the dose is adjusted to a dose adjustment selected from the group consisting of: (a) continuous iv infusion for several hours to (b) every two weeks; (c) more than 5 mg/m ² /day; (d) gradually increasing from 1 mg/m ² /day depending on patient tolerance; (e) using caffeine Regulates metabolism; (f) uses isoniazid to regulate metabolism; (g) selective and intermittent additional dose; (h) single dose via bolus injection and multiple doses from 5 mg/m ² /day (i) oral doses below 30 mg/m ² ; (j) oral doses above 130 mg/m ² ; (k) oral doses up to 40 mg/m ² for 3 days, followed by a minimum of 18-21 days / recovery period; (l) administration of lower dose extension period; (m) administration of higher dose; (n) lowest dose/recovery period of more than 21 days; (o) dose level for cerebrospinal fluid (CSF) The concentration of the substituted hexitol derivative (such as di-dehydrated galactitol) is equal to or greater than 5 μM; (p) the dose level is such that the degree of cytotoxicity is achieved in CSF; (q) is derived using substituted hexitol Object (such as di-dehydrated galactitol) as a single cytotoxic agent; (r) a cumulative dose of about 9 mg/m ² in a 33-day cycle; (s) a cumulative dose of about 10 mg/m ² in a 33-day cycle; (t) The cumulative dose was about 20 mg/m ² in a 33-day cycle; (u) the cumulative dose was about 40 mg/m ² in a 33-day cycle; (v) the cumulative dose was about 80 mg/m ² in a 33-day cycle; (w) to 33 The cumulative dose of the daily cycle administration is about 160 mg/m ² ; (x) the cumulative dose of about 240 mg/m ^{2 is} administered in a 33-day cycle; (y) the administration causes the plasma half-life to be about 1-2 hours; (z) the administration makes C _max < 200 ng/ml; and (aa) administration such that the half-life of the substituted hexitol derivative in cerebrospinal fluid is >20 hours. The method of claim 16, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a route of administration, and the route of administration is selected from the group consisting of: (a) topical administration; (b) oral administration; c) slow release orally; (d) intrathecal administration via the spinal cord; (e) intra-arterial administration; (f) continuous infusion; (g) intermittent infusion; (h) intravenous administration, such as intravenous administration (i) administration via a longer infusion; (j) administration via IV bolus; and (k) administration to achieve the highest concentration of substituted hexitol derivatives in CSF. The method of claim 18, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a dosing schedule, and wherein the dosing schedule is selected from the group consisting of: (a) daily dosing; (b) each Weekly administration; (c) weekly administration for 3 weeks; (d) every two weeks; (e) every 3 weeks for 3 consecutive weeks, at intervals of 1-2 weeks of withdrawal; (f) intermittent additional administration; (g) daily administration for several weeks, for several weeks; h) Administration on days 1, 2 and 3 in the 33 day cycle. The method of claim 20, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a disease stage selection, and wherein the disease stage is selected from the group consisting of: (a) for pediatric GBM (including high degree of malignancy) Glioma (HGG) or appropriate stage of disease in pediatric medulloblastoma; (b) use of angiogenesis inhibitors to prevent or limit metastatic spread; (c) for newly diagnosed diseases; (d) for recurrence Disease; and (e) for resistant or resistant disease. The method of claim 22, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a patient selection, wherein the patient selection is based on a criterion selected from the group consisting of: (a) the selection is characterized by a high level of a disease condition in a group of metabolic enzymes selected from the group consisting of histone deacetylase and ornithine decarboxylase; (b) selection of a group selected from low platelet counts and neutrophils The group of patients with low or high sensitivity; (c) select patients who cannot tolerate GI toxicity; (d) the selection is characterized by selected from c-Jun, GPCR, signal transduction protein, VEGF, prostate specific Patients with sexual genes, genes that are grouped with protein kinases that are too high or too low; (e) patients with an extra copy of the EGFR gene with pediatric GBM; (f) selection features selected from children with GBM a patient whose TP53, PDGFRA, IDH1, and at least one gene of NF1 are mutated; (g) a patient whose selection is characterized by methylation or lack of methylation of the promoter of the MGMT gene; (h) selection characteristics In patients with IDH1 mutations; (i) selection features in For patients with the IDH1 wild-type gene; (j) select patients characterized by the presence of a 1p/19q combination deletion; (k) select patients with no 1p/19q combination deletion; (1) the selection is characterized by MGMT (O ⁶ - a patient with an unmethylated promoter region of methylguanine methyltransferase); (m) a patient selected to be characterized by a methylated promoter region of MGMT; (n) a patient characterized by a high degree of performance of MGMT; (o) selecting a patient characterized by low performance of MGMT; and (p) selecting a patient characterized by mutations in EGFR including, but not limited to, EGFR variant III. The method of claim 24, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is an analysis of a patient or a disease phenotype, wherein the analysis of the patient or disease phenotype is performed by a method selected from the group consisting of: Patient or disease phenotypic analysis: (a) confirm the patient's specific phenotype using diagnostic tools, diagnostic techniques, diagnostic kits, or diagnostic assays; (b) use markers that determine the group selected from the following: Methods: histone deacetylase, adenine decarboxylase, VEGF, protein of jun gene product, and protein kinase; (c) drug replacement compound; and (d) low dose preliminary test for enzymatic state . The method of claim 26, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is an analysis of a patient or a disease genotype, wherein the analysis of the patient or disease genotype is performed by a method selected from the group consisting of: Patient or disease genotype analysis: (a) use diagnostic tools, diagnostic techniques, diagnostic kits, or diagnostic assays to identify a patient's specific genotype; (b) use of gene chips; (c) use of gene expression analysis; (d) use of single nucleotide polymorphism (SNP) analysis; (e) determination of metabolite or metabolite content; (f) determination of PDGFRA gene Mutation; (g) determination of IDH1 gene mutation; (h) determination of NF1 gene mutation; (i) determination of EGFR gene copy number; (j) determination of MGMT gene promoter methylation status; (k) determination of IDH1 mutation presence (1) determining the presence of the IDH1 wild type; (m) determining the presence of the 1p/19q combined deletion; (n) determining the absence of the 1p/19q combined deletion; (o) determining the unmethylated promoter region of the MGMT gene (p) determining the presence of the methylated promoter region of the MGMT gene; (q) determining the presence of highly expressed MGMT; and (r) determining the presence of low performance MGMT. The method of claim 28, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is preparation before/after treatment, wherein the preparation before/after the treatment is preparation before/after treatment selected from the group consisting of the following: Method: (a) using colchicine or an analogue thereof; (b) use of a diuretic; (c) use of uric acid; (d) use of urate oxidase; (e) use of non-oral nicotine amide; (f) use of sustained release nicotine amide; (g) use Inhibitors of poly-ADP ribose polymerase; (h) use of caffeine; (i) use of leucovorin rescue; (j) control of infection; and (k) use of antihypertensive agents. The method of claim 30, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a toxic treatment, and wherein the toxic treatment is a toxic treatment method selected from the group consisting of: (a) using colchicine or Analogs; (b) use of diuretics; (c) use of uric acid; (d) use of urate oxidase; (e) use of non-oral nicotinic guanamine; (f) use of sustained release nicotine amide; g) using an inhibitor of poly-ADP ribose polymerase; (h) using caffeine; (i) using calcium leucovorin rescue; (j) use of sustained release allopurinol; (k) use of non-oral allopurinol; (l) use of bone marrow transplants; (m) use of blood cell stimulating agents; (n) use of blood or platelet transfusion; (o) administration Formulations selected from the group consisting of: filgrastim, G-CSF, and GM-CSF; (p) pain management techniques; (q) administration of anti-inflammatory agents; (r) administration fluids (s) administration of corticosteroids; (t) administration of insulin-regulating medicine; (u) administration of antipyretic agents; (v) administration of anti-nausea therapeutic agents; (w) administration of anti-diarrhea therapeutic agents; (x) administration of N-acetyl Cysteamine; and (y) administration of antihistamine. The method of claim 32, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is to track pharmacokinetic/pharmacodynamics, and wherein the pharmacokinetic/pharmacodynamic tracking is selected from the group consisting of: Methods: (a) determining plasma concentration multiple times; and (b) measuring at least one metabolite in blood or urine multiple times. The method of claim 34, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a drug combination, and wherein the drug combination is a combination of drugs selected from the group consisting of: (a) a pseudo-nucleoside in combination; And using a pseudonucleotide; (c) in combination with a thymidylate synthetase inhibitor; (d) using a signal transduction inhibitor; (e) using cisplatin or a platinum analog; (f) using an alkylating agent; g) in combination with an anti-tubulin agent; (h) in combination with an antimetabolite; (i) in combination with berberine; (j) in combination with apigenin; (k) in combination with colchicine or an analogue thereof; (l) Combine genistein; (m) use etoposide; (n) use cytarabine; (o) use camptothecin; (p) and use periwinkle (q) in combination with a topoisomerase inhibitor; (r) in combination with 5-fluorouracil; (s) in combination with curcumin; (t) in combination with NF-κB inhibitor; (u) in combination with rosmarinic acid; And use mitoguazone; (w) and use isomethoside (meisoindigo); (x) and imatinib (imatinib); (y) together with dasatinib (dasatinib); (z) and use nilotin Nilotinib; (aa) with an additional gene modulator; (ab) and a transcription factor inhibitor; (ac) in combination with paclitaxel; (ad) in combination with homoharringtonine; (ae) in combination with pyridoxal; (af) in combination with spirogermanium; (ag) Caffeine; (ah) combined with nicotinamide; (ai) with methylglyoxal oxime; (aj) with Rho kinase inhibitor; (ak) with 1,2,4-benzotriazine oxide (al) combined with alkyl glycerol; (am) combined with inhibitors of Mer, Ax1, or Tyro-3 receptor kinase; (an) combined with inhibitor of ATR kinase; (ao) combined with Fms kinase, Kit kinase, MAP4K4 kinase , TrkA kinase, or a modulator of TrkB kinase; (ap) combined with endoxifen (aq) and mTOR inhibitor; (ar) combined with Mnk1a kinase, Mkn1b kinase, Mnk2a kinase, or Mnk2b kinase inhibitor (as) in combination with a modulator of pyruvate kinase M2; (at) in combination with a phospholipid inositol 3-kinase modulator; (au) in combination with a cysteine protease inhibitor; (av) in combination with phenformin; (aw) combined with a vector based on Sindbis virus; (ax) combined with a peptide mimetic that initiates apoptosis by acting as a mimetic of Smac and inhibiting the action of IAP (ay) in combination with Raf kinase inhibitor; (az) with nuclear transport modulator; (ba) with an acidic neuraminidase inhibitor and a choline kinase inhibitor; (bb) with a tyrosine kinase inhibitor; (bc) And anti-CS1 antibody; (bd) combined with inhibitor of protein kinase CK2; (be) combined with anti-guanylate cyclase C (GCC) antibody; (bf) combined with histone deacetylase inhibitor; (bg ) with cannabinoids; (bh) in combination with a glycoside peptide-1 (GLP-1) receptor agonist; (b) with an inhibitor of Bcl-2 or Bcl-xL; (bj) with a Stat3 pathway inhibitor (bk) in combination with inhibitors of Polo kinase 1 (Plk1); (bl) combined with GBPAR1 activator; (bm) with serine-threonine protein kinase and poly(ADP-ribose) polymerase (PARP) activity a modulating agent; (b) a taxane in combination; (bo) an inhibitor of dihydrofolate reductase; (bp) an inhibitor of an aromatase; (bq) and a benzimidazole-based antitumor agent; Br) combined with O6-methylguanine-DNA-methyltransferase (MGMT) inhibitor; (bs) with CCR9 inhibitor; (bt) with acid sphingomyelinase inhibitor; (bu) with peptidomimetic macrocycle a compound; (bv) in combination with guanyl cholinate; (bw) and Substituted oxazaphosphabenzene; (bx) combined with anti-TWEAK receptor antibody; (by) combined with ErbB3 protein; (bz) and glutathione S-convertase-activated anti-tumor compound; a combination of substituted diamino phosphate; (cb) with an inhibitor of MEKK protein kinase; (cd) with a COX-2 inhibitor; (ce) with cimetidine and a cysteine derivative (cf) combined anti-IL-6 receptor antibody; (cg) combined with antioxidant; (ch) combined with tubulin polymerization An azole inhibitor; (ci) in combination with a PARP inhibitor; (cj) in combination with an Aurora protein kinase inhibitor; (ck) in combination with a peptide that binds to a prostate specific membrane antigen; (cl) in combination with a CD19 binding agent; (cm) in combination with benzene And diazonium; (cn) combined with Toll receptor (TLR) agonist; (co) combined with bicyclic sulfonamide; (cp) combined with inhibitor of epidermal growth factor receptor kinase; (cq) combined a T2 family ribonuclease with actin-binding activity; (cr) combined with myrsinoic acid A or its analog; (cs) with an inhibitor of cyclin-dependent kinase; (ct) with p53 An inhibitor of interaction with MDM2; (cu) an inhibitor of the receptor tyrosine kinase MET; (cv) with largazole or an analog of ergos; (cw) with AKT protein kinase Inhibitor; (cx) in combination with 2 ' -fluoro-5-methyl- β -L-arabinofuranosyluridine or L-deoxythymidine; (cy) in combination with HSP90 modulator; (cz) combined with JAK kinase Inhibitors; (da) in combination with an inhibitor of PDK1 protein kinase; (db) in combination with a PDE4 inhibitor; (de) in combination with an inhibitor of the original oncogene c-Met tyrosine kinase; (df) in combination with indoleamine 2, 3- An inhibitor of oxygenase; (dg) a preparation that inhibits ATDC (TRIM29); (dh) a protein mimetic inhibitor that interacts with a nuclear receptor and a coactivator peptide; (di) a combination of XIAP family proteins Antagonist; (dj) combined with a tumor-targeting superantigen; (dk) with an inhibitor of Pim kinase; (dl) with an inhibitor of CHK1 or CHK2 kinase; (dm) with an inhibitor of angiopoietin-like protein; (dn) in combination with a Smo antagonist; (do) in combination with a nicotinic acetylcholine receptor antagonist; (dp) and a farnesyl protein invertase inhibitor; (dq) with an adenosine A3 receptor antagonist; And use a cancer vaccine; (ds) and use a JAK2 inhibitor; (dt) with a Src inhibitor; (du) with a preparation that can suppress the growth or replication of glioma or medulloblastoma stem cells; (dv) and reduce YB-1 Formulation of activity or performance; (dw) in combination with an inhibitor of Akt; and (dx) in combination with an inhibitor of RSK. The method of claim 36, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is sensitizing to chemotherapy, and wherein the chemotherapeutic sensitizing system uses a substituted hexitol derivative as a chemotherapeutic sensitizer, and the combination is selected from the group consisting of Formulations of the following groups: (a) topoisomerase inhibitor; (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) Signal transduction inhibitor; (f) cisplatin or platinum analogue; (g) alkylating agent; (h) antitubulin agent; (i) antimetabolite; (j) berberine; (k) Apigenin; (1) amonafide; (m) colchicine or analogue; (n) genistein; (o) etoposide; (p) cytarabine; (q) camptothecin; (r) vinca alkaloid; (s) topoisomerase inhibitor; (t) 5-fluorouracil; (u) curcumin; (v) NF-κB inhibitor; Rosmarinic acid; (x) acetamiprid; (y) tetrandrine; (z) tyrosine kinase inhibitor; (aa) inhibitor of EGFR; and (ab) inhibitor of PARP. The method of claim 38, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is synergistic with chemotherapy, and wherein the chemotherapy is synergized to use a substituted hexitol derivative as a chemotherapy synergist, and the combination is selected from the group consisting of Formulations of the following groups: (a) topoisomerase inhibitor; (b) pseudonucleoside; (c) pseudonucleotide; (d) thymidylate synthase inhibitor; (e) Signal transduction inhibitor; (f) cisplatin or platinum analogue; (g) an alkylating agent; (h) an anti-tubulin agent; (i) an antimetabolite; (j) berberine; (k) apigenin; (1) naphthoquine; (m) colchicine Or an analogue; (n) genistein; (o) etoposide; (p) cytarabine; (q) camptothecin; (r) vinca alkaloid; (s) 5-fluorouracil; t) curcumin; (u) NF-κB inhibitor; (v) rosmarinic acid; (w) acetaminophen; (x) tetrandrine; (y) tyrosine kinase inhibitor; (z) An inhibitor of EGFR; and (aa) an inhibitor of PARP. The method of claim 40, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or the parameter The number is post-treatment treatment, and wherein the post-treatment treatment is a method selected from the group consisting of: (a) a treatment associated with pain management; (b) administration of an antiemetic; (c) anti-nausea therapy; (d) administering an anti-inflammatory agent; (e) administering a detoxifying agent; and (f) administering an immunostimulating agent. The method of claim 42, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is an alternative medical/post-treatment support method, and wherein the alternative medical/post-treatment support method is an herb produced by synthesis or extraction, wherein Herbs produced by synthesis or extraction are selected from the group consisting of: (a) NF-κB inhibitors; (b) natural anti-inflammatory agents; (c) immunostimulants; (d) antimicrobial agents; (e) Flavonoids, isoflavones, or flavonoids. The method of claim 44, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is improved by using a drug substance product, and wherein the drug substance product improvement is selected from the group consisting of: (a) forming a salt; (b) forming a homogeneous crystalline structure; (c) making a pure isomer; (d) increasing purity; (e) using a method of reducing the residual solvent content; and (f) using a reduced heavy metal The method of preparation. The method of claim 46, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is the use of a diluent, and the diluent is selected from the group consisting of: (a) an emulsion; (b) dimethyl hydrazine ( DMSO); (c) N-methylformamide (NMF); (d) DMF; (e) ethanol; (f) benzyl alcohol; (g) water for injection containing dextrose; (h) 蓖Sesame oil Cremophor; (i) cyclodextrin; and (j) PEG. The method of claim 48, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or the parameter The number is a solvent system, and the solvent system is a group selected from the group consisting of (a) an emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF). (d) DMF; (e) ethanol; (f) benzyl alcohol; (g) water for injection containing dextrose; (h) castor oil polyoxyethylene ether (Cremophor); (i) cyclodextrin; And (j) PEG. The method of claim 50, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is the use of an excipient, and wherein the excipient is in a group 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; (1) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibition (o) an organic resin; (p) a detergent; (q) perillyl alcohol or an analogue thereof; and (r) an activator of a channel-forming receptor. The method of claim 52, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a dosage form, and the dosage form is selected from the group consisting of: (a) a tablet; (b) a capsule; (c) a portion a gel; (d) a topical cream; (e) a patch; (f) a suppository; (g) a lyophilized dose filler; (h) an immediate release formulation; (i) a sustained release formulation; (j) a controlled release formulation; and (k) a liquid contained in the capsule. The method of claim 54, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a drug delivery system, and the drug delivery system is selected from the group consisting of: (a) an oral dosage form; (b) a nanometer; (c) nanoparticle; (d) cosolvent; (e) slurry; (f) syrup; (g) biodigestible polymer; (h) liposome; (i) sustained release gel for injection (j) microspheres; and (k) a targeting composition having an epidermal growth factor receptor-binding peptide. The method of claim 56, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a drug conjugate type selected from the group consisting of: (a) a polymer system; (b) Polylactic acid; (c) polyglycolide; (d) amino acid; (e) peptide; (f) multivalent linker; (g) immunoglobulin; (h) cyclodextrin polymer; (i) Modified transferrin; (j) a hydrophobic or hydrophobic-hydrophilic polymer; (k) a conjugate with a phosphonic acid partial ester; (1) a binding to a cell binding agent incorporating a charged valent crosslinker And (m) a conjugate of a linker with β -glucuronide. The method of claim 58, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a prodrug system, and the prodrug system is selected from the group consisting of: (a) using an enzyme-sensitive ester; Using a dimer; (c) using a Schiff base; (d) using a pyridoxal complex; (e) using a caffeine complex; and (f) using a drug that releases nitrogen oxides; a drug that uses a fibrillated activated protein alpha cleavable oligopeptide; (h) a drug that is used as a reaction product with an acetylation agent or an amine carbamate; (i) a hexanoate conjugate The prodrug (j) is used as a prodrug of the polymer-formulation conjugate; and (k) is used before the redox activation reaction. The method of claim 60, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a multi-drug system, and the multi-drug system is selected from the group consisting of: (a) a multi-drug resistance inhibitor; (b) Specific inhibitors of resistance; (c) specific inhibitors of selective enzymes; (d) signal transduction inhibitors; (e) meisoindigo; (f) imatinib; g) hydroxyurea; (h) dasatinib; (i) capecitabine; (j) nilotinib; (k) repair inhibitor; (l) Topoisomerase inhibitors without overlapping side effects. The method of claim 62, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a biomedical agent strengthening method, and wherein the biomedical agent strengthening method is used as a sensitizer/potentiator, and the combination is selected from the following Groups of medical agents or techniques: (a) biological response modifiers; (b) cytokines; (c) lymphokines; (d) medical antibodies; (e) antisense therapy; (f) gene therapy; g) ribozyme; (h) RNA interference; and (i) vaccine. The method of claim 64, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a biomedical agent resistance regulation method, and wherein the biomedical agent resistance regulation method is used to combat malignant diseases, and the group is selected from the following Group of medical agents or technical resistance: (a) biological response modifiers; (b) cytokines; (c) lymphokines; (d) medical antibodies; (e) antisense therapy; (f) gene therapy; (g) ribozyme; (h) RNA interference; and (i) vaccine. The method of claim 66, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is booster radiation therapy, and wherein the booster radiation therapy is a radiation therapy booster or technique selected from the group consisting of: (a) combined use Hypoxic cell sensitizer; (b) combined with radiosensitizer/protective agent; (c) combined with photo-sensitizer; (d) combined with radiation repair inhibitor; (e) combined with mercaptan consumer; (f) combined a vascular targeting agent; (g) a DNA repair inhibitor; (h) a combination of radioactive particles; (i) a radionuclide in combination; (j) a radiolabeled antibody; and (k) combined with in vivo radiation therapy (brachytherapy). The method of claim 68, wherein the substituted The hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a novel action, and wherein the novel action machine is converted to a target or machine for a group selected from the group consisting of: Novel interactions of sexual interactions: (a) inhibitors of poly-ADP ribose polymerase; (b) preparations that affect vascular structure or vasodilation; (c) agents that target carcinogenicity; (d) signal-to-signal Inhibitors; (e) EGFR inhibition; (f) protein kinase C inhibition; (g) phospholipase C downregulation; (h) Jun downregulation; (i) histone genes; (j) VEGF; Adenine decarboxylase; (1) ubiquitin C; (m) Jun D; (n) v-Jun; (o) GPCR; (p) protein kinase A; (q) protein kinase A other than protein kinase A (r) prostate specific gene; (s) telomerase; (t) histone deacetylase; and (u) tyrosine kinase inhibitor. The method of claim 70, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a medical method using a selective target cell population, and wherein the method of the selective target cell population medical method is selected from the group consisting of the following: Usage: (a) for combating radiosensitive cells; (b) for combating radioresistant cells; and (c) for combating energy-consuming cells. The method of claim 72, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a combination of a preparation for enhancing the activity of an alkylated hexitol derivative, and wherein the preparation for enhancing the activity of the alkylated hexitol derivative is It is a group selected from the group consisting of (a) nicotinamide; (b) caffeine; (c) tetandrine; and (d) berberine. The method of claim 74, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or the parameter The number is a combination of a anti-myelosuppressive preparation, and wherein the anti-myelosuppressive preparation is a dithiocarbamate. The method of claim 76, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 15, wherein the factor or parameter is a combination of the ability to increase the ability of the substituted hexitol to pass the blood-brain barrier, and wherein the increased hexitol is passed through the blood-brain barrier The formulation of the ability is selected from the group consisting of: (a) a chimeric peptide of the structure of formula (D-III): Wherein: (A) A is somatostatin, thyroid stimulating hormone releasing hormone (TRH), angiotensin, alpha interferon, endorphin, cell wall dipeptide or ACTH 4-9 analogue; (B) B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of formula (D-III), wherein the A The disulfide-bonded bridge chain between B is replaced by a small molecule (D-III(a)) bridge: A-NH(CH ₂ ) ₂ SSB (cleavable linker) (D-III(a)), Wherein the bridge chain forms a bridge chain using cysteamine and EDAC as a bridging agent; or a chimeric peptide of the structure of formula (D-III), wherein the disulfide bridge between the A and B is as small as Molecular Formula (D-III(b)) Bridge Chain Replacement: A-NH=CH(CH ₂ ) ₃ CH=NH-B (non-cleavable linker) (D-III(b)), wherein the bridge is used Glutaraldehyde is formed as a bridging agent; (b) a substituted hexitol derivative comprising avidin or avidin fusion protein-bonded biotinylated to form avidin-biotin-formulation complex a composition of matter comprising a protein selected from the group consisting of: pancreas , transferrin, anti-receptor monoclonal antibody, cationized protein, and lectin; (c) neutral liposome, which is glycosylated and incorporated into the substituted hexitol And wherein the polyethylene glycol strand is conjugated to at least one transportable peptide or targeting agent; (d) a humanized murine antibody that is linked to the trans-avidin-biotin linkage a human insulin receptor binding of a hexitol derivative; and (e) a fusion protein comprising a first segment and a second segment: the first segment comprises a variable region of an antibody that recognizes an antigen on a cell surface Performing antibody-receptor-mediated endocytosis after binding to the variable region of the antibody, and further comprising at least one functional domain of the constant region of the antibody, if desired; and the second segment comprises a material selected from the group consisting of Group of protein domains: avidin, avidin mutein, chemically modified avidin derivative, streptavidin, streptavidin mutein, and chemically modified Streptavidin derivative, wherein The fusion protein utilizes a covalent linkage to link the substituted hexitol to biotin. The method of claim 78, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 1, wherein the method further comprises administering a medically effective amount of a PARP inhibitor. The method of claim 80, wherein the PARP inhibitor is in a group selected from the group consisting of: iniparib, talazoparib, olaparib ), rucaparib, veliparib, CEP-9722 (CEP-8983 prodrug (11-methoxy-4,5,6,7-tetrahydro-1H-cyclopenta) [a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione), MK 4827((S)-2-(4-(piperidin-3-yl)phenyl)- 2H-carbazole-7-carboxyguanamine), and BGB-290. The method of claim 80, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 1, wherein the method further comprises administering a medically effective amount of a formulation that counteracts the PTEN function deficiency. The method of claim 83, wherein the preparation for counteracting the PTEN function is selected from the group consisting of: temsirolimus, everolimus, AZD6482 ((R)-2-(1-(7-Methyl-2-morpholinyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylamino) Benzoic acid), MK-2206(8-(4-(1-aminocyclobutyl)phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1 , 6] naphthyridine-3(2H)-one), and 17-AAG ([(3 S , 5 S , 6 R , 7 S , 8 E , 10 R , 11 S , 12 E , 14 E )-21 -(allylamino)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trisethoxy-17-azabicyclo [16.3.1] Twenty carbon-8,12,14,18,21-pentenyl-10-yl]carbamate). The method of claim 83, wherein the substituted hexitol derivative is dihydrated galactitol. The method of claim 1, wherein the at least two anti-tumor medical agents are administered. The method of claim 86, wherein the at least two anti-tumor medical agents are administered simultaneously or substantially simultaneously. The method of claim 86, wherein the at least two anti-tumor lines are administered sequentially. The method of claim 86, wherein the at least two anti-tumor agents are administered simultaneously and are administered as a single pharmaceutical composition. The method of claim 86, wherein the anti-tumor agent is di-dehydrated galactitol and temozolomide. The method of claim 90, wherein the di-dehydrated galactitol and the Dimensional multi-line are administered sequentially, wherein the second dehydrated galactitol is administered after administration of Dimension. For example, the method described in claim 91, wherein after three days of administration of Dimension, the second dose of galactitol is administered for three days. The method of claim 86, wherein the anti-tumor agent is an inhibitor of bis-galactositol and a Polo-like kinase. The method of claim 86, wherein the anti-tumor agent is diglycolic galactitol and a preparation for reducing the activity or performance of YB-1. The method of claim 86, wherein the anti-tumor agent is an inhibitor of di-dehydrated galactitol and Akt. The method of claim 86, wherein the anti-tumor agent is an inhibitor of sedated galactitol and RSK. The method of claim 86, wherein the anti-tumor agent is an inhibitor of sedated galactitol and PARP. The method of claim 97, wherein the inhibitor of PARP is olaparib. The method of claim 86, wherein the anti-tumor agent is a preparation of di-dehydrated galactitol and a counter-PTEN function-deficient. The method of claim 86, wherein the anti-tumor agent is di-dehydrated galactitol and cisplatin or oxaliplatin. The method of claim 86, wherein the anti-tumor agent is di-dehydrated galactitol and etoposide. A composition for improving efficacy in suboptimal administration of a drug when treating a central nervous system malignancy in a pediatric patient, such as glioblastoma multiforme or medulloblastoma, using a substituted hexitol as described above And/or reducing side effects comprising an option selected from the group consisting of: (a) a medically effective amount of a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative. A derivative, analog, or prodrug of the modified hexitol derivative or a derivative, analog or prodrug of the modified hexitol derivative for treating a central nervous system malignant disease in a pediatric patient When, for example, glioblastoma multiforme or medulloblastoma, compared to unmodified hexitol derivatives, there is an increase in the doctor Efficacy or reduced side effects; (b) a composition comprising: (i) a medically effective amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified one a derivative, analog, or prodrug of a sugar alcohol derivative; and (ii) at least one other medical agent, a medical agent that is sensitized by chemotherapy, a medical agent that is synergized with chemotherapy, a diluent, an excipient, a solvent system, a drug delivery system, or a preparation for counteracting myelosuppressive action, or a modification of the hexitol derivative, a modified hexitol derivative, or a hexitol derivative or a modified hexitol derivative a preparation of a derivative, analog, or prodrug that passes the blood-brain barrier, wherein the composition is used in the treatment of a central nervous system malignancy in a pediatric patient, such as glioblastoma multiforme or medulloblastoma. An unmodified hexitol derivative having improved medical efficacy or reduced side effects; (c) a pharmaceutically acceptable amount of a hexitol derivative, a modified hexitol derivative, or a hexose that has been included in the dosage form Alcohol derivative or modified hexitol a biological derivative, analog, or prodrug, wherein the hexitol derivative, modified hexitol derivative, or hexitol derivative or modified hexitol derivative of the dosage form is derived , analogs, or prodrugs for the treatment of pediatric patients with central nervous system malignancies, such as glioblastoma multiforme or medulloblastoma, have improved medical efficacy compared to unmodified hexitol derivatives Or reduced side effects; (d) a medically effective amount of a hexitol derivative, a modified hexitol derivative, or a hexitol derivative that has been included in the dosage kit and packaged or a derivative, analog, or prodrug of a modified hexitol derivative, wherein the hexitol derivative, modified hexitol derivative, or hexitol is included in the dosage kit and packaged a derivative, analog, or prodrug of a modified hexitol derivative for treating a central nervous system malignancy in a pediatric patient, such as glioblastoma multiforme or medulloblastoma, compared to The modified hexitol derivative has improved medical efficacy or reduced side effects; (e) a pharmaceutically acceptable amount of a hexitol derivative, a modified hexitol derivative, or a hexitol that has been modified by a drug substance product. a derivative, analog, or prodrug of a derivative or modified hexitol derivative, wherein the hexitol derivative, modified hexitol derivative, or hexitol has been modified by the drug substance product A derivative, analog, or prodrug of a derivative or modified hexitol derivative for treating a central nervous system malignant disease in a pediatric patient, such as glioblastoma multiforme or medulloblastoma, compared to Modified hexitol derivative has The medical efficacy or reduce the side effects. The composition of claim 102, wherein the substituted hexitol derivative is a group selected from the group consisting of derivatives or analogs of di-desaled galactitol and di-dehydrated galactitol. The composition according to claim 103, wherein the substituted hexitol derivative selected from the group consisting of derivatives or analogs of didehydrated galactitol and didehydrated galactitol is Two dehydrated galactitol. The composition of claim 103, wherein the derivative or the like selected from the group consisting of di-dehydrated galactitol and di-dehydrated galactitol The group of substituted hexitol derivatives are derivatives or analogs of di-desaled galactitol. The composition of claim 105, wherein the derivative or analog of the dehydrated galactitol is a derivative of dihydrated galactitol selected from the group consisting of: (i) a derivative of two dehydrated galactitols in which two or two hydrogens of two dehydrated galactitols are replaced by a lower alkyl group; (ii) one of two epoxide rings is attached thereto Or a derivative of a dihydrogalactitol in which a plurality of hydrogens are replaced by a lower alkyl group; (iii) wherein one or two methyl groups attached to the same carbon having a hydroxyl group are attached to the second dehydrated galactitol a derivative of a C ₂ -C ₆ lower alkyl substituted second dehydrated galactitol; and (iv) one of the same carbons having a halo-substituted hydroxy group attached to the di-dehydrated galactitol Or a derivative of two dehydrated galactitols in which two methyl groups are replaced by a halogen group, which is a hydrogen of a methyl group, which is replaced by a halogen group. The composition of claim 102, wherein the hexitol derivative is a derivative or the like selected from the group consisting of diethylaminosodium galactitol and diethyl hydrazine galactitol. Grouped into groups. The composition according to claim 107, wherein the derivative or the like selected from the group consisting of diethyl hydrazine dihydrogalactitol and diethyl hydrazine galactitol derivative or the like The sugar alcohol derivative is diethylaminodihydrogalactitol. The composition of claim 108, wherein the derivative or the like selected from the group consisting of diethyl decyl squamous galactitol and diethyl hydrazine galactose derivative or the like The sugar alcohol derivative is diethyl hydrazine A derivative or analog of quaternary galactitol. The composition according to claim 109, wherein the derivative or analog of the diethylaminosodium galactitol is a diacetyl hydrazine half group selected from the group consisting of the following: a derivative of lactitol: (i) a di-hydrazino-dehydrated half in which one or two methyl groups as a part of the ethyl thiol moiety are replaced by a C ₂ -C ₆ lower alkyl group a derivative of lactitol; (ii) a derivative of diethylaminobisdehydrogalactitol in which one or two hydrogens of the epoxide ring are replaced by a lower alkyl group; (iii) attached thereto a derivative of diethylamino-dehydrated galactitol with one or two methyl groups of the same carbon of the acetamidine group replaced by a C ₂ -C ₆ lower alkyl group; and (iv) an attachment band therein A derivative of diethylamino-dehydrogalactitol having one or two methyl groups of the same carbon having a halogen-substituted hydroxy group replaced by a halogen group (which is a hydrogen group substituted by a halogen group). The composition of claim 102, wherein the composition has improved medical efficacy or reduced side effects in the treatment of pediatric patient glioblastoma multiforme. The composition of claim 111, wherein the glioblastoma multiforme is a highly malignant glioma. The composition of claim 104, wherein the composition has improved medical efficacy or reduced side effects when treating medulloblastoma in a pediatric patient. The composition according to claim 113, wherein the composition is improved in the treatment of the medulloblastoma (Sonic Hedgehog) type and the third subtype medulloblastoma. Efficacy or reduced side effects. The composition of claim 102, wherein the composition is formulated to have cytotoxic efficacy against cancer stem cells. The composition of claim 102, wherein the composition comprises a pharmaceutical combination comprising: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkane a derivative, analog, or prodrug of a modified hexitol derivative or modified alkylated hexitol derivative; and (ii) other medical agent selected from the group consisting of: (a a topoisomerase inhibitor; (b) a pseudonucleoside; (c) a pseudonucleotide; (d) a thymidylate synthase inhibitor; (e) a signal transduction inhibitor; (f) cisplatin or Platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) antimetabolite; (j) berberine; (k) apigenin; (l) naphthoquine; Vinca alkaloid; (n) 5-fluorouracil; (o) curcumin; (p) NF-κB inhibitor; (q) rosmarinic acid; (r) acetaminophen; and (s) tetrandrine. The composition of claim 102, wherein the composition comprises: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol a derivative, analog, or prodrug of a derivative or modified alkylated hexitol derivative; and (ii) a medical agent that is selected from the group consisting of: a pseudonucleotide; (b) a pseudonucleotide; (c) a thymidylate synthase inhibitor; (d) a signal transduction inhibitor; (e) a cisplatin or a platinum analog; (f) an alkylating agent (g) anti-tubulin agent; (h) antimetabolite; (i) berberine; (j) apigenin; (k) colchicine or colchicine analogue; (l) genistein (m) etoposide; (n) cytarabine; (o) camptothecin; (p) vinca alkaloid; (q) topoisomerase inhibitor; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; (v) propylene bromide; and (w) biomedical agent; wherein the alkylated hexitol derivative, modified alkylated hexitol is derived The action of a derivative, analog, or prodrug of a compound, or an alkylated hexitol derivative or a modified alkylated hexitol derivative, acts as a chemotherapy potentiator. The composition of claim 102, wherein the composition comprises: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol a derivative, analog, or prodrug of a derivative or modified alkylated hexitol derivative; and (ii) a chemotherapeutic sensitizing medical agent selected from the group consisting of: (a a topoisomerase inhibitor; (b) a pseudonucleotide; (c) a pseudonucleotide; (d) thymidylate synthase inhibitor; (e) signal transduction inhibitor; (f) cisplatin or platinum analogue; (g) alkylating agent; (h) anti-tubulin agent; (i) Antimetabolite; (j) berberine; (k) apigenin; (l) colchicine or colchicine analogue; (m) genistein; (n) etoposide; (o) arabinose Cytidine; (p) camptothecin; (q) vinca alkaloid; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; v) propylene bromide; wherein the alkylated hexitol derivative, modified alkylated hexitol derivative, or alkylated hexitol derivative or modified alkylated hexitol derivative The derivative, analog, or prodrug acts as a sensitizer for chemotherapy. The composition of claim 102, wherein the composition And comprising: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a modified alkylated hexitol derivative a drug, an analog, or a prodrug; and (ii) a medical agent that is selected from the group consisting of: (a) a pseudonucleotide; (b) a pseudonucleotide; (c) Thymidylate synthase inhibitor; (d) signal transduction inhibitor; (e) cisplatin or platinum analog; (f) alkylating agent; (g) anti-tubulin agent; (h) antimetabolite (i) berberine; (j) apigenin; (k) colchicine or colchicine analogue; (l) genistein; (m) etoposide; (n) cytarabine; (o) camptothecin; (p) vinca alkaloid; (q) topoisomerase inhibitor; (r) 5-fluorouracil; (s) curcumin; (t) NF-κB inhibitor; (u) rosmarinic acid; (v) propylene bromide; and (w) biomedical agent; wherein the alkylated hexitol derivative, The modified alkylated hexitol derivative, or the alkylated hexitol derivative or the modified alkylated hexitol derivative derivative, analog, or prodrug acts as a chemotherapy synergist . The composition of claim 102, wherein the alkylated hexitol derivative of the composition, the modified alkylated hexitol derivative, or the alkylated hexitol derivative or The derivative, analog, or prodrug of the modified alkylated hexitol derivative is modified by a drug substance product, wherein the drug substance product modification is selected from the group consisting of: (a) forming a salt; (b) forming a homogeneous crystalline structure; (c) making a pure isomer; (d) increasing the purity; (e) using a method for reducing the residual solvent content; and (f) using a method for reducing the heavy metal content. The composition of claim 102, wherein the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug and diluent of the modified alkylated hexitol derivative, wherein the diluent The release agent is selected from the group consisting of: (a) an emulsion; (b) dimethyl hydrazine (DMSO); (c) N-methylformamide (NMF); (d) dimethyl ketone Indoleamine (DMF); (e) dimethylacetamide (DMA); (f) ethanol; (g) benzyl alcohol; (h) water for injection containing dextrose; (i) polyoxyl of castor oil Cremophor; (j) cyclodextrin; and (k) PEG. The composition of claim 102, wherein the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or A derivative, analog, or prodrug and solvent system of a modified alkylated hexitol derivative, 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 for injection containing dextrose; (i) castor oil polyoxyethylene ether (Cremophor); (j) PEG; and (k) salt system. The composition of claim 102, wherein the composition comprises an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug and excipient of the modified alkylated hexitol derivative, wherein the excipient is 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; A; (j) vitamin D; (k) vitamin E; (1) esterase inhibitor; (m) cytochrome P450 inhibitor; (n) multidrug resistance (MDR) inhibitor; (o) organic resin; (p) a detergent; (q) perillyl alcohol or an analogue thereof; and (r) an activator of a channel-forming receptor. The composition of claim 102, wherein the alkylated hexitol derivative, the modified alkylated hexitol derivative, or the alkylated hexitol derivative or modified The derivative, analog, or prodrug of the alkylated hexitol derivative is incorporated into a dosage form selected from the group consisting of: (a) a tablet; (b) a capsule; (c) a topical gel (d) topical cream; (e) patch; (f) suppository; (g) lyophilized dose filler; (h) immediate release formulation; (i) sustained release formulation; a controlled release formulation; and (k) a liquid contained in the capsule. The composition of claim 102, wherein the composition comprises: (i) an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol a derivative, analog, or prodrug of a modified alkylated hexitol derivative; and (ii) a drug delivery system, wherein the drug delivery system is selected from the group consisting of Group: (a) oral dosage form; (b) nanocrystals; (c) nanoparticle; (d) cosolvent; (e) syrup; (f) syrup; (g) biodigestible polymer; Liposomes; (i) a sustained release gel for injection; (j) microspheres; and (k) a targeting composition having an epidermal growth factor receptor-binding peptide. The composition of claim 102, wherein the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or A derivative or analog of a modified alkylated hexitol derivative, and the medical agent is contained in the composition in a drug conjugate form, wherein the drug conjugate type is selected from the group consisting of the following Drug conjugate type: (a) polymer system; (b) polylactic acid; (c) polyglycolide; (d) amino acid; (e) peptide; (f) multivalent linker; (g) immunization a globulin; (h) a cyclodextrin polymer; (i) a modified transferrin; (j) a hydrophobic or hydrophobic-hydrophilic polymer; (k) a conjugate with a phosphonic acid partial ester; l) a conjugate with a cell binding agent incorporating a charged crosslinker; and (m) a conjugate of a linker with β -glucuronide. The composition of claim 102, wherein the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or A derivative or analog of a modified alkylated hexitol derivative, and the medical agent is in the form of a prodrug system wherein the prodrug system is selected from the group consisting of: (a) enzyme sensitivity (b) dimer; (c) Schiff base; (d) pyridoxal complex; and (e) caffeine complex; (f) prodrug releasing nitrogen; (g) An oligopeptide prodrug having a fibroblast activated protein alpha cleavable; (h) a reaction product with a thiolation agent or an amine mercaptoylating agent; (i) a hexane ester conjugate; (j) a polymer- a formulation conjugate; and (k) a drug that can be subjected to a redox activation reaction. The composition of claim 102, wherein the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug of a modified alkylated hexitol derivative and further comprising at least one other medical agent to form a multi-drug system, wherein the at least one other medical agent is selected from the group consisting of Groups of agents: (a) multidrug resistance inhibitors; (b) specific resistance inhibitors; (c) specific inhibitors of selective enzymes; (d) signal transduction inhibitors; (e) repair An inhibitor of the enzyme; and (f) a topoisomerase inhibitor having no overlapping side effects. The composition of claim 102, wherein the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug of a modified alkylated hexitol derivative, and the composition further comprises a preparation for inhibiting myelosuppression, wherein the anti-myelosuppressive preparation is dithiouric acid ester. The composition of claim 97, wherein the medical agent is an alkylated hexitol derivative, a modified alkylated hexitol derivative, or an alkylated hexitol derivative or a derivative, analog, or prodrug of a modified alkylated hexitol derivative, and the composition further comprises a formulation that increases the ability of the substituted hexitol to cross the blood-brain barrier, wherein the increase may be substituted The preparation of the hexitol to pass the blood-brain barrier ability is selected from the group consisting of: (a) a chimeric peptide of the formula (D-III): Wherein: (A) A is somatostatin, thyroid stimulating hormone releasing hormone (TRH), angiotensin, alpha interferon, endorphin, cell wall dipeptide or ACTH 4-9 analogue; (B) B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of formula (D-III), wherein the A The disulfide-bonded bridge chain between B is replaced by a small molecule (D-III(a)) bridge: A-NH(CH ₂ ) ₂ SSB (cleavable linker) (D-III(a)), Wherein the bridge chain forms a bridge chain using cysteamine and EDAC as a bridging agent; or a chimeric peptide of the structure of formula (D-III), wherein the disulfide bridge between the A and B is as small as Molecular Formula (D-III(b)) Bridge Chain Replacement: A-NH=CH(CH ₂ ) ₃ CH=NH-B (non-cleavable linker) (D-III(b)), wherein the bridge is used Glutaraldehyde is formed as a bridging agent; (b) a substituted hexitol derivative comprising avidin or avidin fusion protein-bonded biotinylated to form avidin-biotin-formulation complex a composition of matter comprising a protein selected from the group consisting of: pancreas , transferrin, anti-receptor monoclonal antibody, cationized protein, and lectin; (c) neutral liposome, which is glycosylated and incorporated into the substituted hexitol And wherein the polyethylene glycol strand is conjugated to at least one transportable peptide or targeting agent; (d) a humanized murine antibody that is linked to the trans-avidin-biotin linkage a human insulin receptor binding of a hexitol derivative; and (e) a fusion protein comprising a first segment and a second segment: the first segment comprises a variable region of an antibody that recognizes an antigen on a cell surface Performing antibody-receptor-mediated endocytosis after binding to the variable region of the antibody, and further comprising at least one functional domain of the constant region of the antibody, if desired; and the second segment comprises a material selected from the group consisting of Group of protein domains: avidin, avidin mutein, chemically modified avidin derivative, streptavidin, streptavidin mutein, and chemically modified Streptavidin derivative, wherein The fusion protein utilizes a covalent linkage to link the substituted hexitol to biotin. The composition of claim 104, wherein the composition is formulated for administration of dehydrated galactitol, which is administered once every three days for 21 consecutive days. The composition of claim 104, wherein the composition The substance comprises: (a) a medically effective amount of dehydrated galactitol; (b) a medically effective amount of another antitumor agent selected from the group consisting of: Dimensions, inhibitors of Polo-like kinases, a preparation for lowering the activity or performance of YB-1, an inhibitor of Akt, an inhibitor of RSK, an inhibitor of PARP, a preparation for counteracting the loss of PTEN function, olaparib, selected from cisplatin and oxaliplatin Group of platinum-containing antitumor agents, and etoposide.