4'-Thio-nucleotide and -nucleoside prodrugs for the treatment of cancer

Abstract

The present disclosure relates to 4'-thio-nucleotides and nucleoside compounds for the treatment of various cancers, such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative tumors and plasma cell neoplasms (myeloma). The abstract is intended to be a scanning tool for the purpose of searching in a specific field and is not intended to limit the present invention.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Application No. 62 / 660,208, filed on April 19, 2018, which is incorporated herein by reference in its entirety. Background Art

[0003] Cancer is a disease characterized by the uncontrolled division of abnormal cells from a given normal tissue and the invasion of adjacent tissues by these malignant cells. Cancer cells can be spread to other parts of the body by blood or lymph transport, resulting in local lymph nodes and distant sites (metastasis). Cancer is a complex multi-step process that begins with tiny pre-tumor changes that may develop into neoplasia under certain conditions. There are more than 100 different types of cancer, which can be divided into more extensive categories. The main classifications include: carcinoma, sarcoma, leukemia, lymphoma and myeloma, and central nervous system cancer. With the increase of the general population age, the development of new cancers, and susceptible populations (e.g., those infected with AIDS or overexposed to sunlight), the incidence of cancer continues to rise. Therefore, there is a huge demand for new methods and compositions that can be used to treat patients with cancer.

[0004] Hematology or hematopoietic malignancies are cancers of the blood or bone marrow, including leukemia and lymphoma. Leukemia is a blood cancer characterized by abnormal aggregation of immature white blood cells. There are four types of leukemia: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Acute leukemia is a rapidly developing disease that causes the accumulation of immature, nonfunctional cells in the bone marrow and blood. The bone marrow usually stops producing enough normal red blood cells (which include cells and platelets). On the other hand, chronic leukemia develops more slowly and allows the manufacture of a greater number of more mature functional cells.

[0005] Leukemia can affect people of any age. The cause of most leukemia cases is unknown. Abnormal doses of radiation and certain cancer therapies are possible causes. About 90% of leukemia cases are diagnosed in adults. Cases of chronic leukemia are 4.5% more common than cases of acute leukemia. The most common types of leukemia in adults are acute myeloid leukemia (AML) (of which 14,590 new cases were estimated in 2013) and chronic lymphocytic leukemia (CLL) (of which about 15,680 new cases were estimated in 2013). It is estimated that about 5,920 people suffered from chronic myeloid leukemia (CML) in 2013 (data from Leukemia and Lymphoma Society, Facts 2013, August 2013).

[0006] In the second half of the 20th century, the significant improvement in the treatment of blood cancers was largely the result of chemotherapy. In addition, there are more than 50 drugs used alone to treat these disorders, and many potential new therapies are being studied in clinical trials. Although current chemotherapy can lead to complete remission, the long-term disease-free survival rate of leukemia (especially AML) is low. For example, from 2003 to 2009, the overall relative survival rate of AML was estimated to be about 59%. Therefore, there is a clear and unmet need for effective therapies for the treatment of blood cancers (including leukemias).

[0007] Treatment options for hepatocellular carcinoma have been limited, especially in cases of advanced or recurrent hepatocellular carcinoma. Surgery and radiation therapy are options for early-stage liver cancer, but are not very effective for advanced or recurrent hepatocellular carcinoma. Systemic chemotherapy is not particularly effective, and there are a very limited number of drugs that can be used. The recently approved kinase inhibitor sorafenib has been shown to be effective in treating hepatocellular carcinoma. However, it can only delay or stop the progression of advanced liver cancer by a few months compared to no treatment.

[0008] In human cancers, DNA methylation patterns become abnormal, leading to hypermethylation and transcriptional silencing of the promoters of many tumor suppressor genes. Therefore, restoring the expression of hypermethylated tumor suppressor genes by inhibiting DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) has become a desired strategy for combating cancer. So far, demethylating agents such as azacytidine and decitabine have been used clinically for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and are experimentally used for some forms of solid tumors. However, the diffusion of these compounds to solid tumor applications (such as bladder cancer, ovarian cancer and colorectal cancer) is still subject to the limitation of its pharmacokinetic profile.

[0009] New therapies are needed for the treatment or prevention of cancer.

[0010] In summary, despite the widespread prevalence of cancer, current treatments still suffer from a number of shortcomings. Therefore, there remains a need for compounds and compositions for treating cancer and methods of making and using the same. Summary of the invention

[0011] In accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention relates in one aspect to compounds and compositions for use in the prevention and treatment of disorders of uncontrolled cell proliferation, such as, for example, cancer, including but not limited to sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasms and plasmacytoma (myeloma).

[0012] Disclosed is a compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by a formula selected from the following:

[0013]

[0014] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0015]

[0016] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3 When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0017]

[0018] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0019]

[0020] Where R 14When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′ are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R 16 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0021] Also disclosed is a compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by a formula selected from the following:

[0022]

[0023] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0024]

[0025] The condition is R 1 and R 2 wherein one is hydrogen; wherein n is selected from 0, 1 and 2; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0026]

[0027] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, fluorine, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein R 4 When present is selected from hydrogen, fluorine and -OR 16 ; and where R 16 When present, is selected from hydrogen, methyl, -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0028]

[0029] The condition is R 1 , R 2and R 3 Not at the same time as hydrogen.

[0030] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0031] Also disclosed are methods of treating a disorder of uncontrolled cell proliferation in a subject, the methods comprising the step of administering to the subject an effective amount of a disclosed compound.

[0032] Also disclosed are kits comprising the disclosed compounds and one or more of: (a) at least one agent associated with treating a disorder of uncontrolled cell proliferation; (b) instructions for administering the compound associated with treating a disorder of uncontrolled cell proliferation; and (c) instructions for treating a disorder of uncontrolled cell proliferation.

[0033] Although various aspects of the present invention may be described and claimed in specific statutory categories (such as the system statutory category), this is for convenience only, and those skilled in the art will understand that each aspect of the present invention may be described and claimed in any statutory category. Unless otherwise expressly stated, it is by no means intended that any method or aspect set forth herein be interpreted as requiring that its steps be performed in a particular order. Therefore, in the absence of a method claim specifically stating in the claim or specification that the steps are to be restricted to a particular order, it is by no means intended that an order be inferred in any respect. This applies to any possible non-express basis for interpretation, including logical matters regarding the arrangement of steps or operational flows, explicit meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects and, together with the description, serve to explain the principles of the invention.

[0035] Figure 1A -D shows representative data demonstrating depletion of DNMT-1 in NCI-H23 cells by Aza-T-dCYd, T-dCyd, and compounds 1-5 within 96 hours.

[0036] Figure 2A -D shows representative data demonstrating depletion of DNMT-1 in NCI-H23 cells by Aza-T-dCYd, T-dCyd, and compounds 1-5 within 96 hours.

[0037] Figure 3A -D shows representative data demonstrating depletion of DNMT-1 in NCI H23 cells by Aza-T-dCYd, T-dCyd, and compounds 1-5 within 96 hours.

[0038] Figure 4A -D shows representative data demonstrating depletion of DNMT-1 in NCI-H23 cells by Aza-T-dCYd, T-dCyd, and compounds 1-5 within 96 hours.

[0039] Additional advantages of the present invention will be described in part in the following description, and will be apparent in part from the description, or may be learned through the practice of the present invention. The advantages of the present invention will be realized and obtained through the elements and combinations specifically pointed out in the appended claims. It should be understood that the above general description and the following detailed description are only exemplary and illustrative, and are not limitations of the present invention as claimed. DETAILED DESCRIPTION

[0040] The present invention may be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0041] Before disclosing and describing the compounds, compositions, articles, systems, devices and / or methods of the present invention, it should be understood that, unless otherwise stated, they are not limited to specific synthetic methods, or, unless otherwise stated, they are not limited to specific reagents, as they can of course vary. It should also be understood that the terms used herein are only used for the purpose of describing specific aspects and are not intended to be limiting. Although any methods and materials similar to or equivalent to the methods and materials described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

[0042] Although various aspects of the present invention may be described and claimed in specific statutory categories (such as the system statutory category), this is for convenience only, and those skilled in the art will understand that each aspect of the present invention may be described and claimed in any statutory category. Unless otherwise expressly stated, it is by no means intended that any method or aspect set forth herein be interpreted as requiring that its steps be performed in a particular order. Therefore, in the absence of a method claim specifically stating in the claim or specification that the steps are to be restricted to a particular order, it is by no means intended that an order be inferred in any respect. This applies to any possible non-express basis for interpretation, including logical matters regarding the arrangement of steps or operational flows, explicit meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0043] Throughout this application, various publications are cited. The full contents of the disclosures of these publications are hereby incorporated by reference into this application, so as to more fully describe the current status of the field to which this application belongs. The disclosed references are also individually and specifically incorporated herein by reference for the materials included therein discussed in the sentences relying on the references. Anything herein should not be construed as admitting that the present invention has no right to precede such disclosure by virtue of previous inventions. In addition, the publication date provided herein may be different from the actual publication date, which may require independent confirmation.

[0044] A. Definition

[0045] As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group", "an alkyl", or "a residue" includes a mixture of two or more such functional groups, alkyl groups, or residues, etc.

[0046] As used in the specification and in the claims, the term "comprising" may include aspects of "consisting of" and "consisting essentially of.

[0047] Ranges can be expressed herein as from "about" a particular value and / or to "about" another particular value. When such a range is expressed, on the other hand, it is included from a particular value and / or to another particular value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it is understood that a specific value forms another aspect. It will be further understood that the endpoints of each range are significant relative to the other endpoint and are independent of the other endpoint. It should also be understood that there are multiple values ​​disclosed herein, and in addition to the value itself, each value is also disclosed herein as "about" this particular value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed.

[0048] As used herein, the terms "about" and "at or about" indicate that the amount or value in question may be a value designated as being approximately or approximately the same as some other value. It is generally believed that, unless otherwise specified or inferred, as used herein, it is a nominal value indicated by ±10% variation. The term is intended to convey that similar values ​​promote equivalent results or effects described in the claims. That is, it should be understood that the amount, size, formula, parameter and other quantities and characteristics are not precise and do not have to be precise, but may be approximate and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those skilled in the art. Typically, the amount, size, formula, parameter or other amount or characteristic is "about" or "approximately", whether or not it is explicitly stated as such. It should be understood that, unless otherwise specifically stated, when "about" is used before a quantitative value, the parameter also includes the specific quantitative value itself.

[0049] References in this specification and in the concluding claims to parts by weight of a particular element or component in a composition indicate the weight relationship between that element or component and any other elements or components in the composition or article expressed in parts by weight. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5 and are present in such a ratio regardless of whether additional components are included in the compound.

[0050] Unless specifically stated to the contrary, the weight percent (wt %) of a component is based on the total weight of the formulation or composition in which the component is contained.

[0051] As used herein, “IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process (including a protein, subunit, organelle, ribonucleoprotein, etc.). In one aspect, IC 50 Can refer to the concentration of a substance required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC 50 It refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0052] As used herein, “EC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% stimulation of a biological process or component of a process (including proteins, subunits, organelles, ribonucleoproteins, etc.). In one aspect, EC 50 Can refer to the concentration of a substance required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC 50 It is the concentration of agonist that elicits a response halfway between baseline and maximal response.

[0053] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.

[0054] As used herein, the term "subject" can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. Therefore, the subject of the method disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cattle, cat, guinea pig or rodent. The term does not represent a specific age or gender. Therefore, adult and neonatal subjects and fetuses (whether male or female) are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and animal subjects.

[0055] As used herein, the term "treatment" refers to medical treatment of a patient with the intention of curing, improving, stabilizing or preventing a disease, pathological condition or disorder. The term includes active treatment, i.e., treatment specifically for the improvement of a disease, pathological condition or disorder, and includes causal treatment, i.e., treatment for the elimination of the cause of the relevant disease, pathological condition or disorder. In addition, the term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological condition or disorder; preventive treatment, i.e., treatment intended to minimize or partially or completely inhibit the development of a relevant disease, pathological condition or disorder; and supportive treatment, i.e., treatment for supplementing another specific therapy for the improvement of a relevant disease, pathological condition or disorder. In various aspects, the term encompasses any treatment of a subject including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease; (ii) inhibiting the disease, i.e., preventing its development; or (iii) alleviating the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and in a further aspect, the subject is a human. The term "subject" also includes domestic animals (eg, cats, dogs, etc.), livestock (eg, cows, horses, pigs, sheep, goats, etc.), and experimental animals (eg, mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0056] As used herein, the term "prevent" or "preventing" means to exclude, divert, avoid, stop, hinder or impede something from happening, especially by taking action in advance. It should be understood that when reduce, inhibit or prevent are used herein, the use of the other two words is also explicitly disclosed unless otherwise specifically stated.

[0057] As used herein, the term "diagnosed" means that the body has been examined by a skilled artisan, such as a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0058] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ocular administration, intraauricular administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable administration such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the formulation may be administered therapeutically; i.e., administered to treat an existing disease or condition. In further various aspects, the formulation may be administered prophylactically; i.e., administered for the prevention of a disease or condition.

[0059] As used herein, the terms "effective amount" and "amount effective" refer to an amount sufficient to achieve the desired result or to have an effect on an undesirable condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on an undesirable symptom, but generally not sufficient to cause adverse side effects. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the patient's age, weight, general health, sex and diet; the time of administration; the route of administration; the excretion rate of the specific compound employed; the duration of treatment; the drugs used in combination or concomitantly with the specific compound employed and similar factors well known in the medical field. For example, it is well known to those skilled in the art to start the dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. If necessary, the effective daily dose can be divided into multiple doses for the purpose of administration. Therefore, a single dose composition may contain such an amount or a submultiple thereof to constitute the daily dose. In the event of any contraindications, the dose may be adjusted by the individual physician. Dosages may vary and may be administered in one or more doses per day for one or more days. Guidance on appropriate dosages for a given class of drug products can be found in the literature. In further various aspects, the formulation may be administered in a "prophylactically effective amount," i.e., an amount effective to prevent a disease or condition.

[0060] As used herein, "dosage form" refers to a pharmacologically active material in a medium, carrier, vehicle or device suitable for administration to a subject. The dosage form may include a compound disclosed herein, a product of a disclosed preparation method, or a salt, solvate or polymorph thereof, and a pharmaceutically acceptable excipient, such as a preservative, a buffer, saline or phosphate buffered saline. The dosage form may be prepared using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can include inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate or citrate) and pH adjusters (e.g., hydrochloric acid, sodium or potassium hydroxide, citrate or acetate, amino acids and their salts), antioxidants (e.g., ascorbic acid, α-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and / or freezing / lyophilization stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic regulators (e.g., salts or sugars), antimicrobial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsiloxane), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymer stabilizers and viscosity modifiers (e.g., polyvinyl pyrrolidone, poloxamer 488, carboxymethyl cellulose) and cosolvents (e.g., glycerol, polyethylene glycol, ethanol). Dosage forms formulated for injectable use may have a disclosed compound, a product of a disclosed method of preparation, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0061] As used herein, "test kit" refers to a collection of at least two components that make up a test kit. These components together constitute a functional unit for a given purpose. The individual member components may be physically packaged together or individually packaged. For example, a test kit including instructions for using the test kit may or may not physically contain the instructions with other individual member components. Instead, the instructions may be provided as a separate member component, in paper form or electronic form, which may be provided on a computer-readable storage device or downloaded from an Internet website, or provided as a recorded presentation.

[0062] As used herein, "instructions" refers to a file describing the relevant materials or methods associated with a test kit. These materials may include any combination of the following: background information, a list of components and their availability information (purchase information, etc.), a brief or detailed protocol for using the test kit, troubleshooting, reference materials, technical support, and any other relevant files. The instructions may be provided with the test kit or as a separate member component, in paper form or electronic form, which may be provided on a computer-readable storage device or downloaded from an Internet website, or provided as a recorded presentation. The instructions may include one or more files and are intended to include future updates.

[0063] As used herein, the term "therapeutic agent" includes any synthetic or naturally occurring biologically active compound or composition of matter that, when administered to an organism (human or non-human animal), induces a desired pharmacological, immunogenic and / or physiological effect by local and / or systemic action. Thus, the term includes those compounds or chemicals traditionally considered to be drugs, vaccines and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc. Examples of therapeutic agents are described in known literature references, such as the Merck Index (14 th edition), Physicians′DeskReference(64 th edition) and The Pharmacological Basis of Therapeutics (12 thedition), and they include, but are not limited to, drugs; vitamins; mineral supplements; substances used in the treatment, prevention, diagnosis, cure, or alleviation of disease or condition; substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active after they are placed in a physiological environment.For example, the term "therapeutic agent" encompasses compounds or compositions used in all major therapeutic areas, including but not limited to adjuvants; anti-infectives such as antibiotics and antivirals; anti-cancer and anti-tumor agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modulators, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelators and other ribonucleotide reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, doxorubicin, irinotecan and platinum compounds, immune checkpoint blockers such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) mAb, cluster of differentiation 47 (CD47) mAb, toll-like receptor ( TLR) agonists and other immunomodulators, cell therapy agents such as chimeric antigen receptor T cells (CAR-T) / chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFN), interleukins (IL) and mAbs; anti-ALS agents such as entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors and integrase inhibitors; analgesics and analgesic combinations, anorexia, anti-inflammatory agents, anti-epileptic drugs, local Local and general anesthetics, hypnotics, sedatives, antipsychotics, tranquilizers, antidepressants, anxiolytics, antagonists, neuron blockers, anticholinergics and cholinergic mimetics, antimuscarinics and muscarinics, antiadrenergics, antiarrhythmics, antihypertensives, hormones and nutrients, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrhythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants medicaments; cough and cold preparations; decongestants; diagnostic agents; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin) and other biologically active macromolecules, such as, for example, proteins and enzymes. The medicaments may be bioactive agents for medical (including veterinary) applications and agricultural (e.g., plants) and other fields.The term "therapeutic agent" also includes, but is not limited to, drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or ameliorate disease or condition; or substances that affect the structure or function of the body; or prodrugs, which become biologically active or more active after having been placed in a predetermined physiological environment.

[0064] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, ie, does not cause unacceptable levels of undesired biological effects or interact in a deleterious manner.

[0065] As used herein, the term "derivative" refers to a compound having a structure derived from a parent compound (e.g., a compound disclosed herein) and having a structure sufficiently similar to those disclosed herein, and based on this similarity, one skilled in the art would expect it to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as a precursor to the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0066] As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for re-formulating into sterile injection solutions or dispersions just before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. For example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants, appropriate fluidity can be maintained. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. By including various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, etc.), it is possible to ensure that microorganisms are prevented. It can also be expected to include isotonic agents such as sugar, sodium chloride, etc. The extended absorption of injectable drug forms can be achieved by including agents (such as aluminum monostearate and gelatin) that delay absorption. Injectable reservoir forms are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer (such as polylactide-polyglycolide, poly(orthoester) and poly(anhydride)). According to the ratio of the drug to the polymer and the properties of the specific polymer adopted, the rate of drug release can be controlled. Depot-type injectable preparations are also prepared by embedding the drug in a liposome or microemulsion compatible with body tissues. Injectable preparations can be sterilized, for example, by filtering through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media just before use. Suitable inert carriers can include sugars such as lactose. Desirably, the particles of at least 95% by weight of the active ingredient have an effective particle size in the range of 0.01 to 10 microns.

[0067] As used herein, the term "substituted" is intended to include all allowed substituents of organic compounds. In a wide range of aspects, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic and aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include substituents such as described below. For appropriate organic compounds, allowed substituents can be one or more and the same or different. For the purpose of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any allowed substituents of organic compounds described herein that satisfy the valence of heteroatoms. This disclosure is not intended to be limited in any way by the allowed substituents of organic compounds. In addition, the term "substituted" or "substituted by ... " includes implicit conditions, i.e., such substitution is consistent with the allowed valence of the substituted atom and substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo a transformation such as by rearrangement, cyclization, elimination, etc. It is also expected that in some aspects, unless explicitly stated to the contrary, a single substituent can be further optionally substituted (i.e., further substituted or unsubstituted).

[0068] In defining various terms, “A 1 ”, “A 2 ”, “A 3 ” and “A 4 " are used as general symbols herein to represent various specific substituents. These symbols can be any substituents, not limited to those disclosed herein, and when they are defined as certain substituents in one instance, they can be defined as some other substituents in another instance.

[0069] As used herein, the term "aliphatic" or "aliphatic group" refers to a hydrocarbon moiety that can be straight (i.e., unbranched), branched or cyclic (comprising fused, bridged and spiro-fused polycyclics), and can be fully saturated or can contain one or more unsaturated units, but is not aromatic. Unless otherwise indicated, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, straight or branched alkyl, alkenyl and alkynyl groups, and their hybrids, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

[0070] As used herein, term " alkyl " is a saturated hydrocarbon group with a branched or unbranched chain having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl etc. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups can also be substituted or unsubstituted. For example, alkyl groups can be substituted by one or more groups, and the groups include but are not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo or mercaptan, as described herein. A " low alkyl " group is an alkyl group containing one to six (e.g., one to four) carbon atoms. The term alkyl group may also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc. up to and including C1-C24 alkyl.

[0071] Throughout the specification, "alkyl" is generally used to refer to unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically mentioned herein by identifying specific substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted by one or more halides such as fluorine, chlorine, bromine or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted by a single halide such as fluorine, chlorine, bromine or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted by two or more halides, i.e., each halide substituent does not have to be the same halide as another halide substituent, and multiple examples of halide substituents do not have to be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted by one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted by one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted by one or more hydroxyl groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another instance, it is not intended that the term "alkyl" also refers to the specific term such as "hydroxyalkyl" and the like.

[0072] This practice also applies to other groups described herein. That is, while terms such as "cycloalkyl" refer to unsubstituted and substituted cycloalkyl moieties, substituted moieties may additionally be specifically identified herein; for example, a specific substituted cycloalkyl may be referred to as, for example, "alkylcycloalkyl". Similarly, a substituted alkoxy may be specifically referred to as, for example, "halogenated alkoxy", a specific substituted alkenyl may be, for example, "alkenyl alcohol", etc. Likewise, the practice of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" does not mean that the general term also includes the specific term.

[0073] As used herein, term " cycloalkyl " is a non-aromatic carbonyl ring consisting of at least three carbon atoms. The example of cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl etc. The term " heterocycloalkyl " is a class of cycloalkyl groups as defined above, and is included in the meaning of the term " cycloalkyl ", wherein at least one carbon atom of the ring is replaced by heteroatoms such as but not limited to nitrogen, oxygen, sulphur or phosphorus. Cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. Cycloalkyl group and heterocycloalkyl group can be substituted by one or more groups, and the group includes but is not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo or thiol as described herein.

[0074] As used herein, the term "polyalkylene group" is a group having two or more CH2 groups connected to each other. The polyalkylene group can be represented by the formula -(CH2) a - represents, wherein "a" is an integer from 2 to 500.

[0075] As used herein, the terms "alkoxy" and "alkoxyl" refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an "alkoxy" group can be defined as -OA 1 , where A 1 is an alkyl or cycloalkyl group as defined above. "Alkoxy" also encompasses polymers of alkoxy groups as just described; that is, the alkoxy group may be a polyether, such as -OA 1 -OA 2 or-OA 1 -(OA 2 ) a -OA 3 , where "a" is an integer from 1 to 200, and A 1 , A 2 and A 3 is an alkyl and / or cycloalkyl group.

[0076] As used herein, the term "alkenyl" is a hydrocarbon group of 2 to 24 carbon atoms having a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A 1 A 2 )C=C(A 3 A 4 ) is intended to encompass both E and Z isomers. This may be inferred in the structural formulas herein where an asymmetric olefin is present, or it may be explicitly indicated by the bond symbol C=C. The alkenyl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0077] As used herein, the term "cycloalkenyl" is a non-aromatic carbonyl ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, etc. The term "heterocycloalkenyl" is a class of cycloalkenyl groups as defined above, and is included in the meaning of the term "cycloalkenyl", wherein at least one carbon atom of the ring is replaced by a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl groups and heterocycloalkenyl groups may be substituted or unsubstituted. Cycloalkenyl groups and heterocycloalkenyl groups may be substituted by one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo or thiol as described herein.

[0078] As used herein, the term "alkynyl" is a hydrocarbon group of 2 to 24 carbon atoms having a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups may be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo or thiol as described herein.

[0079] As used herein, the term "cycloalkynyl" is a non-aromatic carbonyl ring consisting of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, etc. The term "heterocycloalkynyl" is a class of cycloalkenyl groups as defined above, and is included in the meaning of the term "cycloalkynyl", wherein at least one carbon atom of the ring is replaced by a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus. Cycloalkynyl groups and heterocycloalkynyl groups can be substituted or unsubstituted. Cycloalkynyl groups and heterocycloalkynyl groups can be substituted by one or more groups, and the groups include, but are not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo or thiol as described herein.

[0080] As used herein, the term "aromatic group" refers to a ring structure having an annular cloud of delocalized π electrons above and below the plane of the molecule, wherein the π cloud contains (4n+2)π electrons. Further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled "Aromaticity," pages 477-497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

[0081] As used herein, term " aryl " is a group containing any carbonyl aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene etc. Aryl group can be substituted or unsubstituted. Aryl group can be substituted by one or more groups, and the group includes but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo or thiol as described herein. Term " biaryl " is a kind of specific type of aryl group, and is included in the definition of " aryl ". In addition, aryl group can be a single ring structure or include multiple ring structures, and these ring structures are condensed ring structures or are connected by one or more bridging groups such as carbon-carbon bonds. For example, biaryl can be two aryl groups combined together by condensed ring structure, as in naphthalene, or connected by one or more carbon-carbon bonds, as in biphenyl.

[0082] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout the specification, "C(O)" is a shorthand notation for a carbonyl group, ie, C=O.

[0083] As used herein, the term "amine" or "amino group" is represented by the formula -NA 1A 2 Indicates that A 1 and A 2 It can be independently hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. A specific example of an amino group is -NH2.

[0084] As used herein, the term "alkylamino" is represented by the formula -NH(-alkyl), wherein alkyl is as described herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, and the like.

[0085] The term "dialkylamino" as used herein is represented by the formula -N(-alkyl)2, wherein alkyl is as described herein. Representative examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, diisopentylamino, di(tert-pentyl)amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, and the like.

[0086] The term "carboxylic acid" as used herein is represented by the formula -C(O)OH.

[0087] As used herein, the term "ester" is a molecule of the formula -OC(O)A 1 or -C(O)OA 1 Indicates that A 1 The term "polyester" as used herein is a group consisting of the formula -(A 1 O(O)CA 2 -C(O)O) a -or-(A 1 O(O)CA 2 -OC(O)) a - indicates that A 1 and A 2 It may be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein, and "a" is an integer from 1 to 500. "Polyester" is a term used to describe a group produced by the reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

[0088] As used herein, the term "ether" is a 1 OA 2 Indicates that A 1 and A 2 The term "polyether" as used herein is a group consisting of the formula -(A 1 OA 2 O) a - indicates that A 1 and A 2 It may be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein, and "a" is an integer from 1 to 500. Examples of the polyether group include polyethylene oxide, polypropylene oxide and polybutylene oxide.

[0089] As used herein, the terms "halo," "halogen," or "halide" are used interchangeably and refer to F, Cl, Br, or I.

[0090] As used herein, the terms "pseudohalide," "pseudohalogen," or "pseudohalogenated" are used interchangeably and refer to functional groups that behave substantially like halides. For example, such functional groups include cyano, thiocyanate, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0091] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl groups may be substituted alkyl groups as defined above.

[0092] As used herein, the term "heteroaryl" refers to an aromatic group that is combined with at least one heteroatom in the ring of an aromatic group. Examples of heteroatoms include but are not limited to nitrogen, oxygen, sulfur and phosphorus, wherein N-oxides, sulfur oxides and dioxides are heteroatom substitutions allowed. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted by one or more groups, and the groups include but are not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo or thiol as described herein. Heteroaryl groups can be monocyclic or alternative condensed ring systems. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolyl, isoquinolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxazolyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0093] As used herein, the terms "heterocycle" or "heterocyclyl" are used interchangeably and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." The heterocyclic ring includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole), triazole (including 1,2,3-triazole, 1,3,4-triazole), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine), tetrazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane and the like. The term heterocyclyl group can also be C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, etc., up to and including C2-C18 heterocyclyl. For example, C2 heterocyclyl includes a group with two carbon atoms and at least one heteroatom, including but not limited to aziridinyl, diazetidinyl, dihydrodiazetidinyl, oxiranyl, thiirane, etc. Alternatively, for example, C5 heterocyclyl includes a group with five carbon atoms and at least one heteroatom, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, etc. It is understood that the heterocyclyl group may be bound via a heteroatom in the ring (where chemically possible) or via one of the carbons constituting the heterocyclyl ring.

[0094] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" refers to a ring system in which at least one ring member is not carbon. Bicyclic heterocyclyls include ring systems in which an aromatic ring is fused to another aromatic ring or in which an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyls include ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms or in which a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0095] As used herein, term "heterocycloalkyl" refers to aliphatic, partially unsaturated or fully saturated 3 to 14 ring systems, monocyclic and bicyclic and tricyclic ring systems comprising 3 to 8 atoms. The heterocycloalkyl ring system comprises one to four heteroatoms independently selected from oxygen, nitrogen and sulphur, wherein nitrogen and sulphur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally substituted. Representative heterocycloalkyl groups include but are not limited to pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl and tetrahydrofuranyl.

[0096]

[0046] The term "hydroxyl" or "hydroxyl" as used herein is represented by the formula -OH.

[0097] As used herein, the term "ketone" is a 1 C(O)A 2 Indicates that A 1 and A 2 and alkyl, ...

[0098] As used herein, the term "azide" or "azido" is represented by the formula -N3.

[0099] The term "nitro" as used herein is represented by the formula -NO2.

[0100]

[0046] The term "nitrile" or "cyano" as used herein is represented by the formula -CN.

[0101] As used herein, the term "silyl group" is represented by the formula -SiA 1 A 2 A 3 Indicates that A 1 , A 2 and A 3 and X is 1 or X. It may independently be hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0102] As used herein, the term "sulfo-oxo" is represented by the formula -S(O)A 1 、-S(O)2A 1 、-OS(O)2A 1 or -OS(O)2OA 1 Indicates that A 1It can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. Throughout this specification, "S(O)" is a shorthand notation for S=O. The term "sulfonyl" is used herein to refer to a sulfonyl radical of the formula -S(O)2A 1 A sulfo-oxy group represented by 1 It can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. As used herein, the term "sulfone" is a radical of formula A 1 S(O)2A 2 Indicates that A 1 and A 2 can be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. As used herein, the term "sulfoxide" is a sulfoxide having the formula A 1 S(O)A 2 Indicates that A 1 and A 2 and alkyl, ...

[0103] The term "thiol" as used herein is represented by the formula -SH.

[0104] As used herein, “R 1 ”, “R 2 ”, “R 3 ”, “R n " ”(where n is an integer) may independently have one or more of the above groups. For example, if R 1 It is a straight chain alkyl alkyl, then one of the hydrogen atoms of the alkyl group can be optionally substituted by a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. According to the selected group, the first group can be incorporated into the second group, or alternatively, the first group can be side-joined (i.e. connected) with the second group. For example, in the phrase "an alkyl group including an amino group", the amino group can be incorporated in the main chain of the alkyl group. Alternatively, the amino group can be connected to the main chain of the alkyl group. The nature of the selected group will determine whether the first group is embedded in or connected to the second group.

[0105] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Typically, the term "substituted" (whether or not preceded by the term "optionally") means that one or more hydrogens of the specified moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. The combination of substituents contemplated by the present invention is preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that in certain aspects, unless expressly stated to the contrary, a single substituent may be further optionally substituted (i.e., further substituted or unsubstituted).

[0106] The term "stable" as used herein refers to compounds that are not substantially altered when subjected to conditions that allow for their production, detection, and in some aspects their recovery, purification, and use for one or more of the purposes disclosed herein.

[0107] Suitable monovalent substituents on substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be o Substitution; -CH=CHPh, which can be replaced by R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2)0-4 N(R o )C(O)NR o 2;-N (R o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N (R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(C H2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-、SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O) C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4OS(O)2R o ; -S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ; -C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3; -(C 1-4 Straight chain or branched alkylene)ON(R o )2; or -(C 1-4 Straight chain or branched alkylene)C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, R o Two independent occurrences of are taken together with their middle atom to form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0108] R o A suitable monovalent substituent on (or by using R o Two independent occurrences of (and the ring formed by the intermediate atoms) are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · )、-(CH2) 0-2 OH, -(CH2) 0-2 OR · 、 -(CH2) 0-2 CH(OR · )2; -O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 Straight chain or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, where preceded by "halo", is substituted only by one or more halogens and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0109] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * , =NR * , =NOR * 、-O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, wherein each independent occurrence of R* is selected from hydrogen, C which may be substituted as defined below 1-6 aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, wherein each independent occurrence of R* is selected from hydrogen, C 1-6aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0110] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, where preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0111] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, and the substituted C 1-6 aliphatic, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definitions, Two independent occurrences of are taken together with their middle atom to form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0112] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, where preceded by "halo", substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2)0- 1Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0113] The term "leaving group" refers to an atom (or group of atoms) with electron-withdrawing ability that can be replaced with bonded electrons as a stable species. Examples of suitable leaving groups include halides and sulfonates, including but not limited to trifluoromethanesulfonate, mesylate, tosylate and brosylate.

[0114] The term "hydrolyzable group" and "hydrolyzable moiety" refer to a functional group that can undergo hydrolysis under, for example, alkaline or acidic conditions. Examples of hydrolyzable residues include, but are not limited to, acyl halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, "Protective Groups in Organic Synthesis," TW Greene, PGM Wuts, Wiley-Interscience, 1999).

[0115] The term "organic residue" defines a carbon-containing residue, i.e. a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues or free radicals defined above. The organic residue may contain various heteroatoms, or may be combined with another molecule by heteroatoms (comprising oxygen, nitrogen, sulfur, phosphorus, etc.). Examples of organic residues include but are not limited to alkyl or substituted alkyl, alkoxy or substituted alkoxy, monosubstituted or disubstituted amino, amide groups, etc. The organic residue may preferably include 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. In a further aspect, the organic residue may include 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms or 2 to 4 carbon atoms.

[0116] A close synonym of the term "residue" is the term "radical", which when used in the specification and the concluding claims refers to a fragment, group or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, the 2,4-thiazolidinedione radical in a particular compound has the following structure:

[0117]

[0118] Whether or not a thiazolidinedione is used to prepare the compound. In some embodiments, a free radical (e.g., an alkyl group) may be further modified (i.e., a substituted alkyl group) by having one or more "substituent free radicals" bonded thereto. The number of atoms in a given free radical is not critical to the present invention unless otherwise indicated herein.

[0119] The term "organic free radical" as defined and used herein contains one or more carbon atoms. An organic free radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic free radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. An organic free radical generally has hydrogen combined with at least some carbon atoms of the organic free radical. An example of an organic free radical that does not include an inorganic atom is a 5,6,7,8-tetrahydro-2-naphthyl free radical. In certain embodiments, an organic free radical can contain 1-10 inorganic heteroatoms combined therewith or therein combined, including halogen, oxygen, sulfur, nitrogen, phosphorus, etc. Examples of organic radicals include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, disubstituted amino, acyloxy, cyano, carboxyl, alkoxycarbonyl, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic or substituted heterocyclic radicals, where the terms are defined elsewhere herein. Some non-limiting examples of organic radicals containing heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals, and the like.

[0120] The compounds described herein may contain one or more double bonds and may therefore give rise to cis / trans (E / Z) isomers as well as other conformational isomers. Unless otherwise specified, the present invention encompasses all such possible isomers and mixtures of such isomers.

[0121] Unless otherwise specified, formulas with chemical bonds represented only by solid lines, rather than wedges or dashed lines, contemplate every possible isomer, such as every enantiomer and diastereomer, and mixtures of isomers, such as racemic or calibrated mixtures. The compounds described herein may contain one or more asymmetric centers, and thus may produce diastereomers and optical isomers. Unless otherwise specified, the present invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Also included are mixtures of stereoisomers and isolated specific stereoisomers. During the synthetic procedures for preparing such compounds, or in the use of racemization or epimerization procedures known to those skilled in the art, the product of such procedures may be a mixture of stereoisomers.

[0122] Many organic compounds exist in optically active forms, with the ability to rotate the plane of plane polarized light. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to represent the rotation sign of the compound to plane polarized light, wherein (-) represents that the compound is left-handed. The compound prefixed with (+) or d is right-handed. For a given chemical structure, these compounds referred to as stereoisomers are identical, except that they are mirror images that cannot be superimposed on each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many compounds described herein may have one or more chiral centers, and therefore may exist in different enantiomeric forms. If desired, chiral carbon may be represented by an asterisk (*). When the bond to a chiral carbon is depicted as a straight line in a disclosed formula, it is understood that both the (R) and (S) configurations of the chiral carbon and therefore both enantiomers and mixtures thereof are included in the formula. As used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon may be depicted as a wedge (the bond to the atom above the plane), while the other may be depicted as a series or wedge of short parallel lines (the bond to the atom below the plane). The Cahn-Ingold-Prelog system may be used to assign a (R) or (S) configuration to a chiral carbon.

[0123] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless otherwise specified, the disclosed compounds contain enantiomers and mixtures of enantiomers, such as a specific 50:50 mixture referred to as a racemic mixture. Enantiomers can be resolved by methods known to those skilled in the art, such as forming diastereomeric salts, which can be separated by, for example, crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); forming diastereomeric derivatives or complexes that can be separated by, for example, crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It should be understood that in the case where the desired enantiomer is converted into another chemical entity by one of the above separation procedures, a further step can release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0124] The designation of the specific absolute configuration on the chiral carbon in the disclosed compound is understood to mean that the designated enantiomeric form of the compound can be provided in enantiomeric excess (ee). Enantiomeric excess as used herein refers to that a specific enantiomer is present at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98% or greater than 99%. In one aspect, the designated enantiomer is substantially free of other enantiomers. For example, the "R" form of the compound can be substantially free of the "S" form of the compound, and is therefore an "S" form of enantiomeric excess. On the contrary, the "S" form of the compound can be substantially free of the "R" form of the compound, and is therefore an "R" form of enantiomeric excess.

[0125] When the disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereomeric form. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S, S) / (R, R) and (R, S) / (S, R)). Enantiomer pairs (e.g., (S, S) / (R, R)) are mirror image stereoisomers of each other. Non-mirror stereoisomers (e.g., (S, S) and (R, S)) are diastereomers. Diastereoisomer pairs can be separated by methods known to those skilled in the art (e.g., chromatography or crystallization), and each enantiomer in each pair can be separated as described above. Unless specifically excluded otherwise, the disclosed compound includes each diastereomer of such a compound and a mixture thereof.

[0126] Compounds according to the present disclosure can use groups such as alkoxy, amino acids as prodrug forming parts to form prodrugs at hydroxyl or amino functional groups. For example, the hydroxymethyl position can form monophosphates, diphosphates or triphosphates, and these phosphates can form prodrugs again. The preparation of such prodrug derivatives is discussed in various literature sources (examples are: Alexander et al., J.Med.Chem.1988,31,318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen functional group converted in the preparation of these derivatives is one (or more) nitrogen atoms of the compounds of the present disclosure.

[0127] "Derivatives" of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, solvates, and combinations thereof. "Combinations" mentioned in this context refer to derivatives belonging to at least two groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, and solvates. Examples of radiolabeled forms include compounds labeled with tritium, phosphorus-32, iodine-129, carbon-11, fluorine-18, and the like.

[0128] The compounds described herein include atoms in their natural isotopic abundance and in non-natural abundance. The disclosed compounds may be isotopically labeled or isotopically substituted compounds identical to those described, but with the exception that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as respectively 2 H. 3 H. 13 C. 14 C. 15 N. 18O. 17 O. 35 S. 18 F and 36 The compounds further include prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention (e.g., compounds into which radioactive isotopes such as 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. Tritiated (i.e. 3 H and carbon-14, i.e. 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the following procedures, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0129] Compound described in the present invention can exist as solvate.In some cases, the solvent for preparing solvate is aqueous solution, and so solvate is usually referred to as hydrate.Compound can exist as hydrate, for example, hydrate can be obtained by crystallization from solvent or from aqueous solution.In this respect, one, two, three or any number of solvents or water molecules can be combined with compound according to the present invention to form solvate and hydrate.Unless otherwise indicated, the present invention includes all such possible solvates.

[0130] The term "co-crystal" refers to a physical association of two or more molecules that generates its stability through non-covalent interactions. One or more components of the molecular complex provide a stable framework in the crystal lattice. In some cases, guest molecules are incorporated into the crystal lattice as anhydrides or solvates, see, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Representa New Path to Improved Medicines?" Almarasson, O., et.al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0131] It is also understood that certain compounds described herein may exist as an equilibrium of tautomers. For example, a ketone with an α-hydrogen may exist in an equilibrium of a keto form and an enol form.

[0132]

[0133] Likewise, an amide with an N-hydrogen can exist in equilibrium between the amide form and the imidic acid form. As another example, as shown below, pyrazole can exist in two tautomeric forms, namely N 1 -Unsubstituted, 3-A 3 and N 1 -Unsubstituted, 5-A 3 .

[0134]

[0135] Unless stated to the contrary, the present invention encompasses all such possible tautomers.

[0136] Chemical substances are known to form solids that exist in different ordered states, which are referred to as polymorphic forms or modifications. Different modifications of polymorphic substances may differ greatly in their physical properties. Compounds according to the present invention may exist in different polymorphic forms, wherein a particular modification may be metastable. Unless otherwise indicated, the present invention encompasses all such possible polymorphic forms.

[0137] In some aspects, the structure of the compound can be represented by the following formula:

[0138]

[0139] It is understood to be equivalent to the following formula:

[0140]

[0141] where n is usually an integer. That is, R n is understood to represent five independent substituents, namely R n(a) , R n(b) , R n(c) , R n(d) , R n(e) "Independent substituents" means that each R substituent can be defined independently. For example, if in one case R n(a) is a halogen, in which case R n(b) Not necessarily halogen.

[0142] Certain materials, compounds, compositions and components disclosed herein are either commercially available or readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used to prepare the disclosed compounds and compositions can be obtained from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or prepared by methods known to those skilled in the art following the procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0143] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Therefore, in the event that a method claim does not actually recite the order in which its steps are to be followed or that it is not otherwise specifically stated in the claim or description that the steps are to be limited to a specific order, no order is intended to be inferred in any respect. This applies to any possible non-express basis for interpretation, including logical issues regarding the arrangement of steps or operational flows, explicit meaning derived from grammatical organization or punctuation, or the number or type of embodiments described in the specification.

[0144] Disclosed are components for preparing the compositions of the present invention and the compositions themselves used in the methods disclosed herein. These and other materials are disclosed herein, and it should be understood that when the combinations, subsets, interactions, groupings, etc. of these materials are disclosed, although specific references to each individual and collective combination and arrangement of these compounds cannot be explicitly disclosed, each is specifically considered and described herein. For example, if a specific compound is disclosed and discussed, and many modifications that can be made to many molecules containing the compound are discussed, then each combination and arrangement of the compound and possible modifications are specifically considered, unless the opposite is specifically indicated. Therefore, if a class of molecules A, B and C, and examples of a class of molecules D, E and F and combined molecules are disclosed, AD is disclosed, then even if each is not listed individually, but the meaning combination of each is considered individually and collectively, then AE, AF, BD, BE, BF, CD, CE and CF are considered to be disclosed. Similarly, any subset or combination of these is also disclosed. Therefore, for example, a subgroup of AE, BF and CE will be considered to be disclosed. This concept applies to all aspects of the application, including but not limited to the steps in the method for preparing and using the composition of the present invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0145] It should be understood that the compounds and compositions disclosed herein have certain functions. Certain structural requirements for performing the disclosed functions are disclosed herein, and it should be understood that there are various structures that can perform the same functions related to the disclosed structures, and these structures will generally achieve the same results.

[0146] B. Compounds

[0147] In one aspect, the invention relates to compounds useful for treating disorders associated with disorders of uncontrolled cell proliferation, such as, for example, cancer, including but not limited to sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).

[0148] In one aspect, compounds of the invention are useful for treating disorders of uncontrolled cell proliferation, as further described herein.

[0149] It is contemplated that each disclosed derivative may optionally be further substituted. It is also contemplated that any one or more derivatives may optionally be omitted from the present invention. It should be understood that the disclosed compounds may be provided by the disclosed methods. It should also be understood that the disclosed compounds may be used in the disclosed methods of use.

[0150] 1. Structure

[0151] In one aspect, disclosed is a compound having a structure represented by a formula selected from the following, or a pharmaceutically acceptable salt thereof:

[0152]

[0153] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0154]

[0155] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2, and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3 When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0156]

[0157] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0158]

[0159] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R 16 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0160] In one aspect, disclosed is a compound having a structure represented by a formula selected from the following, or a pharmaceutically acceptable salt thereof:

[0161]

[0162] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0163]

[0164] The condition is R 1 and R 2 wherein one is hydrogen; wherein n is selected from 0, 1 and 2; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0165]

[0166] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, fluorine, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein R 4 When present is selected from hydrogen, fluorine and -OR 16 ; and where R 16 When present, is selected from hydrogen, methyl, -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0167]

[0168] The condition is R 1 , R 2 and R 3 Not hydrogen at the same time.

[0169] In a further aspect, the compound has a structure represented by the following formula:

[0170]

[0171] In a further aspect, the compound has a structure represented by the following formula:

[0172]

[0173] In a further aspect, the compound has a structure represented by the following formula:

[0174]

[0175] In a further aspect, the compound has a structure represented by the following formula:

[0176]

[0177] In a further aspect, the compound has a structure represented by the following formula:

[0178]

[0179] In a further aspect, the compound has a structure represented by the following formula:

[0180]

[0181] In a further aspect, the compound has a structure represented by the following formula:

[0182]

[0183] In a further aspect, the compound has a structure represented by the following formula:

[0184]

[0185] In a further aspect, the compound has a structure represented by the following formula:

[0186]

[0187] In a further aspect, the compound has a structure represented by the following formula:

[0188]

[0189] In a further aspect, the compound has a structure represented by the following formula:

[0190]

[0191] In a further aspect, the compound has a structure represented by the following formula:

[0192]

[0193] Where R 30 It is a C1-C30 alkyl group.

[0194] In a further aspect, the compound has a structure represented by the following formula:

[0195]

[0196] In a further aspect, the compound has a structure represented by the following formula:

[0197]

[0198] In a further aspect, the compound has a structure represented by the following formula:

[0199]

[0200] In a further aspect, the compound has a structure represented by the following formula:

[0201]

[0202] In a further aspect, the compound has a structure represented by the following formula:

[0203]

[0204] In a further aspect, the compound has a structure represented by the following formula:

[0205]

[0206] In a further aspect, the compound has a structure represented by the following formula:

[0207]

[0208] In a further aspect, the compound has a structure represented by the following formula:

[0209]

[0210] In a further aspect, the compound has a structure represented by the following formula:

[0211]

[0212] Where R 30 It is a C1-C30 alkyl group.

[0213] In a further aspect, the compound has a structure represented by the following formula:

[0214]

[0215] In a further aspect, the compound has a structure represented by the following formula:

[0216]

[0217] In a further aspect, the compound has a structure represented by the following formula:

[0218]

[0219] In a further aspect, the compound has a structure represented by the following formula:

[0220]

[0221] In a further aspect, the compound has a structure represented by the following formula:

[0222]

[0223] In a further aspect, the compound has a structure represented by the following formula:

[0224]

[0225] In a further aspect, the compound has a structure represented by the following formula:

[0226]

[0227] In a further aspect, the compound has a structure represented by the following formula:

[0228]

[0229] In a further aspect, the compound has a structure represented by the following formula:

[0230]

[0231] Where R 30 It is a C1-C30 alkyl group.

[0232] In a further aspect, the compound has a structure represented by the following formula:

[0233]

[0234] In a further aspect, the compound has a structure represented by the following formula:

[0235]

[0236] In a further aspect, the compound has a structure represented by the following formula:

[0237]

[0238] In a further aspect, the compound has a structure represented by the following formula:

[0239]

[0240] In a further aspect, the compound has a structure represented by the following formula:

[0241]

[0242] In a further aspect, the compound has a structure represented by the following formula:

[0243]

[0244] In a further aspect, the compound has a structure represented by the following formula:

[0245]

[0246] In a further aspect, the compound has a structure represented by the following formula:

[0247]

[0248] In a further aspect, the compound has a structure represented by the following formula:

[0249]

[0250] In a further aspect, the compound has a structure represented by the following formula:

[0251]

[0252] Where R 30 It is a C1-C30 alkyl group.

[0253] In one aspect, n is selected from 0, 1, and 2. In a further aspect, n is selected from 0 and 1. In a still further aspect, n is 0. In a still further aspect, n is 1. In a still further aspect, n is 2.

[0254] aX Group

[0255] In one aspect, X when present is selected from O and S. In a further aspect, X when present is O. In a further aspect, X when present is S.

[0256] B R 1 and R 2 Group

[0257] In one aspect, R 1 and R 2 are each independently selected from hydrogen, C(O)R10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0258]

[0259] The condition is R 1 and R 2 One is hydrogen, or R 1 and R 2 Each together includes the structure represented by the formula:

[0260]

[0261] In a further aspect, R 1 and R 2 are each independently selected from hydrogen, C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0262]

[0263] The condition is R 1 and R 2 One is hydrogen.

[0264] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by a formula selected from the following:

[0265]

[0266] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by a formula selected from the following:

[0267]

[0268] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by a formula selected from the following:

[0269]

[0270] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by a formula selected from the following:

[0271]

[0272] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by the following formula:

[0273]

[0274] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by the following formula:

[0275]

[0276] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and a structure represented by the following formula:

[0277]

[0278] In a further aspect, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 AND-P(O)(OR 11 ) 2. In a further aspect, R 1 and R 2 are each independently selected from hydrogen, C(O)R 10 And the structure represented by the following formula:

[0279]

[0280] In a further aspect, R 1 and R 2 are each independently selected from hydrogen, -P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by the following formula:

[0281]

[0282] In a further aspect, R 1 and R 2 are each independently selected from hydrogen and -C(O)R 10 In a still further aspect, R 1 and R 2 are each independently selected from hydrogen and -P(O)(OR 11 ) 2. In a further aspect, R 1 and R2 are each independently selected from hydrogen and a structure represented by the following formula:

[0283]

[0284] In a further aspect, R 1 and R 2 Each is independently selected from hydrogen and -P(O)(OH)OP(O)(OH)OP(O)(OH)2.

[0285] In a further aspect, R 1 and R 2 Each together includes the structure represented by the formula:

[0286]

[0287] In a further aspect, R 1 and R 2 Each is hydrogen.

[0288] In a further aspect, R 1 Selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by the following formula:

[0289]

[0290] In a further aspect, R 1 Selected from hydrogen, -C(O)R 10 AND-P(O)(OR 11 ) 2. In a further aspect, R 1 Selected from hydrogen, -C(O)R 10 And the structure represented by the following formula:

[0291]

[0292] In a further aspect, R 1 Selected from hydrogen, -P(O)(OR 11 )2 and a structure represented by the following formula:

[0293]

[0294] In a further aspect, R 1 Selected from hydrogen and -C(O)R 10 In a still further aspect, R 1 Selected from hydrogen and -P(O)(OR 11 ) 2. In a further aspect, R 1Selected from hydrogen and a structure represented by the following formula:

[0295]

[0296] In a further aspect, R 1 is hydrogen. In a further aspect, R 1 Yes-C(O)R 10 In a still further aspect, R 1 Yes-P(O)(OR 11 ) 2. In a further aspect, R 1 The structure represented by the following formula:

[0297]

[0298] In a further aspect, R 2 Selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0299]

[0300] In a further aspect, R 2 Selected from hydrogen, -C(O)R 10 AND-P(O)(OR 11 ) 2. In a further aspect, R 2 Selected from hydrogen, -C(O)R 10 And the structure represented by the following formula:

[0301]

[0302] In a further aspect, R 2 Selected from hydrogen, -P(O)(OR 11 )2 and a structure represented by the following formula:

[0303]

[0304] In a further aspect, R 2 Selected from hydrogen and -C(O)R 10 In a still further aspect, R 2 Selected from hydrogen and -P(O)(OR 11 ) 2. In a further aspect, R 2 Selected from hydrogen and a structure represented by the following formula:

[0305]

[0306] In a further aspect, R 2is hydrogen. In a further aspect, R 2 Yes-C(O)R 10 In a still further aspect, R 2 Yes-P(O)(OR 11 ) 2. In a further aspect, R 2 The structure represented by the following formula:

[0307]

[0308] C 3 Group

[0309] In one aspect, R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl). In a further aspect, R 3 is selected from hydrogen, -C(O)(C1-C15 alkyl) and -C(O)(C2-C15 alkenyl). In yet a further aspect, R 3 is selected from hydrogen, -C(O)(C1-C8 alkyl) and -C(O)(C2-C8 alkenyl). In yet a further aspect, R 3 is selected from hydrogen, fluorine, -C(O)(C1-C4 alkyl) and -C(O)(C2-C4 alkenyl). In a further aspect, R 3 is selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In yet a further aspect, R 3 Selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3 and -C(O)CH=CH2.

[0310] In a further aspect, R 3 is selected from hydrogen and -C(O)(C1-C30 alkyl). In yet a further aspect, R 3 is selected from hydrogen and -C(O)(C1-C15 alkyl). In yet a further aspect, R 3 is selected from hydrogen and -C(O)(C1-C8 alkyl). 3 is selected from hydrogen and -C(O)(C1-C4 alkyl). In yet a further aspect, R 3 is selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2 and -C(O)CH2CH2CH3. In yet a further aspect, R3 is selected from hydrogen, -C(O)CH3 and -C(O)CH2CH3. In a further aspect, R 3 is selected from hydrogen and -C(O)CH2CH3. In yet a further aspect, R 3 Selected from hydrogen and -C(O)CH3.

[0311] In a further aspect, R 3 is selected from hydrogen and -C(O)(C2-C30 alkenyl). In yet a further aspect, R 3 is selected from hydrogen and -C(O)(C2-C15alkenyl). In yet a further aspect, R 3 is selected from hydrogen and -C(O)(C2-C8alkenyl). In a further aspect, R 3 is selected from hydrogen and -C(O)(C2-C4alkenyl). In yet a further aspect, R 3 is selected from hydrogen, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In yet a further aspect, R 3 Selected from hydrogen and -C(O)CH=CH2.

[0312] In a further aspect, R 3 is selected from -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl). In yet a further aspect, R 3 is selected from -C(O)(C1-C15 alkyl) and -C(O)(C2-C15 alkenyl). In yet a further aspect, R 3 is selected from -C(O)(C1-C8 alkyl) and -C(O)(C2-C8 alkenyl). In a further aspect, R 3 is selected from -C(O)(C1-C4 alkyl) and -C(O)(C2-C4 alkenyl). In yet a further aspect, R 3 is selected from the group consisting of -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In yet a further aspect, R 3 Selected from -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2 and -C(O)CH=CH2.

[0313] In a further aspect, R 3 is -C(O)(C1-C30 alkyl). In yet a further aspect, R 3is -C(O)(C1-C15 alkyl). In yet a further aspect, R 3 is -C(O)(C1-C8 alkyl). In a further aspect, R 3 is -C(O)(C1-C4 alkyl). In yet a further aspect, R 3 In yet a further aspect, R 3 is selected from -C(O)CH3 and -C(O)CH2CH3. In a further aspect, R 3 is -C(O)CH2CH3. In yet a further aspect, R 3 It is -C(O)CH3.

[0314] In a further aspect, R 3 is -C(O)(C2-C30 alkenyl). In yet a further aspect, R 3 is -C(O)(C2-C15alkenyl). In yet a further aspect, R 3 is -C(O)(C2-C8alkenyl). In a further aspect, R 3 is -C(O)(C2-C4alkenyl). In yet a further aspect, R 3 is selected from -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In yet a further aspect, R 3 It is -C(O)CH=CH2.

[0315] In a further aspect, R 3 It's hydrogen.

[0316] dR 4 and R 4′ Group

[0317] In one aspect, when present, R 4 and R 4′ Each is independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 .

[0318] In a further aspect, when present, R 4 and R 4′ are each independently selected from hydrogen and -CN.

[0319] In a further aspect, when present, R 4 and R 4′Each is independently selected from hydrogen, C2-C4 alkenyl, C2-C4 alkynyl and C1-C4 haloalkyl. In a further aspect, when present, R 4 and R 4′ Each is independently selected from hydrogen, ethenyl, propenyl, ethynyl, propynyl, -CH2CF2, -CH2CH2CF2, -CH(CH3)CH2CF2, and -CH2CH2CH2CF2. In yet a further aspect, when present, R 4 and R 4′ Each is independently selected from hydrogen, vinyl, ethynyl, -CH2CF2 and -CH2CH2CF2. In a further aspect, when present, R 4 and R 4′ Each is independently selected from hydrogen and -CH2CF2.

[0320] In a still further aspect, when present, R 4 and R 4′ are each independently selected from hydrogen and -OR 16 In a still further aspect, when present, R 4 and R 4′ Each independently selected from fluorine and -OR 16 In a further aspect, when present, R 4 and R 4′ are each independently selected from hydrogen and fluorine. In a further aspect, when present, R 4 and R 4′ In a further aspect, when present, R 4 and R 4′ Each is -OR 16 In a further aspect, when present, R 4 and R 4′ Each is hydrogen.

[0321] eR 10 Group

[0322] In one aspect, R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 In a further aspect, R 10 When present, it is selected from C1-C15 alkyl, C2-C15 alkenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present, it is selected from C1-C8 alkyl, C2-C8 alkenyl and -CH(NH2)R 20 In a still further aspect, R 10When present, it is selected from C1-C4 alkyl, C2-C4 alkenyl and -CH(NH2)R 20 In a further aspect, R 10 When present is selected from methyl, ethyl, isopropyl, n-propyl, vinyl, propenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from methyl, ethyl, isopropyl, vinyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from methyl and -CH(NH2)R 20 .

[0323] In a further aspect, R 10 When present, R is selected from C1-C30 alkyl and C2-C30 alkenyl. 10 When present, R is selected from C1-C15 alkyl and C2-C15 alkenyl. 10 When present, R is selected from C1-C8 alkyl and C2-C8 alkenyl. 10 When present, R is selected from C1-C4 alkyl and C2-C4 alkenyl. 10 When present, R is selected from methyl, ethyl, isopropyl, n-propyl, vinyl and isopropenyl. 10 When present it is selected from methyl, ethyl and vinyl.

[0324] In a further aspect, R 10 When present, it is selected from C1-C30 alkyl and -CH(NH2)R 20 In a still further aspect, R 10 When present, it is selected from C1-C15 alkyl and -CH(NH2)R 20 In a still further aspect, R 10 When present, it is selected from C1-C8 alkyl and -CH(NH2)R 20 In a further aspect, R 10 When present, it is selected from C1-C4 alkyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from methyl, ethyl, isopropyl, n-propyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from methyl, ethyl and -CH(NH2)R 20 In a further aspect, R 10 When present is selected from methyl and -CH(NH2)R 20.

[0325] In a further aspect, R 10 When present, it is selected from C2-C30 alkenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from C2-C15 alkenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from C2-C8 alkenyl and -CH(NH2)R 20 In a further aspect, R 10 When present is selected from C2-C4 alkenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from ethenyl, propenyl and -CH(NH2)R 20 In a still further aspect, R 10 When present is selected from vinyl and -CH(NH2)R 20 .

[0326] In a further aspect, R 10 When present, it is C1-C30 alkyl. In a further aspect, R 10 When present, it is C1-C15 alkyl. In a further aspect, R 10 When present, it is C1-C8 alkyl. In a further aspect, R 10 When present, it is C1-C4 alkyl. In a further aspect, R 10 When present, R is selected from methyl, ethyl, isopropyl and n-propyl. 10 When present, R is selected from methyl and ethyl. 10 When present, it is ethyl. In a further aspect, R 10 When present it is methyl.

[0327] In a further aspect, R 10 When present, it is C2-C30 alkenyl. In a further aspect, R 10 When present, it is C2-C15 alkenyl. In a further aspect, R 10 When present, it is C2-C8 alkenyl. In a further aspect, when R 10 When present, it is C2-C4 alkenyl. In a further aspect, R 10 When present, R is selected from ethenyl and propenyl. 10 When present, it is propenyl. In a further aspect, R 10 When present it is vinyl.

[0328] In a further aspect, R 10 When present it is -CH(NH2)R 20 .

[0329] f 11 Group

[0330] In one aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C8 alkyl)CO2(C1-C8 alkyl), -(C1-C8 alkoxy)CO2(C1-C8 alkyl), -(C1-C8 alkyl)CO2(C1-C8 alkylthio), -(C1-C8 alkyl)-SS-(C1-C8 alkyl), and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C4 alkyl)CO2(C1-C4 alkyl), -(C1-C4 alkoxy)CO2(C1-C4 alkyl), -(C1-C4 alkyl)CO2(C1-C4 alkylthio), -(C1-C4 alkyl)-SS-(C1-C4 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CO2CH2CH2CH3, -CH2CO2CH(CH3)2, -OCH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CO2CH2CH2CH3, -OCH2CO2CH(CH3)2, -CH2CO2CH2SH, -CH2CO2CH2CH2SH, -CH2CO2CH2CH2SH, -CH2CO2CH(CH3)CH2SH, -CH2-SS-CH3, -CH2-SS-CH2CH3, -CH2-SS-CH2CH2CH3, -CH2-SS-CH(CH3)2, and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -OCH2CO2CH3, -OCH2CO2CH2CH3, -CH2CO2CH2SH, -CH2CO2CH2CH2SH, -CH2-SS-CH3, -CH2-SS-CH2CH3, and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -OCH2CO2CH3, -CH2CO2CH2SH, -CH2-SS-CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH.

[0331] In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkyl)-SS-(C1-C10 alkyl) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C8 alkyl)CO2(C1-C8 alkyl), -(C1-C8 alkyl)-SS-(C1-C8 alkyl) and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C4 alkyl)CO2(C1-C4 alkyl), -(C1-C4 alkyl)-SS-(C1-C4 alkyl) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CO2CH2CH2CH3, -CH2CO2CH(CH3)2, -CH2-SS-CH3, -CH2-SS-CH2CH3, -CH2-SS-CH2CH2CH3, -CH2-SS-CH(CH3)2, and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2-SS-CH3, -CH2-SS-CH2CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2-SS-CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH.

[0332] In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C8 alkoxy)CO2(C1-C8 alkyl), -(C1-C8 alkyl)CO2(C1-C8 alkylthio) and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11Each occurrence of (when present) is independently selected from hydrogen, -(C1-C4 alkoxy)CO2(C1-C4 alkyl), -(C1-C4 alkyl)CO2(C1-C4 alkylthio) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -OCH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CO2CH2CH2CH3, -OCH2CO2CH(CH3)2, -CH2CO2CH2SH, -CH2CO2CH2CH2SH, -CH2CO2CH2CH2CH2SH, -CH2CO2CH(CH3)CH2SH, and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -OCH2CO2CH3, -OCH2CO2CH2CH3, -CH2CO2CH2SH, -CH2CO2CH2CH2SH and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -OCH2CO2CH3, -CH2CO2CH2SH and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH.

[0333] In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C8 alkyl)CO2(C1-C8 alkyl), -(C1-C8 alkoxy)CO2(C1-C8 alkyl) and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11Each occurrence of (when present) is independently selected from hydrogen, -(C1-C4 alkyl)CO2(C1-C4 alkyl), -(C1-C4 alkoxy)CO2(C1-C4 alkyl) and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CO2CH2CH2CH3, -CH2CO2CH(CH3)2, -OCH2CO2CH3, -OCH2CO2CH2CH3, -OCH2CO2CH2CH2CH3, -OCH2CO2CH(CH3)2, and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -CH2CO2CH2CH3, -OCH2CO2CH3, -OCH2CO2CH2CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH3, -OCH2CO2CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH.

[0334] In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl) and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C8 alkyl)CO2(C1-C8 alkylthio), -(C1-C8 alkyl)-SS-(C1-C8 alkyl) and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C4 alkyl)CO2(C1-C4 alkylthio), -(C1-C4 alkyl)-SS-(C1-C4 alkyl) and Ar2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH2SH, -CH2CO2CH2CH2SH, -CH2CO2CH2CH2CH2SH, -CH2CO2CH(CH3)CH2SH, -CH2-SS-CH3, -CH2-SS-CH2CH3, -CH2-SS-CH2CH2CH3, -CH2-SS-CH(CH3)2, and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH2SH, -CH2CO2CH2CH2SH, -CH2-SS-CH3, -CH2-SS-CH2CH3 and Ar 2 , wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -CH2CO2CH2SH, -CH2-SS-CH3 and Ar 2 , and wherein each alkyl group is substituted with 0, 1, 2 or 3 groups independently selected from halogen and -OH.

[0335] In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted with 0, 1 or 2 groups independently selected from halogen and -OH. In yet a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted with 0 or 1 group selected from halogen and -OH. In a further aspect, R 11Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is monosubstituted with a group selected from halogen and -OH. In a further aspect, R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is unsubstituted.

[0336] In a further aspect, R 11 Each occurrence of (when present) is hydrogen.

[0337] G JZ 12 Group

[0338] In one aspect, R 12 When present, R is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl, and -(CH2)aryl. 12 When present, R is selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylamino, -(C1-C4)C(O)NH2, aryl and -(CH2)aryl. 12 When present, R is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -CH2CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH(CH3)CH2NH2, -CH2CH2CH2NH2, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH(CH3)CH2C(O)NH2, -CH2CH2CH2C(O)NH2, aryl, and -(CH2)aryl. In yet a further aspect, R 12 When present, R is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2C(O)NH2, -CH2CH2C(O)NH2, aryl, and -(CH2)aryl.12 When present it is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, -CH2OH, -CH2NH2, -CH2C(O)NH2, aryl and -(CH2)aryl.

[0339] In a further aspect, R 12 When present, R is selected from hydrogen, aryl and -(CH2)aryl. In a further aspect, 12 When present, R is selected from hydrogen and aryl. 12 When present, R is selected from hydrogen and -(CH2)aryl. 12 When present, R is selected from aryl and -(CH2)aryl. 12 When present, it is aryl. In a further aspect, R 12 When present it is -(CH2)aryl.

[0340] In a further aspect, R 12 When present, is selected from hydrogen, phenyl and the structure In a further aspect, R 12 When present, R is selected from hydrogen and phenyl. 12 When present is selected from hydrogen and the structure In a further aspect, R 12 When present, is selected from the group consisting of phenyl and the structure In a further aspect, R 12 When present, it is phenyl. In a further aspect, R 12 When present, it is a structure

[0341] In a further aspect, R 12 When present, R is selected from hydrogen, C1-C8 hydroxyalkyl and C1-C8 alkylamino. 12 When present, R is selected from hydrogen, C1-C4 hydroxyalkyl and C1-C4 alkylamino. 12 When present, R is selected from hydrogen, -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -CH2CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH(CH3)CH2NH2, and -CH2CH2CH2NH2. In a further aspect, 12 When present, R is selected from hydrogen, -CH2OH, -CH2CH2OH, -CH2NH2 and -CH2CH2NH2. 12 When present, R is selected from hydrogen, -CH2OH and -CH2NH2.12 When present, R is selected from hydrogen, -CH2OH and -(CH2)4NH2. 12 When present, R is selected from hydrogen and -CH2OH. 12 When present, R is selected from hydrogen and -(CH2)4NH2. 12 When present, it is -CH2OH. In a further aspect, R 12 When present it is -(CH2)4NH2.

[0342] In a further aspect, R 12 When present, it is selected from hydrogen and -(C1-C8)C(O)NH2. In a further aspect, R 12 When present, R is selected from hydrogen and -(C1-C4)C(O)NH2. 12 When present, R is selected from hydrogen, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH(CH3)CH2C(O)NH2, and -CH2CH2CH2C(O)NH2. In a further aspect, R 12 When present, R is selected from hydrogen, -CH2C(O)NH2 and -CH2CH2C(O)NH2. 12 When present, R is selected from hydrogen and -CH2C(O)NH2. 12 When present, R is selected from hydrogen and -CH2CH2C(O)NH2. 12 When present it is -CH2CH2C(O)NH2.

[0343] In one aspect, R 12 When present, R is selected from hydrogen and C1-C8 alkyl. 12 When present, R is selected from hydrogen and C1-C4 alkyl. 12 When present, R is selected from hydrogen, methyl, ethyl, isopropyl and n-propyl. 12 When present, R is selected from hydrogen, methyl and ethyl. 12 When present, R is selected from hydrogen and ethyl. 12 When present is selected from hydrogen and methyl.

[0344] In a further aspect, R 12 When present, it is C1-C8 alkyl. In a further aspect, R 12 When present, R is selected from methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl and n-butyl.12 When present, R is selected from methyl, ethyl, isopropyl and n-propyl. 12 When present, R is selected from methyl and ethyl. 12 When present, it is ethyl. In a further aspect, R 12 When present it is methyl.

[0345] In a further aspect, R 12 When present it is hydrogen.

[0346] HkD 13 Group

[0347] In one aspect, R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 In a further aspect, R 13 When present, it is selected from C1-C8 alkyl, C3-C8 cycloalkyl and Ar 3 In a still further aspect, R 13 When present, it is selected from C1-C4 alkyl, C3-C6 cycloalkyl and Ar 3 In a still further aspect, R 13 When present, it is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Ar 3 .

[0348] In a further aspect, R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 In a further aspect, R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 .

[0349] In a further aspect, R 13 When present, R is selected from C1-C10 alkyl and C3-C10 cycloalkyl. 13 When present, R is selected from C1-C8 alkyl and C3-C8 cycloalkyl. 13 When present, R is selected from C1-C4 alkyl and C3-C6 cycloalkyl. 13 When present it is selected from methyl, ethyl, 2-ethylbutyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0350] In a further aspect, R 13 When present, it is selected from C3-C10 cycloalkyl and Ar 3In a still further aspect, R 13 When present, is selected from C3-C8 cycloalkyl and Ar 3 In a still further aspect, R 13 When present, it is selected from C3-C6 cycloalkyl and Ar 3 In a further aspect, R 13 When present, it is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Ar 3 .

[0351] In a further aspect, R 13 When present, it is C1-C10 alkyl. In a further aspect, R 13 When present, it is C1-C8 alkyl. In a further aspect, R 13 When present, it is C1-C4 alkyl. In a further aspect, R 13 When present, R is selected from 2-ethylbutyl, methyl, ethyl, isopropyl and n-propyl. 13 When present, R is selected from 2-ethylbutyl, methyl and ethyl. 13 When present, R is selected from 2-ethylbutyl and ethyl. 13 When present, R is selected from 2-ethylbutyl and methyl. 13 When present it is 2-ethylbutyl.

[0352] In a further aspect, R 13 When present, it is C3-C10 cycloalkyl. In a further aspect, R 13 When present, it is C3-C8 cycloalkyl. In a further aspect, R 13 When present, R is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 13 When present, R is selected from cyclopropyl, cyclobutyl and cyclopentyl. 13 When present, R is selected from cyclopropyl and cyclobutyl. 13 When present, it is cyclohexyl. In a further aspect, R 13 When present, it is cyclopentyl. In a further aspect, R 13 When present, it is cyclobutyl. In a further aspect, R 13 When present it is cyclopropyl.

[0353] In a further aspect, R 13 When present, it is Ar 3 .

[0354] In a further aspect, R 13When present, it is aryl substituted with 0 or 1 C1-C10 alkyl groups. In a further aspect, R 13 When present, it is aryl substituted with 0 or 1 C1-C8 alkyl groups. In a further aspect, R 13 When present, it is aryl substituted with 0 or 1 C1-C4 alkyl groups. In a further aspect, R 13 When present, it is aryl substituted with 0 or 1 groups selected from methyl, ethyl, isopropyl and n-propyl. In a further aspect, R 13 When present, it is aryl substituted with 0 or 1 groups selected from methyl and ethyl. In a further aspect, R 13 When present, it is aryl substituted with 0 or 1 ethyl groups. In a further aspect, R 13 When present it is aryl substituted with 0 or 1 methyl groups.

[0355] In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 C1-C10 alkyl groups. In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 C1-C8 alkyl groups. In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 C1-C4 alkyl groups. In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 groups selected from methyl, ethyl, isopropyl and n-propyl. In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 groups selected from methyl and ethyl. In a further aspect, R 13 When present, it is phenyl substituted with 0 or 1 ethyl groups. In a further aspect, R 13 When present it is phenyl substituted with 0 or 1 methyl groups.

[0356] i 14 Group

[0357] In one aspect, R 14 When present, it is C1-C8 alkyl. In a further aspect, R 14 When present, R is selected from methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl and n-butyl. 14 When present, R is selected from methyl, ethyl, isopropyl and n-propyl. 14 When present, R is selected from methyl and ethyl. 14 When present, it is ethyl. In a still further aspect, R 14 When present it is methyl.

[0358] JR 15 Group

[0359] In one aspect, R 15 When present, R is selected from C1-C10 alkyl, C3-C10 cycloalkyl, and aryl substituted with 0 or 1 C1-C10 alkyl groups. 15 When present, R is selected from C1-C8 alkyl, C3-C8 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups. 15 When present, R is selected from C1-C4 alkyl, C3-C6 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups. In a further aspect, 15 When present is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl substituted with 0 or 1 C1-C10 alkyl groups.

[0360] In a further aspect, R 15 When present, R is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl monosubstituted with a C1-C10 alkyl group. 15 When present it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and unsubstituted aryl.

[0361] In a further aspect, R 15 When present, R is selected from C1-C10 alkyl and C3-C10 cycloalkyl. 15 When present, R is selected from C1-C8 alkyl and C3-C8 cycloalkyl. 15 When present, R is selected from C1-C4 alkyl and C3-C6 cycloalkyl. 15 When present it is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0362] In a further aspect, R 15 When present, R is selected from C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups. 15 When present, R is selected from C3-C8 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups. 15 When present, R is selected from C3-C6 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups. 15When present is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and aryl substituted with 0 or 1 C1-C10 alkyl groups.

[0363] In a further aspect, R 15 When present, it is C1-C10 alkyl. In a further aspect, R 15 When present, it is C1-C8 alkyl. In a further aspect, R 15 When present, it is C1-C4 alkyl. In a further aspect, R 15 When present, R is selected from methyl, ethyl, isopropyl and n-propyl. 15 When present, R is selected from methyl and ethyl. 15 When present, it is ethyl. In a further aspect, R 15 When present it is methyl.

[0364] In a further aspect, R 15 When present, it is C3-C10 cycloalkyl. In a further aspect, R 15 When present, it is C3-C8 cycloalkyl. In a further aspect, R 15 When present, R is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 15 When present, R is selected from cyclopropyl, cyclobutyl and cyclopentyl. 15 When present, R is selected from cyclopropyl and cyclobutyl. 15 When present, it is cyclohexyl. In a further aspect, R 15 When present, it is cyclopentyl. In a further aspect, R 15 When present, it is cyclobutyl. In a further aspect, R 15 When present it is cyclopropyl.

[0365] In a further aspect, R 15 When present, it is aryl substituted with 0 or 1 C1-C10 alkyl groups. In a further aspect, R 15 When present, it is aryl substituted with 0 or 1 C1-C8 alkyl groups. In a further aspect, R 15 When present, it is aryl substituted with 0 or 1 C1-C4 alkyl groups. In a further aspect, R 15 When present, it is aryl substituted with 0 or 1 groups selected from methyl, ethyl, isopropyl and n-propyl. In a further aspect, R 15 When present, it is aryl substituted with 0 or 1 groups selected from methyl and ethyl. In a further aspect, R 15When present, it is aryl substituted with 0 or 1 ethyl groups. In a further aspect, R 15 When present it is aryl substituted with 0 or 1 methyl groups.

[0366] In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 C1-C10 alkyl groups. In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 C1-C8 alkyl groups. In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 C1-C4 alkyl groups. In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 groups selected from methyl, ethyl, isopropyl and n-propyl. In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 groups selected from methyl and ethyl. In a further aspect, R 15 When present, it is phenyl substituted with 0 or 1 ethyl groups. In a further aspect, R 15 When present it is phenyl substituted with 0 or 1 methyl groups.

[0367] k 16 Group

[0368] In one aspect, R 16 When present is selected from hydrogen, methyl and -C(O)R 10 In a further aspect, R 16 When present, R is selected from hydrogen and methyl. 16 When present is selected from hydrogen and -C(O)R 10 .

[0369] In a further aspect, R 16 When present, is selected from hydrogen, methyl, -C(O)R 10 And the structure represented by the following formula:

[0370]

[0371] In a further aspect, R 16 When present, it is selected from hydrogen and structures represented by the formula:

[0372]

[0373] In a further aspect, R 16 When present is selected from hydrogen and -C(O)R 10 In a further aspect, R 16 When present, it is a structure represented by the formula:

[0374]

[0375] In a further aspect, R 16 When present it is -C(O)R 10 .

[0376] In a further aspect, R 16 When present, is selected from hydrogen, -P(O)(OR 11 )2 and a structure represented by the following formula:

[0377]

[0378] In a further aspect, R 16 When present, is selected from hydrogen and -P(O)(OR 11 ) 2. In a further aspect, R 16 When present it is -P(O)(OR 11 )2.

[0379] In a further aspect, R 16 When present, selected from -C(O)R 10 、-P(O)(OR 11 )2 and a structure represented by the following formula:

[0380]

[0381] In a further aspect, R 16 When present, selected from -C(O)R 10 And the structure represented by the following formula:

[0382]

[0383] In a further aspect, R 16 When present, selected from -C(O)R 10 AND-P(O)(OR 11 )2.

[0384] In a further aspect, R 16 When present, R is selected from hydrogen and methyl. 16 When present, it is methyl. In a further aspect, R 16 When present it is hydrogen.

[0385] oeLh 20 Group

[0386] In one aspect, R 20When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 In a further aspect, R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2C6H5 and -CH2Cy 1 In a still further aspect, R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2C6H5 and -CH2Cy 1 .

[0387] In a further aspect, R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -CH2C6H5 and -CH2Cy 1 In a still further aspect, R 20 When present, it is selected from hydrogen, methyl, isopropyl, -CH2C6H5 and -CH2Cy 1 In a still further aspect, R 20 When present, it is selected from hydrogen, methyl, -CH2C6H5 and -CH2Cy 1 In a further aspect, R 20 When present, it is selected from hydrogen, -CH2C6H5 and -CH2Cy 1 In a still further aspect, R 20 When present, R is selected from hydrogen and -CH2C6H5. 20 When present, it is selected from hydrogen and -CH2Cy 1 .

[0388] In a further aspect, R 20When present, R is selected from methyl, isopropyl, isobutyl and sec-butyl. 20 When present, R is selected from methyl and isopropyl. 20 When present, it is sec-butyl. In a further aspect, R 20 When present, it is isobutyl. In a further aspect, R 20 When present, it is isopropyl. In a further aspect, R 20 When present it is methyl.

[0389] In a further aspect, R 20 When present, it is selected from -CH2C6H5 and -CH2Cy 1 In a still further aspect, R 20 When present, it is -CH2C6H5. In a further aspect, R 20 When present it is -CH2Cy 1 .

[0390] In a further aspect, R 20 When present, R is selected from hydrogen, -(CH2)3NHC(NH)NH2 and -(CH2)4NH2. 20 When present, R is selected from hydrogen and -(CH2)3NHC(NH)NH2. 20 When present, R is selected from hydrogen and -(CH2)4NH2. 20 When present, it is -(CH2)3NHC(NH)NH2. In a further aspect, R 20 When present it is -(CH2)4NH2.

[0391] In a further aspect, R 20 When present, R is selected from hydrogen, -CH2CO2H, -(CH2)2CO2H, -CH2C(O)NH2, and -(CH2)2C(O)NH2. In yet a further aspect, 20 When present, R is selected from hydrogen, -CH2CO2H and -(CH2)2CO2H. 20 When present, R is selected from hydrogen, -CH2C(O)NH2 and -(CH2)2C(O)NH2. 20 When present, R is selected from hydrogen and -CH2CO2H. 20 When present, R is selected from hydrogen and -(CH2)2CO2H. 20 When present, R is selected from hydrogen and -CH2C(O)NH2. 20When present, R is selected from hydrogen and -(CH2)2C(O)NH2. 20 When present, it is -CH2CO2H. In a further aspect, R 20 When present, it is -(CH2)2CO2H. In a further aspect, R 20 When present, it is -CH2C(O)NH2. In a further aspect, R 20 When present it is -(CH2)2C(O)NH2.

[0392] In a further aspect, R 20 When present, R is selected from hydrogen, -CH2OH, -CH(OH)CH3, -CH2SH, -(CH2)2SCH3, and -CH2SeH. 20 When present, R is selected from hydrogen, -CH2OH and -CH(OH)CH3. 20 When present, R is selected from hydrogen, -CH2SH and -(CH2)2SCH3. 20 When present, R is selected from hydrogen and -CH2SeH. 20 When present, it is selected from -CH2OH and -CH(OH)CH3. In a further aspect, R 20 When present, it is selected from -CH2SH and -(CH2)2SCH3. In a further aspect, R 20 When present, it is -CH2SeH. In a further aspect, R 20 When present, it is -CH2OH. In a further aspect, R 20 When present, it is -CH(OH)CH3. In a further aspect, R 20 When present, it is -CH2SH. In a further aspect, R 20 When present it is -(CH2)2SCH3.

[0393] In a further aspect, R 20 When present it is hydrogen.

[0394] mxD 30 Group

[0395] In one aspect, R 30 When present is a structure selected from the following:

[0396]

[0397] In a further aspect, R 30 When present it is:

[0398]

[0399] In a further aspect, R 30 When present it is:

[0400]

[0401] nR 31 Group

[0402] In one aspect, R 31 When present, R is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl). 31 When present, R is selected from hydrogen, -C(O)(C1-C15 alkyl) and -C(O)(C2-C15 alkenyl). 31 When present, R is selected from hydrogen, -C(O)(C1-C8 alkyl) and -C(O)(C2-C8 alkenyl). 31 When present, R is selected from hydrogen, fluorine, -C(O)(C1-C4 alkyl) and -C(O)(C2-C4 alkenyl). 31 When present, R is selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3, and -C(O)CH2CH=CH2. In yet a further aspect, R 31 When present it is selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3 and -C(O)CH=CH2.

[0403] In a further aspect, R 31 When present, R is selected from hydrogen and -C(O)(C1-C30 alkyl). 31 When present, R is selected from hydrogen and -C(O)(C1-C15 alkyl). 31 When present, R is selected from hydrogen and -C(O)(C1-C8 alkyl). 31 When present, R is selected from hydrogen and -C(O)(C1-C4 alkyl). 31 When present, R is selected from hydrogen, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, and -C(O)CH2CH2CH3. 31When present, R is selected from hydrogen, -C(O)CH3 and -C(O)CH2CH3. 31 When present, R is selected from hydrogen and -C(O)CH2CH3. 31 When present is selected from hydrogen and -C(O)CH3.

[0404] In a further aspect, R 31 When present, R is selected from hydrogen and -C(O)(C2-C30 alkenyl). 31 When present, R is selected from hydrogen and -C(O)(C2-C15alkenyl). 31 When present, R is selected from hydrogen and -C(O)(C2-C8alkenyl). 31 When present, R is selected from hydrogen and -C(O)(C2-C4alkenyl). 31 When present, R is selected from hydrogen, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In yet a further aspect, R 31 When present is selected from hydrogen and -C(O)CH=CH2.

[0405] In a further aspect, R 31 When present, it is selected from -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl). In a further aspect, R 31 When present, it is selected from -C(O)(C1-C15 alkyl) and -C(O)(C2-C15 alkenyl). In a further aspect, R 31 When present, it is selected from -C(O)(C1-C8 alkyl) and -C(O)(C2-C8 alkenyl). In a further aspect, R 31 When present, it is selected from -C(O)(C1-C4 alkyl) and -C(O)(C2-C4 alkenyl). In a further aspect, R 31 When present, it is selected from -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH2CH3, -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In a further aspect, R 31 When present is selected from -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2 and -C(O)CH=CH2.

[0406] In a further aspect, R 31When present, it is -C(O)(C1-C30 alkyl). In a further aspect, R 31 When present, it is -C(O)(C1-C15 alkyl). In a further aspect, R 31 When present, it is -C(O)(C1-C8 alkyl). In a further aspect, R 31 When present, it is -C(O)(C1-C4 alkyl). In a further aspect, R 31 When present, it is selected from -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2 and -C(O)CH2CH2CH3. In a further aspect, R 31 When present, it is selected from -C(O)CH3 and -C(O)CH2CH3. In a further aspect, R 31 When present, it is -C(O)CH2CH3. In a further aspect, R 31 When present it is -C(O)CH3.

[0407] In a further aspect, R 31 When present, it is -C(O)(C2-C30 alkenyl). In yet a further aspect, R 31 When present, it is -C(O)(C2-C15alkenyl). In a further aspect, R 31 When present, it is -C(O)(C2-C8alkenyl). In a further aspect, R 31 When present, it is -C(O)(C2-C4alkenyl). In a further aspect, R 31 When present, it is selected from -C(O)CH=CH2, -C(O)C(CH3)=CH2, -C(O)CH=CHCH3 and -C(O)CH2CH=CH2. In a further aspect, R 31 When present it is -C(O)CH=CH2.

[0408] In a further aspect, R 31 When present it is hydrogen.

[0409] o.CY 1 Group

[0410] In one aspect, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl. In a further aspect, Cy 1 When present, it is selected from monocyclic aromatic groups and para-hydroxy monocyclic aromatic groups. In a further aspect, Cy 1 When present, it is selected from 4-imidazolyl and 3-indolyl. In a further aspect, Cy 1When present, it is selected from monocyclic aryl and 4-imidazolyl. In a further aspect, Cy 1 When present is selected from p-hydroxy monocyclic aryl and 3-indolyl.

[0411] In a further aspect, Cy 1 When present, it is a monocyclic aryl group. In a further aspect, Cy 1 When present it is a monocyclic aromatic radical to the hydroxyl radical.

[0412] In a further aspect, Cy 1 When present, it is 4-imidazolyl. In a further aspect, Cy 1 When present it is 3-indolyl.

[0413] p.AR 1 Group

[0414] In one aspect, Ar 1 When present, Ar is selected from aryl and heteroaryl, and is substituted by 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. 1 When present, Ar is selected from aryl and heteroaryl, and is substituted by 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, Ar is selected from aryl and heteroaryl, and is substituted by 0 or 1 group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyl, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, Ar is selected from aryl and heteroaryl, and is monosubstituted with a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 When present is selected from aryl and heteroaryl, and is unsubstituted.

[0415] In a further aspect, Ar 1 When present, Ar is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, Ar is aryl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is aryl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is an aryl group that is monosubstituted with a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present it is unsubstituted aryl.

[0416] In a further aspect, Ar 1 When present, Ar is phenyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is phenyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1When present, it is phenyl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is phenyl monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present it is unsubstituted phenyl.

[0417] In a further aspect, Ar 1 When present, it is naphthyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is naphthyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is naphthyl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is a naphthyl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present it is unsubstituted naphthyl.

[0418] In a further aspect, Ar 1When present, Ar is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, Ar is substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, Ar is substituted with 0 or 1 group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is a heteroaryl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present it is unsubstituted heteroaryl.

[0419] In a further aspect, Ar 1 When present, it is pyridyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is pyridyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1When present, it is pyridyl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present, it is a pyridyl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 1 When present it is unsubstituted pyridyl.

[0420] q.Ar 2 Group

[0421] In one aspect, Ar 2 When present, Ar is selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. 2 When present is selected from aryl and heteroaryl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present is selected from aryl and heteroaryl substituted with 1 group selected from C1-C10 alkyl and nitro.

[0422] In a further aspect, Ar 2 When present, it is aryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present, it is aryl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present it is aryl substituted with 1 group selected from C1-C10 alkyl and nitro.

[0423] In a further aspect, Ar 2 When present, is phenyl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present, it is phenyl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present it is phenyl substituted with one group selected from C1-C10 alkyl and nitro.

[0424] In a further aspect, Ar 2When present, it is naphthyl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present, it is naphthyl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present it is naphthyl substituted with 1 group selected from C1-C10 alkyl and nitro.

[0425] In a further aspect, Ar 2 When present, is heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. In yet a further aspect, Ar 2 When present, is heteroaryl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In yet a further aspect, Ar 2 When present is heteroaryl substituted with 1 group selected from C1-C10 alkyl and nitro.

[0426] In a further aspect, Ar 2 When present, it is pyridyl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present, it is pyridyl substituted with 2 groups independently selected from C1-C10 alkyl and nitro. In a further aspect, Ar 2 When present it is pyridyl substituted with 1 group selected from C1-C10 alkyl and nitro.

[0427] r.AR 3 Group

[0428] In one aspect, Ar 3 When present, Ar is selected from aryl and heteroaryl, and is substituted by 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. 3 When present, Ar is selected from aryl and heteroaryl, and is substituted by 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3When present, Ar is selected from aryl and heteroaryl, and is substituted with 0 or 1 group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, Ar is selected from aryl and heteroaryl, and is monosubstituted with a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present is selected from aryl and heteroaryl, and is unsubstituted.

[0429] In a further aspect, Ar 3 When present, Ar is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is aryl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is aryl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is aryl monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted aryl.

[0430] In a further aspect, Ar 3 When present, Ar is phenyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, Ar is phenyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is phenyl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is phenyl monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted phenyl.

[0431] In a further aspect, Ar 3 When present, it is naphthyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is naphthyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3When present, it is naphthyl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is a naphthyl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted naphthyl.

[0432] In a further aspect, Ar 3 When present, Ar is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, Ar is substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is heteroaryl substituted with 0 or 1 groups selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is a heteroaryl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted heteroaryl.

[0433] In a further aspect, Ar 3When present, it is pyridyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is pyridyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is pyridyl substituted with 0 or 1 group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is a pyridyl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted pyridyl.

[0434] In a further aspect, Ar 3 When present, it is furanyl substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is furanyl substituted with 0, 1 or 2 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3When present, it is furanyl substituted with 0 or 1 group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present, it is a furanyl group monosubstituted by a group selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C10 alkylamino and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Ar 3 When present it is unsubstituted furanyl.

[0435] 2. Exemplary compounds

[0436] In one aspect, the compound may exist as one or more of the following structures:

[0437]

[0438]

[0439]

[0440] or a pharmaceutically acceptable salt thereof.

[0441] 3. Examples of predictive compounds

[0442] The following examples of compounds are predictive and can be prepared using the synthetic methods described herein above and other desired generalized methods that will be known to those skilled in the art. It is expected that the predictive compounds will be useful in treating disorders of uncontrolled cell proliferation, such as, for example, cancer, and such utility can be determined using the assay methods described herein below.

[0443] In one aspect, the compound can be selected from:

[0444]

[0445]

[0446] In one aspect, the compound can be:

[0447]

[0448] In one aspect, the compound can be selected from:

[0449]

[0450] In one aspect, the compound can be selected from:

[0451]

[0452]

[0453] In one aspect, the compound can be selected from:

[0454]

[0455] In one aspect, the compound can be selected from:

[0456]

[0457]

[0458]

[0459] In one aspect, the compound can be selected from:

[0460]

[0461]

[0462] In one aspect, the compound can be:

[0463]

[0464] In one aspect, the compound can be selected from:

[0465]

[0466] In one aspect, the compound can be selected from:

[0467]

[0468] In one aspect, the compound can be selected from:

[0469]

[0470]

[0471] It is contemplated that one or more compounds may optionally be omitted from the disclosed invention.

[0472] It is to be understood that the disclosed compounds can be used in conjunction with the disclosed methods, compositions, kits and uses.

[0473] It should be understood that pharmaceutically acceptable derivatives of the disclosed compounds may also be used in conjunction with the disclosed methods, compositions, kits and uses. Pharmaceutically acceptable derivatives of the compounds may include any suitable derivatives, such as pharmaceutically acceptable salts, isomers, radiolabeled analogs, tautomers, etc., as discussed below.

[0474] C. Pharmaceutical Compositions

[0475] In one aspect, disclosed is a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0476] In one aspect, a pharmaceutical composition comprising an effective amount of at least one compound or a pharmaceutically acceptable salt thereof is disclosed, wherein the compound has a structure represented by a formula selected from the group consisting of:

[0477]

[0478] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0479]

[0480] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3 When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0481]

[0482] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0483]

[0484] Where R 14 When present, it is C1-C8 alkyl; wherein R 15When present, R is selected from C1-C10 alkyl, C3-C10 cycloalkyl, and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R3 is selected from hydrogen, -C(O)(C1-C30 alkyl), and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′ are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R 16 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0485] In various aspects, the compounds and compositions of the present invention can be administered in the form of a pharmaceutical composition, which is formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, the pharmaceutical composition can be formulated for local or systemic administration, such as by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical or oral administration.

[0486] The properties of the pharmaceutical composition for administration depend on the mode of administration and can be easily determined by a person of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic composition described in the present invention may contain a carrier or excipient, many of which are known to the technician. The excipients that can be used include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohol, ascorbic acid, phospholipids, polypeptides (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other regulatory compounds described in the present invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. According to the corresponding route of administration, the regulatory compound can be formulated in various ways. For example, a liquid solution can be prepared for administration by dripping into the ear, for injection, or for ingestion; a gel or powder can be prepared for ingestion or topical application. Methods for the preparation of such formulations are well known and can be found, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0487] In various aspects, the disclosed pharmaceutical composition includes the disclosed compound (including its pharmaceutically acceptable salt) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The composition of the present invention includes compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the administration of the active ingredient. The pharmaceutical composition can be conveniently provided in unit dosage form and prepared by any method known to the pharmaceutical field.

[0488] In various aspects, the pharmaceutical composition of the present invention can include a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt of the compound of the present invention. The compound of the present invention or its pharmaceutically acceptable salt can also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0489] The pharmaceutical carrier used can be, for example, solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0490] In preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc. may be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. may be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units due to their ease of administration, and therefore solid pharmaceutical carriers are used. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0491] Tablets containing compositions of the present invention can be prepared by compression or molding, optionally using one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient such as powder or granules in a free-flowing form in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be prepared by molding in a suitable machine, which is a mixture of powdered compounds moistened with an inert liquid diluent.

[0492] The pharmaceutical composition of the present invention includes a compound of the present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally one or more other therapeutic agents or adjuvants. The composition of the present invention includes compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the administration of the active ingredient. The pharmaceutical composition can be conveniently provided in unit dosage form and prepared by any method known to the pharmaceutical field.

[0493] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. Suitable surfactants can be included, such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0494] The pharmaceutical composition of the present invention suitable for injection comprises a sterile aqueous solution or dispersion. In addition, the composition can be a sterile powder form for the temporary preparation of such a sterile injectable solution or dispersion. In all cases, the final injectable form must be sterile and must be effectively fluid for injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it should preferably be preserved to resist the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0495] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwash, gargle, etc. In addition, the composition can be in a form suitable for transdermal devices. These preparations can be prepared by conventional processing methods using the compounds of the present invention or their pharmaceutically acceptable salts. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water and about 5% to about 10% by weight of the compound to prepare a cream or ointment with a desired consistency.

[0496] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or molten carrier, then cooling and molding in a mold.

[0497] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also appropriately include one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants) etc. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compounds of the present invention and / or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

[0498] In a further aspect, the effective amount is a therapeutically effective amount.In a still further aspect, the effective amount is a prophylactically effective amount.

[0499] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0500] In a further aspect, the pharmaceutical composition is used to treat a disorder of uncontrolled cell proliferation, such as, for example, cancer, including but not limited to sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).

[0501] It is to be understood that the disclosed compositions can be prepared from the disclosed compounds. It is also to be understood that the disclosed compositions can be used in the disclosed methods of use.

[0502] D. Methods of preparing compounds

[0503] In addition to other standard operations known in the literature, illustrated in the experimental section, or apparent to those skilled in the art, the compounds of the present invention can be prepared by employing the reactions shown in the following schemes. For clarity, examples with a single substituent are shown, where multiple substituents are allowed under the definitions disclosed herein.

[0504] The reaction for generating the compound of the present invention is prepared by adopting the reaction as shown in the following reaction scheme, as described below and illustrated. In some specific examples, the disclosed compound can be prepared by the route I-VIII as described below and illustrated. The following examples are provided so that the present invention will be more fully understood, and these examples are only illustrative and should not be construed as restrictive.

[0505] 1. Route I

[0506] In one aspect, 4'-thio-nucleotide prodrug analogs can be prepared as follows.

[0507] Scheme 1A

[0508]

[0509] The compounds are represented in a general form where LG is a leaving group and has other substituents as indicated in the description of the compound elsewhere herein. More specific examples are set forth below.

[0510] Option 1B

[0511]

[0512] In one aspect, compounds of type 1.14 and similar compounds can be prepared according to reaction scheme 1B above. Thus, compounds of type 1.10 can be prepared by alkylation of a suitable carboxylic acid, such as 1.8 as shown above. Suitable carboxylic acids are commercially available or prepared by methods known to those skilled in the art. The alkylation reaction is carried out in the presence of a suitable alcohol (e.g., 1.9 as shown above) and a suitable activating agent (e.g., trimethylsilyl chloride as shown above) in a suitable solvent (e.g., dichloromethane). Compounds of type 1.12 can be prepared by phosphorylation between a suitable amine (e.g., 1.10 as shown above) and a suitable halophosphate (e.g., 1.11 as shown above). Suitable halophosphates are commercially available or prepared by methods known to those skilled in the art. The phosphorylation is carried out in the presence of a suitable base (e.g., triethylamine) in a suitable solvent (e.g., dichloromethane) at a suitable temperature (e.g., -70°C) for a suitable time, such as 1 hour. Compounds of type 1.14 can be prepared by substitution reaction of an appropriate electrophile (e.g., 1.12 as shown above). The substitution reaction is carried out in the presence of an appropriate nucleophile (e.g., 1.13 as shown above) and an appropriate base (e.g., triethylamine) in an appropriate solvent (e.g., dichloromethane), followed by trituration in an appropriate solvent system (e.g., hexane:ethyl acetate). As will be appreciated by one skilled in the art, the above reaction provides an example of a generalized method in which compounds structurally similar to the above specific reactants (compounds similar to compounds of types 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6) can be substituted in the reaction to provide analogs similar to formula 1.7.

[0513] 2. Route II

[0514] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0515] Option 2A

[0516]

[0517] The compounds are represented in a general form where LG is a leaving group and has other substituents as indicated in the description of the compound elsewhere herein. More specific examples are set forth below.

[0518] Option 2B

[0519]

[0520] In one aspect, compounds of type 2.5 and similar compounds can be prepared according to the above reaction scheme 2B. Thus, compounds of type 2.5 can be prepared by substitution reactions of a suitable nucleophile (e.g., 2.4 as shown above) and a suitable electrophile (e.g., 1.14 as shown above). Suitable nucleophiles are commercially available or prepared by methods known to those skilled in the art. The substitution reaction is carried out in the presence of a suitable Lewis acid (e.g., Al(Me)2Cl) and a suitable base (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)) in a suitable solvent (e.g., pyridine) for a suitable time, such as three days. As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized method in which compounds structurally similar to the above specific reactants (compounds similar to compounds of types 2.1a, 2.1b, and 2.2) can be substituted in the reaction to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formulas 2.3a and 2.3b.

[0521] 3. Route III

[0522] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0523] Option 3A.

[0524]

[0525] The compounds are represented in a general form where PG is a hydroxy protecting group, LG is a leaving group, and R is N or -CH, and have other substituents as indicated in the description of the compounds elsewhere herein. More specific examples are set forth below.

[0526] Option 3B

[0527]

[0528] In one aspect, compounds of type 3.12 and similar compounds can be prepared according to the above reaction scheme 3B. Thus, compounds of type 3.9 can be prepared by protecting a suitable alcohol (e.g., 3.7 as shown above) with a suitable hydroxyl protecting group reagent (e.g., 3.8 as shown above). Suitable hydroxyl protecting group reagents are commercially available or prepared by methods known to those skilled in the art. Protection is carried out in a suitable solvent such as pyridine in the presence of a suitable base such as 4-dimethylaminopyridine. Compounds of type 3.11 can be prepared by substitution reactions of a suitable nucleophile (e.g., 3.9 as shown above) and a suitable electrophile (e.g., 3.10 as shown above). Suitable nucleophiles are commercially available or prepared by methods known to those skilled in the art. The substitution reaction is carried out in a suitable solvent (e.g., pyridine) in the presence of a suitable Lewis acid (e.g., Al(Me)2Cl) and a suitable base (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)) for a suitable time, such as three days. Compounds of type 3.12 can be prepared by deprotecting an appropriate protected alcohol (e.g., 3.11 as shown above). The deprotection is carried out in the presence of a suitable deprotecting agent (e.g., trifluoroacetic acid as described above) in a suitable solvent (e.g., dichloromethane as shown above). As will be appreciated by one skilled in the art, the above reaction provides an example of a generalized method in which compounds structurally similar to the above specific reactants (similar to types 3.1, 3.2,

[0529] Compounds of formula 3.3, 3.4, and 3.5) can be substituted in the reaction to provide 4'-thio-nucleotide and -nucleoside prodrug analogs similar to formula 3.6.

[0530] 4. Route IV

[0531] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0532] Option 4A

[0533]

[0534] The compounds are represented in a general form where PG is a hydroxy protecting group and R is N or -CH, and have other substituents as indicated in the description of the compounds elsewhere herein. More specific examples are set forth below.

[0535] Option 4B

[0536]

[0537] In one aspect, compounds of type 4.11 and similar compounds can be prepared according to the above reaction scheme 4B. Thus, compounds of type 4.8 can be prepared by protecting an appropriate alcohol (e.g., 4.6 as shown above). Suitable alcohols are commercially available or prepared by methods known to those skilled in the art. Protection is carried out in the presence of a suitable alcohol protecting group reagent such as trimethylsilyl chloride. Compounds of type 4.10 can be prepared by alkylation or acylation of an appropriate amine (e.g., 4.8 as shown above). Alkylation or acylation is carried out in the presence of an appropriate alkylating agent or acylating agent (e.g., 4.9 as shown above) and an appropriate base (e.g., N,N-diisopropylethylamine as shown above) in an appropriate solvent (e.g., dichloromethane as shown above). Compounds of type 4.11 can be prepared by deprotecting an appropriate protected alcohol (e.g., 4.10 as shown above). Deprotection is carried out in the presence of a suitable deprotecting agent (e.g., tetrabutylammonium fluoride as shown above). As will be appreciated by those skilled in the art, the above reactions provide an example of a generalized method in which compounds structurally similar to the specific reactants described above (compounds similar to compounds of types 3.2, 4.1, 4.2, 4.3 and 4.4) can be substituted in the reactions to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 4.5.

[0538] 5. Route V

[0539] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0540] Option 5A.

[0541]

[0542] The compounds are represented in a general form where R is N or -CH, and have other substituents as indicated in the description of the compounds elsewhere herein. More specific examples are set forth below.

[0543] Option 5B.

[0544]

[0545] In one aspect, compounds of type 5.6 and similar compounds can be prepared according to the above reaction scheme 5B. Thus, compounds of type 5.6 can be prepared by substitution reactions of a suitable dinucleophile (e.g., 5.4 as shown above) and a suitable dielectrophile (e.g., 5.5 as shown above). Suitable dinucleophiles and suitable dielectrophiles are commercially available or prepared by methods known to those skilled in the art. The substitution reaction is carried out in the presence of a suitable base (e.g., 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU)) in a suitable solvent system (e.g., dichloromethane / tetrahydrofuran / acetonitrile). As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized method in which compounds structurally similar to the above specific reactants (compounds similar to compounds of types 5.1 and 5.2) can be substituted in the reaction to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 3.1.

[0546] 6. Route VI

[0547] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0548] Scheme 6A.

[0549]

[0550] Compounds are represented in the general form where R is C or N, R 2 is P(O)(OH)OP(O)(OH)OP(O)(OH)2, and has other substituents as indicated in the description of the compound elsewhere herein. More specific examples are set forth below.

[0551] Option 6B

[0552]

[0553] In one aspect, compounds of type 6.4 and similar compounds can be prepared according to the above reaction scheme 6B. Thus, as shown above, compounds of type 6.3 can be prepared by substitution reaction with 2-chloro-4H-benzo[d][1,3,2]dioxaphosphinane-4-one. The substitution reaction is carried out in the presence of a suitable oxidant (e.g., pyrophosphoric acid, ammonium salts) in a suitable solvent such as dimethylformamide for a suitable time, such as 30 minutes. The substitution reaction is followed by hydrolysis using, for example, iodine in pyridine and water. As will be appreciated by those skilled in the art, the above reactions provide examples of generalized methods, where compounds structurally similar to the above specific reactants (compounds similar to compounds of type 6.1a and 6.1b) can be substituted in the reaction to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 6.2a and 6.2b.

[0554] 7. Route VII

[0555] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0556] Scheme 7A.

[0557]

[0558] Compounds are expressed in generic form, where PG 1 is an amine protecting group, PG 2 and PG 3 Each is independently an alcohol protecting group, R is CH or N, and has other substituents as indicated in the description of the compounds elsewhere herein. More specific examples are set forth below.

[0559] Scheme 7B

[0560]

[0561] In one aspect, compounds of type 7.6 and similar compounds can be prepared according to the above reaction scheme 7B. Thus, compounds of type 7.8 can be prepared by protecting an appropriate amine (e.g., 7.7 as shown above). Protection is performed by first protecting the primary alcohol using an appropriate alcohol protecting agent (e.g., 1,3-chloro-1,1,3,3-tetraisopropyl-1,3-disiloxane) and an appropriate base (e.g., pyridine), followed by protecting the amine using an appropriate amine protecting agent (e.g., acetyl chloride) and an appropriate base (e.g., N,N-diisopropylethylamine) in a suitable solvent (e.g., dichloromethane). The alcohol protecting group is then removed using an appropriate deprotecting agent such as fluorinated tetra-n-butylammonium fluoride (TBAF) in the presence of a suitable solvent such as tetrahydrofuran (THF). Compounds of type 7.9 can be prepared by protection of an appropriate alcohol (e.g., 7.8 as shown above). Protection is carried out in the presence of a suitable protecting agent (e.g., 4,4′-dimethoxytrityl chloride) and a suitable base (e.g., pyridine). Compounds of type 7.10 can be prepared by phosphorylation of a suitable secondary alcohol (e.g., 7.9 as shown above). The reaction is carried out in the presence of a suitable phosphorylating agent (e.g., 1-chloro-N,N-diisopropyl-1-methoxyphosphine) and a suitable base (e.g., 1H-tetrazole). Compounds of type 7.12 can be prepared by oxidation of a suitable phosphite (e.g., 7.10 as shown above). The oxidation reaction is carried out in the presence of a suitable nucleoside (e.g., 7.11 as shown above), a suitable electrophile (e.g., iodine) and a suitable base (e.g., 2,6-lutidine). The oxidation is followed by deprotection of the alcohol using a suitable acid (e.g., trichloroacetic acid in dichloromethane) and deprotection of the amine using a suitable base (e.g., ammonium hydroxide). As will be appreciated by those skilled in the art, the above reactions provide examples of generalized methods in which compounds structurally similar to the specific reactants described above (compounds similar to compounds of types 7.1, 7.2, 7.3, 7.4, 7.5, and 7.6) can be substituted in the reactions to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 7.7.

[0562] 8. Route VIII

[0563] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0564] Scheme 8A.

[0565]

[0566] Compounds are represented in the general form where R is N or CH, PG 1 is an alcohol protecting group, PG 2is an amine protecting group, and has other substituents as indicated in the description of the compound elsewhere herein. More specific examples are set forth below.

[0567] Scheme 8B

[0568]

[0569] In one aspect, compounds of type 8.4 and similar compounds can be prepared according to the above reaction scheme 8B. Thus, compounds of type 8.6 can be prepared by phosphorylation of an appropriate secondary alcohol (e.g., 8.5 as shown above). For phosphorylation, the primary alcohol can first be protected using a suitable alcohol protecting agent (e.g., 1,3-chloro-1,1,3,3-tetraisopropyl-1,3-disiloxane) and a suitable base (e.g., pyridine), followed by protection of the free amine on the base using a suitable amine protecting agent (e.g., acetyl chloride) and a suitable base (e.g., N,N-diisopropylethylamine) in a suitable solvent (e.g., dichloromethane). The alcohol protecting group is then removed using a suitable deprotecting agent such as tetra-n-butylammonium fluoride (TBAF) in the presence of a suitable solvent such as tetrahydrofuran (THF). Next, the primary alcohol is protected using a suitable protecting agent (e.g., 4,4′-dimethoxytrityl chloride) and a suitable base (e.g., pyridine). Finally, the phosphorylation reaction is carried out in the presence of a suitable phosphorylating agent (e.g., 1-chloro-N,N-diisopropyl-1-methoxyphosphine) and a suitable base (e.g., 1H-tetrazole). Compounds of type 8.8 can be prepared by oxidation of a suitable phosphite (e.g., 8.6 as shown above). The oxidation reaction is carried out in the presence of a suitable nucleoside (e.g., 8.7 as shown above), a suitable electrophile (e.g., iodine), and a suitable base (e.g., 2,6-lutidine). The oxidation is followed by deprotection of the alcohol using a suitable acid (e.g., trichloroacetic acid in dichloromethane), and deprotection of the amine using a suitable base (e.g., ammonium hydroxide). As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized method in which compounds structurally similar to the above specific reactants (compounds similar to compounds of types 8.1, 8.2, and 8.3) can be substituted in the reaction to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 8.4.

[0570] 9. Route IX

[0571] In one aspect, 4'-thio-nucleotide and -nucleoside prodrug analogs can be prepared as shown below.

[0572] Scheme 9A.

[0573]

[0574] Compounds are expressed in generic form, where PG 1 is an alcohol protecting group, PG 2 is an amine protecting group, R is N or CH, and has other substituents as indicated in the description of the compounds elsewhere herein. More specific examples are set forth below.

[0575] Option 9B

[0576]

[0577] In one aspect, compounds of type 9.3 and similar compounds can be prepared according to the above reaction scheme 9B. Thus, compounds of type 9.5 can be prepared by protecting appropriate thionucleoside analogs (e.g., 9.4 as shown above). Protect the primary alcohol by first protecting it with a suitable alcohol protecting group (e.g., tert-butyldiphenylsilyl chloride (TBDPSCl)), followed by protecting the amine and secondary alcohol with a suitable protecting group (e.g., benzoyl chloride). Finally, the primary alcohol can be deprotected using a suitable deprotecting agent (e.g., tetrabutylammonium fluoride). Compounds of type 9.6 can be prepared by phosphorylation of an appropriate nucleoside (e.g., 9.5 as shown above). Phosphorylation is carried out in the presence of an appropriate phosphorylating agent (e.g., di-tert-butyldiisopropylphosphoramidite) and an appropriate base (e.g., 1H-tetrazole). Next, the resulting phosphorylated compound is oxidized at an appropriate temperature (e.g., -40°C) using an appropriate oxidizing agent (e.g., m-chloroperbenzoic acid). The reaction can then be quenched using an appropriate quencher (e.g., sodium sulfite), and the resulting compound protonated by the addition of an appropriate acid (e.g., hydrochloric acid as described above). Finally, the resulting nucleotide analog can be deprotected using an appropriate deprotecting agent (e.g., ammonia in methanol). As will be appreciated by those skilled in the art, the above reactions provide examples of generalized methods in which compounds structurally similar to the above specific reactants (compounds similar to compounds of types 9.1 and 9.2) can be substituted in the reactions to provide 4′-thio-nucleotide and -nucleoside prodrug analogs similar to formula 9.3.

[0578] E. Methods of using these compounds

[0579] The compounds and pharmaceutical compositions of the present invention are useful for treating or controlling disorders associated with uncontrolled cell proliferation, and in particular cancer.

[0580] Examples of disorders of uncontrolled cell proliferation that the compounds and compositions can be used to treat include, but are not limited to, cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).

[0581] In order to treat or control the disorder, the compound and the pharmaceutical composition comprising the compound are administered to a subject in need, such as, for example, a vertebrate, such as a mammal, fish, bird, reptile or amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cattle, cat, guinea pig or rodent. The term does not represent a specific age or gender. Therefore, adult and neonatal subjects and fetuses (whether male or female) are intended to be covered. The subject is preferably a mammal, such as a human. Before administering the compound or composition, it can be diagnosed that the subject needs to treat an obstacle of uncontrolled cell proliferation, such as cancer.

[0582] Compound or composition can be administered to the subject according to any method. Such methods are well known to those skilled in the art, and include but are not limited to oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ocular administration, intraauricular administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable administration such as intravenous administration, intraarterial administration, intramuscular administration and subcutaneous administration. Administration can be continuous or intermittent. Preparations can be administered therapeutically; i.e., administered to treat existing diseases or conditions. Preparations can also be administered prophylactically; i.e., administered to prevent obstacles such as cancers of uncontrolled cell proliferation.

[0583] The therapeutically effective amount or dosage of a compound can vary within a wide range. In each specific case, such dosage is adjusted to individual needs, including the specific compound applied, the route of administration, the condition treated, and the patient treated. Generally speaking, in the case of oral or parenteral administration to an adult weighing about 70Kg or more, about 10mg to about 10,000mg, preferably about 200mg to about 1,000mg daily dose should be suitable, although the upper limit may be exceeded. The daily dose can be administered in a single dose or in divided doses, or for parenteral administration, administered with continuous infusion. A single dose composition can contain a compound or composition of such an amount or its approximate number constituting a daily dose. In the case of any contraindications, the dosage can be adjusted by an individual doctor. The dosage can vary, and can be administered with one or more doses per day, for one or several days.

[0584] 1. Treatment Methods

[0585] The compounds disclosed herein can be used to treat or control disorders associated with uncontrolled cell proliferation, particularly cancer. Therefore, a method is provided, comprising administering to a subject a therapeutically effective amount of a composition comprising the disclosed compounds. In a further aspect, the method can be a method for treating disorders of uncontrolled cell proliferation.

[0586] a. Treatment of disorders of uncontrolled cell proliferation

[0587] In one aspect, disclosed are methods of treating a disorder of uncontrolled cell proliferation in a subject suffering from the disorder, the method comprising the step of administering to the subject a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0588] In one aspect, a method for treating a disorder of uncontrolled cell proliferation in a subject is disclosed, the method comprising the step of administering to the subject an effective amount of a compound having a structure represented by the following formula or a pharmaceutically acceptable salt thereof, the formula being selected from the following:

[0589]

[0590] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0591]

[0592] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3 When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0593]

[0594] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0595]

[0596] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′ are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R 16 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0597] Examples of disorders of uncontrolled cell proliferation include, but are not limited to, cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).

[0598] In a further aspect, prior to the administering step, the subject has been diagnosed as being in need of treatment for the disorder.

[0599] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[0600] In a further aspect, the method further comprises the step of identifying a subject in need of treatment for a disorder of uncontrolled cell proliferation.

[0601] In a further aspect, the obstacle of uncontrolled cell proliferation is cancer. In a further aspect, cancer is selected from sarcoma, carcinoma, hematological cancer, solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative tumor and plasma cell tumor (myeloma). In a further aspect, cancer is selected from leukemia, colorectal cancer, pancreatic cancer, ovarian cancer, non-small cell lung cancer and breast cancer. In a further aspect, cancer is liver cancer. In a further aspect, liver cancer is selected from hepatocellular carcinoma, cholangiocarcinoma and biliary carcinoma. In a further aspect, liver cancer is the transfer from another cancer.

[0602] In a further aspect, the effective amount is a therapeutically effective amount.In a still further aspect, the effective amount is a prophylactically effective amount.

[0603] In a further aspect, the method further comprises the step of administering a therapeutically effective amount of at least one agent associated with treating an obstacle to uncontrolled cell proliferation. In a further aspect, the at least one agent is a chemotherapeutic agent. In a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, and an mTor inhibitor. In a further aspect, the at least one agent is a chemotherapeutic agent or an antitumor agent. In a further aspect, the chemotherapeutic or anti-tumor agent is selected from kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response regulators, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelators and other ribonucleotide reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, doxorubicin, irinotecan and platinum compounds, immune checkpoint blockers such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) mAb, cluster of differentiation 47 (CD47) mAb, toll-like receptor (TLR) Agonists and other immunomodulators, cell therapies such as chimeric antigen receptor T cells (CAR-T) / chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs.

[0604] In a further aspect, the anti-tumor antibiotic is selected from doxorubicin, mitoxantrone, bleomycin, daunomycin, actinomycin D, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin and valrubicin or a pharmaceutically acceptable salt thereof.

[0605] In a further aspect, the antimetabolite is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate and thioguanine, or a pharmaceutically acceptable salt thereof.

[0606] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mesityl, temozolomide, thiotepa, bendamustine and streptozotocin or a pharmaceutically acceptable salt thereof.

[0607] In a further aspect, the mitotic inhibitor is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine and teniposide or a pharmaceutically acceptable salt thereof.

[0608] In a further aspect, the mTor inhibitor is selected from everolimus, sirolimus and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0609] In a further aspect, the kinase inhibitor is selected from p38 inhibitors, CDK inhibitors, TNF inhibitors, matrix metalloproteinase (MMP) inhibitors, COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib and etoricoxib, SOD mimetics and α v β3-inhibitors.

[0610] In a further aspect, the PARP inhibitor is selected from eneparib, talazoparib, olaparib, rucaparib, veliparib, CEP 9722, AK 4827, BGB-290 and 3-aminobenzamide.

[0611] In a further aspect, the epigenetic agent is selected from a histone deacetylase inhibitor and a DNA methylation inhibitor. In a still further aspect, the epigenetic agent is a BET inhibitor. In a further aspect, the BET inhibitor is selected from JQ1, 1-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010 (Tensha Therapeutics), CPI-203, RVX-208 (Resverlogix Corp), LY294002, MK-8628 (Merck / Mitsubishi Tanabe), BMS-986158 (Bristol-Myers Squibb), INCB54329 (Incyte Pharmaceuticals), ABBV-075 (Abb Vie, also known as ABV-075), CPI-0610 (Constellation Pharmaceuticals / Roche), FT-1101 (Forma Therapeutics / Celgene), GS-5829 (Gilead Sciences) and PLX51107 (Daiichi Sankyo).

[0612] In a further aspect, the HDAc inhibitor is selected from the group consisting of procistat and panobinostat.

[0613] In another aspect, the ribonucleic acid reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, tropine, motexafin gadolinium, hydroxyurea, gallium maltolate and gallium nitrate. In a still further aspect, the ribonucleic acid reductase inhibitor is an iron chelator.

[0614] In a further aspect, the proteasome inhibitor is selected from lactacystin and bortezomib.

[0615] In a further aspect, the NAE inhibitor is a 1-substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.

[0616] In a further aspect, the immune checkpoint blocker is selected from anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TEVI3 antibodies, antibodies to PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD160, TIGIT, LAIR1 and 2B4, antibodies to the corresponding ligands of these receptors, including but not limited to PD-L1 (for PD-1), PD-L2 (for PD-1), CD80 and CD86 (for CTLA-4), HVEM (for BTLA), galectin-9 and HMGB1 (for TIM-3), MHC II (for LAG-3), HVEM (for CD160), CD155, CD112 and CD113 (for TIGIT), Clq and collagen (for LAIR1) and CD48 (for 2B4). In a still further aspect, the immune checkpoint blocker is selected from CTL-4 mAb, PD-1 / PD-L1 mAB and CD47 mAB.

[0617] In a further aspect, the TLR agonist is selected from CRX-527 and OM-174.

[0618] In a further aspect, the cell therapy agent is selected from CAR-T cell therapy and CAR-NK cell therapy.

[0619] In a further aspect, the at least one compound and the at least one pharmaceutical agent are administered sequentially. In a still further aspect, the at least one compound and the at least one pharmaceutical agent are administered simultaneously.

[0620] In a further aspect, the at least one compound and the at least one pharmaceutical agent are co-formulated. In a still further aspect, the at least one compound and the at least one pharmaceutical agent are co-packaged.

[0621] 2. Uses of the compound

[0622] In one aspect, the invention relates to the use of the disclosed compounds or products of the disclosed methods. In a further aspect, the use relates to the manufacture of a medicament for treating a disorder of uncontrolled cell proliferation in a subject.

[0623] Also provided are uses of the disclosed compounds and products. In one aspect, the invention relates to uses of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In a further aspect, the compound used is the product of the disclosed preparation method.

[0624] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed preparation method or a pharmaceutically acceptable salt, solvate or polymorph thereof for use as a medicament.

[0625] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of the disclosed compound or the product of the disclosed preparation method, or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with the therapeutically effective amount of the compound or the product of the disclosed preparation method.

[0626] In various aspects, the use relates to treating a disorder of uncontrolled cell proliferation in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the disorder is a disorder of uncontrolled cell proliferation.

[0627] In a further aspect, the use relates to the manufacture of a medicament for treating a disorder of uncontrolled cell proliferation in a subject.

[0628] In a further aspect, the use relates to modulating viral activity in a subject. In a still further aspect, the use relates to modulating viral activity in a cell. In a still further aspect, the subject is a human.

[0629] It should be understood that the disclosed uses can be used in combination with the disclosed compounds, products of the disclosed preparation methods, methods, compositions and kits. In a further aspect, the present invention relates to the use of the disclosed compounds or disclosed products in the manufacture of a medicament for treating a disorder of uncontrolled cell proliferation in a mammal. In a further aspect, the disorder of uncontrolled cell proliferation is cancer.

[0630] 3. Drug manufacturing

[0631] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a disorder of uncontrolled cell proliferation in a subject suffering from the disorder, the method comprising combining a therapeutically effective amount of a disclosed compound or a product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0632] With regard to these applications, the present method comprises administering to an animal (particularly a mammal, and more particularly a human) a therapeutically effective amount of a compound that is effective in treating an obstacle to uncontrolled cell proliferation. In the context of the present invention, the dosage administered to an animal (particularly a human) should be sufficient to affect the therapeutic response of the animal within a reasonable time frame. Those skilled in the art will recognize that the dosage will depend on a variety of factors, including the condition of the animal and the weight of the animal.

[0633] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg / kg to about 100 mg / kg body weight for mice, and preferably between about 0.05 mg / kg to about 50 mg / kg body weight for mice, and between about 100 mg / kg to about 500 mg / kg body weight for humans per day, and more preferably between about 200 mg / kg to about 400 mg / kg body weight. This total amount is typically, but not necessarily, administered in a series of smaller doses over a period of about once a day to about three times a day for about 24 months, and preferably administered in a period of twice a day for about 12 months.

[0634] The size of the dose will also be determined by the route, time and frequency of administration, as well as the existence, nature and extent of any adverse side effects that may accompany the administration of the compound and the desired physiological effect. It will be appreciated by those skilled in the art that various conditions or disease states, particularly chronic conditions or disease states, may require long-term treatment involving multiple administrations.

[0635] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of preparation, or a pharmaceutically acceptable salt, solvate or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

[0636] 4. Test kit

[0637] In one aspect, the present invention relates to a kit comprising at least one compound having a structure represented by a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent associated with treating a disorder of uncontrolled cell proliferation; (b) instructions for administering the compound associated with treating a disorder of uncontrolled cell proliferation; and (c) instructions for treating a disorder of uncontrolled cell proliferation:

[0638]

[0639] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11)2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0640]

[0641] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10 When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 When present, it is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0642]

[0643] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0644]

[0645] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′ are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R1 6 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0646] In a further aspect, the obstacle of uncontrolled cell proliferation is cancer. In a further aspect, cancer is selected from sarcoma, carcinoma, hematological cancer, solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative tumor and plasma cell tumor (myeloma). In a further aspect, cancer is selected from leukemia, colorectal cancer, pancreatic cancer, ovarian cancer, non-small cell lung cancer and breast cancer. In a further aspect, cancer is liver cancer. In a further aspect, liver cancer is selected from hepatocellular carcinoma, cholangiocarcinoma and biliary carcinoma. In a further aspect, liver cancer is the transfer from another cancer.

[0647] In a further aspect, the at least one agent is a chemotherapeutic agent. In a still further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, and an mTor inhibitor.

[0648] In a further aspect, the anti-tumor antibiotic is selected from doxorubicin, mitoxantrone, bleomycin, daunomycin, actinomycin D, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin and valrubicin or a pharmaceutically acceptable salt thereof.

[0649] In a further aspect, the antimetabolite is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate and thioguanine, or a pharmaceutically acceptable salt thereof.

[0650] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mesityl, temozolomide, thiotepa, bendamustine and streptozotocin or a pharmaceutically acceptable salt thereof.

[0651] In a further aspect, the mitotic inhibitor is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine and teniposide or a pharmaceutically acceptable salt thereof.

[0652] In a further aspect, the mTor inhibitor is selected from everolimus, sirolimus and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0653] In a further aspect, the at least one compound and the at least one agent associated with treating a disorder of uncontrolled cell proliferation are co-formulated. In a further aspect, the at least one compound and the at least one agent associated with treating a disorder of uncontrolled cell proliferation are co-packaged.

[0654] In a further aspect, the compound and the agent associated with treating a disorder of uncontrolled cell proliferation are administered sequentially. In a still further aspect, the compound and the agent associated with treating a disorder of uncontrolled cell proliferation are administered simultaneously.

[0655] Kits can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, doctor, compounding shop, or pharmacist can provide a kit comprising a disclosed compound and / or product and another component to deliver to a patient.

[0656] It should be understood that the disclosed kits can be prepared from the disclosed compounds, products and pharmaceutical compositions. It should also be understood that the disclosed kits can be used in combination with the disclosed methods of use.

[0657] 5. Combination dosage form

[0658] In one aspect, the present invention relates to a combination dosage form, the combination dosage form comprising at least one compound having a structure represented by a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent associated with treating a disorder of uncontrolled cell proliferation; (b) instructions for administering the compound associated with treating a disorder of uncontrolled cell proliferation; and (c) instructions for treating a disorder of uncontrolled cell proliferation:

[0659]

[0660] Among them, R 1 and R 2 are each independently selected from hydrogen, -C(O)R 10 、-P(O)(OR 11 )2, -P(O)(OH)OP(O)(OH)OP(O)(OH)2 and a structure represented by a formula selected from the following:

[0661]

[0662] The condition is R 1 and R 2 wherein n is selected from 0, 1 and 2; wherein X, when present, is selected from O and S; wherein R 10When present, it is selected from C1-C30 alkyl, C2-C30 alkenyl and -CH(NH2)R 20 ; where R 20 When present, it is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NHC(NH)NH2, -(CH2)4NH2, -CH2CO2H, -(CH2)2CO2H, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -(CH2)2C(O)NH2, -CH2SH, -(CH2)2SCH3, -CH2SeH, -CH2C6H5 and -CH2Cy 1 ; Among them, Cy 1 When present, it is selected from monocyclic aryl, p-hydroxy monocyclic aryl, 4-imidazolyl and 3-indolyl; wherein R 11 Each occurrence of (when present) is independently selected from hydrogen, -(C1-C10 alkyl)CO2(C1-C10 alkyl), -(C1-C10 alkoxy)CO2(C1-C10 alkyl), -(C1-C10 alkyl)CO2(C1-C10 alkylthio), -(C1-C10 alkyl)-SS-(C1-C10 alkyl), and Ar 2 , and wherein each alkyl group is substituted by 0, 1, 2 or 3 groups independently selected from halogen and -OH; wherein Ar 2 When present, selected from aryl and heteroaryl substituted with 1 or 2 groups independently selected from C1-C10 alkyl and nitro; wherein R 12 When present, it is selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino, -(C1-C8)C(O)NH2, aryl and -(CH2)aryl; wherein R 13 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and Ar 3 ; Among them, Ar 3 When present, Ar is selected from aryl and heteroaryl and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein Ar 1 when present is selected from aryl and heteroaryl, and is substituted with 0, 1, 2 or 3 groups independently selected from halogen, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxy, C1-C4 aminoalkyl, C1-C4 alkylamino and (C1-C4)(C1-C4)dialkylamino; wherein R 30 When present is a structure selected from the following:

[0663]

[0664] Where R 31 When present, it is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); or wherein R 1 and R 2 Each together includes the structure represented by the formula:

[0665]

[0666] Where R 14 When present, it is C1-C8 alkyl; wherein R 15 When present, it is selected from C1-C10 alkyl, C3-C10 cycloalkyl and aryl substituted with 0 or 1 C1-C10 alkyl groups; wherein R 3 is selected from hydrogen, -C(O)(C1-C30 alkyl) and -C(O)(C2-C30 alkenyl); wherein when present, R 4 and R 4′ are each independently selected from hydrogen, fluorine, -CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl and -OR 16 ; and where R 16 When present is selected from hydrogen, methyl and -C(O)R 10 , the condition is R 1 , R 2 and R 3 Not at the same time hydrogen.

[0667] In a further aspect, the obstacle of uncontrolled cell proliferation is cancer. In a further aspect, cancer is selected from sarcoma, carcinoma, hematological cancer, solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative tumor and plasma cell tumor (myeloma). In a further aspect, cancer is selected from leukemia, colorectal cancer, pancreatic cancer, ovarian cancer, non-small cell lung cancer and breast cancer. In a further aspect, cancer is liver cancer. In a further aspect, liver cancer is selected from hepatocellular carcinoma, cholangiocarcinoma and biliary carcinoma. In a further aspect, liver cancer is the transfer from another cancer.

[0668] In a further aspect, the at least one agent is a chemotherapeutic agent. In a still further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a mitotic inhibitor, and an mTor inhibitor.

[0669] In a further aspect, the anti-tumor antibiotic is selected from doxorubicin, mitoxantrone, bleomycin, daunomycin, actinomycin D, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin and valrubicin or a pharmaceutically acceptable salt thereof.

[0670] In a further aspect, the antimetabolite is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate and thioguanine, or a pharmaceutically acceptable salt thereof.

[0671] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mesityl, temozolomide, thiotepa, bendamustine and streptozotocin or a pharmaceutically acceptable salt thereof.

[0672] In a further aspect, the mitotic inhibitor is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine and teniposide or a pharmaceutically acceptable salt thereof.

[0673] In a further aspect, the mTor inhibitor is selected from everolimus, sirolimus and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0674] In a further aspect, the at least one compound and the at least one agent associated with treating a disorder of uncontrolled cell proliferation are co-formulated. In a further aspect, the at least one compound and the at least one agent associated with treating a disorder of uncontrolled cell proliferation are co-packaged.

[0675] In a further aspect, the compound and the agent associated with treating a disorder of uncontrolled cell proliferation are administered sequentially. In a still further aspect, the compound and the agent associated with treating a disorder of uncontrolled cell proliferation are administered simultaneously.

[0676] Combination dosage forms can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, doctor, compounding workshop, or pharmacist can provide a combination dosage form including a disclosed compound and / or product and another component to deliver to a patient.

[0677] It should be understood that the disclosed combination dosage forms can be prepared from the disclosed compounds, products and pharmaceutical compositions. It should also be understood that the disclosed combination dosage forms can be used in combination with the disclosed methods of use.

[0678] The foregoing description illustrates and describes the present disclosure. In addition, the present disclosure only shows and describes preferred embodiments, but as described above, it should be understood that the present disclosure can be used in various other combinations, modifications and environments, and can be changed or modified within the scope of the inventive concept as expressed herein, commensurate with the above teachings and / or the skills or knowledge of the relevant fields. The embodiments described above are further intended to explain the best mode known to the applicant, and to enable other technicians in the field to utilize the present disclosure in such or other embodiments, and with various modifications required for specific applications or their use. Therefore, this description is not intended to limit the present invention to the form disclosed herein. Moreover, the appended claims are intended to be interpreted as including alternative embodiments.

[0679] All publications and patent applications cited in this specification are incorporated herein by reference and are for any and all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event of any inconsistency between the present disclosure and any publication or patent application incorporated herein by reference, the present disclosure controls.

[0680] F. Example

[0681] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and evaluate the compounds, compositions, articles, devices and / or methods claimed herein, and are intended to be purely exemplary of the present invention and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, temperatures are in ° C or are ambient temperature, and pressures are at or near atmospheric pressure.

[0682] Examples are provided herein to illustrate the present invention and should not be construed as limiting the present invention in any way. Examples are provided herein to illustrate the present invention and should not be construed as limiting the present invention in any way.

[0683] 1. Chemical Experiment

[0684] a. General Experiment

[0685] All reactions were carried out in oven-dried or flame-dried glassware using standard gas-tight syringes, cannulas and septa under argon atmosphere. Reaction temperature was measured externally. Stirring was achieved using an oven-dried magnetic bar. All reactions were carried out in anhydrous solvents (DMF, THF, CH2Cl2, 1,4-dioxane, 1-butanol, CHCl3, DME, pyridine, DMPU) purchased from Sigma-Aldrich. Microwave reactions were carried out in the CEMdiscover Labmate system with the intelligent technology (Explorer 48) of a focused microwave synthesizer. All commercially purchased reagents were used without purification. Reaction was monitored by thin layer chromatography (TLC) on a pre-coated silica gel (60F254) glass plate from EMD Millipore, and visualized using UV light (254nm). The purification of compounds was carried out using methanol as mobile phase on a Teledyne-ISCO CombiflashRf 200 purification system or on a chiral supercritical fluid chromatography (SFC). Use 230-400 mesh Redisep Normal phase silica gel column. Proton NMR spectra were recorded on a Varian Unity 400 NMR spectrometer operating at 400 MHz and calibrated to the solvent peak and TMS peak. The chemical formula and accurate mass of the target compound were determined from (M+H)+ by high resolution mass spectrometry using an Agilent 6210 electrospray time of flight.

[0686] b. General Procedure for the Synthesis of 4′-Thio-Nucleotide Analogs

[0687]

[0688] c. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-YL)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine benzyl ester (4a)

[0689]

[0690] i. Preparation of intermediate (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester (2a)

[0691] To a mixture of L-alanine benzyl ester hydrochloride 1a (2.00 g, 9.27 mmoles, 1.0 equivalents) and dichloromethane (20 mL) was added phenyl dichlorophosphate (1.52 mL, 10.2 mmoles, 1.1 equivalents). The mixture was cooled to -70 ° C, and then a solution of triethylamine (2.71 mL, 19.5 mmoles, 2.1 equivalents) in dichloromethane (10 mL) was added dropwise at -65 ° C. After the addition was complete, the reaction mixture was stirred at -70 ° C for 1 hr, warmed to 20 ° C, and then stirred under argon for 2 hrs. The reaction mixture was concentrated in vacuo to obtain a crude solid, which was ground in methyl tert-butyl ether (50 mL) at 20 ° C under argon for 18 hrs. The mixture was filtered by vacuum filtration to remove triethylamine hydrochloride, which was rinsed with methyl tert-butyl ether (10 mL). The filtrate was concentrated in vacuo to give 3.55 g of intermediate 2a as a light yellow oil which was used as such without further purification.

[0692] ii. Preparation of ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine benzyl ester (3a)

[0693] The solution of intermediate 2a (3.55g, 10.04 mmoles, 1.0 equivalent) in dichloromethane (20mL) was cooled to -10 ℃, and then the solution of pentafluorophenol (2.03g, 11.04 mmoles, 1.1 equivalents) and triethylamine (1.54mL, 1.1 equivalents) in dichloromethane (10mL) was added dropwise at -5 ℃. After the addition was completed, the reaction mixture was stirred for 2hr at 0 to -10 ℃, and then heated to 20 ℃ under argon and stirred for 18hr. The reaction mixture was concentrated in a vacuum to obtain a white solid, which was suspended in ethyl acetate (200mL), and then ground for 30min at 20 ℃. The mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed with water (100mL), 10% Na2CO3 (2x 100mL), and then washed with salt water (100mL). The organic layer was separated, dried (Na2SO4), filtered, and the filtrate was then concentrated in vacuo to give 5.39 g of an off-white solid. Purification by trituration in 20% ethyl acetate in hexanes (50 mL) at 20°C for 3 days provided 2.33 g (50% in two steps) of 3a as a single diastereomer. 1 H NMR (400MHz, DMSO-d6) δ7.48-7.15(m,10H),6.96(dd,J=14.1,9.9Hz,1H),5.12 (s,2H),4.15-4.00(m,1H),1.33(dd,J=7.1,1.3Hz,3H); 31 P NMRδ p0.24; LCMS: m / z 502 (M+H) + .

[0694] III. Preparation of 4a

[0695] To a solution of 5-aza-4′-thio-2′-deoxycytidine (aza-T-dCyd) (100 mg) DMPU (247 μL, 5 eq.) and 3a (246 mg, 1.2 eq.) in 1.2 mL of pyridine was added 0.22 mL of a 1 M solution of Al(Me)Cl (0.5 eq.) at 0°C. The slurry mixture was allowed to warm to room temperature over 10 min, and the reaction mixture was stirred at room temperature under argon for 3 days. After removal of the solvent, the resulting crude product was first chromatographed using DCM:MeOH (9:1) as the eluent, and then purified by SFC to afford 4a in 23% yield. 1 H NMR (400MHz, DMSO-d6)δ8.56(s,1H),7.58-7.52(m,2H),7.40-7.26(m,7H),7.24-7.11(m, 3H),6.13-6.03(m,2H),5.40(s,1H),5.09(d,J=2.5Hz,2H),4.34(d,J=3.8Hz,1H),4.25 (dd,J=10.6,7.2Hz,1H),4.08-3.83(m,2H),3.49-3.41(m,1H),2.37(ddd,J=12.7,8.1, 4.0Hz,1H),2.23(ddd,J=13.4,8.6,5.0Hz,1H),1.29-1.20(m,3H); 31 P NMRδ p 3.17; HR-MS: for C 24 H 28 N5O7PS.H calculated (M+H) 562.1520, found 562.1509; HPLC purity = 94 (% of AUC), t R =6.7 minutes.

[0696] d. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isobutyl ester (4b)

[0697]

[0698] Preparation of L-alanine 2-methyl-1-propyl ester hydrochloride (1b)

[0699] To a solution of N-Boc-L-alanine (3.00 g, 15.9 mmol, 1.0 eq) in 2-methyl-1-propanol (100 mL, 69.0 eq) was added trimethylsilyl chloride (10.0 mL, 79.28 mmol, 5.0 eq). The reaction mixture was stirred at 20 °C under argon for 18 hr. The reaction mixture was concentrated under vacuum to give a residue, which was triturated in anhydrous diethyl ether (50 mL) for 1 hr. The mixture was filtered by vacuum filtration to collect the solid, which was rinsed with diethyl ether (20 mL) and then dried to provide 2.66 g (92%) of Intermediate 1b as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 3H), 4.09 (q, J = 7.2Hz, 1H), 4.04-3.89 (m, 2H), 1.94 (dh, J = 13.4, 6.6 Hz, 1H), 1.45 ( d, J = 7.2 Hz, 3H), 0.93 ( dd, J = 6.7, 0.7 Hz, 6H).

[0700] ii. Preparation of (chloro(phenoxy)phosphoryl)-L-alanine isobutyl ester (2b)

[0701] Intermediate 2b was prepared from Intermediate 1b (L-alanine-2-methyl-1-propyl ester hydrochloride) (2.0 g, 11.0 mmol, 1.0 eq) and phenyl dichlorophosphate (1.81 mL, 12.1 mmol, 1.1 eq) by the procedure described for the preparation of Intermediate 2a to provide 3.83 g of a colorless oil.

[0702] iii. Preparation of ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine isobutyl ester (3b)

[0703] Compound 3b was prepared from 2b (3.83 g, 12.0 mmol, 1.0 eq) and pentafluorophenol (2.43 g, 13.2 mmol, 1.1 eq) according to the procedure described for the preparation of 3a to give a solid. Trituration in a mixture of 20% ethyl acetate in hexane (50 mL) provided 1.43 g of 3b as a single diastereomer. 1H NMR(400 MHz, DMSO-d6)δ7.43(dd,J=8.5,7.3Hz,2H),7.32-7.18(m,3H),6.91(dd,J=14.2,9.9Hz ,1H),4.11-3.95(m,1H),3.84(d,J=6.5Hz,2H),1.86(dh,J=13.3,6.7Hz,1H)1.32(dd,J =7.1,1.2Hz,3H),0.88(d,J=6.7Hz,6H); 31 P NMRδ p 0.29; LCMS: m / z 468 (M+H) + .

[0704] Preparation of iv.4b

[0705] Compound 4b was prepared from aza-T-dCyd (100 mg) and 3b (230 mg, 1.2 equiv) according to the procedure described for the preparation of 4a. 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 7.55 (s, 2H), 7.36 (dd, J= 8.5,7.2Hz,2H),7.26-7.09(m,3H),6.15-5.88(m,2H),5.39(d,J=3.7Hz,1H),4.35(t,J= 3.7Hz,1H),4.27(dt,J=10.7,7.2Hz,1H),4.10-3.97(m,1H),3.92-3.72(m,3H),3.44(td, J=6.9,2.8Hz,1H),2.38(ddd,J=12.8,8.4,4.0Hz,1H),2.23(dt,J=13.2,5.7 Hz,1H),1.84(hept,J=6.7Hz,1H),1.27-1.22(m,3H),0.86(d,J=6.8Hz,6H); 31 P NMRδ p 3.17; HR-MS: for C 21 H 30 N5O7PS.H calculated (M+H) 528.1676, found 528.1669; HPLC purity = 97 (% of AUC), t R =6.65 minutes.

[0706] e. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (4c)

[0707]

[0708] i. Preparation of 2-ethylbutyl-L-alanine hydrochloride (1c)

[0709] Intermediate 1c was prepared from N-Boc-L-alanine (6.00 g, 31.7 mmol, 1.0 eq) and 2-ethyl-1-butanol (100 mL, 812 mmol, 26.0 eq) according to the procedure described for the preparation of Intermediate 1a to give 5.19 g (78%) of a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 3H), 4.19-3.98 (m, 3H), 1.53 (h, 1H), 1.44 (d, J = 7.2Hz, 3H), 1.40-1.29 (m, 4H), 0.93-0.82 (m, 6H).

[0710] ii. Preparation of (chloro(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (2c)

[0711] Intermediate 2c was prepared from Intermediate 1c (2.00 g, 9.54 mmol, 1.0 eq) and phenyl dichlorophosphate (1.56 mL, 10.5 mmol, 1.1 eq) according to the procedure described for the preparation of Intermediate 2a to give 3.58 g of a yellow oil.

[0712] iii. Preparation of ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine isobutyl ester (3c)

[0713] Compound 3c was prepared from intermediate 2c (3.58 g, 10.29 mmol, 1.0 eq) and pentafluorophenol (2.08 g, 11.3 mmol, 1.1 eq) according to the procedure described for the preparation of 3a. Trituration in 5% ethyl acetate in hexanes (25 mL) provided 1.70 g of a white cottony solid. 1 H NMR(400MHz,DMSO-d6)δ7.48-7.38 (m,2H),7.30-7.19(m,3H),6.90(dd,J=14.2,9.9Hz,1H),4.12-3.88(m,3H),1.46(h,J=6.1Hz,1H),1.37-1.22(m,7H),0.84(t,J=7.5Hz,6H); 31 P NMRδ p 0.26; LCMS: m / z 496 (M+H) + .

[0714] Preparation of iv.4c

[0715] Compound 4c was prepared from aza-T-dCyd (100 mg) and 3c (243 mg, 1.2 eq.) according to the procedure described for the preparation of 4a. 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.55(s,2H),7.40-7.31(m, 2H),7.24-7.12(m,3H),6.14-6.05(m,1H),6.02(dd,J=13.1,10.1Hz,1H),5.39(d,J=3 .8Hz,1H),4.39-4.32(m,1H),4.27(dt,J=10.7,7.2Hz,1H),4.09-3.76(m,4H),3.44(m, 1H),2.38(ddd,J=12.7,8.3,4.0Hz,1H),2.28-2.17(m,1H),1.45(p,J=6.2Hz,1H),1.23(m,7H),0.89-0.77(m,6H); 31 P NMRδ p 3.17; HR-MS: for C 23 H 34 N5O7PS.H calculated (M+H) 556.1989, found 556.1983; HPLC purity = 99 (% of AUC), t R =7.62 minutes.

[0716] f. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (4d)

[0717]

[0718] Compound 4d was prepared from aza-T-dCyd (100 mg) and 3d (222 mg, 1.2 eq.) (which was prepared as (S, S P ) diastereomer purchased) was prepared according to the procedure described for Preparation 4a. 1H NMR(400MHz,DMSO-d6)δ 8.57(s,1H),7.55(s,2H),7.41-7.31(m,2H),7.25-7.09(m,3H),6.09(dd,J=8.3,6.5Hz, 1H),5.99(dd,J=13.2,10.1Hz,1H),5.41(s,1H),4.86(hept,J=6.2Hz,1H),4.36(s,1H), 4.26(ddd,J=10.7,7.8,6.5Hz,1H),4.11-3.99(m,1H),3.77(tq,J=10.3,7.1Hz,1H),3. 49-3.33(m,1H),3.15(d,J=5.2Hz,1H),2.39(ddd,J=12.8,8.4,4.0Hz,1H),2.23(ddd,J= 13.2,6.5,4.0Hz,1H),1.18(ddd,J=23.5,6.7,2.0Hz,9H); 31 P NMRδ p 3.19; HPLC purity = 98 (% of AUC), t R =5.66 minutes.

[0719] g. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophene-2-yl)-methoxy)(phenoxy)-phosphoryl)-L-alanine methyl ester (4E)

[0720]

[0721] i. Preparation of ((S)-chloro(phenoxy)-phosphoryl)-L-alanine methyl ester (2e)

[0722] Intermediate 2e was prepared from intermediate (L-alanine-2-methyl-1-methyl ester hydrochloride) (10.0 g, 71.6 mmol, 1.0 eq) and phenyl dichlorophosphate (11.8 mL, 12.1 mmol, 1.1 eq) by the procedure described for the preparation of intermediate 2a to provide 21.3 g of a yellow oil.

[0723] ii. Preparation of ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester (3e)

[0724] Compound 3e was prepared from 2e (19.9 g, 71.6 mmol, 1.0 eq) and pentafluorophenol (14.5 g, 78.8 mmol, 1.1 eq) according to the procedure described for the preparation of 3a to obtain a solid. Trituration in a mixture of 5% ethyl acetate in hexane (100 mL) provided 4.14 g of 3e as a single diastereomer. The filtrate was purified by flash chromatography (220 g silica gel column, 100-70% hexane in ethyl acetate, gradient elution) to obtain 4.25 g of additional product 3e as a single diastereomer. 1 H NMR(400MHz,DMSO-d6)δ7.48-7.39(m, 2H),7.30-7.21(m,3H),6.91(dd,J=14.1,9.9Hz,1H),4.01(ddq.J=10.9,9.9,7.1Hz,1H),3.61(s,3H),1.29(dd,J=7.1,1.2Hz,3H); 31 P NMRδ p 0.35; LCMS: m / z 426 (M+H) + .

[0725] III. Preparation of 4e

[0726] Compound 4e was prepared from aza-T-dCyd (100 mg) and 3e (209 mg, 1.2 eq.) according to the procedure described for the preparation of 4a. 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.58(s,2H),7.45-7.35(m, 2H),7.28-7.15(m,3H),6.17-6.01(m,2H),5.43(d,J=3.9Hz,1H),4.43-4.36(m,1H),4. 30(ddd,J=10.7,7.7,6.6Hz,1H),4.08(dt,J=10.7,6.6Hz,1H),3.94-3.81(m,1H),3.62 (s,3H),3.48(ddd,J=7.4,6.2,3.0Hz,1H),2.42(ddd,J=12.7,8.3,4.0Hz,1H),2.27(ddd,J=13.3,6.6,4.2Hz,1H),1.26(dd,J=7.2,1.0Hz,3H); 31 P NMRδ p 3.11; HR-MS: for C 18 H 24N5O7PS.H calculated (M+H) 486.12023, found 485.1131; HPLC purity = 98 (% of AUC), t R =8.68 minutes.

[0727] h. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)-methoxy)(phenoxy)-phosphoryl)-L-alanine ethyl ester (4f)

[0728]

[0729] i. Preparation of ((S)-chloro(phenoxy)-phosphoryl)-L-alanine ethyl ester (2f)

[0730] Intermediate 2f was prepared from intermediate (L-alanine-2-methyl-1-ethyl ester hydrochloride) (6.50 g, 42.3 mmol, 1.0 eq) and phenyl dichlorophosphate (6.94 mL, 46.6 mmol, 1.1 eq) by the procedure described for the preparation of intermediate aa to provide 14.0 g of 2f as a colorless oil.

[0731] ii. Preparation of ((S)-(perfluorophenoxy)-(phenoxy)phosphoryl)-L-alanine ethyl ester (3f)

[0732] Compound 3f was prepared from 2f (19.9 g, 71.6 mmol, 1.0 eq) and pentafluorophenol (12.4 g, 42.3 mmol, 1.1 eq) according to the procedure described for the preparation of 3a to obtain a solid. Trituration in a mixture of 5% ethyl acetate in hexane (500 mL) provided 5.54 g of 3f as a single diastereomer. The filtrate was purified by flash chromatography (220 g silica gel column, 100-80% hexane in ethyl acetate, gradient elution) to obtain 2.74 g of additional product 3f as a single diastereomer. 1 H NMR(400MHz, DMSO-d6)δ7.48-7.38(m, 2H),7.26(dddt,J=9.8,7.7,2.3,1.1Hz,3H),6.89(ddd,J=13.9,9.9,6.4Hz,1H),4.12-4.04 (m,2H),4.04-3.92(m,1H),1.30(ddd,J=7.1,5.0,1.2Hz,3H),1.17(t,J=7.1Hz,3H); 31 P NMRδ p 0.33; LCMS: m / z 440 (M+H) + .

[0733] III. Preparation of 4f

[0734] Compound 4f was prepared from aza-T-dCyd (100 mg) and 3f (216 mg, 1.2 equiv) according to the procedure described for the preparation of 4a. 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.58(s,2H),7.44-7.35(m, 2H),7.28-7.15(m,3H),6.13(dd,J=8.3,6.5Hz,1H),6.05(dd,J=13.2,10.0Hz,1H),5.43 (d,J=3.9Hz,1H),4.39(p,J=3.8Hz,1H),4.30(ddd,J=10.7,7.7,6.5Hz,1H),4.08(qd,J= 7.1,1.0Hz,3H),3.91-3.79(m,1H),3.51-3.44(m,1H),2.42(ddd,J=12.7,8.4,4.1Hz, 1H), 2.26 (ddd, J=13.2, 6.5, 4.0Hz, 1H), 1.26 (dd, J=7.1, 1.0Hz, 3H), 1.18 (t, J=7.1Hz, 3H); 31 PNMRδ p 3.15; HR-MS: for C 19 H 26 N5O7PS.H calculated (M+H) 500.13574, found 499.1286; HPLC purity = 95 (% of AUC), t R =9.41 minutes.

[0735] i. Synthesis of (5-nitrofuran-2-yl)methyl ((S)-(((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydro-thiophen-2-yl)-methoxy)(phenoxy)-phosphoryl)-L-alanine ester (4 g)

[0736]

[0737] i. Preparation of (5-nitrofuran-2-yl)methyl L-alaninate (1 g)

[0738] Intermediate 1g was prepared from N-Boc-L-alanine (10.0 g, 52.85 mmol, 1.0 eq) and hydroxy-[5-(hydroxymethyl)-2-furyl]-oxo-ammonium (264.26 mmol, 5.0 eq) following the procedure described for the preparation of Intermediate 1a to provide 8 g (60.15%) of Intermediate 1g as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 3H), 7.69 (d, J = 3.7 Hz, 1H), 7.13-6.87 (m, 1H), 5.33 (s, 2H), 4.14 (q, J = 7.1 Hz, 1H), 1.41 (d, J = 7.2 Hz, 3H).

[0739] ii. Preparation of (5-nitrofuran-2-yl)methyl ((S)-(perfluorophenoxy)-(phenoxy)phosphoryl)-L-alaninate (3 g)

[0740] Intermediate 3g was prepared from intermediate (1 g) (5-nitrofuran-2-yl)methyl L-alaninate following the procedure described for the preparation of intermediate 3f to give 8 g (64%) of 3g as a single diastereomer. 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=3.8Hz,1H),7.37(t,J=7.9Hz,2H),7.28-7.08(m,3H),6. 98(dd,J=14.0,9.8Hz,1H),6.88(d,J=3.8Hz,1H),5.19(d,J=1.9Hz,2H),4.12-3.96(m,1H), 1.30(dd,J=7.2,1.3Hz,3H).

[0741] iii. Preparation of 4g

[0742] Compound 4g was prepared from aza-T-dCyd (100 mg) and 3g (216 mg, 1.2 eq) according to the procedure described for the preparation of 4a. 1H NMR (400MHz, DMSO-d6) δ8.55 (s, 1H), 7.64 (d, J = 3.8Hz, 1H), 7.54(d,J=2.7Hz,2H),7.39-7.27(m,2H),7.22-7.08(m,3H),6.95-6.84(m,1H),6.21- 6.00(m,2H),5.73(s,0H),5.38(d,J=4.0Hz,1H),5.23-5.16(m,2H),4.34(p,J=3.9Hz, 1H),4.26(dt,J=10.7,7.2Hz,1H),4.11-3.85(m,3H),3.42(ddd,J=9.6,6.7,3.0Hz,1H), 3.15(d,J=5.2Hz,1H),2.42-2.30(m,1H),2.22(ddd,J=13.2,6.4,4.3Hz,1H),1.25(dt,J= 7.1,1.6Hz,3H); 31 P NMR (162 MHz, DMSO-d6) δ 3.093; HR-MS: for C 22 H 25 N6O 10 PS.H Calculated (M+H) 597.1163, found 597.11; HPLC purity = 95.3 (% of AUC).

[0743] j. Synthesis of ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine cyclopentyl ester (4h)

[0744]

[0745] i. Preparation of ((S)-chloro(phenoxy)-phosphoryl)-L-alanine ethyl ester (1h)

[0746] Intermediate 1h was prepared from N-Boc-L-alanine (10.0 g, 52.85 mmol, 1.0 eq) and cyclopentanol (264.26 mmol, 5.0 eq) following the procedure described for the preparation of Intermediate 1a to provide 7.0 g (84%) of Intermediate 1h as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.50 (s, 3H), 5.15 (tt, J = 5.9, 2.3Hz, 1H), 4.31 (s, 3H), 3.97 (q, J=7.2Hz, 1H), 1.83 (ddddd, J=12.1, 8.1, 6. 0,4.1,1.7Hz,2H),1.73-1.48(m,10H),1.48-1.39(m,7H),1.39-1.34(m,3H).

[0747] ii. Preparation of ((S)-(perfluorophenoxy)-(phenoxy)phosphoryl)-L-alanine ethyl ester (3h)

[0748] Intermediate 3h is prepared by intermediate (1h) 2-aminopropionic acid cyclopentyl ester according to the procedure described for preparing intermediate 3a, to obtain a solid. The solid is stirred in EtOAc, and heated slightly so that all materials enter the solution, then cooled, and a solid is formed. The solid is filtered and dried to provide 15 grams (44%) of 3h as a single diastereomer. 31 P NMR (162 MHz, DMSO-d6) δ 0.28. 1 H NMR(400MHz, DMSO-d6)δ 7.39(t,J=7.9Hz,2H),7.29-7.09(m,3H),6.83(dd,J=14.2,9.9Hz,1H),5.02(tt,J=5.4, 2.5Hz, 1H), 3.90 (tq, J=10.3, 7.1Hz, 1H), 1.90-1.69 (m, 2H), 1.66-1.41 (m, 6H), 1.24 (dd, J=7.2, 1.2Hz, 3H).

[0749] III. Preparation of 4H

[0750] Compound 4h was prepared from aza-T-dCyd (100 mg) and 3h (216 mg, 1.2 eq) according to the procedure described for the preparation of 4a. Diastereomer 1: 1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),7.55(d,J =4.1Hz,2H),7.40-7.29(m,2H),7.24-7.07(m,3H),6.16-6.03(m,1H),5.95(dd,J=12.8, 10.0Hz,1H),5.42(d,J=3.8Hz,1H),5.09-4.94(m,1H),4.45-4.33(m,1H),4.33-4.20(m, 1H),4.18-4.03(m,1H),3.81-3.67(m,1H),3.58-3.42(m,2H),2.36-2.16(m,2H),1.85-1.68(m,2H),1.67-1.41(m,2H),1.24-1.08(m,3H); 31 P NMR (162 MHz, DMSO-d6) δ 3.36; HR-MS: for C 22 H 30 N5O7PS.H calculated (M+H) 540.16, found 540.16; HPLC purity = 97.8 (% of AUC). Diastereomer 2: 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J = 1.3Hz, 1H), 7.68-7.47(m,2H),7.41-7.28(m,2H),7.25-7.06(m,3H),6.10(ddd,J=8.5,6.5,4.5Hz, 1H),5.96(td,J=12.7,10.0Hz,1H),5.41(dd,J=9.1,3.9Hz,1H),5.08-4.95(m,1H),4.37 (dp,J=11.1,3.8Hz,1H),4.31-4.22(m,1H),4.16-3.98(m,2H),3.84-3.69(m,1H),3.54- 3.38(m,1H),3.18-3.12(m,3H),2.44-2.29(m,1H),2.29-2.17(m,1H),1.76(s,1H),1.65- 1.41(m,2H),1.19(td,J=7.3,1.0Hz,3H); 31 P NMR (162 MHz, DMSO-d6) δ 3.21; HR-MS: for C 22 H 30 Calculated (M+H) for N5O7PS.H 540.16, found 540.16; HPLC purity = 97.5 (% of AUC).

[0751] k. Synthesis of ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl-L-alanine benzyl ester (4i)

[0752]

[0753] i. Preparation of ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanine benzyl ester (3i)

[0754] Intermediate 2i is prepared according to the procedure described for the preparation of 2a. A solution of 2i (5.79 g, 14.3 mmoles, 1.0 equivalent) in dichloromethane (30 mL) was cooled to -5 ° C, and then a solution of pentafluorophenol (2.90 g, 15.8 mmoles, 1.1 equivalents) and triethylamine (2.20 mL, 15.8 mmoles, 1.1 equivalents) in dichloromethane (10 mL) was added dropwise at -5 ° C. After the addition was completed, the reaction mixture was stirred at -5 to -10 ° C for 1 hr, and then stirred for 18 hr when warming to 20 ° C under argon. The reaction mixture was concentrated in a vacuum to obtain a white solid, which was suspended in ethyl acetate (200 mL), and then ground at 20 ° C for 30 min. The mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed with water (100 mL), 10% Na2CO3 (2x100 mL), and then with brine (100 mL). The organic layer was separated, dried (Na2SO4), filtered, and then the filtrate was concentrated in vacuo to obtain 6.79 g of a tan oil. Purification by flash chromatography (silica gel, 99% to 95% dichloromethane in ethyl acetate, gradient elution) provided 830 mg (11%) of 3i as a mixture of two diastereomers. Diastereomer 1: 1 H NMR (400MHz, DMSO-d6) δ8.18-8.09(m,1H),8.06-7.95(m,1H),7.83(dd,J=8.2, 1.1Hz,1H),7.68-7.44(m,4H),7.40-7.26(m,5H),7.15(dd,J=13.5,9.8Hz,1H),5.13(s,2H),4.25-4.09(m,1H),1.36(dd,J=7.1,1.2Hz,3H); 31 P NMRδ p 0.81; 19 F NMR; LCMS: m / z 552 (M+H) + . Diastereomer 2: 1H NMR(400MHz,DMSO-d6)δ8.22-8.06(m,1H),8.04-7.95(m, 1H),7.83(dt,J=8.1,1.1Hz,1H),7.68-7.43(m,4H),7.31(s,5H),7.17(dd,J=14. 0,9.9Hz,1H),5.12-5.03(m,2H),4.27-4.11(m,1H),1.39(dd,J=7.2,1.3Hz,3H); 31 P NMRδ p 0.52; 19 F NMR; LCMS: m / z 552 (M+H) + .

[0755] ii. Preparation of 4i

[0756] Compound 4i was prepared from aza-T-dCyd (100 mg) and 3i (270 mg, 1.2 eq.) according to the procedure described for the preparation of 4a. Diastereomer 1: 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.15-8.06 (m,1H),7.99-7.88(m,1H),7.76-7.65(m,1H),7.59-7.51(m,4H),7.49-7.39(m,2H),7 .36-7.26(m,5H),6.26(dd,J=12.8,10.0Hz,1H),6.08(dd,J=8.2,6.5Hz,1H),5.39(d,J =3.9Hz,1H),5.07(d,J=2.0Hz,2H),4.39-4.25(m,2H),4.09(dt,J=10.6,6.9Hz,1H),4 .03-3.90(m,1H),3.46(dt,J=7.1,3.8Hz,1H),2.36(ddd,J=12.7,8.3,4.0Hz,1H),2.21 (ddd,J=13.2,6.6,4.2Hz,1H),1.27(dd,J=7.2,0.9Hz,3H). 31 P NMRδ p 3.63; HR-MS: for C 28 H 30 N5O7PS.H calculated (M+H) 612.1675, found 612.1676; HPLC purity = 99 (% of AUC), t R =7.53 minutes. Diastereomer 2: 1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.15 -8.06(m,1H),7.99-7.88(m,1H),7.76-7.65(m,1H),7.59-7.51(m,4H),7.49-7.39(m,2 H),7.36-7.26(m,5H),6.26(dd,J=12.8,10.0Hz,1H),6.08(dd,J=8.2,6.5Hz,1H),5.39 (d,J=3.9Hz,1H),5.07(d,J=2.0Hz,2H),4.39-4.25(m,2H),4.09(dt,J=10.6,6.9Hz,1 H),4.03-3.90(m,1H),3.46(dt,J=7.1,3.8Hz,1H),2.36(ddd,J=12.7,8.3,4.0Hz,1H), 2.21(ddd,J=13.2,6.6,4.2Hz,1H), 1.27(ddd,J=7.2,0.9Hz,3H); 31 P NMRδ p 3.69; HR-MS: for C 28 H 30 N5O7PS.H calculated (M+H) 612.1675, found 612.1671; HPLC purity = 97 (% of AUC), t R =7.88 minutes.

[0757] l. Synthesis of ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine isobutyl ester (4j)

[0758]

[0759] i. Preparation of ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanine isobutyl ester (3j)

[0760] Compound 3j was prepared from 2j (5.64 g, 15.3 mmol, 1.0 eq) and pentafluorophenol as a mixture of two diastereomers according to the procedure described for the preparation of 3i. 1H NMR(400MHz,DMSO-d6)δ8.22-8.07 (m,1H),8.05-7.96(m,1H),7.84(DDD,J=8.1,2.6,1.3Hz,1H),7.71-7.46(m,4H),7.11(ddd, J=15.3,13.8,9.9Hz,1H),4.22-4.01(m,1H),3.94-3.68(m,2H),1.82(dhept,J=11.7,6.7Hz, 1H),1.36(ddd,J=11.1,7.1,1.2Hz,3H),0.94-0.75(m,6H); 19 F NMRδ F -153.32 to -154.10 (m, 2F), -159.86 to -160.61 (m, 1F), -163.07 (dtd, J = 33.5, 23.2, 3.9 Hz, 2F); 31 PNMRδ p 0.93, 0.48; LCMS: m / z 518(M+H) + .

[0761] ii.4j Preparation

[0762] Compound 4j was prepared from aza-T-dCyd (100 mg) and 3j (254 mg, 1.2 eq.) according to the procedure described for the preparation of 4a. Diastereomer 1: 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.13-8.03 (m,1H),7.97-7.86(m,1H),7.72(dd,J=5.7,3.7Hz,1H),7.59-7.42(m,6H),6.19(dd,J=1 2.9,10.0Hz,1H),6.09(dd,J=8.2,6.5Hz,1H),5.42(d,J=4.0Hz,1H),4.48-4.26(m,2H), 4.19(dt,J=10.7,6.4Hz,1H),3.91(ddt,J=17.1,9.9,7.1Hz,1H),3.80-3.62(m,2H),3.52(td,J=7.1,3.0H z,1H),2.38-2.11(m,2H),1.77(dp,J=13.3,6.6Hz,1H),1.25(dd,J=7.3,1.1Hz,3H),0.80(d,J=6.7Hz,6H); 31 P NMRδ p 3.60; HR-MS: for C 25 H32 N5O7PS.H calculated (M+H) 578.1833, found 578.1832; HPLC purity = 97 (% of AUC), t R =7.55 minutes. Diastereomer 2: 1 HNMR(400MHz,DMSO-d6)δ8.55(s,1H),8.14-8.03(m,1H),7.97- 7.86(m,1H),7.73(dd,J=5.4,3.9Hz,1H),7.63-7.39(m,6H),6.20(dd,J=12.8,10.1Hz, 1H), 6.09 (dd, J=8.2, 6.5Hz, 1H), 5.39 (d, J=3.9Hz, 1H), 4.43-4.26 (m, 2H), 4.10 (dt, J= 10.7,6.8Hz,1H),3.97-3.87(m,1H),3.78(t,J=6.4Hz,2H),3.48-3.40(m,1H),2.37(ddd, J=12.7,8.4,4.1Hz,1H),2.22(ddd,J=13.2,6.6,4.2Hz,1H),1.79(dq,J=13.3,6.7Hz,1H), 1.26(dd,J=7.1,1.0Hz,3H),0.83(d,J=6.7Hz,6H); 31 P NMRδ p 3.71; HR-MS: for C 25 H 32 N5O7PS.H calculated (M+H) 578.1833, found 578.1832; HPLC purity = 97 (% of AUC), t R =7.81 minutes.

[0763] m. Synthesis of ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine 2-ethylbutyl ester (4k)

[0764]

[0765] i. Preparation of ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (3k)

[0766] Compound 4k was prepared from 3k and pentafluorophenol as a mixture of two diastereomers according to the procedure described for the preparation of 3i. 1H NMR(400MHz, DMSO-d6)δ8.19-8.07(m,1H),8.00(dtt,J=5.5,3.5,0.60Hz,1H),7.87-7.78(m,1H),7.69-7 .47(m,4H),7.10(ddd,J=16.3,13.8,9.9Hz,1H),4.20-3.80(m,3H),1.49-1.20(m,7H),0.83-0.73(m,6H); 19 F NMRδ F -153.22 to -154.29 (m, 2F), -160.22 (dtd, J = 27.3, 23.4, 3.4 Hz, 1F), -163.08 (dtd, J = 38.6, 23.7, 4.0 Hz, 2F); 31 P NMRδ p 0.91 and 0.45; LCMS: m / z 546(M+H) + .

[0767] ii. Preparation of 4k

[0768] Compound 4k was prepared from aza-T-dCyd (100 mg) and 3k (254 mg, 1.2 eq.) according to the procedure described for the preparation of 4a. Diastereomer 1: 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.15-8.07 (m,1H),7.98-7.87(m,1H),7.71(q,J=4.6,4.0Hz,1H),7.59-7.39(m,6H),6.18(dd,J=1 2.9,10.0Hz,1H),6.09(dd,J=8.1,6.6Hz,1H),5.42(d,J=3.9Hz,1H),4.42-4.27(m,2H), 4.19(dt,J=10.7,6.5Hz,1H),3.93-3.81(m,3H),3.52(td,J=7.2,3.0Hz,1H),2.37-2 .14(m,2H),1.38(hept,J=6.0Hz,1H),1.27-1.15(m,8H),0.76(td,J=7.5,1.0Hz,6H); 31 P NMRδ p 3.63; HR-MS: for C 27 H 36 N5O7PS.H calculated (M+H) 606.2146, found 606.2145; HPLC purity = 97 (% of AUC), t R= 8.75 minutes. Diastereomer 1: 1 H NMR(400MHz,DMSO-d6) δ8.55(s,1H),8.16-8.05(m,1H),8.01-7.88(m,1H),7.80-7.67(m,1H),7.62-7.38(m, 6H), 6.19 (dd, J=12.8, 10.0Hz, 1H), 6.09 (dd, J=8.2, 6.5Hz, 1H), 5.39 (d, J=3.9Hz, 1H), 4.39-4.25(m,2H),4.10(dt,J=10.7,6.8Hz,1H),4.00-3.85(m,3H),3.46(td,J=7.1,3.0H z,1H),2.37(ddd,J=12.7,8.2,4.0Hz,1H),2.21(ddd,J=13.3,6.5,4.1Hz,1H),1.41(hept, J=6.1Hz,1H),1.28-1.20(m,7H),0.78(t,J=7.5Hz,6H); 31 P NMRδ p 3.72; HR-MS: for C 27 H 36 N5O7PS.H calculated (M+H) 606.2146, found 606.2145; HPLC purity = 98 (% of AUC), t R =8.95 minutes.

[0769] n. Synthesis of ((((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazine-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine isopropyl ester (4l)

[0770]

[0771] i. Preparation of ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanine isopropyl ester (3l)

[0772] Intermediate 31 was prepared from 21 (5.17 g, 14.5 mmol, 1.0 eq) and pentafluorophenol (2.94 g, 16.0 mmol, 1.1 eq) to give 1.76 g (24%) of a white solid as a mixture of two diastereomers. 1H NMR (400 MHz, DMSO-d6) δ8.19-8.08 (m, 1H), 8.06-7.95 (m, 1H), 7.88-7.80 (m, 1H), 7.70-7.48 (m, 4H), 7.08 (ddd, J = 23.0, 13.8, 9.9 Hz, 1H), 4.88 (dhept, J = 22.8, 6.3 Hz, 1H), 4.16-3.89 (m, 1H), 1.34 (ddd, J = 10.9, 7.1, 1.2 Hz, 3H), 1.22-1.06 (m, 6H), 31P NMR δp 0.90 (diastereomer 1), 0.49 (diastereomer 2); 19F NMR (400 MHz, DMSO-d6) δf -153.40 to -154.04 (m, 2F), -159.98 to -160.57 (m, 1F), -163.07 (dtd, J=28.0, 23.9, 4.1 Hz, 2F); LCMS: m / z 504 (M+H)+.

[0773] II. Preparation of 4L

[0774] Compound 41 was prepared from aza-T-dCyd (100 mg) and 31 (247 mg, 1.2 eq) according to the procedure described for the preparation of 4a. Diastereomer 1: 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.17-8.03 (m,1H),7.94-7.85(m,1H),7.72(dd,J=5.7,3.7Hz,1H),7.62-7.30(m,7H),6.15(dd,J= 12.9,10.0Hz,1H),6.11-6.05(m,1H),5.42(d,J=3.9Hz,1H),4.80(hept,J=6.2Hz,1H), 4.44-4.27(m,2H),4.19(dt,J=10.7,6.5Hz,1H),3.52(td,J=7.0,3.0Hz,1H),2.36-2.2 7(m,1H),2.22(ddd,J=13.2,6.6,4.1Hz,1H),1.22(d,J=1.1Hz,4H),1.08(dd,J=7.8,6.2 Hz,6H); 31 P NMRδ p 3.60; HR-MS: for C24 H 30 N5O7PS.H calculated (M+H) 564.1676, found 564.1676; HPLC purity = 98 (% of AUC), t R = 6.80 min. Diastereomer 2: 1 H NMR(400 MHz, DMSO-d6)δ8.55(s,1H),8.19-8.05(m,1H),8.00-7.87(m,1H),7.79-7.66(m,1H), 7.64-7.43(m,6H),6.23-6.02(m,2H),5.39(d,J=3.9Hz,1H),4.85(hept,J=6.3Hz,1H),4 .42-4.29(m,2H),4.11(dt,J=10.7,6.8Hz,1H),3.86(tq,J=10.2,7.1Hz,1H),3.47(td,J =7.2,2.9Hz,1H),2.39(ddt,J=12.7,8.3,4.4Hz,1H),2.22(ddd,J=13.3,6.6,4.1Hz,1H),1.23(dd,J=7.2,0.9Hz,3H),1.13(dd,J=6.3,1.5Hz,6H); 31 P NMRδ p 3.74; HR-MS: for C 24 H 30 N5O7PS.H calculated (M+H) 564.1676, found 564.1676; HPLC purity = 98 (% of AUC), t R =7.00 minutes.

[0775] o. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isobutyl ester (5b)

[0776]

[0777] Compound 5b was prepared from aza-T-dCyd (100 mg) and 3b (222 mg, 1.2 equiv) according to the procedure described for the preparation of 4a. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.5 Hz, 1H), 7.43-7.28 (m, 2H), 7.22-7.10 (m, 6H), 6.36 (dd, J = 8.3, 6.7 Hz, 1H), 6.04 (dd, J = 13.2, 10.1 Hz, 1H), 5.74 (d, J = 7.4 Hz, 1H), 5.37 (d, J = 3.8 Hz, 1H), 4.31 (p, J = 3.5 Hz, 1H), 4.19 (ddd, J = 10.6, 7.7, 6.4 Hz, 1H), 4.03 (dt, J = 10 .6,6.4Hz,1H),3.88-3.71(m,4H),2.13(ddd,J=8.6,6.6,3.5Hz,2H),1.87-1.79(m,1H),1.24(dd,J=7.1,0.9Hz,3H),0.86-0.84(m,6H); HR-MS: (M+H) calculated for C22H31N4O7PS.H is 527.1724, found to be 527.1724; 31P NMR δp 3.20; HPLC purity=97(% of AUC), tR=16.62min.

[0778] p. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (5c)

[0779]

[0780] Compound 5c was prepared from aza-T-dCyd (100 mg) and 3c (244 mg, 1.2 equiv) according to the procedure described for the preparation of 4a. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.5 Hz, 1H), 7.35 (tt, J = 7.4, 2.2 Hz, 2H), 7.22-7.10 (m, 5H), 6.35 (dd, J = 8.4, 6.7 Hz, 1H), 6.03 (dd, J = 13.1, 10.1 Hz, 1H), 5.74 (d, J = 7.4 Hz, 1H), 5.37 (d, J = 3.7 Hz, 1H), 4.31 (p, J = 3.5 Hz, 1H), 4.19 (ddd, J = 10.7, 7.7, 6.4 Hz, 1H), 4.02-3.79 (m, 4H), 3.42 (dd, J = 4.7, 2.8 Hz, 2H), 2.20-2.04 (m, 2H), 1.43 (dp, J = 12.6, 6.3 Hz, 1H), 1.29-1.19 (m, 7H), 0.82 (dd, J = 7.4, 2.6 Hz, 6H); HR-MS: (M+H) calculated for C24H35N4O7PS.H is 555.2037, found 555.2036; 31P NMR δp 3.20; HPLC purity = 99 (% of AUC), tR = 20.0 min.

[0781] q. Synthesis of ((S)-(((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (5d)

[0782]

[0783] Compound 5d was prepared from aza-T-dCyd (100 mg) and 3d (222 mg, 1.2 equiv) according to the procedure described for the preparation of 4a. 1H NMR (400MHz, DMSO-d6) δ7.85 (d, J=7.5Hz, 1H), 7.40-7.31 (m, 2H),7.25-7.08(m,6H),6.36(dd,J=8.3,6.8Hz,1H),6.00(dd,J=13.2,10.0Hz,1H),5.80 -5.67(m,1H),5.37(d,J=3.8Hz,1H),4.85(dq,J=12.6,6.3Hz,1H),4.32(q,J=3.5Hz,1H), 4.19 (ddd, J = 10.6, 7.7, 6.4 Hz, 1H), 4.10-3.98 (m, 1H), 3.86-3.67 (m, 1H), 3.43 (ddd, J = 8.2, 5.9, 2.6 Hz, 1H), 2.13 (dt, J = 8.7, 4.0 Hz, 2H), 1.21 (dd, J = 7.1, 0.9 Hz, 4H), 1.18-1.08 (m, 9H); HR-MS: for C 21 H 29 The calculated (M+H) of N4O7PS.H is 513.1567, and the found is 513.1571; 31 P NMRδ p 3.13; HPLC purity = 94 (% of AUC), t R =16.05 minutes.

[0784] r. Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxytetrahydrothiophen-2-yl)methyl dihydrogen phosphate (16: SRI-43590)

[0785]

[0786] i. Preparation of 4-amino-1-((2R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxytetrahydrothiophen-2-yl)pyrimidin-2(1H)-one (A)

[0787] A solution of 4-amino-1-[(2R, 4R, 5R)-4-hydroxy-5-(hydroxymethyl)thiolan-2-yl]pyrimidin-2-one (130.0 mg, 0.534 mmol) T-dCyd, tert-butyl(chloro)diphenylsilane (190.0 mg, 0.691 mmol) and imidazole (94.0 mg, 1.38 mmol) in DMF (2 mL) was stirred at room temperature for 2.5 h. The reaction mixture was diluted with 20 mL of H2O and extracted with EtOAc (40 mL×3). The organic layers were combined and washed with brine (50 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 330 mg (crude) of 4-amino-1-[(2R,4R,5R)-5-[[(tert-butyldiphenylsilyl)oxy]methyl]-4-hydroxythiolan-2-yl]pyrimidin-2-one A. This was used in the next step without further purification. LCMS [M+1] + =482.

[0788] ii. Preparation of (2R,3S,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrothiophene-3-ylbenzoate (B)

[0789] Benzoyl chloride (260.0 mg, 1.85 mmol) was added to a solution of 4-amino-1-[(2R, 4R, 5R)-5-[[(tert-butyldiphenylsilyl)oxy]methyl]-4-hydroxythiolan-2-yl]pyrimidin-2-one A (330.0 mg, crude) in pyridine (2 mL) at 0°C. The resulting solution was stirred at room temperature for 1.5 h. The resulting solution was diluted with 50 mL of H2O and extracted with EtOAc (40 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was concentrated under vacuum and the residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (60%-80%) to give 280 mg of (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-2-[[(tert-butyldiphenylsilyl)oxy]methyl]thiolan-3-ylbenzoate B as a white solid. LCMS [M+1] + =690.

[0790] iii. Preparation of (2R,3S,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrothiophene-3-yl benzoate (C)

[0791] At room temperature, to a solution of (2R, 3R, 5R) -5- (4- benzamido -2- oxopyrimidine -1-yl) -2- [[ (tert-butyldiphenylsilyl) oxy] methyl] thiolane -3- ylbenzoate B (280.0 mg, 0.405 mmol) in THF (2mL) was added a solution of TBAF in THF (1M, 0.8mL). The solution was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (20mL) and extracted with EtOAc (30mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (ca. 98%) to give 150 mg of (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-2-(hydroxymethyl)thiolan-3-yl benzoate C as a white solid. LCMS [M+1] + =452. 1 H NMR (300MHz, DMSO-d6) δ11.30(s,1H),8.62(d,J=7.6Hz,1H),8.02(dd,J=7.5,2.1 Hz,4H),7.72(t,J=7.4Hz,1H),7.67-7.48(m,5H),7.44(d,J=7.5Hz,1H),6.48(t,J=7.6H z,1H),5.79-5.68(m,1H),5.38(t,J=5.3Hz,1H),3.73(dt,J=7.9,4.3Hz,3H),2.65(td,J =9.4,8.2,3.5Hz,2H).

[0792] iv. Preparation of (2R,3S,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-(((hydroxyphosphinoyl)oxy)methyl)tetrahydrothiophen-3-ylbenzoate (D)

[0793] To a solution of (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-2-(hydroxymethyl)thiolan-3-ylbenzoate C (130.0 mg, 0.288 mmol) in pyridine (1 mL) at 0°C was added diphenylphosphonate (336.0 mg, 1.435 mmol). The reaction was stirred at room temperature for 2 h. A solution of Et3N (0.2 mL) and H2O (0.2 mL) was then added at 0°C, and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (0-100% CH3CN (0.05% NH4HCO3) in H2O) to give 105 mg of [(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-3-(benzoyloxy)thiolan-2-yl]methoxyphosphinic acid D as a white solid. LCMS [M+1] + =516.

[0794] v. Preparation of (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrothiophen-3-ylbenzoate (E)

[0795] To a solution of [(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-3-(benzoyloxy)thiolan-2-yl]methoxyphosphinic acid D (105.0 mg, 0.205 mmol) in pyridine (1.5 mL) at 0°C was added N,O-bis(trimethylsilyl)acetamide (207.0 mg, 1.02 mmol) and stirred at room temperature for 0.5 h. A solution of I2 in DMF (0.6 M, 0.34 mL) was then added at 0°C and the resulting solution was stirred at room temperature for 0.5 h. H2O (0.36 mL) was then quickly injected into the reaction mixture and stirred at room temperature for 0.5 h. The residue was purified by reverse phase flash chromatography (0-100% CH3CN (0.05% NH4HCO3) in H2O) to give 60 mg of [(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-3-(benzoyloxy)thiolan-2-yl]methoxyphosphonic acid E as a white solid. LCMS [M+1] + =482.

[0796] Preparation of vi.16

[0797] A solution of [(2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1-yl)-3-(benzoyloxy)thiolan-2-yl]methoxyphosphonic acid E (60.0 mg, 0.112 mmol) in 7M NH3 / MeOH (1 mL) was stirred at room temperature for 20 h. The solution was concentrated under vacuum. The residue was purified by Prep-HPLC (column: XBridge Prep Amide OBD Column, 5 μm 13 nm; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 95B to 70B in 9 minutes; 254 / 220 nm; RT1: 8.6;) to give 16.1 mg of [(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxythiolan-2-yl]methoxyphosphonic acid 16 as a white solid. LCMS [M+1] + =324. 1 H NMR (300MHz, D2O) δ8.24 (d, J=7.7 Hz,1H),6.26(t,J=7.1Hz,1H),6.07(d,J=7.7Hz,1H),4.54(q,J=4.2Hz,1H),4 .10-3.88(m,2H),3.55(q,J=4.8Hz,1H),2.52-2.35(m,1H),2.30-2.15(m,1H).

[0798] 2. Biological Experiments

[0799] a. Cell viability assay

[0800] KG1a (CCL-246.1, ATCC) and CCRF-CEM (CCL-199, ATCC) cells were cultured in T-75 flasks in RPMI-1640 medium containing 10% FBS to a concentration of 1 × 10 6 Exponential cells were used for the assay. Day 1: 7.5 × 10 cells / mL were seeded in each well of a 96-well plate. 3 cells. Day 2: Treat cells for 72 hours with serial dilutions of each compound (starting at 20 μM) or DMSO as a control. Day 5: Add CellTiter Glo (G9241, Promega) to the culture medium of each well and measure by a plate reader (Synergy 4, Biotek). Data analysis: Use GraphPad Prism 7 (GraphPad).

[0801] b. Western Blot Analysis

[0802] Cells were treated with serial dilutions of each compound (starting at 100 μM for HCT-116 and NCI-H23 cells and 20 μM for KG-1a and CCRF-CEM cells) or DMSO as a control for 96 hours. Cell lysates were collected and proteins were separated using SDS-PAGE gels, transferred to nitrocellulose membranes, blocked in 5% skim milk in TBS-T, and probed overnight with anti-DNMT-1 (1:7000) rabbit polyclonal antibody (cat# ab19905, Abcam) in 5% skim milk in TBS-T. The membrane was washed three times with TBS-T. At room temperature, anti-rabbit IgG (7074p2, Cell Signaling) secondary antibodies were added to 5% skim milk in TBS-T at a concentration of 1:5000 within two hours. The membrane was then washed three times with TBS-T for 5 minutes each. The membrane was then incubated with SuperSignal West Pico chemiluminescent substrate (#34080 Thermo) and exposed to the membrane. The membrane was stripped with stripping buffer (#21059, Thermo) and reprobed with mouse anti-tubulin 1:10,000 (T9026, Sigma) and anti-mouse IgG 1:5,000 (7076p2, Cell Signaling).

[0803] c. Cytidine deaminase activity

[0804] 77.5×10 3 Cells / well were placed in duplicate in 96-well plates. Tetrahydrouridine (THU), a cytidine deaminase inhibitor, was administered in a 10-point serial dilution of 1:5, with the highest dose being 100 μM, as a control. Compound 2 and Aza-T-dCyd were administered in a 10-point serial dilution of 1:5, with the highest dose being 20 μM, in the presence of 20 μM THU. Cells were cultured for 72 hours in the presence of the compounds, and then viability was determined by cell titer glow.

[0805] d. Deoxycytidine kinase activity

[0806] 7.5×10 3Cells / well were placed in duplicate in a 96-well plate. In the presence of 20 μM 2-deoxycytidine (dCyd, Sigma Cat#: D3897, CAS 951-77-9), a deoxycytidine kinase inhibitor, both compound 2 and Aza-T-dCyd were administered in a 10-point serial dilution of 1:5, with the highest dose being 5 μM. Cells were cultured for 72 hours in the presence of the compounds. CellTiter Glo (G9241, Promega) was added to the culture medium of each well and measured by a plate reader (Synergy 4, Biotek). The results were analyzed by GraphPad Prism 7 (GraphPad).

[0807] e. Nucleoside transporter (HENT-1) activity

[0808] 7.5×10 3 Cells / well were placed in duplicate in 96-well plates. In the presence of 5 μM of dipyridamole (DPD, Sigma Cat#: D9766 CAS 58-32-2) (a hENT-1 inhibitor), compound 2 and Aza-T-dCyd were administered in 10-point serial dilutions of 1:5, with the highest dose being 5 μM. Cells were cultured for 72 hours in the presence of the compound. CellTiter Glo (G9241, Promega) was added to the culture medium of each well and measured by a plate reader (Synergy 4, Biotek). The results were analyzed by GraphPad Prism 7 (GraphPad).

[0809] 3. Characterization of 4′-thio-nucleotides and nucleoside analogs

[0810] A list of compounds evaluated for anticancer activity is shown in Table 1 below.

[0811] Table 1.

[0812]

[0813]

[0814]

[0815]

[0816]

[0817] 4. Anticancer activity of 4′-thio-nucleotides and nucleoside analogs

[0818] The activity of the compounds in various cell lines was Figure 1A -D (KG-1 cells) and Figure 2A -D (CEM cells) and are shown in Table 2 below.

[0819] Table 2.

[0820]

[0821] 4. Effects of HENT-1 transporter on nucleotide 3 and its parent drug AZA-T-DCYD

[0822] Table 3 below shows representative data illustrating the effect of the hENT-1 transporter on nucleotide 3 and its parent drug Aza-T-dCyd (hENT inhibitor: dipyridamole (DPD)). Without wishing to be bound by theory, compound 3 does not significantly rely on hENT-1 to enter cancer cells and exert its anticancer effects.

[0823] Table 3.

[0824]

[0825] 5. Effects of cytidine deaminase (CDA) on nucleotide 3 and its parent AZA-T-DCYD

[0826] Table 4 below shows representative data illustrating the effects of CDA on nucleotide 3 and its parent Aza-T-dCyd (CDA inhibitor: tetrahydrouridine (THU)). Without wishing to be bound by theory, compound 3 does overcome CAD compared to its parent drug.

[0827] Table 4.

[0828]

[0829] 6. Effects of deoxycytidine kinase (DCK) activation on nucleotide 3 and its parent AZA-T-DCYD

[0830] Table 5 below shows representative data illustrating the effect of dCK activation on nucleotide 3 and its parent Aza-T-dCyd (dCK inhibitor: 2'-deoxycytidine (dCyd)). Without wishing to be bound by theory, compound 3 is independent of dCK activation compared to its parent drug.

[0831] Table 5.

[0832]

[0833] It will be apparent to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the present invention. Other embodiments of the present invention will be apparent to those skilled in the art by considering the specification and practice of the present invention disclosed herein. This specification and examples are intended to be considered as merely exemplary, with the true scope and spirit of the present invention being indicated by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by a formula selected from the following: Where R 12 is methyl; Where R 13 Selected from C1-C10 alkyl and C3-C10 cycloalkyl; Among them, Ar 1 is selected from phenyl, naphthyl and pyridyl, and is unsubstituted.

2. The compound according to claim 1, wherein the compound has a structure represented by the following formula:

3. The compound according to claim 1, wherein the compound has a structure represented by the following formula:

4. The compound according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is selected from:

6. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for treating cancer in a subject, wherein the cancer is selected from leukemia, colorectal cancer and myelodysplastic syndrome.

9. The use according to claim 8, wherein the cancer is leukemia.

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