KR20170005492A - Nucleoside derivatives for the treatment of cancer - Google Patents

Abstract

Methods for treating cancer, including compounds, compositions, and leukemias, are provided herein. In one embodiment, compounds and compositions of nucleoside derivatives that can be administered alone or in combination with other anti-cancer agents are disclosed.

Description

[0001] NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF CANCER [0002]

Nucleoside derivatives, pharmaceutical compositions comprising such compounds, methods for their preparation, and uses thereof for treating cancer are provided herein.

Cancer is a disease characterized mainly by uncontrolled division of abnormal cells derived from a given normal tissue and invasion of adjacent tissue by these malignant cells. Blood or lymphatic transport can cause cancer cells to spread to other parts of the body to reach the site lymph nodes and the distal site (metastasis). Cancer is a complex, multistage process that begins with secondary systemic biological changes that can proceed to neoplasms under certain conditions. There are over 100 different types of cancer, which can be grouped into broader categories. Major categories include carcinoma, sarcoma, leukemia, lymphoma and myeloma and central nervous system cancer. The incidence of cancer continues to increase as the general population gets older, as new cancers develop, and as the number of suspected populations (for example, those who become infected with AIDS or are overexposed to sunlight) increase. There is therefore a great need for new methods and compositions that can be used to treat patients with cancer.

Blood or hematopoietic malignancies are cancers of the blood or bone marrow, including leukemia and lymphoma. Leukemia is a type of blood cancer characterized by abnormal accumulation of immature leukocytes. There are four types: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). Acute leukemia is a rapidly progressive disease that causes accumulation of immature, dysfunctional cells in bone marrow and blood. Bone marrow often stops production of sufficient normal red blood cells, white blood cells and platelets. On the other hand, chronic leukemia progresses more slowly and leads to the production of a greater number of more mature, functional cells.

Leukemia can affect people of any age. The cause of most cases of leukemia is not known. Excessive doses of radiation and certain cancer therapies are possible causes. Approximately 90% of leukemia is diagnosed in adults. In 2000, some 256,000 children and adults worldwide developed some form of leukemia, resulting in 209,000 deaths. The case of chronic leukemia was 4.5 percent more common than acute leukemia. The most common types of leukemia in adults are chronic lymphocytic leukemia (CLL) with an estimated 14,590 new cases of acute myelogenous leukemia (AML) in 2013 and about 15,680 new cases in 2013. Chronic myelogenous leukemia (CML) was estimated to affect approximately 5,920 people in 2013 (data from Leukemia and Lymphoma Society, Facts 2013, August 2013).

The dramatic improvement in hematologic cancer treatment in the second half of the 20th century is mainly a result of chemotherapy. In addition, there are over 50 drugs that are used individually to treat these disorders, and a number of potential new therapies are under investigation in clinical trials. Current chemotherapy may cause complete relief, but the long-term disease-free survival rate for leukemia, especially AML, is low. For example, the overall relative survival rate for AML was estimated to be around 59% from 2003 to 2009. Thus, there is a clear and unmet need for an effective therapeutic agent for the treatment of blood cancer, including leukemia.

Methods of treating various cancers, including derivatives of various therapeutic agents, in one embodiment, phosphoramidate derivatives and cyclic phosphate derivatives, as well as pharmaceutical compositions and hematopoietic malignancies, are provided. The therapeutic agent is, for example, an anticancer agent derivatized to contain or contain a reactive group for attachment of a phosphoramidate and cyclic phosphate moiety, such as hydroxyl. Such therapeutic agents include, but are not limited to, nucleoside analogs, including nucleoside and non-cyclic nucleosides. Nucleoside analogs refer to structurally modified nucleosides. In one embodiment, a nucleoside or nucleoside analog is derivatized to remove hydrogen from the hydroxyl group at the 5'- and / or 3'-position to bind to the phosphoramidate and cyclic phosphate groups. In one embodiment, a nucleoside or nucleoside analog is derivatized to remove hydrogen from the hydroxyl group at the 5'- and / or 2'-position to bind to the phosphoramidate and cyclic phosphate groups. In one embodiment, phosphorodiamidates of nucleoside and nucleoside analogs are provided. In another embodiment, the compound is S-pivaloyl-2-thioethyl phosphoroamidate or S-hydroxypivaloyl-2-thioethyl phosphoroamidate. In yet another embodiment, S-pivaloyl-2-thioethyl disulfide phosphoramidate or S-2,2-dimethyl-3-oxopropanoate 2-thioethylbenzyl phosphoroamidate or nucleoside And benzyl phosphoramidate of nucleoside analogs. In another embodiment, the derivative is 1-methyl-2-nitro-1H-imidazole-5-methoxymethyl N-benzylphosphoramidate or 5-nitrofuran-2-methoxymethyl N-benzylphosphoramidate to be. In one embodiment, the derivative is 3 ', 5 ' -cyclic phosphate. In another embodiment, the derivative is 2 ', 5 ' -cyclic phosphate.

Phosphoramidates and cyclic phosphate compounds of various anticancer agents are provided. Anticancer agents include, but are not limited to, modified nucleosides. In another embodiment, the anti-cancer agent is clofarabine, cytarabine, isocradrivin, cladribine, fludarabine or nelalabine. In another embodiment, the anti-cancer agent is clofarabine, cytarabine, isocradrivin, cladribine or fludarabine. In another embodiment, the anticancer agent is clofarabine or cytarabine.

Justice

In order to facilitate an understanding of the disclosure provided herein, a number of terms are defined below.

In general, the nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutical chemistry, and pharmacology described herein are well known in the art and are commonly used. Unless otherwise defined, all technical scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The term "alkyl" as used herein, unless otherwise specified, refers to a saturated straight chain or branched hydrocarbon. In one embodiment, the alkyl group is a primary, secondary or tertiary hydrocarbon. In one embodiment, the alkyl group contains from 1 to 10 carbon atoms, i.e., C ₁ to C ₁₀ alkyl. In one embodiment, the alkyl group is methyl, CF _3, CCl _3, CFCl _2, CF ₂ Cl, _{ethyl, CH 2 CF 3, CF 2} CF 3, propyl, isopropyl, butyl, isobutyl, sec- butyl, t- Butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, preferably unsubstituted or halogenated alkyl groups, including halogenated alkyl groups. In one embodiment, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties in which an alkyl group may be substituted include, for example, those described in Greene, et < RTI ID = 0.0 > al., & (Fluoro, chloro, bromo, or iodo), oxo, hydroxyl, amino, alkylamino, and the like, as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition Alkoxy, aryloxy, thioalkoxy, thioaryloxy, alkylthio, aryloxy, aryloxy, aryloxy, aryloxy, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

The term "lower alkyl" as used herein, unless otherwise specified, refers to saturated straight-chain or branched hydrocarbons having 1 to 6 carbon atoms, i.e., C ₁ to C ₆ alkyl. In one embodiment, the lower alkyl group is a primary, secondary or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties, preferably unsubstituted.

The term "cycloalkyl ", as used herein, unless otherwise specified, refers to saturated cyclic hydrocarbons. In one embodiment, the cycloalkyl group may be saturated and / or bridged and / or non-bridged and / or fused bicyclic groups. In one embodiment, the cycloalkyl group contains from 3 to 10 carbon atoms, i.e., C ₃ to C ₁₀ cycloalkyl. In some embodiments, the cycloalkyl has 3 to 15 carbon atoms (C _3-15), 3 to 10 (C _3-10), or 3 to 7 (C _{3- 7).} In one embodiment, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, / RTI > or adamantyl. The term includes both substituted and unsubstituted cycloalkyl groups, including halogenated cycloalkyl groups. Non-limiting examples of moieties in which the cycloalkyl group may be substituted are, for example, those described in Greene, et < RTI ID = 0.0 > al. Halogen (fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkyl (optionally substituted), as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition Amino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate. In a preferred embodiment, the cycloalkyl is unsubstituted or substituted with one or more halogens.

"Alkenyl ", in certain embodiments, has about 11 or fewer carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, which may be linear or branched, Refers to a monovalent olefinically unsaturated hydrocarbon group having two olefinically unsaturated moieties. The term "alkenyl" refers to radicals having a "cis" or "trans" configuration or a mixture thereof, or alternatively a "Z" or "E" configuration or mixture thereof, as understood by those of ordinary skill in the relevant art . For example, C _2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of two to six carbon atoms or a branched unsaturated monovalent hydrocarbon radical of three to six carbon atoms. In certain embodiments, alkenyl of 2 to 20 (C _2-20), from 2 to 15 (C _2-15), from 2 to 10 (C _2-10), or 2 to ₆ (C _2- 6) carbon of a linear one-atom hydrocarbon radical, or from 3 to 20 (C _3-20), 3 to 15 (C _3-15), 3 to 10 (C _3-10), or 3 to ₆ (C _3- 6) Lt; / RTI > is a branched monovalent hydrocarbon radical of carbon atoms. Examples of alkenyl groups include but are not limited to ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl and 4-methylbutenyl. The term includes both substituted and unsubstituted alkenylene groups including halogenated cycloalkyl groups, preferably unsubstituted or halogenated cycloalkyl. Non-limiting examples of moieties in which the alkenylene group may be substituted are, for example, those described in Greene, et < RTI ID = 0.0 > al. Halogen (fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkyl (optionally substituted), as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition Amino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

The term "cycloalkenyl " as used herein, unless otherwise specified, refers to unsaturated cyclic hydrocarbons, including both substituted and unsubstituted cycloalkenyl groups, preferably unsubstituted. Non-limiting examples of moieties in which the cycloalkenyl group may be substituted are, for example, those described in Greene, et < RTI ID = 0.0 > al Halogen (fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkylamino, alkylamino, arylamino or alkylamino groups as protected, as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Alkylamino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

The term "alkenylene" means a linear or branched hydrocarbon chain containing 1, 2, 3, 4 or 5, in one embodiment, 1 or 2, in one embodiment, 1 or 2 carbon- Refers to branched divalent hydrocarbon radicals. The term "alkenylene" refers to radicals having a "cis" or "trans" configuration or a mixture thereof, or alternatively, a "Z" or "E" configuration, or mixtures thereof, as understood by those of ordinary skill in the relevant art . For example, C _2-6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenylene of 2 to 20 (C _2-20), from 2 to 15 (C _2-15), from 2 to 10 (C _2-10), or 2 to ₆ (C _2- 6) carbon 2 of the linear atoms in the hydrocarbon radical, or from 3 to 20 (C _3-20), 3 to 15 (C _3-15), 3 to 10 (C _3-10), or 3 to 6 (C _3-6) Lt; / RTI > is a branched divalent hydrocarbon radical of a carbon atom. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, prophenylene, butenylene, and 4-methylbutenylene. The term includes both substituted and unsubstituted groups, including halogenated groups, preferably unsubstituted. Non-limiting examples of moieties in which the alkenylene group may be substituted are, for example, those described in Greene, et < RTI ID = 0.0 > al. Halogen (fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkyl (optionally substituted), as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition Amino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

"Alkynyl ", in certain embodiments, may be straight or branched, having up to about 11 carbon atoms or having from 2 to 6 carbon atoms and having at least one or from one to two alkynyl unsaturation Refers to an acetylenically unsaturated hydrocarbon group. Non-limiting examples of the alkynyl group include acetylenic, ethynyl (-C? CH), propargyl (-CH ₂ C? CH), and the like. The term also includes both substituted and unsubstituted alkynyl groups, preferably unsubstituted. Non-limiting examples of moieties in which the alkynyl group may be substituted are, for example, those described in Greene, et al., Protective Groups in Organic Synthesis (Fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkylamino, arylamino, alkyl (methanesulphonyl), and the like, as taught in Wiley and Sons, Alkylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, Arylaminocarbonyl, acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

The term "aryl ", as used herein, unless otherwise indicated, refers to phenyl, biphenyl or naphthyl. The term includes both substituted and unsubstituted moieties. The aryl groups may be unsubstituted or as known to those of ordinary skill in the relevant arts, for example, by the methods described in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition Halogen, fluoro, chloro, bromo or iodo), alkyl, haloalkyl, alkenyl, alkynyl (for example, Alkyl, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, alkylcarbonyl, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphine, phosphonoacetic acid, Or at least one moiety selected from the group consisting of a phosphite and a phosphonate.

"Alkoxy" means a group -OR'where R is alkyl or cycloalkyl, wherein alkyl and cycloalkyl are as defined herein. The alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, Dimethylbutoxy and the like.

"Aryloxy" means a group -OR 'where R' is aryl or heteroaryl, wherein aryl and heteroaryl are as defined herein.

"Alkoxycarbonyl" refers to a radical-C (O) -alkoxy wherein alkoxy is as defined herein.

"Amino" refers to the radical -NH ₂ .

"Carboxyl" or "carboxy" refers to the radical -C (O) OH. "Carbonyl" refers to the radical -C (O) -.

The term "alkylamino "," arylamino ", or "alkylarylamino" refers to alkyl having 1 or 2 alkyl substituents (-NHR 'or -NR'R', wherein R 'is alkyl as defined herein) Or two aryl substituents (-NHR 'or -NR'R', where R 'is aryl as defined herein), or one alkyl substituent and one aryl substituent (-NR'R ", where R' And R "are alkyl as defined herein and the others are aryl as defined herein. In one embodiment, the alkyl substituent is lower alkyl. In another embodiment, the alkyl or lower alkyl is unsubstituted.

"Halogen" or "halo " refers to fluoro, chloro, bromo or iodo.

"Oxo" refers to ═O or ➝O.

"Thioalkoxy" means a group -SR 'where R is alkyl or cycloalkyl, each of which is as defined herein. "Thioaryloxy" refers to the group -SR 'where R' is aryl or heteroaryl, each of which is as defined herein.

"Alkyl disulfanyl" refers to the group R'-S-S-, wherein R 'is alkyl or cycloalkyl, each of which is as defined herein.

The term "heterocyclyl" or "heterocyclic" means that at least one of the non-aromatic ring atoms is a heteroatom independently selected from O, S or N; Refers to monovalent monocyclic non-aromatic ring systems and / or multicyclic ring systems containing at least one non-aromatic ring wherein the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclyl group is bonded to the remainder of the molecule through a non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system wherein the nitrogen or sulfur atom may optionally be oxidized And the nitrogen atom may optionally be quatemized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl can be attached to the main structure at any heteroatom or carbon atom to produce a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azetidinyl, benzodioxanyl, benzodioxolyl, benzofuranyl, benzopyranyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl , Benzoxazinyl,? -Carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroxy A pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinylimidazolyl group, Isoquinolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, imidazolinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isoquimarinyl, isoindolinyl, Naphthyl, octahydroindolyl, ox Pyridazinyl, pyrazolidinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, But are not limited to, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl and 1,3,5-trithianyl, But is not limited to. The term also includes both substituted and unsubstituted heterocyclyl groups. Non-limiting examples of moieties in which the heterocyclyl group may be substituted include, but are not limited to, unsubstituted or as known to those of ordinary skill in the relevant arts, for example, those disclosed in Greene, et al Halogen (fluoro, chloro, bromo or iodo), oxo, hydroxyl, amino, alkylamino, alkylamino, arylamino or alkylamino groups as protected, as taught in Protective Groups in Organic Synthesis, John Wiley and Sons, Alkylamino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaryl, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate.

The term "heteroaryl" refers to a monovalent monocyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring And / or multicyclic aromatic groups. The heteroaryl group is bonded to the remainder of the molecule via an aromatic ring. Each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms and / or 1 to 4 N atoms, with the proviso that the total number of heteroatoms in each ring is 4 or less, Each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl But are not limited to, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, Imidazolyl, imidazolyl, imidazolyl, imidazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolyl, But are not limited to, pyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl and thienopyridyl, But is not limited thereto. Examples of tricyclic heteroaryl groups include acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, But are not limited to, naphthalene and xanthanyl. Heteroaryl groups may be unsubstituted or substituted with one or more substituents as taught by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, as is known to those of ordinary skill in the relevant art Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl (such as, for example, but not limited to, Alkoxy, aryloxy, thioalkoxy, thioaryloxy, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycaryl, Acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfonic acid, phosphonic acid, phosphate or < RTI ID = 0.0 & Phosphonate, and the like.

The term "alkylaryl" refers to an aryl group having an alkyl substituent. The term "aralkyl" or "arylalkyl" includes alkyl groups having allyl substituents.

The term "alkylheterocyclyl" refers to a heterocyclyl group having an alkyl substituent. The term "alkylheterocyclyl" includes alkyl groups having heterocyclyl substituents.

The term "alkylheteroaryl" refers to a heteroaryl group having an alkyl substituent. The term "alkylheteroaryl" includes alkyl groups having heteroaryl substituents.

As used herein, the term "protecting group " refers to a group that is attached to an oxygen, nitrogen, or phosphorus atom to prevent further reaction or for other purposes, unless otherwise defined. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

A "pharmaceutically acceptable salt" refers to any salt of a compound provided herein, which retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical applications. Such salts can be derived from a variety of organic and inorganic counter-ions well known in the relevant art. Such salts include, but are not limited to, (1) organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, But are not limited to, tartaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- Examples of the acid addition salts include acid addition salts such as phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, , Camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl acetic acid, Citric acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, Acid addition salts formed with florisil acid, stearic acid, sulfamic acid cyclohexylsulfonyl, kwinsan, mu acid; Or (2) the acidic proton present in the parent compound is selected from the group consisting of (a) metal ions such as alkali metal ions, alkaline earth ions or aluminum ions or alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, (B) an organic base such as an aliphatic, alicyclic or aromatic organic amine such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanol But are not limited to, amine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N, N'- dibenzylethylenediamine, chloropropane, diethanolamine, N-methylglucamine piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, and the like, It is not.

Pharmaceutically acceptable salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and salts of non-toxic organic or inorganic acids, Such as hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionic acids, glycolates, But are not limited to, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3- (4-hydroxybenzoyl) Benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate ), Ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate 2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, , Lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexyl sulfamate, quinide, muconate, and the like.

The term "purine" or "pyrimidine" bases adenine, guanine, adenine, hypoxanthine, guanine, 7-to-aza, 7-aza having adenine, 2,6-diamino purine, 6-chloro-purine, N ⁶ - alkyl purine , N ⁶ -acyl purine wherein acyl is C (O) (alkyl, aryl, alkylaryl, or arylalkyl), N ⁶ -benzylpurine, ⁶ -halopurine, N ⁶ -vinylpurine, N ⁶ -acetylene based purine, N ⁶ - hydroxyalkyl purine, N ⁶ - alkylamino purine, N ⁶ - thioalkyl purine, N ² - alkyl purine, N ² - alkyl-6-thio-purine, thymine, cytosine, 5-fluoro-cytosine , 5-methylcytosine, 6-azapyrimidines such as ⁶ -azacytosine, 2- and / or 4-mercaptopyrimidine, uracil, 5-haloacyls such as 5-fluorouracil, pyrimidine, C ⁵ - benzyl pyrimidine, C ⁵ - halo-pyrimidine, C ⁵ - vinyl pyrimidine, C ⁵ - acetylenic pyrimidine, C ⁵ - acyl pyrimidine, C ⁵ - hydroxyalkyl purine, C ⁵ - amino escape limiter Dean, C ⁵ - cyano-pyrimidine, C ⁵ - EO escape limiter Dean, C ^{6-iodo-pyrimidine,} C ⁵ -Br- vinyl pyrimidine, C ⁶ -Br- vinyl pyrimidine, C ⁵ - Needle trophy limiter Dean, C ^{5-amino-pyrimidin-5-} But are not limited to, azacytinyl, azaclidinyl, 5-azuracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. When necessary or desired, the functional oxygen and nitrogen groups on the base can be protected. Suitable protecting groups are well known to those of ordinary skill in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and propionyl, Methanesulfonyl and p-toluenesulfonyl.

The term "acyl" or "O-linked ester" refers to a radical of the formula -OC (O) R 'wherein R' is alkyl or cycloalkyl (including lower alkyl), carboxylate residue of amino acid, Acyl, arylalkyl, such as benzyl, alkoxyalkyl, such as methoxymethyl, aryloxyalkyl, such as phenoxymethyl. For example, R 'is phenyl substituted with a substituted alkyl (including lower alkyl), aryl, such as chloro, bromo, fluoro, iodo, C ₁ to C ₄ alkyl or C ₁ to C ₄ alkoxy , Sulfonate esters such as alkyl or arylalkylsulfonyl such as methanesulfonyl, mono, di or triphosphate esters, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl such as benzyl , Alkoxyalkyl such as methoxymethyl, aryloxyalkyl, such as phenoxymethyl. The aryl group in the ester ultimately contains a phenyl group. Particularly, the acyl group is selected from the group consisting of acetyl, trifluoroacetyl, methyl acetyl, cyclopropyl acetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, , Diphenylacetyl, alpha -methoxy- alpha -trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2- Chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiophenacetyl, chlorosulfonylacetyl, 3- Methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodecafluoro Heptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro- Heptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodecafluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-di Methyl-3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4- (1,1, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1- Benzene-carboxy, O-acetylmandelyl, pivaloyl-acetyl, 1-adamantanecarboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropanecarboxyl, Methyl-1H-indazole-3-carbonyl, 2-methyl-1H-indazole-3-carbonyl, perfluorocyclohexylcarboxyl, perfluorocyclohexylcarboxyl, Propenyl, isobutyl Lauryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl.

The term "amino acid" refers to naturally occurring and synthetic alpha, beta, gamma or delta amino acids and includes amino acids found in proteins such as glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, But are not limited to, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. In one embodiment, the amino acid is an L-configuration. Alternatively, the amino acid is selected from the group consisting of alanyl, valinyl, leucinyl, isoleucinyl, furolinyl, phenylalaninyl, tryptophanyl, methionyl, glycinyl, serinyl, threoninyl, Β-alanyl, β-leucinyl, β-leucinyl, β-leucinyl, thiazinyl, thiazinyl, asparaginyl, glutaminyl, aspartate, glutaryl, ricinyl, argininyl, histidinyl, Isoleucinyl, isoleucinyl,? -Proprionyl,? -Phenylalaninyl,? -Tripitopanil,? -Methionyl,? -Glycinyl,? -Serinyl,? -Threoninyl, Butyryl, beta -cyclohexyl, isenyl, beta -tryrosinyl, beta -asparaginyl, beta -glutaminyl, beta -aspartoyl, beta -glutaryl, Lt; / RTI >

The term " substantially free of " or "substantially absent" for the nucleoside composition means that at least 85 or 90 wt%, in certain embodiments 95 wt%, 98 wt%, 99 wt%, or 100 wt% Refers to a nucleoside composition comprising a nucleoside, a specified diastereomer of such a nucleoside, or a designated enantiomer of such a nucleoside. In one embodiment, in the methods and compounds provided herein, the compound is substantially free of other unspecified compounds, other nucleosides, other diastereomers, or other enantiomers.

Similarly, the term "isolated " for a nucleoside composition includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight of nucleosides, Refers to a nucleoside composition comprising a chemical species or an enantiomer.

"Solvate" refers to a compound provided herein, or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by a non-shared intermolecular force. When the solvent is water, the solvate is a hydrate.

"Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance ratio for a given atom. An atom containing its natural isotopic composition may also be referred to herein as a "non-enriched" atom. Unless otherwise specified, the atoms of the compounds referred to herein are intended to represent any stable isotope of that atom. For example, unless specifically indicated otherwise, it is understood that when the position is specifically designated as "H" or "hydrogen ", the position has hydrogen in its natural isotopic composition.

"Isotopic enrichment" refers to the incorporation percentage of a particular isotopic amount at a given atom in a molecule, replacing the natural isotope abundance ratio of a given atom. For example, 1% deuterium enrichment at a given location means that 1% of the molecules in a given sample contain deuterium at the specified location. Since the spontaneous distribution of deuterium is about 0.0156%, the deuterium concentration at any position in the synthesized compound using the non-condensed starting material is about 0.0156%. Isotopic enrichment of the compounds provided herein may be determined using conventional analytical methods known to those of ordinary skill in the relevant art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

"Isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of the atom of interest. An "isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of the atom of interest.

The terms "alkyl", "cycloalkyl", "alkenyl", "cycloalkenyl", "alkynyl", "aryl", "alkoxy", "alkoxycarbonyl", " Quot ;, " alkylamino ", "arylamino "," thioalkoxy ", "heterocyclyl "," heteroaryl ", "alkylheterocyclyl "," alkylheteroaryl ", " The "alkaryl", "purine", "pyrimidine", "carboxyl" and "amino acid" groups optionally include deuterium at one or more sites where hydrogen atoms are present, wherein the deuterium composition of atoms or atoms is a natural isotopic composition .

The terms "alkyl", "cycloalkyl", "alkenyl", "cycloalkenyl", "alkynyl", "aryl", "alkoxy", "alkoxycarbonyl", " The term "alkylamino", "arylamino", "thioalkoxy", "heterocyclyl", "heteroaryl", "alkylheterocyclyl", "alkylheteroaryl", "acyl" Quot; caryl ", " purine ", "pyrimidine "," carboxyl ", and "amino acid" groups optionally contain carbon-13 in an amount different from the natural isotopic composition.

In addition, examples of moieties in which a particular functional group may be substituted include "alkyl", "cycloalkyl", "alkenyl", "cycloalkenyl", "alkynyl", "aryl" Cycloalkyl "and" heteroaryl "groups may be further substituted.

The term " proliferative disorder or disease "refers to undesired cell proliferation of one or more subset of cells in a multicellular organism that causes harm to the multicellular organism (i. E., Discomfort or reduced life expectancy). Proliferative disorders or diseases can occur in different types of animals and humans. For example, "proliferative disorder or disease " as used herein includes neoplastic disorders and other proliferative disorders.

The term " neoplastic disorder or disease "or" cancer "refers to a tumor caused by abnormal or uncontrolled cell growth. Examples of neoplastic disorders include, but are not limited to, hematopoietic disorders such as myeloproliferative disorders, thrombocythemia, essential thrombocytosis (ET), unidentified myelogenous leukemia, myelofibrosis (MF), myelofibrosis (MMM) Fibrosis (IMF), polycythemia vera (PV), cytopenias and total malignant myelodysplastic syndrome; But are not limited to, cancer, such as glioma, lung, breast, colon, prostate, gastric, esophageal, colon, pancreatic, ovarian, and hematologic malignancies.

The term "hematologic malignancy" refers to the blood-forming and immune system in the body - cancer of the bone marrow and lymphoid tissue. Examples of hematologic malignancies include, but are not limited to, bone marrow dysplasia, lymphoma, leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also referred to as Hodgkin's lymphoma) and myeloma, such as acute lymphocytic leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic enterohemorrhagic leukemia (CNL), acute undifferentiated leukemia (AMLL), lymphocytic leukemia (PML), pediatric bone marrow mononuclear leukemia (JMML), adult T-cell ALL, AML with three lineage dysplasia, AML / TMDS, mixed leukemia (MLL) (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM).

The term "leukemia" refers to malignant neoplasms of blood-forming tissues such as, but not limited to, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myelogenous leukemia. Leukemia may be recurrent, refractory or resistant to conventional therapy.

The term "recurrent" refers to a condition in which a subject or a stray animal that has had relief of cancer after therapy has a return of cancer cells.

The term " refractory or resistant "refers to a situation in which a subject or mammal has residual cancer cells in its body, even after intensive therapy.

The term " drug resistance "refers to a condition when the disease is not responsive to the treatment of the drug or drugs. Drug tolerance is inherent (meaning that the disease is not reactive to the drug or drugs), or it may be acquired (which stops the disease from responding to drugs or drugs for which the disease was previously reactive) ). ≪ / RTI > In certain embodiments, drug resistance is essential. In certain embodiments, drug resistance is acquired.

The term "EC50" as used herein refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response to 50% of the maximal expression of a particular response induced, induced or enhanced by a particular test compound.

The term "Emax" as used herein refers to the amount, concentration or dose of a particular test compound that achieves 100% inhibition of the maximal response in assays measuring such response.

The term "Eo" as used herein refers to the amount, concentration or dosage of a particular test compound that achieves 0% inhibition of the maximal response in assays measuring such response.

The terms "subject" and "patient ", as used herein, are used interchangeably herein. The terms "subject" and "subject" refer to an animal, such as a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat and mouse) and a primate Cynomolgus monkeys, chimpanzees and humans), and, for example, humans. In another embodiment, the subject is a livestock (e. G., Horse, cow, pig, etc.) or a pet (e. In one embodiment, the subject is a human.

The term "drug", "therapeutic agent" and "chemotherapeutic agent" as used herein refers to any agent (s), compound or pharmaceutical composition thereof, which can be used for the treatment or prevention of a disorder or one or more symptoms thereof have. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In one embodiment, the therapeutic agent is an agent that is known or used or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

"Therapeutically effective amount" refers to an amount of a compound or composition sufficient to effect treatment for the disease when administered to a subject for treating the disease. The "therapeutically effective amount" will vary, inter alia, with the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.

"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating a disease or disorder present in the subject. In another embodiment, "treating" or "treating" includes ameliorating at least one physical parameter that may not be identified by the subject. In another embodiment, "treating" or "treating" refers to modulating a disease or disorder either physically (e.g., stabilizing a recognizable symptom) or physiologically (e.g., stabilizing a physical parameter) . In another embodiment, "treating" or "treating" includes delaying the onset of a disease or disorder.

As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any agent (s) that can be used to prevent a disorder or one or more symptoms thereof. In certain embodiments, the term "prodrug" encompasses the compounds provided herein. In certain other embodiments, the term "prodrug" does not refer to a compound provided herein. For example, prophylactic agents are agents that are known or used or are currently being used to prevent or prevent the onset, development, progression and / or severity of a disorder.

The phrase "prophylactically effective amount ", as used herein, refers to an amount of a compound that causes the development, recurrence, or prevention or reduction of one or more symptoms associated with a disorder, or the prevention effect (s) of another therapy (E. G., Prophylactic agent) sufficient to promote or ameliorate < / RTI >

compound

Prodrug compounds of various therapeutic agents may be formed using methods available in the art and those disclosed herein. The therapeutic agent may be derivatized to include a reactive group for attachment of the phosphate moiety. Such therapeutic agents include, but are not limited to, nucleoside analogs including nucleosides and non-cyclic nucleosides.

As used herein, a " phosphoramidate or cyclic phosphate compound of a therapeutic agent "includes a therapeutic agent that is derivatized to include a phosphoramidate or cyclic phosphate group. The therapeutic agent is, for example, an anticancer agent derivatized to contain or contain a reactive group for attachment of a phosphoramidate and cyclic phosphate moiety, such as hydroxyl. Such therapeutic agents include, but are not limited to, nucleoside analogs including nucleosides and non-cyclic nucleosides. Nucleoside analogs refer to structurally modified nucleosides. In one embodiment, nucleoside or nucleoside analogs are prepared by removing hydrogen from the hydroxyl group at the 5'- and / or 3'-position to include a phosphate moiety containing a phosphoramidate and cyclic phosphate group Lt; / RTI > In another embodiment, a nucleoside or nucleoside analog includes a phosphate moiety containing a phosphoramidate and cyclic phosphate group by removing hydrogen from the hydroxyl group at the 5'- and / or 2'-position Lt; / RTI >

Modified phosphate derivatives of phosphoramidate and cyclic phosphate derivatives of nucleoside analogues, including natural and non-natural nucleosides described herein, are formed as described herein and can be used in the treatment of cancer. In one embodiment, the derivative moiety may be at the 3 ' position. In another embodiment, the derivative moiety may be in the 5 ' position. In another embodiment, derivative moieties may be connected at the 3 ', 5 ' positions to form cyclic derivatives together. In one embodiment, prodrug moieties may be connected at the 2 ', 5 ' positions to form cyclic derivatives together.

In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

(I)

here

Each X and Y is independently hydrogen, -OR ^a , -NR ^a R ^b , an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;

Wherein R ^a and R ^b are independently in each occurrence hydrogen, alkyl, aryl, arylalkyl, or heteroarylalkyl;

R is a nucleobase;

R ¹ is hydrogen, halo, cyano, alkynyl or -OR ⁶ ;

R ⁶ is hydrogen, alkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, or alkylarylaminocarbonyl.

In one embodiment, R ¹ is hydrogen, halo, or -OR ⁶ .

In one embodiment, when one of X and Y is a hydroxyl, the other is something other than hydroxyl.

In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

(I)

here

Y is

ego;

X is

ego;

R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

W is NH _2, halo, OMe, or OH;

T is NH _2, F, Cl or hydrogen;

R ¹ is hydrogen, halo, OH, protected OH, cyano, or alkynyl;

Q is OR < ³ >;

E is CR ⁴ R ⁵ ;

L is H, p-Me, p-OMe, p-Cl, or 3,4-Cl;

n is 1;

m is 1 or 2;

p is absent or O;

R ^y is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each of which is independently optionally substituted;

R < ² > is hydrogen or alkyl;

R ³ is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Optionally substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

≪ / RTI >

이거나, 또는R ⁶ is hydrogen,

Or

Items 1 R ⁶ and X and Y are combined together with the atom to which they are attached to form a 6-membered heterocyclic ring, where R ^6, and X and Y are one of the single divalent -O- with Or; or

R 1 out of ⁶ and X and Y dogs in combination with the atoms to which they are attached to form a 7-12- membered heterocyclic ring;

이고, X 및 Y 둘 다가

인 경우에, 적어도 1개의 R^y는 알킬 이외의 것이다.Where R is

, And both X and Y are

, At least one R ^y is other than alkyl.

In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

(I)

here

Y is

ego;

X is

ego;

R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

W is NH _2, Cl, OMe or OH;

T is NH _2, F, Cl or hydrogen;

R ¹ is hydrogen, OH, F, cyano or alkynyl;

Q is OR < ³ >;

E is independently CR < ⁴ > R < ⁵ >;

L is H, p-Me, p-OMe, p-Cl, or 3,4-Cl;

n is 1;

m is 1 or 2;

p is absent or O;

R ^y is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each of which is independently optionally substituted;

R < ² > is hydrogen or alkyl;

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

≪ / RTI >

이고, X 및 Y 둘 다가

인 경우에, 적어도 1개의 R^y는 알킬 이외의 것이다.Wherein R < ^{1 &}

, And both X and Y are

, At least one R ^y is other than alkyl.

In one of each of the above embodiments,

가 아니고;Y is

Not;

가 아니고;X is

Not;

R is Not;

T is not hydrogen;

W is not OH;

R < ¹ > is not cyano or alkynyl;

R ³ is not aralkyl.

Variator as provided herein, X, Y, Z, E, L, Q, W, T, n, m, p, R, R y, R z, R 1, R 2, R 3, R 4, R ⁵ , and R ⁶ are defined as follows. All combinations of these embodiments are within the scope of this disclosure.

In one embodiment, R ^y is alkyl, alkenyl, or alkynyl. In one embodiment, R ^y is alkyl.

In one embodiment, R ^y is alkenyl. In one embodiment, R ^y is alkynyl. In one embodiment, R ^y is hydroxyalkyl. In one embodiment, R ^y is 2-hydroxymethylprop-2-yl.

In one embodiment, Q is OR ^3, wherein R ³ are as defined herein. In one embodiment, Q is _{OCH 3, OCH 2 CH 3,} OCH (CH 3) 2 or OCH ₂ -phenyl. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

In one embodiment, R ^z is hydrogen.

In one embodiment, R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) _2, or CH ₂ phenyl.

In one embodiment, E is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each as defined herein. In one embodiment, R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is lower alkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is alkyl or cycloalkyl. In one embodiment, one of R < ⁴ > and R < ⁵ > is hydrogen and the other is lower alkyl. In one embodiment, one of R < ⁴ > and R < ⁵ > is hydrogen and the other is methyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is isobutyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is C ₃ -C ₅ cycloalkyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is cyclopentyl.

In one embodiment, Z is an oleic acid chain.

In one embodiment, W is NH ₂ and T is Cl or F. In one embodiment, W is Cl or OMe, T is NH _2. In one embodiment, W is OMe, T is NH _2. In one embodiment, W is Cl, T is NH _2.

In one embodiment, R ¹ is hydroxyl or fluoro. In one embodiment, R < ¹ > is hydroxyl. In one embodiment, R < ¹ > is fluoro.

In one embodiment, R < ² > is hydrogen or alkyl. In one embodiment, R < ² > is lower alkyl. In one embodiment, R < ² > is methyl. In one embodiment, R < ² > is hydrogen.

In one embodiment, R < ⁶ > is hydrogen.

인 경우에, 이는

중 어느 하나이다.R is

, Then this is

≪ / RTI >

이다.In one embodiment, R is < RTI ID = 0.0 >

to be.

이고, X 및 Y가 둘 다

인 경우에, R^y는 알킬 이외의 것이도록 선택된다.In certain embodiments, the compound of formula (I)

, And both X and Y are

, R ^y is selected to be other than alkyl.

인 경우에, R^y는 알킬 이외의 것이도록 선택된다.In certain embodiments, the compounds of formula (I) have both X and Y

, R ^y is selected to be other than alkyl.

인 경우에; X 또는 Y 중 적어도 1개는

이외의 것이도록 선택된다.In certain embodiments, the compound of formula (I)

in case of; At least one of X or Y is

Is selected to be other.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

In one embodiment, when X is OH, Y is p-NO ₂ PhCH ₂ O-.

In one embodiment, when X is OH, Y is -NHCH ₂ Ph.

In one embodiment, in the case where X is OH, Y is _{─N (CH 3) CH 2 Ph} .

In one embodiment, when X is OH, Y is -NHR ² .

In one embodiment, when X is OH, Y is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

In one embodiment, in the case where X is OH, Y is ─BH _3.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

이다.In one embodiment, when X is OH, Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 p-NO₂PhCH₂O─이다.In one embodiment, X is

, Y is p-NO ₂ PhCH ₂ O-.

인 경우에, Y는 ─NHCH₂Ph이다.In one embodiment, X is

, Y is -NHCH ₂ Ph.

인 경우에, Y는 ─N(CH₃)CH₂Ph이다.In one embodiment, X is

In the case where, Y is a _{─N (CH 3) CH 2 Ph} .

인 경우에, Y는 ─NHR²이다.In one embodiment, X is

, Y is -NHR < ^{2 &} gt ;.

인 경우에, Y는 ─NH(CH₂)₅N(CH₃)₂이다.In one embodiment, X is

, Y is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

인 경우에, Y는 ─BH₃이다.In one embodiment, X is

, Y is -BH < _{3 &} gt ;.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is p-NO ₂ PhCH ₂ O-.

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, then Y is -NHCH ₂ Ph.

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, then Y is -N (CH ₃ ) CH ₂ Ph.

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, then Y is -NHR ² .

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, then Y is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

In one embodiment, when X is p-NO ₂ PhCH ₂ O-, then Y is -BH ₃ .

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

이다.In one embodiment, when X is p-NO ₂ PhCH ₂ O-, Y is

to be.

In one embodiment, when X is -NHCH ₂ Ph, Y is -NHCH ₂ Ph.

In one embodiment, when X is -NHCH ₂ Ph, Y is -N (CH ₃ ) CH ₂ Ph.

In one embodiment, when X is -NHCH ₂ Ph, then Y is -NHR ² .

In one embodiment, when X is -NHCH ₂ Ph, Y is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

In one embodiment, when X is -NHCH ₂ Ph, then Y is -BH ₃ .

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

to be.

In one embodiment, when X is -NHCH ₂ Ph, then Y is

.

이고, R^y는 알킬이다. 한 실시양태에서, R^y는 히드록시알킬이다. 한 실시양태에서, R^y는 2-히드록실메틸프로프-2-일이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

And R ^y is alkyl. In one embodiment, R ^y is hydroxyalkyl. In one embodiment, R ^y is 2-hydroxymethylprop-2-yl.

이고, Q는 OR³이다. 한 실시양태에서, R³은 알킬이다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, when X is -NHCH ₂ Ph, then Y is

And Q is OR < ^{3 &} gt ;. In one embodiment, R < ³ > is alkyl. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is a _{─N (CH 3) CH 2 Ph} .

In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is a ─NHR ^2.

In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is a _{─NH (CH 2) 5 N (} CH 3) 2.

In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is a ─BH _3.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

이다.In one embodiment, when X is _{─N (CH 3) CH 2 Ph} , Y is

to be.

In one embodiment, when X is -NHR ² , then Y is -NHR ² .

In one embodiment, when X is -NHR ² , Y is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

In one embodiment, when X is -NHR ² , Y is - BH ₃ .

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

이다.In one embodiment, when X is -NHR < ^{2 &} gt ;, Y is

to be.

In one embodiment, when X is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is -NH (CH ₂ ) ₅ N (CH ₃ ) ₂ .

In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is - BH ₃ .

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

이다.In one embodiment, when X is - NH (CH ₂ ) ₅ N (CH ₃ ) ₂ , Y is

to be.

In one embodiment, in the case where X is ─BH _3, Y is a ─BH _3.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

이다.In one embodiment, in the case where X is ─BH _3, Y is

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는 이다.In one embodiment, X is

Y is < RTI ID = 0.0 > to be.

인 경우에, Y는

이고, Q는 OR³이고, 여기서 n, R², R³, R⁴, R⁵, R⁶, 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

And Q is OR ³ , wherein n, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and all other variables are as described elsewhere herein. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬 또는 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 이소부틸이다. 한 실시양태에서, R⁴ 또는 R⁵는 C₃-C₅ 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 시클로펜틸이다. 한 실시양태에서, Q는 OR³이고, 여기서 R³ 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, R ² is hydrogen and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, Q is OR ³ , wherein R ³ and all other variables are as described elsewhere herein.

인 경우에, Y는

이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 이소부틸이다. 한 실시양태에서, Q는 OR³이다. 한 실시양태에서, R³은 알킬이다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, R ² is hydrogen and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, Q is OR < ^{3 &} gt ;. In one embodiment, R < ³ > is alkyl. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이고, m은 1이고, Q는 OR³이고, 여기서 n, R², R³, R⁴, R⁵, R⁶ 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

M is 1 and Q is OR ³ wherein n, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and all other variables are as described elsewhere herein. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이고, m은 1이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬 또는 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 이소부틸이다. 한 실시양태에서, R⁴ 또는 R⁵는 C₃-C₅ 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 시클로펜틸이다. 한 실시양태에서, Q는 OR³이고, 여기서 R³ 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, M is 1, R ² is hydrogen, and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, Q is OR ³ , wherein R ³ and all other variables are as described elsewhere herein.

인 경우에, Y는

이고, m은 1이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 이소부틸이다. 한 실시양태에서, Q는 OR³이다. 한 실시양태에서, R³은 알킬이다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, M is 1, R ² is hydrogen, and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, Q is OR < ^{3 &} gt ;. In one embodiment, R < ³ > is alkyl. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

이고; X 및 Y 둘 다가

인 경우에, 적어도 1개의 R^y는 알킬 이외의 것이고, 다른 가변기는 본원의 다른 부분에 기재된 바와 같다.In one embodiment, R is < RTI ID = 0.0 >

ego; Both X and Y

, At least one R ^y is other than alkyl and the other variable groups are as described elsewhere herein.

이고; X 및 Y 둘 다가

인 경우에, R^y는 히드록시알킬이다. 한 실시양태에서, R^y는 2-히드록실메틸프로프-2-일이고, 다른 가변기는 본원의 다른 부분에 기재된 바와 같다.In one embodiment, R is < RTI ID = 0.0 >

ego; Both X and Y

, R ^y is hydroxyalkyl. In one embodiment, R ^y is 2-hydroxymethylprop-2-yl and the other variables are as described elsewhere herein.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이고, Q는 OR³이고, 여기서 n, R², R³, R⁴, R⁵, R⁶ 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

And Q is OR ³ , wherein n, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and all other variables are as described elsewhere herein. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬 또는 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 메틸이다. 한 실시양태에서, R⁴ 또는 R⁵는 C₃-C₅ 시클로알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 시클로펜틸이다. 한 실시양태에서, Q는 OR³이고, 여기서 R³ 및 다른 모든 가변기는 본원의 다른 부분에 기재된 바와 같다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, R ² is hydrogen and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, Q is OR ³ , wherein R ³ and all other variables are as described elsewhere herein.

인 경우에, Y는

이고, R²는 수소이고, R⁴ 또는 R⁵는 수소이다. 한 실시양태에서, R⁴ 또는 R⁵는 알킬이다. 한 실시양태에서, R⁴ 또는 R⁵는 메틸이다. 한 실시양태에서, Q는 OR³이다. 한 실시양태에서, R³은 알킬이다. 한 실시양태에서, Q는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

, R ² is hydrogen and R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, Q is OR < ^{3 &} gt ;. In one embodiment, R < ³ > is alkyl. In one embodiment, Q is OCH _3, OCH ₂ CH _3, or OCH (CH _{3) 2.}

인 경우에, Y는

이다. 한 실시양태에서, L은 수소이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be. In one embodiment, L is hydrogen.

인 경우에, Y는

이다. 한 실시양태에서, L은 수소이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be. In one embodiment, L is hydrogen.

인 경우에, Y는

이다. 한 실시양태에서, L은 수소이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be. In one embodiment, L is hydrogen.

인 경우에, Y는

이다. 한 실시양태에서, L은 수소이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be. In one embodiment, L is hydrogen.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

인 경우에, Y는

이다.In one embodiment, X is

Y is < RTI ID = 0.0 >

to be.

In one embodiment, L is hydrogen.

In some embodiments, when the phosphoramidate is substituted with at least one amino acid group, the amino acid is in the L-configuration. In one embodiment, the amino acid is alanine. In one embodiment, the amino acid is leucine.

In some embodiments, the phosphoramidate compound provided herein possesses a chiral center. In some embodiments, the phosphoramidate is diastereomerically enriched.

In some embodiments, the following is provided herein:

(a) a compound as described herein, for example, a compound of formula I and its pharmaceutically acceptable salts and compositions;

(b) a compound as described herein for use in therapy, for example, a compound of formula I and its pharmaceutically acceptable salts and compositions;

(c) a compound as described herein for use in the treatment and / or prevention of cancer, including leukemia, for example a compound of formula I and its pharmaceutically acceptable salts and compositions;

(d) compounds as described herein, e. g., compounds of formula (I) as described in more detail elsewhere herein;

(e) a pharmaceutical composition comprising a compound as described herein, for example a pharmaceutically acceptable carrier, diluent or excipient, together with a compound of formula I or a pharmaceutically acceptable salt thereof;

(f) a method of treating and / or preventing leukemia, in one embodiment, comprising administering an effective amount of a compound as described herein, for example, a compound of formula I, or a pharmaceutically acceptable salt or composition thereof. .

(g) an effective amount of a compound as described herein, e. g., a compound of formula I, or a pharmaceutically acceptable salt thereof, and one, two, three or more other therapeutic agents, Combination water.

In one embodiment, a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIa>

here

, 또는 OR⁷이고;Y is OH,

, Or OR &lt; ⁷ &gt;;

이고;R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

W is NH _2, halo, or OMe, and;

T is NH _2, F, or Cl, and;

R ¹ is hydrogen, halo, OH, or protected OH;

Q is OR &lt; ³ &gt;;

E is CR ⁴ R ⁵ ;

n is 1;

R &lt; ⁷ &gt; is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

.

In one embodiment, R &lt; ³ &gt; is not aralkyl.

In one embodiment, a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIa>

here

, 또는 OR⁷이고;Y is OH,

, Or OR &lt; ⁷ &gt;;

이고;R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

W is NH ₂ or Cl, and;

T is NH _2, Cl or F, and;

R &lt; ¹ &gt; is hydrogen, OH or F;

Q is OR &lt; ³ &gt;;

E is CR ⁴ R ⁵ ;

n is 1;

R &lt; ⁷ &gt; is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

.

In one embodiment, R &lt; ³ &gt; is not aralkyl.

The variables X, Y, Z, E, Q, W, T, n, R, R ^y , R ^z , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ as provided herein, As defined herein.

In one embodiment, E is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each as defined herein. In one embodiment, R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl, or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is lower alkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is alkyl or cycloalkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is lower alkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is methyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is isobutyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is C ₃ -C ₅ cycloalkyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is cyclopentyl.

In one embodiment, Z is an oleic acid chain.

In one embodiment, W is NH ₂ and T is Cl or F. In one embodiment, W is Cl, T is NH _2. In one embodiment, W is OMe, T is NH _2.

In one embodiment, R &lt; ¹ &gt; is hydrogen. In one embodiment, R &lt; ¹ &gt; is hydroxy or halo. In one embodiment, R &lt; ¹ &gt; is fluoro.

In one embodiment, R &lt; ² &gt; is hydrogen or alkyl. In one embodiment, R &lt; ² &gt; is lower alkyl. In one embodiment, R &lt; ² &gt; is methyl. In one embodiment, R &lt; ² &gt; is hydrogen.

In one embodiment, R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) _2, or CH ₂ phenyl.

이다. 한 실시양태에서, Y는 OR⁷이고, 여기서 R⁷은 본원에 정의된 바와 같다. 한 실시양태에서, Y는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH₂CH₃ 또는 OCH₂페닐이다.In one embodiment, Y is &lt; RTI ID = 0.0 &gt;

to be. In one embodiment, Y is OR ⁷ , wherein R ⁷ is as defined herein. In one embodiment, Y is OCH ₃ , OCH ₂ CH ₃ , or OCH (CH ₃ ) ₂ . In one embodiment, Q is OCH (CH _{3) 2.} In one embodiment, Q is OCH ₂ CH ₃ or OCH ₂ phenyl.

In some embodiments, when the phosphoramidate is substituted with an amino acid group, the amino acid is in the L-configuration. In one embodiment, the amino acid is alanine. In one embodiment, the amino acid is leucine.

In some embodiments, the phosphoramidate compound provided herein possesses a chiral center. In some embodiments, the phosphoramidate is diastereomerically enriched.

In one embodiment, a compound of formula IIb, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIb>

here

, 또는 OR⁷이고;Y is OH,

, Or OR &lt; ⁷ &gt;;

이고;R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

Q is OR &lt; ³ &gt;;

E is CR ⁴ R ⁵ ;

n is 1;

R &lt; ⁷ &gt; is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Optionally substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

.

In one embodiment, R &lt; ³ &gt; is not aralkyl.

The variables X, Y, Z, E, Q, W, T, n, R, R ^y , R ^z , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ as provided herein, As defined herein.

In one embodiment, E is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each as defined herein. In one embodiment, R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl, or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is lower alkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is alkyl or cycloalkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is lower alkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is methyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is isobutyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is C ₃ -C ₅ cycloalkyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is cyclopentyl.

In one embodiment, Z is an oleic acid chain.

In one embodiment, R &lt; ² &gt; is hydrogen or alkyl. In one embodiment, R &lt; ² &gt; is lower alkyl. In one embodiment, R &lt; ² &gt; is methyl. In one embodiment, R &lt; ² &gt; is hydrogen.

In one embodiment, R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) _2, or CH ₂ phenyl.

이다. 한 실시양태에서, Y는 OR⁷이고, 여기서 R⁷은 본원에 정의된 바와 같다. 한 실시양태에서, Y는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH₂CH₃ 또는 OCH₂페닐이다.In one embodiment, Y is &lt; RTI ID = 0.0 &gt;

to be. In one embodiment, Y is OR ⁷ , wherein R ⁷ is as defined herein. In one embodiment, Y is OCH ₃ , OCH ₂ CH ₃ , or OCH (CH ₃ ) ₂ . In one embodiment, Q is OCH (CH _{3) 2.} In one embodiment, Q is OCH ₂ CH ₃ or OCH ₂ phenyl.

In one embodiment, a compound of formula IIc, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIc>

here

, 또는 OR⁷이고;Y is OH,

, Or OR &lt; ⁷ &gt;;

이고;R is

ego;

R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;

Q is OR &lt; ³ &gt;;

E is CR ⁴ R ⁵ ;

n is 1;

R &lt; ⁷ &gt; is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

R ⁴ and R ⁵ are

i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Optionally substituted; or

ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.

.

In one embodiment, R &lt; ³ &gt; is not aralkyl.

The variables X, Y, Z, E, Q, W, T, n, R, R ^y , R ^z , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ as provided herein, As defined herein.

In one embodiment, E is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each as defined herein. In one embodiment, R ⁴ or R ⁵ is hydrogen. In one embodiment, R ⁴ or R ⁵ is alkyl, or cycloalkyl. In one embodiment, R ⁴ or R ⁵ is lower alkyl. In one embodiment, R ⁴ or R ⁵ is methyl. In one embodiment, R ⁴ or R ⁵ is isobutyl. In one embodiment, R ⁴ or R ⁵ is C ₃ -C ₅ cycloalkyl. In one embodiment, R ⁴ or R ⁵ is cyclopentyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is alkyl or cycloalkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is lower alkyl. In one embodiment, one of R &lt; ⁴ &gt; and R &lt; ⁵ &gt; is hydrogen and the other is methyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is isobutyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is C ₃ -C ₅ cycloalkyl. In one embodiment, one of R ⁴ and R ⁵ is hydrogen and the other is cyclopentyl.

In one embodiment, Z is an oleic acid chain.

In one embodiment, R &lt; ² &gt; is hydrogen or alkyl. In one embodiment, R &lt; ² &gt; is lower alkyl. In one embodiment, R &lt; ² &gt; is methyl. In one embodiment, R &lt; ² &gt; is hydrogen.

In one embodiment, R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) _2, or CH ₂ phenyl.

이다. 한 실시양태에서, Y는 OR⁷이고, 여기서 R⁷은 본원에 정의된 바와 같다. 한 실시양태에서, Y는 OCH₃, OCH₂CH₃, 또는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH(CH₃)₂이다. 한 실시양태에서, Q는 OCH₂CH₃ 또는 OCH₂페닐이다.In one embodiment, Y is &lt; RTI ID = 0.0 &gt;

to be. In one embodiment, Y is OR ⁷ , wherein R ⁷ is as defined herein. In one embodiment, Y is OCH ₃ , OCH ₂ CH ₃ , or OCH (CH ₃ ) ₂ . In one embodiment, Q is OCH (CH _{3) 2.} In one embodiment, Q is OCH ₂ CH ₃ or OCH ₂ phenyl.

In some embodiments, when the phosphoramidate is substituted with an amino acid group, the amino acid is in the L-configuration. In one embodiment, the amino acid is alanine. In one embodiment, the amino acid is leucine.

In some embodiments, the phosphoramidate compound provided herein possesses a chiral center. In some embodiments, the phosphoramidate is diastereomerically enriched.

In one embodiment, a compound of formula IId, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IId>

Wherein R and R &lt; ¹ &gt; are as defined herein.

In one embodiment, a compound of formula IIe, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIe>

Wherein R, R ¹ , R ² , R ⁶ , E, n, and Q are as defined herein.

In one embodiment, R ² is hydrogen; R &lt; ³ &gt; is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen.

In one embodiment, a compound of formula IIf, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

(IIf)

Wherein R, R ¹ , R ² , R ⁶ , E, m, n, and Q are as defined herein.

In one embodiment, R ² is hydrogen; R &lt; ³ &gt; is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen.

In one embodiment, a compound of Formula IIg, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIg>

Wherein R, R ¹ , and R ⁶ are as defined herein.

In one embodiment, a compound of formula IIh, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorphic form thereof is provided herein.

<Formula IIh>

Wherein R, R ¹ , R ² , R ⁶ , E, n, and Q are as defined herein.

In one embodiment, R ² is hydrogen; R &lt; ³ &gt; is alkyl; R ⁴ is hydrogen, R ⁵ is alkyl, or R ⁴ is alkyl and R ⁵ is hydrogen.

In one embodiment, the compounds provided herein are one of the following compounds:

Wherein E, Q, n, R ^z , R ² , and R ⁶ are as described in Formula I.

In another embodiment, the compounds provided herein are one of the following compounds:

Wherein R ^y , R ^z , and R ⁶ are as described in Formula I.

In another embodiment, the compounds provided herein are one of the following compounds:

Wherein E, Q, R ² , R ^z , and R ⁶ are as described in Formula I.

In another embodiment, the compounds provided herein are one of the following compounds:

Wherein E, Q, R ² , and R ^z are as described in Formula II.

In another embodiment, the compounds provided herein are one of the following compounds:

Where Q and R ^z are as described in Formula II.

In another embodiment, the compounds provided herein are one of the following compounds:

Wherein E, Q, R ² , and R ^z are as described in Formula IIb.

In another embodiment, the compounds provided herein are one of the following compounds:

Where Q, and R ^z are as described in Formula IIb.

In one embodiment, for example, a nucleoside that can be derivatized to include a phosphoramidate at the 5 'position includes:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

In one embodiment, the compounds provided herein are one of the following compounds:

Optically active compound

It is recognized that the compounds provided herein have multiple chiral centers, exist in optically active and racemic forms and can be isolated. Some compounds may exhibit polymorphism. It is to be understood that any racemic, optically-active, diastereoisomeric, polymorphic or stereoisomeric forms of the compounds provided herein, possessing the useful properties described herein, or mixtures thereof, are within the scope of the present invention. It is also possible to prepare optically active forms (for example, by resolution in racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases ) Are well known in the relevant art.

In particular, since the 1 ' and 4 ' carbons of the nucleoside are chiral, their nonhydrogen substituents (each a base and a CHOR group) can be either a cis (on the same side) or a trans . The four optical isomers are thus represented by the following formulas (when the sugar moiety is cultured on a horizontal plane so that the oxygen atom is at the rear): cis (both moieties are "stomach ", which is attributed to the coordination of the naturally occurring? -D nucleoside (C2 'substituent is "above" and C4' substituent is "below"), and a trans (C2 'substituent) Quot; below "and C4 'substituent is" above "). "D-nucleoside" is the cis nucleoside of the natural coordination and "L-nucleoside" is the cis nucleoside of the non-naturally occurring coordination.

Likewise, most amino acids are chiral (designated as L or D, where the L enantiomer is a naturally occuring enantiomer) and may exist as separate enantiomers.

Examples of methods for obtaining an optically active substance are known in the related art and include at least the following.

i) Physical Separation of Crystals - Technique for the manual separation of macroscopic determinations of individual enantiomers. This technique can be used when there are separate enantiomeric crystals present, i.e. when the material is an aggregate and the crystals are visually distinguishable;

ii) Simultaneous Crystallization - a technique of crystallizing individual enantiomers separately from a solution of a racemate, only if the latter is a solid state aggregate;

iii) enzymatic degradation - techniques for partially or completely separating racemates by different reaction rates for enantiomers using enzymes;

iv) Enzymatic Asymmetric Synthesis - a synthetic technique in which at least one synthetic step uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) Synthetic techniques for synthesizing the desired enantiomers from achiral precursors under conditions that produce asymmetric (i.e., chirality) within the product, which can be achieved using chemical asymmetric synthesis-chiral catalysts or chiral auxiliaries;

vi) Separation of diastereoisomeric racemic compounds by reaction with enantiomerically pure reagents (chiral auxiliaries) which convert the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatographic or crystallization by a more distinctive structural difference, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

vii) primary and secondary asymmetric conversions - equilibrating the diastereomers from the racemate to predominantly produce a solution of the diastereoisomers from the desired enantiomer, or preferentially the diastereomer from the desired enantiomer Crystallization and ultimately, in principle, disturb the equilibrium so that all of the material is converted to the crystalline diastereomeric form from the desired enantiomer. Then releasing the desired enantiomer from the diastereomer;

viii) Dynamic Decomposition - This technique involves the partial or complete decomposition of a racemate (or the addition of a partially decomposed compound) by the unequal reaction rate of the enantiomer and the chiral non-racemic reagent or catalyst under dynamic conditions Decomposition);

ix) Enantiomer-Specific Synthesis from Non-Racemic Precursors-The desired enantiomer is obtained from the non-chiral starting material, wherein the stereochemical integrity is a synthetic technique that is not damaged or only marginally damaged over the course of the synthesis ;

x) chiral liquid chromatography-techniques for separating the enantiomers of racemates by their different interactions with the stationary phase in the liquid mobile phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral materials that cause different interactions;

xi) chiral gas chromatography-techniques for volatilizing racemates and separating the enantiomers by different interactions with columns containing fixed non-racemic chiral adsorbent phases on the gas transfer phase;

xii) Extraction with chiral solvents - techniques for separating enantiomers by preferential dissolution of one enantiomer into a particular chiral solvent;

xiii) Technique for placing a transport-racemate across a chiral membrane in contact with a thin-film barrier. The barrier typically separates the two compatible fluids (one containing the racemate) and causes a preferential transport of driving forces, such as concentration or pressure differences, across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass.

In some embodiments, compositions of the present disclosure are provided that are substantially free of unqualified enantiomers of nucleoside or nucleoside derivatives. In one embodiment, in the methods and compounds of the present invention, the compound is substantially free of unconjugated enantiomers. In some embodiments, the composition comprises a compound that is at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%, and 100 wt% of the specified compound, with the remainder being other chemical species or enantiomers .

Isotopically enriched compound

Isotopically enriched compounds including but not limited to isotopically enriched nucleoside derivatives are also provided herein.

Pharmacokinetics ("PK"), pharmacodynamics ("PD") and isotopic enrichment of pharmaceuticals (eg, deuteration) to improve toxicity profiles have been previously demonstrated using some class of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

Isotopic enrichment of a drug may be achieved by, for example, (1) reducing or eliminating unwanted metabolites, (2) increasing the half-life of the parent drug, (3) reducing the number of doses required to achieve the desired effect, (5) an increase in the formation of active metabolites thereof, and / or (6) a reduction in the production of harmful metabolites in a particular tissue, and / or a combination therapy is intended May be used for the production of more effective drugs and / or safer drugs for combination therapies.

Replacing an atom with one of its isotopes will often result in a change in the rate of reaction of the chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if the CH bond is destroyed during the rate-determining step of the chemical reaction (i.e., the stage with the highest transition state energy), replacing the hydrogen with deuterium will cause a decrease in the reaction rate, It will be slower. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). (1985); Kushner et al., Can. J. Physiol. Pharmacol., Vol. 77, pp. 79-88 (1999)).

The size of the DKIE can be expressed as the ratio of the rate between the given reaction in which the C-H bond is destroyed and the same reaction in which hydrogen is replaced by deuterium. The DKIE can range from about 1 (no isotopic effect) to a very large number, such as 50 or more, which means that the reaction can be 50 times slower if hydrogen is replaced by deuterium. Although not limited by any particular theory, the high DKIE values may be due in part to phenomena known as tunneling, which is a consequence of the uncertainty principle. Tunneling is due to the small mass of hydrogen atoms and occurs because the transition state involving the protons can sometimes be formed in the absence of the required activation energy. Since deuterium has a larger mass than hydrogen, the probability of experiencing this phenomenon is much lower.

Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators, and radioactive pharmaceuticals. Tritium is a hydrogen atom that has two neutrons in its nucleus and has an atomic weight close to three. It naturally occurs in very low concentrations in the environment, most commonly found as T ₂ O. Tritium slowly disintegrates (half-life = 12.3 years) and releases low-energy beta particles that can not penetrate the outer layers of human skin. Internal exposure is a major risk associated with these isotopes, but must be ingested in large quantities to induce significant health risks. Compared with deuterium, a smaller amount of tritium must be consumed before reaching the hazard level. Substitution of tritium ("T") for hydrogen causes a much stronger bond than deuterium, and provides a numerically greater isotope effect. Likewise, including but not limited to replacing carbon with ¹³ C or ¹⁴ C, sulfur with ³³ S, ³⁴ S or ³⁶ S, nitrogen with ¹⁵ N, and oxygen with ¹⁷ O or ¹⁸ O , Replacing other elements with isotopes can lead to similar kinetic isotope effects.

For example, DKIE has been used to reduce the hepatotoxicity of halothane by restricting the production of reactive species, such as possibly trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can cause metabolic switching. The concept of metabolic switching asserts that heterologous species can transiently bind and recombine in various stereogenic forms when isolated by I-phase enzymes, prior to chemical reactions (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pocket of many I-phase enzymes and the disordered nature of many metabolic reactions. Metabolic switching can potentially lead to different ratios of known metabolites, as well as entirely new metabolites. This new metabolic profile can give more or less toxicity.

The animal body expresses a variety of enzymes for the purpose of removing foreign substances, such as therapeutic agents, from its circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYP") which react with these foreign substances and convert them to more polar intermediates or metabolites for kidney excretion, esterases, proteases, reductases, dehydrogenases, Amine oxydase. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (C-H) bonds to carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bonds. The resulting metabolite may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long term toxicity profiles as compared to the parent compound. In the case of many drugs, this oxidation is rapid. Thus, these drugs often require administration of multiple or high daily doses.

Thus, isotopic enrichment at a particular position of a compound provided herein produces a detectable KIE that will affect the pharmacokinetics, pharmacodynamics, and / or toxicological profile of the compounds provided herein as compared to a similar compound having a natural isotopic composition will be.

Preparation of compounds

The compounds provided herein may, in some cases, be prepared, isolated or obtained by any method apparent to those of ordinary skill in the relevant art. Those skilled in the relevant art will recognize that the compounds provided herein may be designed or prepared by, for example, reaction of the anticancer drugs via condensation or dehydration, for example, in a hydroxy group will be.

In other instances, the compounds provided herein may be prepared according to the exemplary preparation scheme provided below. In certain embodiments, the compounds provided herein may be prepared according to Scheme 1-6. Reaction conditions, steps, and reactants not provided in the exemplary preparation reaction schemes will be apparent to those of ordinary skill in the relevant art and will be known by those skilled in the art and are therefore within the scope of this disclosure.

<Reaction Scheme 1>

<Reaction Scheme 2>

<Reaction Scheme 3>

<Reaction Scheme 3bis>

<Reaction Scheme 4>

<Reaction Scheme 5>

<Reaction Scheme 6>

<Reaction Scheme 7>

<Reaction Scheme 8>

<Reaction Scheme 9>

<Reaction formula 10>

General Procedure A

Step 1: To a stirred solution of compound 22a or 22b (9.97 mmol) in THF (10 mL / mmol) at -10 <0> C was added phosphorus oxychloride (11.96 mmol). The reaction mixture was stirred overnight at -10 ° C to room temperature and then a solution of reagent Bl (9.97 mmol) and triethylamine (49.85 mmol) in acetonitrile (2.4 mL / mmol) was added at 0 ° C. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. Reagent B2 (29.91 mmol) and DMAP (29.91 mmol) were then added at 0 &lt; 0 &gt; C and the reaction mixture was stirred at 0 &lt; 0 &gt; C for 2 h. The reaction mixture was then diluted with ethyl acetate and washed with 1N HCl solution, water and brine. The organic layer was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM / methanol: 0 to 5%) to give the title compound.

Step 2: To a stirred suspension of compound 23a-c (2.40 mmol) in DCM (50 mL / mmol) at -80 <0> C under nitrogen was added a solution of boron trichloride, 1.0 M (12.02 mmol) in DCM. The reaction mixture was stirred at-80 C to-40 C for 4 hours. MeOH (2 mL) was then added at -80 [deg.] C and the reaction mixture was concentrated at 25 [deg.] C under reduced pressure. The crude residue was purified by RP18 chromatography (H ₂ O / CH ₃ CN) to give the title compound as a solid. In some cases, mixtures of diastereomers were purified by chiral HPLC to give the expected diastereoisomers.

General Procedure B

Step 1: To a stirred solution of 22a (1.86 mmol) in THF (10 mL / mmol) at -10 <0> C under nitrogen was added phosphorus oxychloride (2.23 mmol). The reaction mixture was stirred overnight at -10 &lt; 0 &gt; C and then cooled to 0 &lt; 0 &gt; C. Then a solution of reagent B3 (3.72 mmol) and triethylamine (9.31 mmol) in acetonitrile (2.4 mL / mmol) was added at 0 &lt; 0 &gt; C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with saturated NH ₄ Cl solution. The organic layer was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM / methanol: 0 to 3%) to give the title compound.

Step 2: Follow step 2 of general procedure A.

General procedure C

Step 1: To a solution of compound Ib (2.20 mmol) in THF (10 mL / mmol) at 0 C was added a solution of tert-butylmagnesium chloride, IM (4.60 mmol) in THF. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 &lt; 0 &gt; C. To this reaction mixture was added a solution of the appropriate reagent C1 (2.40 mmol) in THF (10 mL / mmol). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl solution, water and brine. The organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM / methanol) to give the expected intermediate as a mixture of diastereomers;

Step 2: To a solution of the previous intermediate (0.52 mmol) in DCM (30 mL / mmol) was added trifluoroacetic acid (10.27 mmol). The reaction mixture was stirred at room temperature for 3 hours and flash chromatography on silica gel (DCM / methanol: 20% 0), followed by RP18 chromatography _{(H 2 O / CH 3 CN} ) to give the diastereomers of the desired compound by Lt; / RTI &gt; as a mixture of isomers. This mixture was purified by MS-purification HPLC or by chiral HPLC to give the two expected diastereomers as pure solid compounds.

General procedure D

Step 1: To a stirred solution of 4-nitrophenol (29.36 mmol) and phosphorus oxychloride (14.68 mmol) in diethyl ether (10 mL / mmol) under nitrogen at -80 <0> C was added triethylamine (29.36 mmol). The reaction mixture was stirred overnight at room temperature. DCM (10 mL / mmol) and the appropriate L-alanine ester hydrochloride (14.68 mmol) were then added at 0 &lt; 0 &gt; C under nitrogen. To the reaction mixture was added dropwise triethylamine (29.36 mmol) at 0 ° C. The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (PE / Et ₂ O: 0 to 50%) to give the expected intermediate 9.

Step 2: To a solution of compound 1a (1.55 mmol) in THF (7 mL / mmol) was added a solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (3.71 mmol) in acetonitrile Solution followed by a solution of the appropriate compound 9 (1.86 mmol) in DCM (12 mL / mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature and then quenched on tamponphosphate pH = 7. The reaction mixture was extracted with DCM and the organic layer was dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM / methanol: 0 to 10%) to yield the title compound as a mixture of diastereomers. This mixture was purified by MS-purification HPLC to give the pure diastereomer.

Compounds 10 and 11

(Two diastereomers)

6-chloro-purin-9-yl) -7-fluoro-2-oxo-4a, 6a, 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate

Compounds 10 and 11 were synthesized from compound 1a according to scheme 3 and general procedure D.

Compound 21

[(2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-purin-9- yl) -3,4- dihydroxy- tetrahydrofuran-2-yl] methoxy- -Benzyl-phosphonamide &lt; / RTI &gt; acid

Compound 21 was synthesized according to Scheme 6 and the following general procedure:

(3.38 mmol) of 2'OCBz fludarabine and 2- (2,2-dimethyl-3-trityloxypropanoyl) -sulfanylethoxyphosphinic acid (5.08 mmol) in pyridine (12 mL / Was slowly added pivaloyl chloride (6.77 mmol). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 2 hours. The reaction was monitored by LC / MS. The reaction mixture was quenched with a 1M solution of NH ₄ Cl, and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated under reduced pressure to give the expected intermediate 17.

To a solution of 17 (1.1 mmol) in carbon tetrachloride (20 mL / mmol) and DCM (15 mL / mmol) was added benzylamine (5.5 mmol) and triethylamine (6.6 mmol) at room temperature. The reaction mixture was stirred overnight, then concentrated under reduced pressure and purified by flash chromatography on silica (DCM / methanol) to give the expected intermediate 18.

To a solution of 18 (0.49 mmol) in DCM (30 mL / mmol) was added trifluoroacetic acid (7.4 mmol) under nitrogen. The reaction mixture was stirred at room temperature overnight and purified by flash chromatography on silica (DCM / methanol: 0 to 20%) followed by MS-purification HPLC to give a mixture of diastereoisomers 19.

Palladium black was added to a solution of 19 in EtOH (5 mL / mmol) under nitrogen. After flushing N ₂ / vacuum and vacuum / H ₂ several times, the reaction mixture was stirred under H ₂ atmosphere at room temperature for 6 hours. The reaction mixture was filtered over celite and concentrated under reduced pressure to give the expected intermediate 20.

Compound 20 (0.35 mmol) was dissolved in a 7N ammonia solution in methanol (50 mL / mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by RP-18 chromatography (H ₂ O + TEAB / CH ₃ CN) to give the title compound as a solid.

Compound 24a

(Two diastereomers)

[(Benzylamino) - [(3-methyl-2-nitro-imidazol-4-yl) methoxy] phospholyl] oxy Methyl] -3,4-dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one

Compound 24a was synthesized from 22a according to scheme 7 and general procedure A using reagents B1 and B2.

Compound 24a: (diastereomer 1): ¹ H NMR (DMSO-d ₆ , 400 MHz) 隆 (ppm) 7.54 (d, J = 7.51 Hz, 1H), 7.32-7.27 (m, 4H), 7.26-7.21 (d, J = 12.73 Hz and 7.20 Hz, 1H), 7.20 (s, 1H) J = 13.26 Hz and 7.34 Hz, 1H), 5.64 (d, J = 7.51 Hz, 1H), 5.59-5.53 (m, 2H), 5.05 (dd, J = 13.26 Hz and 7.79 Hz, , &Lt; / RTI &gt; 1H), 4.14-3.88 (m, 7H), 3.86 (s, 3H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.27 (s, 1P); MS (ESI) m / z = 550.1 (MH &lt;&quot;& gt ^; ).

Compound 24a: (diastereomer 2): ¹ H NMR (DMSO-d ₆ , 400 MHz) 隆 (ppm) 7.59 (d, J = 7.43 Hz, 1H), 7.323-7.29 (m, 4H), 7.26-7.20 (d, J = 12.55 Hz and 7.14 Hz, 1H), 7.19 (s, 1H) J = 13.24 Hz and 7.31 Hz, 1H), 5.63 (d, J = 7.43 Hz, 1H), 5.58-5.56 (m, 2H), 5.05 (dd, J = 13.24 Hz and 7.83 Hz, , 4.18-4.09 (m, 1H), 4.06-3.91 (m, 5H), 3.90-3.88 (m, 1H), 3.85 (s, 3H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.19 (s, 1P); MS (ESI) m / z = 552.1 (MH ^&lt; ⁺ & gt ^; ).

Compound 24b

[(2R, 3S, 4S, 5R) -5- (4-Amino-2-oxo-pyrimidin- 1 -yl) -3,4-dihydroxy-tetrahydrofuran- 2-nitrothiazol-5-yl) methyl] phosphate

Compound 24b was synthesized from compound 22a using Reagent B3 according to scheme 7 and general procedure B.

Compound 24b: ¹ H NMR (DMSO-d ₆ , 400 MHz) 隆 (ppm) 8.07 (s, 1 H); 8.05 (s, 1 H); (M, 3H), 5.47-5.40 (brs, 1H), 7.51 (d, J = (m, 4H), 4.32-4.21 (m, 2H), 4.00-3.91 (m, 2H), 3.90-3.84 (m, 1H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) -1.37 (s, 1P); MS (ESI) m / z = 608.0 (MH ^&lt; ⁺ & gt ^; ).

Compound 24c

(Mixture of diastereoisomers 64/36)

Yl] methyl (3- (4-amino-2-oxo-pyrimidin-1 -yl) -3,4-dihydroxy-tetrahydrofuran- Methyl-2-nitro-imidazol-4-yl) methyl (2-nitrothiazol-5- yl) methyl phosphate

Compound 24c was synthesized from compound 22a using reagents B2 and B3 according to scheme 7 and general procedure A.

Compound 24c: ¹ H NMR (DMSO-d ₆ , 400 MHz)? (Ppm) 8.06 (s, 0.64H), 8.04 (s, 0.36H), 7.57 (d, J = 7.49 Hz, 0.64H), 7.56 J = 7.49 Hz, 0.36H), 7.31-7.25 (m, IH), 7.11 (brs, IH), 7.02 (brs, IH), 6.10 (d, J = 3.48 Hz, 1H), 5.65-5.57 , 3H), 5.44-5.37 (m, 2H), 5.28-5.21 (m, 2H), 4.28-4.18 (m, 2H), 3.98-3.83 (m, 6H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) -1.43 (s, 1P); MS (ESI) m / z = 605.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 24d

(Two diastereomers)

[(2R, 3S, 4S, 5R) -5 - [[(benzylamino) - [(5-nitro-2- thienyl) methoxy] phospholyl] oxymethyl] -Dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one

Compound 24d was prepared from compound 22b using Reagent B1 and B5 according to Scheme 7 and General Procedure A.

Compound 24d: (diastereomer ^{1): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.02 (d, J = 4.21Hz, 1H), 7.54 (d, J = 7.49Hz, 1H), 7.35 (M, 2H), 7.19 (d, J = 4.21 Hz, 1 H), 7.10 (brs, 1H), 5.85 (dt, J = 12.62 Hz and 7.13 Hz, 1H), 5.62 (d, J = 7.50 Hz, 1H), 5.58-5.53 (m, 2H), 5.17 (dd, J = 8.51 Hz, 1 H), 5.11 (dd, J = 13.81 Hz and 8.51 Hz, 1 H), 4.15-3.87 (m, 7H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.37 (s, 1P); MS (ESI) m / z = 554.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 24d: (diastereomer ^{2): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.01 (d, J = 4.20Hz, 1H), 7.59 (d, J = 7.49Hz, 1H), 7.33 (M, 2H), 7.18 (d, J = 4.18 Hz, 1 H), 7.09 (brs, 1H), 5.17 (dd, J = 13.90 Hz and 8.62 Hz, 1 H), 5.61 (d, J = 7.51 Hz, 5.11 (dd, J = 13.90 Hz and 8.43 Hz, 1 H), 4.17-4.11 (m, 1 H), 4.07-3.92 m, 5H), 3.89-3.88 (m, 1H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.28 (s, 1P); MS (ESI) m / z = 554.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 24e

[(2R, 3S, 4S, 5R) -5- (4-Amino-2-oxo-pyrimidin- 1 -yl) -3,4-dihydroxy-tetrahydrofuran- 5-nitro-2-furyl) methyl] phosphate

Compound 24e was synthesized from compound 22a using Reagent B4 according to Scheme 7 and General Procedure B.

Compound ^{24e: 1 H NMR (DMSO-} d 6, 400MHz) δ (ppm) 7.65 (d, J = 3.77Hz, 1H), 7.64 (d, J = 3.77Hz, 1H), 7.54 (d, J = 7.48Hz , 6.94 (d, J = 3.77 Hz, 1 H), 6.09 (d, J = 3.48 Hz, (M, 4H), 4.27 (m, 2H), 5.63 (d, J = -4.21 (m, 2H), 3.98-3.90 (m, 2H), 3.89-3.84 (m, 1H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) -1.27 (s, 1P); MS (ESI) m / z = 574.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 24f

(Two diastereomers)

Benzyl (2S) -2 - [[[(2R, 3S, 4S, 5R) -5- Yl] methoxy - [(5-nitro-2-thienyl) methoxy] phosphoryl] amino] propanoate

Compound 24f was synthesized from compound 22c using Reagents B6 and B5 according to Scheme 9 and General Procedure A, Step 1. In this case, the addition of phosphorus oxychloride followed by the addition of a proton sponge. Step 2 was performed according to Step 2 of general procedure C.

Compound 24f: (diastereomer ^{1): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.03 (d, J = 4.21Hz, 1H), 7.53 (d, J = 7.41Hz, 1H), 7.38 (Brs, 1H), 7.02 (brs, 1H), 6.08 (d, J = 3.69 Hz, 1H), 5.90 (dd, J = J = 9.96 Hz and 12.07 Hz, 1H), 5.64 (d, J = 7.41 Hz, 1H), 5.58-5.54 (m, 2H), 5.20-5.15 (m, 2H), 5.15-5.07 4.13-4.03 (m, 2H), 3.99-3.80 (m, 4H), 1.31 (d, J = 7.17 Hz, 3H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 8.57 (s, 1P); MS (ESI) m / z = 626.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 24f: (diastereomer ^{2): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.02 (d, J = 4.21Hz, 1H), 7.57 (d, J = 7.41Hz, 1H), 7.38 (Brs, 1H), 7.01 (brs, 1H), 6.10 (d, J = 3.69 Hz, 1H), 5.95 (dd, J = J = 10.15 Hz and 12.64 Hz, 1H), 5.61 (d, J = 7.41 Hz, 1H), 5.59-5.55 (m, 2H), 5.20-5.06 (m, 4H), 4.19-4.03 3.99-3.91 (m, 2H), 3.90-3.78 (m, 2H), 1.31 (d, J = 7.17 Hz, 3H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 8.16 (s, 1P); MS (ESI) m / z = 626.2 (MH ^&lt; ⁺ & gt ^; ).

Compound 25

(Two diastereomers)

[(2R, 3S, 4S, 5R) -5 - [[(Benzylamino) - [(5-nitro- 2- furyl) methoxy] phospholyl] oxymethyl] Dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one

Compound 25 was synthesized using Reagent C1 according to Scheme 8 and General Procedure C.

Compound 25: (diastereomer ^{1): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 7.66 (d, J = 3.74Hz, 1H), 7.54 (d, J = 7.40Hz, 1H), 7.33 (Brs, 1H), 7.08 (d, J = 3.74 Hz, 1H), 7.09 (d, J = 1H), 5.81 (d, J = 12.52 Hz and 7.15 Hz, 1H), 5.63 (d, J = 7.40 Hz, 1H), 5.58-5.56 (m, 2H), 5.04-4.94 4.10-4.05 (m, 2H), 4.02-3.88 (m, 5H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.49 (s, 1P); MS (ESI) m / z = 538 (MH ^&lt; ⁺ & gt ^; ).

Compound 25: (diastereomer ^{2): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 7.65 (d, J = 3.78Hz, 1H), 7.58 (d, J = 7.43Hz, 1H), 7.33 (M, 4H), 7.25-7.21 (m, IH), 7.10 (brs, IH), 7.02 (brs, IH), 6.87 (d, J = 3.78 Hz, 1H), 5.82 (d, J = 12.45 Hz and 7.17 Hz, 1H), 5.63 (d, J = 7.43 Hz, 1H), 5.58-5.56 (m, 2H), 5.04-4.93 4.15-4.09 (m, 1H), 4.06-3.91 (m, 5H), 3.89-3.87 (m, 1H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 10.39 (s, 1P); MS (ESI) m / z = 538 (MH ^&lt; ⁺ & gt ^; ).

Compound 26:

(Two diastereomers)

Benzyl (2S) -2 - [[(4aR, 6R, 7S, 7aR) -6- 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate

Compound 26 was synthesized from compound 1a according to scheme 3 and procedure D below.

Compound 26a (diastereomer ^{1): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.35 (d, J = 1.43Hz, 1H), 7.97 (brs, 2H), 7.41-7.29 (m, 5H ), 6.60 (dd, J = 5.14 Hz and 6.61 Hz, 1H), 6.14 (dd, J = 10.15 Hz and 13.40 Hz, 1H), 5.80 (td, J = 55.34 Hz and 7.34 Hz, 1H) 1H), 5.18 (d, J = 12.62 Hz, 1H), 5.14 (d, J = 12.62 Hz, 1H), 4.63-4.52 (m, 1H), 4.52-4.42 4.18 (m, 1H), 4.00-3.87 (m, 1H), 1.37 (d, J = 7.15 Hz, 3H); ³¹ P NMR (DMSO-d ₆ , 162 MHz)? (Ppm) 2.75 (s, ¹ P); ¹⁹ F NMR (DMSO-d ₆ , 376 MHz)? (Ppm) -199.64 (s, 1F); MS (ESI) m / z = 527.0 (MH ^&lt; ⁺ & gt ^; ).

Compound 26a (diastereomer ^{2): 1 H NMR (DMSO} -d 6, 400MHz) δ (ppm) 8.55 (d, J = 1.41Hz, 1H), 7.95 (brs, 2H), 7.40-7.34 (m, 5H ), 6.60-6.57 (m, 1H), 6.30 (dd, J = 13.69 Hz and 9.94 Hz, 1H), 5.75 (td, J = 55.52 Hz and 7.13 Hz, 1H), 5.48-5.39 1H), 1.37 (d, J &lt; RTI ID = 0.0 &gt; = 7.10 Hz, 3 H); _{^{31 P NMR (DMSO-d 6}} , 162MHz) δ (ppm) 4.82 (s, 1P); ¹⁹ F NMR (DMSO-d ₆ , 376 MHz)? (Ppm) -199.46 (s, 1F); MS (ESI) m / z = 527.0 (MH ^&lt; ⁺ & gt ^; ).

Compounds 28a and 28b

(Two diastereomers)

6-amino-2-fluoro-purin-9-yl) -7-hydroxy-2-oxo-4a, 6 , 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate

Compound 28 was synthesized from 2'OCBz-fludarabine according to scheme 3bis and procedure D: In this case, _two additional predicted diastereoisomers were obtained using an additional step of deprotection using H ₂ , Pd / C 5% in ethanol.

Compound 28a (diastereomer 1): ³¹ P NMR (DMSO-d ₆ , 162 MHz) 隆 (ppm) 3.01 (s, 1 P); MS (ESI) m / z = 447 (MH ^&lt; ⁺ & gt ^; ).

Compound 28b (diastereomer 2): ³¹ P NMR (DMSO-d ₆ , 162 MHz) 隆 (ppm) 4.97 (s, ¹ P); MS (ESI) m / z = 447 (MH ^&lt; ⁺ & gt ^; ).

Compound 29

(Mixture of diastereomers)

Methyl (2S) -2 - [[[(2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-purin-9-yl) -3,4-dihydroxy-tetrahydrofuran 2-yl] methoxy- (2-methoxy-2-oxo-ethoxy) phospholyl] amino] -4-methyl-pentanoate

Compound 29 was synthesized according to Scheme 10 and the procedure below.

To a solution of 2'OCBz-fludarabine (1.19 mmol) in THF (10 mL / mmol) at 0 ° C was added tert-butylmagnesium chloride (3.70 mmol), 1 M solution in THF. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 &lt; 0 &gt; C. The appropriate reagent D1 (1.31 mmol) in THF (10 mL / mmol) was added and the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of NH ₄ Cl, water and brine. The combined organic layers were dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica (DCM / ethanol or DCM / methanol) to give the expected intermediate;

Palladium black (0.28 mmol) was added to a solution of this intermediate (0.07 mmol) in EtOH (5 mL / mmol) under nitrogen. N ₂ / vacuum and vacuum / H ₂ were flushed several times and the reaction mixture was stirred under H ₂ atmosphere at room temperature for 1 hour. The reaction mixture was filtered over celite and concentrated under reduced pressure. The crude residue was triturated with a DCM / pentane mixture and then purified by flash chromatography on silica gel (DCM / methanol: 0 to 5%) to yield the desired compound as a mixture of diastereomers as a solid.

Compound ^{29: 1 H NMR (DMSO-} d 6, 400MHz) δ (ppm) 8.13 (s, 0.4H), 8.11 (s, 0.6H), 7.83 (brs, 2H), 6.18-6.16 (m, 1H), (M, 1H), 3.68-3.69 (m, 1H), 3.68 (s, 2H) (M, 2H), 3.66 (s, 1.2H), 3.62 (s, , 6H); ³¹ P NMR (DMSO-d ₆ , 162 MHz)? (Ppm) 8.68 (s, 0.6 P), 8.51 (s, 0.4 P); ¹⁹ F NMR (DMSO-d ₆ , 376 MHz)? (Ppm) -52.38 (m, 1F); MS (ESI) m / z = 565 (MH ^&lt; ⁺ & gt ^; ).

Characterization data of the compounds provided herein are set forth in Table 1:

Using a similar procedure, the following additional compounds were also prepared.

Using a similar procedure, the following additional compounds were also prepared:

Pharmaceutical compositions and methods of administration

Derivatives of various therapeutic agents can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Therapeutic agents that may be derivatized with a phosphate derivative include any anticancer agent that has been derivatized to include or contain a reactive group for attachment of a phosphate moiety such as, but not limited to, a nucleoside and a non-cyclic nucleoside Nucleoside analogs. Any of the compounds disclosed herein may be provided with suitable pharmaceutical compositions and administered by a suitable route of administration.

The methods provided herein may be used alone or in combination with one or more compatible, pharmaceutically acceptable carriers, such as excipients, diluents or adjuvants, or in combination with another anticancer agent, Comprising administering a pharmaceutical composition comprising at least one compound as described herein, including a compound of Formula I, IIa, IIb, or IIc.

In certain embodiments, the second agent may be formulated or packaged with the compound provided herein. Of course, the second agent will be formulated with the compounds provided herein only if, at the discretion of the ordinarily skilled artisan, such co-formulation does not interfere with the activity or method of administration of either agent. In certain embodiments, the compounds provided herein and the second agent are formulated separately. They may be packaged together or individually packaged for convenience of care in the relevant art.

In clinical practice, the active agents provided herein may be administered by any conventional route, particularly orally, parenterally, rectally, or by inhalation (e. G. In the form of an aerosol). In certain embodiments, the compounds provided herein are administered orally.

As a solid composition for oral administration, tablets, pills, hard gelatin capsules, powders or granules may be used. In these compositions, the active product is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch.

These compositions may include materials other than diluents, for example lubricants such as magnesium stearate or coatings intended for controlled release.

As liquid compositions for oral administration, pharmaceutically acceptable suspensions, emulsions, syrups and elixirin solutions containing inert diluents such as water or liquid paraffin may be used. These compositions may also contain substances other than diluents, for example wetting agents, sweeteners or flavoring products.

The composition for parenteral administration may be an emulsion or sterile solution. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters such as ethyl oleate may be used. These compositions may also contain adjuvants, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizers. Sterilization can be performed in a number of ways, for example using a bacteriological filter, by radiation, or by heating. It can also be prepared in the form of a sterile solid composition which, in use, can be dissolved in sterile water or any other injectable sterile medium.

Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The composition may also be an aerosol. For use in the form of a liquid aerosol, the composition may be a solid composition that is soluble in use in a stable sterile solution or non-heat-sterilizing water, saline or any other pharmaceutically acceptable vehicle. For use in the form of a dry aerosol intended to be inhaled directly, the active ingredient is finely divided and combined with a water soluble solid diluent or vehicle, for example dextran, mannitol or lactose.

In one embodiment, the compositions provided herein are in the form of pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein may contain a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent) and typically one or more pharmaceutically acceptable carriers or &Lt; / RTI &gt; The term "pharmaceutically acceptable" in the context of a specific embodiment and in the present context means that it has been approved by a federal or state regulatory agency or listed for use in animals, more particularly humans, in the United States Pharmacopoeia or other generally recognized pharmacopoeia . The term "carrier" includes diluents, such as adjuvants (e.g. Freund &apos; s adjuvant (complete and incomplete)), excipients or vehicles to be administered with the therapeutic agent. Such pharmaceutical carriers may be sterile liquids such as water and oils, such as those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water may be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used, in particular, as liquid carriers for injection solutions. Examples of suitable pharmaceutical carriers are described in "Remington &apos; s Pharmaceutical Sciences" Martin.

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts and examples of suitable excipients include but are not limited to starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol Monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form will depend upon a variety of factors well known in the pertinent art including, but not limited to, the manner in which the dosage form is administered to the subject and the particular active ingredient within the dosage form &Lt; / RTI &gt; If desired, the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents or pH buffering agents.

The lactose-free compositions provided herein may include excipients well known in the relevant art and listed, for example, in the US Pharmacopoeia (USP) SP (XXI) / NF (XVI). Generally, the lactose-free composition comprises the active ingredient, the binder / filler and the lubricant in a pharmaceutically compatible and pharmaceutically acceptable amount. Exemplary lactose-free dosage forms comprise the active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

As water may facilitate the degradation of some compounds, ahydrous pharmaceutical compositions and dosage forms comprising the active ingredient are further covered herein. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine characteristics such as shelf life or stability of the formulation over time in the field of pharmaceutical technology. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. &Lt; / RTI &gt; In fact, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on the formulation can be very noticeable since it is typically encountered with moisture and / or moisture during manufacture, handling, packaging, storage, transport and use of the formulation.

The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients, and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising at least one active ingredient, including lactose, and a primary or secondary amine, may be formulated as a pharmaceutical composition and dosage form in anhydrous form when substantial contact with moisture and / Lt; / RTI &gt;

The anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Thus, the anhydrous composition can be packaged using materials known to prevent exposure to water such that he may be included in a suitable kit. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, unit dose containers (e.g. vials), blister packs and strip packs.

There is further provided a pharmaceutical composition and dosage form comprising one or more compounds that reduce the rate at which the active ingredient is degraded. Such compounds, referred to herein as "stabilizers " include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

Pharmaceutical compositions and single unit dosage forms may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. Oral preparations may include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in purified form, in a particular embodiment, in an amount suitable for providing a form for proper administration to the subject. The formulation should be appropriate for the mode of administration. In certain embodiments, the pharmaceutical composition or single unit dosage form is sterile and is in a form suitable for administration to a subject, e. G., An animal subject, such as a mammalian subject, e.

The pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, intracapsular, intratumoral, But is not limited thereto. In a specific embodiment, the composition is formulated according to commercial procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In one embodiment, the pharmaceutical composition is formulated according to commercial procedures for subcutaneous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If desired, the composition may also contain a solubilizer and a local anesthetic to relieve pain at the injection site.

Examples of dosage forms include, but are not limited to, tablets; Caplet; Capsules, e. G., Soft elastic gelatin capsules; Cashew; Troches; Rosenji; Dispersion; Suppository; Ointment; A wetting agent (a fomenting agent); Paste; powder; dressing; cream; Plaster; solution; patch; Aerosols (e. G., Nasal sprays or inhalers); Gel; Liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e. G., Aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; Liquid dosage forms suitable for parenteral administration to a subject; And sterile solid (e. G., Crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a subject.

The composition, shape and type of dosage form provided herein will typically vary depending on the use thereof. For example, the dosage form used in the initial treatment of a viral infection may contain one or more of the active ingredients it contains in an amount greater than the dosage form used for the maintenance treatment of the same infection. Similarly, parenteral dosage forms may contain one or more of the active ingredients it comprises in less than the oral dosage form used to treat the same disease or disorder. These and other ways in which the specific dosage forms encompassed by this disclosure may be different will be readily apparent to those of ordinary skill in the relevant art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

In general, the components of the compositions are supplied in unit dosage form, for example, as dry lyophilized powders or anhydrous concentrates in an airtight container such as an ampoule or sachet indicating the amount of active agent, either separately or mixed together. When the composition is administered by injection, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or salt water. When the composition is administered by injection, an ampoule of injectable sterile water or saline can be provided so that the ingredients can be mixed prior to administration.

A typical dosage form is a compound provided herein within a range of about 0.1 mg to about 1000 mg per day as a single once-a-day dose in the morning or as a divided dose over the day taken with the food, or a pharmaceutically acceptable salt thereof, Solvate or hydrate thereof. A particular dosage form may have an active compound of about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, have.

Oral dosage form

Pharmaceutical compositions suitable for oral administration may be presented as separate dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of the active ingredient and may be prepared by means of pharmaceutical methods well known to those of ordinary skill in the art. Generally, see Remington ' s Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

In certain embodiments, the oral dosage form is solid and is prepared under anhydrous conditions using a dry component as described in detail in the section above. However, the category of compositions provided herein extends beyond anhydrous, solid oral dosage forms. Accordingly, additional forms are described herein.

Exemplary oral dosage forms are prepared by combining the active ingredient (s) with intimate admixture with at least one excipient, according to conventional pharmaceutical compounding techniques. The excipient can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules and caplets) include starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents, But is not limited thereto.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid excipients are used. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmaceutical methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier, finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired form.

For example, tablets may be prepared by compression or molding. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules optionally mixed with excipients, in a suitable machine. Molded tablets may be prepared by molding a mixture of the wetted powdered compound in an appropriate machine with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starch, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, And derivatives thereof (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., 2208 , 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, Starch, pregelatinized starch, and mixtures thereof. Binders or fillers in pharmaceutical compositions are typically present at from about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (FMC Corporation, Markus Hook, Pa., American Viscose Division, (Available from Avicel Sales), and mixtures thereof. The specific binding agent is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as Avicel RC 581. Suitable anhydrous or low moisture excipients or additives include Avicel PH 103 (TM) and Starch 1500 LM.

Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant can be disintegrated at storage, while too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Thus, solid oral dosage forms should be formed using a sufficient amount of a disintegrant that is neither too much nor too small to detrimentally alter the release of the active ingredient. The amount of disintegrant used will depend on the type of formulation, and can be readily determined by one of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of a disintegrant, especially from about 1 to about 5 weight percent of a disintegrant.

Disintegrants which may be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, But are not limited to, starch, other starches, clays, other alginates, other celluloses, rubbers, and mixtures thereof.

Lubricants that may be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, hard mineral oil, glycerin, sorbitol, mannitol, polyethylene glycols, other glycols, stearic acid, sodium lauryl sulfate, But are not limited to, vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, But is not limited to. Additional lubricants include, for example, silylated silica gels (AEROSIL 200 manufactured by WR Grace Co., Baltimore, Maryland), solidification aerosols of synthetic silica (Commercially available from Degussa Co. of Plano), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, Mass.), ) And mixtures thereof. When used in minor amounts, lubricants are typically employed in amounts of less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

Delayed release dosage form

The active ingredients, such as the compounds provided herein, may be administered by controlled release means or by delivery devices well known to those of ordinary skill in the art. Examples include U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; And 6,699, 500; Each of which is incorporated herein by reference in its entirety. Such dosage forms may be formulated to provide the desired release profile in varying proportions, for example, in the form of tablets or capsules, such as, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, May be used to provide slow release or controlled release of one or more active ingredients. Suitable controlled release formulations known to those of ordinary skill in the relevant art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus, encompassed herein are suitable single unit dosage forms, such as, but not limited to, tablets, capsules, gel caps, and caplets, which are adapted for controlled release, including but not limited to oral administration.

All controlled release pharmaceutical products have a common goal of improving pharmacotherapy over that achieved by its uncontrolled counterparts. Ideally, the use of an optimally designed controlled release formulation in medical therapy is characterized by the use of minimal drug substance to heal or control the condition within a minimum amount of time. Advantages of controlled release formulations include prolonged drug activity, decreased frequency of administration, and increased subject compliance. Controlled release formulations can also be used to affect the onset time of action or other characteristics, such as the blood level of a drug, and thus affect the occurrence of side effects (e. G., Adverse effects).

Most controlled-release preparations initially release a quantity of drug (active ingredient) that quickly produces the desired therapeutic effect and a different amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time Lt; RTI ID = 0.0 &gt; gradually &lt; / RTI &gt; To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug metabolized and released from the body. Controlled release of an active ingredient can be stimulated by a variety of conditions including, but not limited to, pH, temperature, enzyme, water or other physiological conditions or compounds.

In certain embodiments, the drug may be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes or other modes of administration. In one embodiment, a pump can be used (Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymeric material may be used. In another embodiment, the controlled release system is located in the appropriate site of the subject determined by the skilled practitioner, i.e. only a fraction of the total dose is required (see, e. G., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Another controlled release system is discussed in the review by Langer (Science 249: 1527-1533 (1990)). The active ingredient may be an external polymer membrane insoluble in body fluids such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, Polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl A solid inner matrix surrounded by an ethylene terephthalate, an ethylene terephthalate, an ethylene terephthalate, an ethylene terephthalate, an alcohol ternary copolymer and an ethylene / vinyloxyethanol copolymer, such as polymethyl methacrylate, polybutyl methacrylate, Terephthalate Polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as esters of acrylic acid and methacrylic acid Of hydrogel, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. The active ingredient then diffuses through the outer polymeric membrane in the release rate control step. The percentage of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.

Parenteral dosage form

In one embodiment, parenteral dosage forms are provided. Parenteral dosage forms may be administered to the subject by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because its administration typically bypasses the natural defense of the subject to contaminants, parenteral dosage forms are typically sterilized or may be sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, an injectable solution, a dry product ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, an injectable suspension, and an emulsion.

Suitable vehicles that can be used to provide parenteral dosage forms are well known to those of ordinary skill in the art. In certain embodiments, examples of suitable vehicles include, but are not limited to, injection water USP; Aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection and lactating Ringer's injection; Water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; And non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be incorporated into parenteral dosage forms.

Percutaneous, topical & mucosal administration forms

Transdermal, topical and mucosal dosage forms are also provided. Transdermal, topical and mucosal administration forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other forms known to those of ordinary skill in the relevant art Do not. See, e.g., ^{[Remington's Pharmaceutical Sciences, 16 th} , 18th and 20 th eds, Mack Publishing, Easton PA (1980, 1990 &2000).; And Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissues may be formulated as oral cleansers or as oral gels. In addition, the transdermal dosage form includes a "repository type" or "matrix type" patch, which may be applied to the skin for a certain period of time to allow penetration of the desired amount of the active ingredient.

Suitable excipients (e. G., Carriers and diluents) and other materials that may be used to provide the transdermal, topical and mucosal dosage forms encompassed herein are well known to those of ordinary skill in the pharmaceutical arts and include, The form depends on the specific organization to which it applies. Considering this fact, typical excipients are non-toxic and pharmaceutically acceptable, such as lotions, tinctures, creams, emulsions, water to form gels or ointments, acetone, ethanol, ethylene glycol, propylene glycol, butane- Diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the relevant art. For example, reference is made to the literature ^{[Remington's Pharmaceutical Sciences, 16 th} , 18th and 20 th eds., Mack Publishing, Easton PA (1980, 1990 & 2000)].

Depending on the specific tissue to be treated, additional ingredients may be used before, during or after treatment with the active ingredient provided. For example, penetration enhancers can be used to assist in delivering the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to, acetone; Various alcohols such as ethanol, oleyl, and tetrahydrofuryl; Alkyl sulfoxides such as dimethyl sulfoxide; Dimethylacetamide; Dimethylformamide; Polyethylene glycol; Pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); Urea; And various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of the pharmaceutical composition or dosage form or the pH of the tissue to which the pharmaceutical composition or dosage form is applied can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength, or its barrier may be adjusted to improve delivery. Compounds such as stearates may also be added to pharmaceutical compositions or dosage forms to improve delivery by beneficially altering the hydrophilicity or lipophilicity of the one or more active ingredients. In this regard, the stearate may serve as a lipid vehicle for the formulation, as an emulsifier or surfactant, and as a delivery enhancer or penetration enhancer. Different salts, hydrates or solvates of the active ingredient may be used to further adjust the properties of the resulting composition.

How to use

In one embodiment, a therapeutically effective amount of a compound provided herein, for example, a compound of formula (I), (IIa), (IIb), or (IIc) (an enantiomer, a mixture of enantiomers, a diastereomer, , Tautomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof for the manufacture of a medicament for the treatment of a proliferative disease in said subject.

In certain embodiments, the therapeutically effective amount is from about 0.1 to about 100 mg / kg / day, from about 0.1 to about 50 mg / kg / day, from about 0.1 to about 40 mg / kg / day, Day, about 0.1 to about 10 mg / kg / day or about 0.1 to about 20 mg / kg / day, about 0.1 to about 25 mg / kg / day, 5 mg / kg / day. In one embodiment, the therapeutically effective amount is in the range of about 0.1 to about 100 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 50 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 40 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 30 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 25 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 20 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 15 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 10 mg / kg / day. In another embodiment, the therapeutically effective amount is in the range of about 0.1 to about 5 mg / kg / day.

It is understood that the dose administered may also be expressed in units other than mg / kg / day. For example, the dose for parenteral administration can be expressed as mg / m ² / day. One of ordinary skill in the relevant arts will readily know how to convert the dose from mg / kg / day to mg / m ² / day for either or both of the height or weight of a given subject (see www.fda. gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / m ² / day for a 65 kg human is roughly equivalent to 38 mg / kg / day.

In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

One embodiment is a compound for use in therapy or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, tautomer or polymorph form thereof.

In certain embodiments, the proliferative disease is selected from the group consisting of carcinoma, including but not limited to, Kit-mediated carcinoma, adenocarcinoma, squamous cell carcinoma, squamous cell carcinoma, teratoma carcinoma, head and neck carcinoma, brain cancer, intracranial carcinoma, glioblastoma (PDGFR- (Including PDGFR-mediated polymorphic glioblastoma), neuroblastoma, cancer of the larynx, multiple endocrine neoplasms 2A and 2B (MENS 2A and MENS 2B) (including RET-mediated MENS), thyroid cancer (Including any RET-mediated thyroid carcinoma), follicular thyroid carcinoma, inverse thyroid carcinoma, bronchial carcinoid, ovarian cell carcinoma, lung cancer, small cell lung carcinoma (including any thyroid carcinoma with sporadic or familial hydronephrosis), papillary thyroid carcinoma, parathyroid carcinoma (Including GIST and PDGFR alpha -mediated GIST), colon cancer, colorectal cancer (including FLT3 and / or Kit-mediated small cell lung cancer), non-small cell lung cancer, gastric cancer / gastric cancer, gastric cancer, gastrointestinal tumor (GIST) , Pancreatic cancer, metastatic cancer (Including Kit-mediated and / or PDGFR-mediated ovarian cancer), uterine cancer, liver cancer, liver cancer, liver cancer, liver metastasis, bladder cancer, renal cell carcinoma (including PDGFR- (Including, but not limited to, endometrial cancer (including CSF-IR-mediated endometrial cancer), cervical cancer, breast cancer (including FLT3-mediated and / or PDGFR-mediated breast cancer), prostate cancer (Including the germinal tumors), topical (including Kit-mediated topical), undifferentiated germ cell (including Kit-mediated undifferentiated germ cell), melanoma (including PDGFR- mediated melanoma), metastasis to bone (CSF- Metastatic tumors (including VEGFR-mediated tumors), metastatic tumors, neuroendocrine tumors, tumor angiogenesis (including VEGFR-mediated tumor angiogenesis), and mixed mesodermal tumors.

In certain embodiments, the proliferative disease is selected from the group consisting of sarcomas such as, but not limited to, PDGFR-mediated sarcoma, osteosarcoma, osteogenic sarcoma, bone cancer, glioma (including PDGFR-mediated and / or CSF- (Including VEGFR3-mediated angio sarcoma) and lymphatic sarcoma (including VEGFR3-mediated lymphatic sarcoma).

In certain embodiments, the proliferative disorder is a hematologic malignancy. In certain embodiments, the proliferative disorder is a recurrent hematologic malignancy. In certain embodiments, the proliferative disease is a refractory hematological malignancy. In certain embodiments, the proliferative disorder is a drug-resistant hematologic malignancy. In certain embodiments, the proliferative disorder is a multiple drug-resistant hematologic malignancy. In certain embodiments, the proliferative disorder is a Bcr-Abl kinase inhibitor-resistant hematologic malignancy. In certain embodiments, the proliferative disorder is an imatinib-resistant hematologic malignancy. In certain embodiments, the proliferative disorder is a dasatinib-resistant hematological malignancy. In certain embodiments, the proliferative disease is a neuritinib-resistant hematological malignancy. In certain embodiments, the proliferative disorder is a conservedinib-resistant hematologic malignancy. In certain embodiments, the proliferative disorder is a cytarabine-resistant hematologic malignancy.

In certain embodiments, the hematological malignancy is selected from the group consisting of myeloma, leukemia, myeloproliferative disease, acute myelogenous leukemia (AML) (including FLT3 mediated and / or KIT-mediated and / or CSF1R mediated acute myelogenous leukemia), chronic myelogenous leukemia ), Myelodysplastic syndromes (including FLT3 mediated and / or Kit-mediated myelogenous syndromes), idiopathic hyperplasia (including leukemia), myelodysplastic syndrome (including FLT3-mediated and / or PDGFR- mediated chronic myelogenous leukemia) (Including PDGFR-mediated HES), chronic eosinophilic leukemia (CEL) with PDGFR-mediated CEL, chronic bone marrow mononuclear leukemia (CMML), mast cell leukemia (including Kit- mediated mast cell leukemia) , Or systemic mastocytosis (including Kit-mediated systemic mastocytosis).

In certain embodiments, the hematological malignancy is selected from the group consisting of lymphoma, lymphoproliferative disease, acute lymphoblastic leukemia ALL, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL) Killer (NK) cell leukemia, B-cell lymphoma, T-cell lymphoma, or natural killer (NK) cell lymphoma.

In one embodiment, the hematological malignancy is a myelodysplastic syndrome (MDS).

In certain embodiments, the hematological malignancies are Langerhans cell histiocytosis (including CSF-IR-mediated and / or FLT3-mediated Langerhans cell histiocytosis), mast cell tumors, or mastocytosis.

In certain embodiments, the hematological malignancy is leukemia. In certain embodiments, the hematological malignancy is recurrent leukemia. In certain embodiments, the hematological malignancy is refractory leukemia. In certain embodiments, the hematological malignancy is drug-resistant leukemia. In certain embodiments, the hematological malignancy is multiple drug-resistant leukemia. In certain embodiments, the hematological malignancy is Bcr-Abl kinase inhibitor-resistant leukemia. In certain embodiments, the hematologic malignancy is imatinib-resistant leukemia. In certain embodiments, the hematological malignancy is dasatinib-resistant leukemia. In certain embodiments, the hematological malignancy is neilotinib-resistant leukemia. In certain embodiments, the hematologic malignancy is curcumin-resistant leukemia. In certain embodiments, the hematological malignancy is cytarabine-resistant leukemia.

In certain embodiments, leukemia is acute leukemia. In certain embodiments, the leukemia is recurrent acute leukemia. In certain embodiments, the leukemia is refractory acute leukemia. In certain embodiments, the leukemia is drug-resistant acute leukemia. In certain embodiments, leukemia is multiple drug-resistant acute leukemia. In certain embodiments, the leukemia is Bcr-Abl kinase inhibitor-resistant acute leukemia. In certain embodiments, the leukemia is imatinib-resistant acute leukemia. In certain embodiments, the leukemia is dasatinib-resistant acute leukemia. In certain embodiments, the leukemia is neilotinib-resistant acute leukemia. In certain embodiments, the leukemia is curcumin-resistant acute leukemia. In certain embodiments, the leukemia is cytarabine-resistant acute leukemia. In certain embodiments, leukemia is hereditary leukemia. In certain embodiments, the hereditary leukemia is severe congenital neutrophilia (SCN). In certain embodiments, the hereditary leukemia is a familial platelet disorder with acute myelogenous leukemia (FDP / AML). In certain embodiments, the leukemia is caused by LEF1. In certain embodiments, the leukemia is mediated by LEF1. In certain embodiments, the leukemia is caused by GSK3.

In certain embodiments, the leukemia is ALL. In certain embodiments, leukemia is recurrent ALL. In certain embodiments, the leukemia is refractory ALL. In certain embodiments, the leukemia is drug-resistant ALL. In certain embodiments, the leukemia is multiple drug-resistant ALL. In certain embodiments, the leukemia is Bcr-Abl kinase inhibitor-resistant ALL. In certain embodiments, the leukemia is imatinib-resistant ALL. In certain embodiments, the leukemia is dasatinib-resistant ALL. In certain embodiments, the leukemia is Nilotinib-resistant ALL. In certain embodiments, the leukemia is conservitinib-resistant ALL. In certain embodiments, the leukemia is cytarabine-resistant ALL.

In one embodiment, ALL is leukemia derived from bone marrow cells (B-cells), thymus (T-cells), or lymph nodes. ALL was classified as L1-mature-appearance lymphoid (T-cell or pre-B-cell), L2-immature and polymorphic (variously shaped) lympho-morphology according to the French-US-UK (FAB) morphological classification scheme T-cell or pre-B-cell), and L3-lymphocyte (B-cell; bucket cell). In another embodiment, ALL is derived from a bone marrow cell (B-cell). In another embodiment, ALL is derived from thymus (T-cell). In another embodiment, ALL is derived from lymph nodes. In another embodiment, ALL is an L1 type characterized by mature-appearance lymphoid (T-cell or pre-B-cell). In another embodiment, ALL is L2 type characterized by immature and polymorphic (variously shaped) lymphoid (T-cell or pre-B-cell). In another embodiment, ALL is of the L3 type, which is characterized by lymphoid cells (B-cells; bucket cells).

In certain embodiments, leukemia is AML. In certain embodiments, the leukemia is recurrent AML. In certain embodiments, the leukemia is refractory AML. In certain embodiments, the leukemia is drug-resistant AML. In certain embodiments, the leukemia is multiple drug-resistant AML. In certain embodiments, the leukemia is Bcr-Abl kinase inhibitor-resistant AML. In certain embodiments, leukemia is imatinib-resistant AML. In certain embodiments, the leukemia is dasatinib-resistant AML. In certain embodiments, the leukemia is Nilotinib-resistant AML. In certain embodiments, leukemia is conservedinib-resistant AML. In certain embodiments, the leukemia is cytarabine-resistant AML. In certain embodiments, the AML has a RAS mutation. In certain embodiments, the RAS mutation is NRAS, KRAS, or HRAS. In certain embodiments, the RAS mutation is NRAS. In certain embodiments, the RAS mutation is KRAS. In certain embodiments, the RAS mutation is HRAS.

In certain embodiments, the AML is selected from the group consisting of undifferentiated AML (M0), myelogenous leukemia (M1), myelogenous leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), bone marrow mononuclear leukemia M4 variants with eosinophilia [M4E]), mononuclear leukemia (M5), autoimmune leukemia (M6) or leukemia (M7). In one embodiment, AML is undifferentiated AML (M0). In another embodiment, AML is myelogenous leukemia (M1). In another embodiment, AML is myelogenous leukemia (M2). In another embodiment, the AML is promyelocytic leukemia (M3 or M3 variant [M3V]). In another embodiment, AML is a bone marrow mononuclear leukemia (M4 or an M4 variant with eosinophilia [M4E]). In another embodiment, AML is mononuclear leukemia (M5). In another embodiment, AML is an autoimmune leukemia (M6). In another embodiment, AML is megakaryocytic leukemia (M7).

In certain embodiments, the leukemia is chronic leukemia. In certain embodiments, the leukemia is recurrent chronic leukemia. In certain embodiments, leukemia is refractory chronic leukemia. In certain embodiments, the leukemia is drug-resistant chronic leukemia. In certain embodiments, the leukemia is multiple drug-resistant chronic leukemia. In certain embodiments, the leukemia is Bcr-Abl kinase inhibitor-resistant chronic leukemia. In certain embodiments, the leukemia is imatinib-resistant chronic leukemia. In certain embodiments, the leukemia is dasatinib-resistant chronic leukemia. In certain embodiments, the leukemia is neilotinib-resistant chronic leukemia. In certain embodiments, leukemia is chronic renin-resistant chronic leukemia. In certain embodiments, the leukemia is cytarabine-resistant chronic leukemia.

In certain embodiments, the leukemia is CLL. In certain embodiments, the leukemia is recurrent CLL. In certain embodiments, the leukemia is a refractory CLL. In certain embodiments, the leukemia is drug-resistant CLL. In certain embodiments, the leukemia is multiple drug-resistant CLL. In certain embodiments, the leukemia is a Bcr-Abl kinase inhibitor-resistant CLL. In certain embodiments, leukemia is an imatinib-resistant CLL. In certain embodiments, the leukemia is dasatinib-resistant CLL. In certain embodiments, the leukemia is a neilotinib-resistant CLL. In certain embodiments, the leukemia is conservitinib-resistant CLL. In certain embodiments, the leukemia is cytarabine-resistant CLL.

In certain embodiments, the leukemia is CML. In certain embodiments, the leukemia is recurrent CML. In certain embodiments, the leukemia is refractory CML. In certain embodiments, leukemia is drug-resistant CML. In certain embodiments, leukemia is multiple drug-resistant CML. In certain embodiments, the leukemia is Bcr-Abl kinase inhibitor-resistant CML. In certain embodiments, the leukemia is imatinib-resistant CML. In certain embodiments, the leukemia is dasatinib-resistant CML. In certain embodiments, the leukemia is neilotinib-resistant CML. In certain embodiments, the leukemia is conservitinib-resistant CML. In certain embodiments, leukemia is cytarabine-resistant CML. In certain embodiments, the leukemia is pediatric CML. In certain embodiments, the leukemia is pediatric CML having one or more NF-1 mutations.

In certain embodiments, leukemia is T-cell leukemia. In one embodiment, T-cell leukemia is peripheral T-cell leukemia, T-cell lymphocytic leukemia, skin T-cell leukemia, and adult T-cell leukemia. In another embodiment, T-cell leukemia is peripheral T-cell leukemia. In another embodiment, T-cell leukemia is T-cell lymphocytic leukemia. In another embodiment, T-cell leukemia is skin T-cell leukemia. In another embodiment, T-cell leukemia is adult T-cell leukemia.

In certain embodiments, the leukemia is Philadelphia-positive. In one embodiment, the Philadelphia positive leukemia is selected from the group consisting of Philadelphia positive AML, such as but not limited to, undifferentiated AML (M0), myelogenous leukemia (M1), myeloproliferative leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), bone marrow mononuclear leukemia (M4 or M4 variant with eosinophilia [M4E]), mononuclear leukemia (M5), autoimmune leukemia (M6) or leukemia leukemia (M7). In another embodiment, the Philadelphia positive leukemia is Philadelphia positive ALL.

In certain embodiments, the proliferative disease is selected from the group consisting of cancer, including, but not limited to, head and neck cancer (oral, oral, ophthalmic, hypopharyngeal, nasopharyngeal, nasopharyngeal, sinus, or salivary gland), lung cancer (including small cell lung cancer and non- (Including cancer of the uterine cervix), cancer of the uterus (including cancer of the uterine cervix), gastric cancer (including esophageal cancer), gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, gallbladder cancer, extrahepatic cholangiocarcinoma, (Including carcinoid and metastatic tumors), vaginal cancer, vulvar cancer, ovarian cancer, gestational trophoblastic cancer neoplasm, testicular cancer, urinary tract cancer (including new cancers), bladder cancer, prostate cancer, penile cancer, ), Chromosome-positive cell, adrenocortical carcinoma, parathyroid, and endocrine.

Further examples of cancer include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, chondrosarcoma (cancer occurring in chondrocytes), mesenchymal-chondrosarcoma, soft tissue sarcoma (mesodermal tissue (blood vessels having muscles, (Including malignant tumors that may arise in any of the joints, joints, and fats), soft tissue sarcoma (including alveolar soft tissue sarcoma), angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, , Schwannomas, peripheral neuroectodermal tumors, rhabdomyosarcoma, synovial sarcoma, gestational trophoblastic tumors (malignant tumors in which the tissues are formed in the uterus and subsequently become cancerous), Hodgkin's lymphoma and laryngeal cancer.

In certain embodiments, the proliferative disease is selected from non-malignant proliferative diseases such as, but not limited to, atherosclerosis (including PDGFR-mediated atherosclerosis), restenosis followed by angioplasty (including PDGFR-mediated restenosis) Fibrotic disorders including obstructive bronchiolitis and idiopathic myelofibrosis.

In certain embodiments, the proliferative disease is selected from the group consisting of inflammatory diseases or disorders associated with immune dysfunction, immune deficiency or immunomodulation, such as, but not limited to, autoimmune diseases, tissue graft rejection, graft- versus host disease, wound healing, Inflammatory bowel disease (including Crohn's disease and ulcerative colitis (UC)), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis , Osteoporosis, asthma, and chronic obstructive pulmonary disease (COPD).

In certain embodiments, the proliferative disease is an infectious disease. In certain embodiments, the infectious disease is a fungal infection. In certain embodiments, the infectious disease is superficial mycosis (e. In certain embodiments, the infectious disease is skin mycosis (e. G., Epidermis). In certain embodiments, the infectious disease is subcutaneous mycosis. In certain embodiments, the infectious disease is systemic mycosis.

In certain embodiments, the proliferative disease is selected from the group consisting of leukemia, adult T-cell leukemia, pre-B-cell leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, breast cancer, pancreatic cancer, prostate cancer, head and neck cancer, Cancer of the thyroid, epidermoid carcinoma, lung cancer, NSC lung cancer, or large cell lung cancer.

In certain embodiments, the proliferative disease is selected from the group consisting of adult T-cell leukemia, pre-B-cell leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer, melanoma, , Renal cancer, colorectal cancer, rhabdomyosarcoma, tongue cancer, gastric cancer, multiple myeloma, bladder cancer, thyroid cancer, epidermoid carcinoma, NSC lung cancer or large cell lung cancer.

In certain embodiments, the proliferative disease is selected from the group consisting of leukemia, adult T-cell leukemia, pre-B-cell leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, breast cancer, head and neck cancer, ovarian cancer, colorectal cancer, It is large cell lung cancer.

In one embodiment, the cancer that can be treated by the compounds described herein is acute lymphoblastic leukemia; Acute myelogenous leukemia; Adrenocortical carcinoma; AIDS-related lymphoma; AIDS-related malignant tumors; Anal cancer; Astrocytoma; Cholangiocarcinoma; Bladder cancer; Bone cancer, osteosarcoma / malignant fibrous histiocytoma; Brainstem glioma; Brain tumor, cerebellar astrocytoma; Brain tumor, brain astrocytoma / malignant glioma; Brain tumor, epithelial cell tumor; Brain tumor, hydroblastoma; Brain tumors, primitive neuroectodermal tumors; Brain tumors, visual pathways and hypothalamic gliomas; Breast cancer; Bronchial adenoma / carcinoid; Carcinoid tumors; Carcinoid tumors, gastrointestinal; Carcinoma, adrenal cortex; Carcinoma, carcinoma; Central nervous system lymphoma, primary; Brain astrocytoma / malignant glioma; Cervical cancer; Chronic lymphocytic leukemia; Chronic myeloid leukemia; Chronic myeloproliferative disorder; Transparent cell sarcoma of hay; Colon cancer; Colorectal cancer; Skin T-cell lymphoma; Endometrial cancer; Cell tumor on the stomach; Epithelium, ovary; Esophagus cancer; Esophagus cancer; Ewing family of tumors; Extracellular germ cell tumor; Extrahepatic cholangiocarcinoma; Angular, guiding melanoma; Retinoblastoma; Gallbladder cancer; Gastric cancer (stomach cancer); Gastric carcinoid tumors; Germ cell tumors, extraocular, childhood; Germ cell tumor, gonadal externa; Germ cell tumor, ovary; Gestational trophoblastic tumor; Glioma, childhood brain stem; Glioma, childhood visual pathway and hypothalamus; Hair cell leukemia; Head and neck cancer; Hepatocyte (liver) cancer; Hodgkin's lymphoma; Hypopharynx; Hypothalamic and visual pathway glioma; Guide melanoma; Metastatic carcinoma (endocrine pancreas); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Leukemia, acute lymphoid component; Leukemia, acute myelogenous; Leukemia, chronic lymphoid organization; Leukemia, chronic bone marrow; Leukemia, hair cell; Cervical cancer and oral cancer; Liver cancer; Lung cancer, non-small cell; Lung cancer, small cell; Lymphocytic leukemia; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, skin T-cell; Lymphoma, hojiquin; Lymphoma during pregnancy, Hojichein; Lymphoma, non-Hodgkin; Lymphoma, primary central nervous system; Macroglobulinemia, valtendroma; Male breast cancer; Malignant mesothelioma; Malignant thymoma; Hydroblastoma, childhood; Melanoma; Melanoma, guide; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous cell carcinoma with latent primary; Multiple endocrine neoplasia syndrome, childhood; Multiple myeloma / plasma cell neoplasms; Fungal sarcoma; Myelodysplastic syndrome; Bone marrow leukemia, chronic; Myeloid leukemia; Myeloma, multiple; Myeloproliferative disorder, chronic; Nasal and sinus cancer; Biotin; Neuroblastoma; Non-Hodgkin's lymphoma; Non-small cell lung cancer; Oral cancer; Oral and lingual cancer; Koo, In - Am; Osteosarcoma of bone / malignant fibrous histiocytoma; Ovarian carcinoma; Ovarian germ cell tumor; Ovarian malignant potential tumor; Pancreatic cancer; Sinus and nasal cancer; Papillary thyroid cancer; Penile cancer; Chromium-rich cell tumor; Pineal and perianal primitive neuroectodermal tumors; Pituitary tumor; Plasma cell neoplasm / multiple myeloma; Pleural pulmonary blastoma; Pregnancy and breast cancer; Pregnancy and Hodgkin lymphoma; Pregnancy and non-Hodgkin lymphoma; Primary central nervous system lymphoma; Primary liver cancer; Prostate cancer; Rectal cancer; Renal cell (kidney) cancer; Renal and bone, transitional cell carcinoma; Retinoblastoma; Rhabdomyosarcoma; Salivary gland cancer; Sarcoma, Ewing family of tumors; Breeding, kaposhi; Bone sarcoma (osteosarcoma) / malignant fibrous histiocytoma; Sarcoma, soft tissue; Trestle syndrome; cutaneous cancer; Skin cancer (melanoma); Skin carcinoma, Merkel cells; Small cell lung cancer; Small bowel cancer; Soft tissue sarcoma; Metastatic, metastatic; Stomach cancer (stomach cancer); Transthoracic primitive neuroectodermal tumors; T-cell lymphoma, skin; Testicular cancer; Thymoma, malignancy; Thyroid cancer; Transitional cell carcinoma of the pyelonephritis and ureter; Trophoblastic tumor, pregnancy; Ureters and kidneys, transitional cell carcinoma; Urethral cancer; Uterine sarcoma; Vaginal cancer; Visual pathways and hypothalamic glioma; Vulvar cancer; Valtendrome macroglobulinemia; &Lt; / RTI &gt; and Wilms' tumor.

In one embodiment, cancers potentially associated with mutant IDH enzyme activity are selected from the group consisting of brain tumors, such as astrocytic tumors (e. G., Glioma-type astrocytoma, lower giant-cell astrocytoma, diffuse astrocytoma, Giant cell glioma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); Papillary cell tumors (e. G., Oligodendrocytes, and inverse oligodendrogliomas); Neoplastic cell tumors (e. G., Pemphasic astrocytoma, and adipogenic mesangial astrocytoma); (E. G., Mucinous papillomatous adenomatoid and adventitial &lt; / RTI &gt;Hydroblastoma; Primitive neuroectodermal tumors, schwannomas, meningiomas, atypical meningiomas, adverse meningiomas; And pituitary adenoma. In another embodiment, the brain cancer is glioma, polymorphic glioblastoma, adenocarcinoma, or perianal primitive neuroectodermal tumor (sPNET).

In another embodiment, cancers potentially associated with mutant IDH enzyme activity are selected from the group consisting of leukemias, such as acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm AML after MPN, AML after MDS, del (5q) -related high-risk MDS or AML, acute phase chronic myeloid leukemia, vascular immunoblastic lymphoma and acute lymphoblastic leukemia.

In one embodiment, the cancer potentially associated with the mutant IDH enzyme activity is skin cancer, including melanoma. In another embodiment, the cancer potentially associated with the mutant IDH enzyme activity is prostate cancer, breast cancer, thyroid cancer, colon cancer or lung cancer. In another embodiment, the cancer potentially associated with the mutant IDH enzyme activity is sarcoma, including central chondrosarcoma, central and periostatic chondroma and fibrosarcoma. In another embodiment, the cancer potentially associated with the mutant IDH enzyme activity is a cholangiocarcinoma.

The compounds described herein for use in the treatments described herein are also provided.

Use of the compounds described herein for the manufacture of a medicament for the treatment described herein is also provided.

In certain embodiments, a subject to be treated with one of the methods provided herein may be a compound provided herein, for example, a compound of formula I, II, or IIa (its enantiomers, mixtures of enantiomers, diastereoisomers, Mixtures of at least two diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variations thereof); Or its prophylactically acceptable salts, solvates, or hydrates thereof.

In certain embodiments, a subject to be treated with one of the methods provided herein may be a compound provided herein, for example, a compound of formula I, IIa, lib, or IIc (including enantiomers, mixtures of enantiomers, diastereomers Mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof for the treatment of a proliferative disease to be treated prior to administration.

In certain embodiments, the subject to be treated with one of the methods provided herein has improved drug resistance to chemotherapy.

The methods provided herein encompass treating a subject irrespective of the age of the subject, although some diseases or disorders are more common in a particular age group. Methods for treating a subject who has undergone surgery in attempting to treat a disease or condition in question, as well as a subject who has not undergone surgery, are further provided herein. Since the subject suffering from cancer has heterogeneous clinical signs and various clinical outcomes, the treatment given to a particular subject may vary according to his / her prognosis. A skilled clinician will readily determine, without undue experimentation, the specific second agent, type of surgery, and type of non-drug based standard therapy that can be effectively used to treat individual subjects with cancer.

Depending on the disease to be treated and the condition of the subject, the compounds provided herein, for example the compounds of formulas I, IIa, IIb, or IIc (including enantiomers, mixtures of enantiomers, diastereomers, , Tautomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, intracavitary, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, Vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. The compounds provided herein, for example, enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variations thereof; Or a pharmaceutically acceptable salt, solvate or hydrate thereof, may be formulated together in a suitable unit for administration, either alone or in combination with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles appropriate for the respective route of administration.

In one embodiment, a compound provided herein, for example, a compound of formula I, IIa, IIb, or IIc (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers , Mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally. In another embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, Isomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered parenterally. In another embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, Isomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered intravenously. In another embodiment, the compounds provided herein, e. G., Diastereoisomeric compounds (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, Mixtures of isomers or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered intramuscularly. In another embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, Isomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered subcutaneously. In another embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, Isomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered topically.

The compounds provided herein, for example, the compounds of formula (I), (IIa), (IIb) or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, Mixtures of isomers or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof can be administered in a single dose, for example, as a single bolus injection or as an oral tablet or pill; Or may be delivered over time, e. G., Over continuous infusion over time or in divided bolus volumes over time. The compounds provided herein may be administered repeatedly, if necessary, for example, until the patient experiences stable disease or degeneration or until the patient experiences a disease regression or toxicity that is not acceptable. For example, stable disease for solid tumors generally means that the vertical diameter of the measurable lesion has not been increased by more than 25% from the last measurement. (RECIST) guidelines for solid tumors, Journal of the National Cancer Institute 92 (3): 205-216 (2000). Stable disease or lack thereof can be determined by methods known in the art, such as evaluation of patient symptoms, physical examination, visualization of tumors imaged using X-ray CAT, PET, or MRI scans, and other commonly accepted assessment forms Lt; / RTI &gt;

The compounds provided herein, for example, the compounds of formula (I), (IIa), (IIb) or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, Mixtures of isomers or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof, may be administered once daily (QD), or divided into multiple daily doses, for example, twice daily (BID) and three times daily (TID). In addition, the administration can be continuous, i.e. daily, or intermittent. The term "intermittently" or "intermittently" as used herein is intended to mean stopping and starting at regular or irregular intervals. For example, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc) (enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, Mixtures of two or more tautomers or isotopic variations thereof); Intermittent administration of a pharmaceutically acceptable salt, solvate or hydrate thereof may be effected by administration for a period of 1 to 6 days per week (for example, daily for 2 to 8 consecutive weeks, followed by up to 1 week For a rest period), or all-day administration.

In certain embodiments, the compounds provided herein, for example, compounds of formulas I, IIa, IIb, or IIc (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers , Mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the patient periodically. Cycling therapy involves the administration of the active agent for a predetermined period followed by a resting period of time and repeating this sequential administration. Cyclic therapy may reduce the incidence of resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies, and / or improve the efficacy of the treatment.

One embodiment provides a compound as provided herein, for example a compound of formula I, IIa, lib or IIc (an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers); Or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, or a polymorphic form thereof and a combination comprising one, two, three or more other therapeutic agents, for example, an anticancer agent.

The compounds provided herein, for example, the compounds of formula (I), (IIa), (IIb) or (IIc) (including enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, Mixtures of isomers or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof may also be used in combination or in combination with other therapeutic agents useful for the treatment and / or prevention of the diseases described herein.

As used herein, the term "combined" includes the use of more than one regimen (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combined " does not limit the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject having a disease or disorder. The first therapy (e.g., prophylactic or therapeutic agent, such as a compound provided herein) may be administered prior to the administration of a second therapy (e.g., prophylactic or therapeutic agent) (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes , 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 (For example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 minutes Time, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks). Triple therapy is also contemplated herein.

Compounds provided herein, for example compounds of formula (I), (IIa), (IIb) or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof is independent of the route of administration of the second therapy. In one embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof is administered orally. In another embodiment, compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof is administered intravenously. Thus, according to these embodiments, the compounds provided herein, for example the compounds of formula (I), (IIa), (IIb) or (IIc), including mixtures of enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers thereof; Or a pharmaceutically acceptable salt or solvate thereof is administered orally or intravenously and the second regimen is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, Into the nasal cavity, into the nasal cavity, into the liposome, through the inhalation, into the vagina, into the eye, through the local delivery by catheter or stent, subcutaneously, into the fat, into the joint, into the spinal cord, . In one embodiment, the compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof, and the second regimen is administered by the same mode of administration, orally or by IV. In another embodiment, compounds provided herein, for example, compounds of formula (I), (IIa), (IIb), or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof is administered by one mode of administration, for example, by IV, while the second agent (anti-cancer agent) is administered by another mode of administration, for example, orally do.

In certain embodiments, each of the methods provided herein may further comprise independently administering a second therapeutic agent. In one embodiment, the second therapeutic agent is an anti-cancer agent. In another embodiment, the anti-cancer agent is an anti-metabolite such as, but not limited to, 5-fluorouracil, methotrexate, cytarabine (also known as cytosine arabinoside or Ara-C) and HDAC (high dose cytarabine) Lt; / RTI &gt; In another embodiment, the anticancer agent is an antimicrobial agent such as, but not limited to, vinca alkaloids (e.g., vincristine and vinblastine), taxanes (e.g., paclitaxel and docetaxel), and epothilones and derivatives thereof (E. G., Ixabepilone). In another embodiment, the anticancer agent is an alkylating agent such as, but not limited to, cyclophosphamide, melphalan, carmustine, and nitroisourea (e.g., bischloroethylnitrosourea and hydroxyurea). In another embodiment, the anticancer agent is a platinum agonist such as, but not limited to, cisplatin, carboplatin, oxaliplatin, satraprapatin (JM-216) and CI-973. In another embodiment, the anticancer agent is anthracycline, such as, but not limited to, doxorubicin and daunorubicin. In another embodiment, the anticancer agent is an antitumor antibiotic such as, but not limited to, mitomycin, dirubicin, adriamycin and daunomycin (also known as daunorubicin). In another embodiment, the anticancer agent is a topoisomerase inhibitor, e. G., Etoposide and camptothecin. In another embodiment, the anticancer agent is selected from the group consisting of adriamycin, bisulfan, cytarabine, cyclophosphamide, dexamethasone, fludarabine, fluorouracil, hydroxyurea, interferon, oblomercene, platinum derivatives, And vincristine.

In another embodiment, the anti-cancer agent is a Bcr-Abl kinase inhibitor. In one embodiment, the Bcr-Abl kinase inhibitor is selected from the group consisting of imatinib, BMS354825 (dasatinib), AMN107 (neilotinib), AP23464, AZD0530, CGP76030, ON012380, INN- ), VX-680 or pyrrolo [2,3-d] pyrimidines such as PD166326, PD173955 and PD180970. In another embodiment, the Bcr-Abl kinase inhibitor is imatinib. In another embodiment, the Bcr-Abl kinase inhibitor is dasatinib. In another embodiment, the Bcr-Abl kinase inhibitor is neilotinib. In another embodiment, the Bcr-Abl kinase inhibitor is AP23464. In another embodiment, the Bcr-Abl kinase inhibitor is AZD0530. In another embodiment, the Bcr-Abl kinase inhibitor is CGP76030. In another embodiment, the Bcr-Abl kinase inhibitor is SKI-606. In another embodiment, the Bcr-Abl kinase inhibitor is ON012380. In another embodiment, the Bcr-Abl kinase inhibitor is INN-0406 (NS-187). In another embodiment, the Bcr-Abl kinase inhibitor is pyrrolo [2,3-d] pyrimidine. In another embodiment, the Bcr-Abl kinase inhibitor is VX-680. In another embodiment, the Bcr-Abl kinase inhibitor is PD166326. In another embodiment, the Bcr-Abl kinase inhibitor is PD173955. In another embodiment, the Bcr-Abl kinase inhibitor is PD180970.

In another embodiment, the anti-cancer agent is a FLT3 kinase inhibitor. In one embodiment, the FLT3 kinase inhibitor is selected from the group consisting of PKC 412, MLN 578, CEP-701, CT 53518, CT-53608, CT-52923, D-64406, D-65476, AGL- 2033, AG1295, AG1296, KN- PKC-412, SU5416, SU5614, SU11248, L-00021649, or CHIR-258. In another embodiment, the FLT3 kinase inhibitor is PKC 412. In another embodiment, the FLT3 kinase inhibitor is MLN 578. In another embodiment, the FLT3 kinase inhibitor is CEP-701. In another embodiment, the FLT3 kinase inhibitor is CT 53518. In another embodiment, the FLT3 kinase inhibitor is CT-53608. In another embodiment, the FLT3 kinase inhibitor is CT-52923. In another embodiment, the FLT3 kinase inhibitor is D-64406. In another embodiment, the FLT3 kinase inhibitor is D-65476. In another embodiment, the FLT3 kinase inhibitor is AGL-2033. In another embodiment, the FLT3 kinase inhibitor is AG1295. In another embodiment, the FLT3 kinase inhibitor is AG1296. In another embodiment, the FLT3 kinase inhibitor is KN-1022. In another embodiment, the FLT3 kinase inhibitor is KN-1022. In another embodiment, the FLT3 kinase inhibitor is SU5416. In another embodiment, the FLT3 kinase inhibitor is SU5614. In another embodiment, the FLT3 kinase inhibitor is SU11248. In another embodiment, the FLT3 kinase inhibitor is L-00021649. In another embodiment, the FLT3 kinase inhibitor is CHIR-258.

Compounds provided herein, for example compounds of formula (I), (IIa), (IIb) or (IIc), including enantiomers, mixtures of enantiomers, mixtures of diastereomers or diastereomers; Or a pharmaceutically acceptable salt or solvate thereof may be administered by any of a variety of routes including surgery, radiation therapy (e.g., gamma-radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, Such as interferon, interleukin, and tumor necrosis factor (TNF), hyperthermia and cryotherapy, agents that attenuate any adverse effects (e. G. And other approved chemotherapeutic drugs such as, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan and iopospamide), antimetabolites (cytarabine (Known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine) and methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, Antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), anticholinergic drugs (anticholinergic, anticholinergic, anticholinergic, ), Nitrosoureas (carmustine and rosmutin), inorganic ions (cisplatin and carboplatin), enzymes (asparaginase) and hormones (tamoxifen, leuprolide, flutamide and megestrol) Adriamycin, dexamethasone, and cyclophosphamide. For a more extensive discussion of updated cancer therapies, see http://www.nci.nih.gov/, a list of FDA-approved endocrine medications, http://www.fda.gov, &Quot; The Merck Manual, Seventeenth Ed. 1999].

In one embodiment, the other anti-cancer agent is selected from the group consisting of a vascular endothelial growth factor (VEGF) receptor inhibitor, a topoisomerase II inhibitor, a spindle inhibitor, an alkylating agent, an antitumor antibiotic, an antimetabolite, a retinoid, , CTLA-4, LAG-3, PD-I antagonist and BET Bromo domain inhibitor.

Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include bevacizumab (sold under the tradename Avastin by Genentech / Roche), acctinib, (N-methyl-2- [ 6-yl] sulfanyl] benzamide, also known as AG013736 and described in PCT Publication No. WO 01/002369, which is also known as &lt; RTI ID = 0.0 & (R) -1- (4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -5-methylpyrrolo [ 2-aminopropanoate, also known as BMS-582664), motesanib (N- (2,2-dimethylpropyl) Indole-6-yl) -2 - [(4-pyridinylmethyl) amino] -3-pyridinecarboxamide and PCT Publication No. WO 02/068470 (Also known as SO 230, described in PCT Publication No. WO 02/010192) and sorafenib (trade name NEXAVAR )), But are not limited thereto.

Examples of topoisomerase II inhibitors include, but are not limited to, etoposide (also known as VP-16 and etoposide phosphate and sold under the trademarks TOPOSAR, VEPESID and ETOPOPHOS) (Also known as VM-26 and sold under the trade name VUMON).

Examples of alkylating agents include 5-azacytidine (sold under the trade name VIDAZA), decitabine (sold under the trademark DECOGEN), temozolomide (Schering-Plow / (Also sold under the trade names TEMODAR and TEMODAL by Merck), dactinomycin (also known as actinomycin-D and sold under the trade name COSMEGEN), melphalan (Also known as L-PAM, L-saccharin and phenylalanine mustard and sold under the trade name ALKERAN), althretamine (also known as hexamethylmelamine (HMM) and sold under the tradename HEXALEN) (Sold under the trademark BCNU), Vendamustine (sold under the trademark TREANDA), Vulcan (sold under the trade names Busulfex (R) and Myleran (R)), ), Carboplatin (sold under the trademark Paraplatin (R)), rostin (also called C (Also known as CNU and sold under the trade name CeeNU (R)), cisplatin (also known as CDDP and sold under the trademarks Platinol (R) and Platinum (R) -AQ), chlorambucil (Sold under the trade names Cytoxan (R) and Neosar (R)), dacarbazine (also sold under the trade name DTIC, DIC and imidazolecar (Also known as hexamethylmelamine (HMM) and sold under the tradename Hexalen (R)), which is known under the trade designation DTIC-Dome (R) (Also sold under the trademark &quot; Ifex &quot;), proccarbine (sold under the trademark Matulane (R)), mechlorethamine (also nitrogen mustard, (Commercially available under the trade name Mustargen (R)), streptozocin (trade name &lt; RTI ID = 0.0 & Zanosar (R)), thiotepa (also known as thiophosphoamides, TESPA and TSPA and sold under the brand name Thioplex (R)).

Examples of antitumor antibiotics include doxorubicin (sold under the trade names Adriamycin® and Rubex®), bleomycin (sold under the trademark lenoxane®), Daunoru (Also known as daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride and sold under the tradename Cerubidine (R)), daunorubicin liposomes (daunorubicin citrate liposomes, (Sold under the DaunoXome®), mitoxantrone (also known as DHAD and sold under the trademark Novantrone®), epirubicin (under the trade name Ellence ™) (Sold under the trade names Idamycin (R), Imidicin PFS (R)) and mitomycin C (under the trade name Mutamycin (R)) , But is not limited thereto.

Examples of antimetabolites include cladribine (2-chlorodeoxyadenosine, sold under the tradename leustatin (R)), 5-fluorouracil (sold under the tradename Adrucil (R)), 6-thioguanine (sold under the trademark Purinethol®), pemetrexed (sold under the trademark Alimta®), cytarabine (also known as arabinosyl cytosine (Ara-C) (Sold under the brand name Cytosar-U (R)), cytarabine liposomes (also known as liposomal Ara-C and sold under the trade name DepoCyt TM), decitabine Dacogen (R)), hydroxyurea (sold under the trade names Hydrea (R), Droxia (TM) and Mylocel (TM)), fluaravarin (Also sold under the trade name Fludara®), floczolidine (sold under the trademark FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) (Also known as ametopterin, methotrexate sodium (MTX) and under the trade names Rheumatrex (R) and Trexall (TM)), methotrexate (also sold under the trade name Leustatin TM) , And pentostatin (sold under the trade name Nipent (R)).

Examples of retinoids are alitretinoin (sold under the trade name Panretin®), tretinoin (all-trans retinoic acid, also known under the trade name ATRA and sold under the trade name Vesanoid®), isotretinoin 13-cis-retinoic acid, the trade names Accutane (R), Amnesteem (R), Claravis (R), Clarus (R), Decutan R), Isotane (R), Izotech (R), Oratane (R), Isotret (R) and Sotret (R) , And Beckaroten (sold under the trade name Targretin (R)).

"PD-1 antagonist" blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells) -1 &lt; / RTI &gt; that blocks the binding of PD-L2 expressed on cancer cells to IL-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 in the case of PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H in the case of PD-L1; And PDCD1L2, PDL2, B7-DC, Btdc and CD273 in the case of PD-L2. In any of the treatment methods, medicaments and uses of the present invention wherein a human individual is to be treated, the PD-I antagonist blocks binding of human PD-L1 to human PD-1 and preferably inhibits the binding of human PD- Thereby blocking the coupling of both PD-L1 and PD-L2. The amino acid sequence of human PD-1 can be found in NCBI Location No: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI locating numbers: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in any of the treatment methods, medicaments, and uses of the present invention specifically bind PD-1 or PD-L1 and preferably bind to human PD-1 or human PD-L1 (MAb) or antigen-binding fragment thereof. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in a preferred embodiment, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F (ab ') ₂ , scFv and Fv fragments.

Examples of mAbs useful in the treatment methods, medicaments and uses of the present invention that bind to human PD-I are described in US 7488802, US 7521051, US 8008449, US 8354509, US 8168757, WO 2004/047771, WO 2004/072286, WO 2004/056875, and US 2011/0271358 .

Examples of mAbs that bind to human PD-L1 and are useful in the treatment methods, medicaments and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634A1 and US8383796. The specific anti-human PD-Ll mAbs useful as PD-I antagonists in the treatment methods, medicaments and uses of the present invention are shown in SEQ ID NOs of MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and WO2013 / 019906, : 24 and the heavy and light chain variable regions of SEQ ID NO: 21.

Other PD-1 antagonists useful in any of the treatment methods, medicaments, and uses of the present invention specifically bind PD-I or PD-Ll, and are preferably specific for human PD-1 or human PD-L1 Binding immunohesin, such as a fusion protein containing an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. A specific fusion protein useful as a PD-1 antagonist in the treatment methods, medicaments and uses of the present invention is PD-L2-FC fusion protein and comprises AMP-224 (also known as B7-DCIg) which binds to human PD-1 do.

Examples of other cytotoxic agents include arsenic trioxide (sold under the trade name Trisenox®), asparaginase (also known as L-asparaginase and Erwinia L-asparaginase, and the trade name Elspar ) (R) and Kidrolase (R)).

In one embodiment, the other anticancer agent is a BET Bromo domain inhibitor. Examples of BET bromo domain inhibitors include the compounds described in U.S. Pat. Nos. 5712274, WO994006802, U.S. Pat. Nos. 8476260 and WO2009 / 084693.

The compounds provided herein may also be provided as articles of manufacture using packaging materials well known to those of ordinary skill in the relevant art. See, for example, U.S. Patent Nos. 5,323,907; 5,052,558; And 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubing, inhalers, pumps, bags, vials, containers, syringes, and any packaging materials suitable for the intended formulation and manner of administration .

Kit

In certain embodiments, kits are provided herein that can simplify administration of an appropriate amount of an active ingredient to a subject when used by a medical practitioner. In certain embodiments, a kit provided herein comprises a compound or composition provided herein (including a single enantiomer thereof, a mixture of enantiomers, a mixture of diastereoisomers or diastereomers); Or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the kit comprises a compound provided herein (including a single enantiomer thereof, a mixture of enantiomers, a mixture of diastereomers or diastereomers) in a container comprising one or more other therapeutic agent (s) as described herein; Or a pharmaceutically acceptable salt or solvate thereof.

The kit provided herein may further comprise an apparatus used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringe drip bags, patches, and inhalers. The kits provided herein may also include condoms for administration of the active ingredient.

The kits provided herein may additionally comprise a pharmaceutically acceptable vehicle that may be used to administer one or more active ingredients. For example, where the active ingredient is provided in the form of a solid that has to be reconstituted for parenteral administration, the kit may contain a suitable vehicle seal, such that the active ingredient is dissolved to form a sterile, particulate- Lt; / RTI &gt; Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles such as, but not limited to, USP Injection Water, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; Water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; And non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

In certain embodiments, a cell is treated with a compound provided herein, for example, a compound of formula I, IIa, lib, or IIc (an enantiomer thereof, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, Tautomers, mixtures of two or more tautomers, or isotopic variations thereof); Or a pharmaceutically acceptable salt, solvate or hydrate thereof for the manufacture of a medicament for inhibiting the growth of a cell.

In certain embodiments, an effective amount of a compound provided herein ranges from about 1 pM to about 1 mM, from about 10 pM to about 10 μM, from about 100 pM to about 2 μM, or from about 1 nM to about 1 μM.

In certain embodiments, the cell is a mammalian cell. In certain embodiments, the mammalian cell is a human cell. In certain embodiments, the cell is a tumor cell. In certain embodiments, the cell is a mammalian tumor cell. In certain embodiments, the cell is a human tumor cell. In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is a mammalian cancer cell. In certain embodiments, the cell is a human cancer cell. In certain embodiments, the cancerous cell is a metastatic cancerous cell. In certain embodiments, the cancerous cell is a metastatic microbial cell. In certain embodiments, the cancerous cell is a metastatic bacterial cell. In certain embodiments, the cancerous cell is a metastatic fungal cell.

In certain embodiments, the cell is a hematologic malignant tumor cell. In certain embodiments, the cell is a leukemia cell. In certain embodiments, the cell is a recurrent leukemia cell. In certain embodiments, the cell is a refractory leukemia cell. In certain embodiments, the cell is a drug-resistant leukemia cell. In certain embodiments, the cell is a multiple drug-resistant leukemia cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant leukemia cell. In certain embodiments, the cell is an imatinib-resistant leukemia cell. In certain embodiments, the cell is a dasatinib-resistant leukemia cell. In certain embodiments, the cell is a neilotinib-resistant leukemia cell. In certain embodiments, the cell is a conservedinib-resistant leukemia cell. In certain embodiments, the cell is a cytarabine-resistant leukemia cell.

In certain embodiments, the cell is a leukemia stem cell. In certain embodiments, the cell is a recurrent leukemia stem cell. In certain embodiments, the cell is a refractory leukemia stem cell. In certain embodiments, the cell is a drug-resistant leukemia stem cell. In certain embodiments, the cell is a multiple drug-resistant leukemia stem cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant leukemia stem cell. In certain embodiments, the cell is an imatinib-resistant leukemia stem cell. In certain embodiments, the cell is a dasatinib-resistant leukemia stem cell. In certain embodiments, the cell is a neuritinib-resistant leukemia stem cell. In certain embodiments, the cell is a conservedinib-resistant leukemia stem cell. In certain embodiments, the cell is a cytarabine-resistant leukemia stem cell.

In certain embodiments, the cell is an acute leukemia cell. In certain embodiments, the cell is a recurrent acute leukemia cell. In certain embodiments, the cell is a refractory acute leukemia cell. In certain embodiments, the cell is a drug-resistant acute leukemia cell. In certain embodiments, the cell is a multiple drug-resistant acute leukemia cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant acute leukemia cell. In certain embodiments, the cell is an imatinib-resistant acute leukemia cell. In certain embodiments, the cell is a dasatinib-resistant acute leukemia cell. In certain embodiments, the cell is a neuritinib-resistant acute leukemia cell. In certain embodiments, the cell is a conservedinib-resistant acute leukemia cell. In certain embodiments, the cell is a cytarabine-resistant acute leukemia cell.

In certain embodiments, the cell is an ALL cell. In certain embodiments, the cell is a recurrent ALL cell. In certain embodiments, the cell is a refractory ALL cell. In certain embodiments, the cell is a drug-resistant ALL cell. In certain embodiments, the cell is a multiple drug-resistant ALL cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant ALL cell. In certain embodiments, the cell is an imatinib-resistant ALL cell. In certain embodiments, the cell is a multiditinib-resistant ALL cell. In certain embodiments, the cell is a neilotinib-resistant ALL cell. In certain embodiments, the cell is a conservedinib-resistant ALL cell. In certain embodiments, the cell is a cytarabine-resistant ALL cell.

In certain embodiments, the cell is an AML cell. In certain embodiments, the cell is a recurrent AML cell. In certain embodiments, the cell is a refractory AML cell. In certain embodiments, the cell is a drug-resistant AML cell. In certain embodiments, the cell is a multiple drug-resistant AML cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant AML cell. In certain embodiments, the cell is an imatinib-resistant AML cell. In certain embodiments, the cell is a multiditinib-resistant AML cell. In certain embodiments, the cell is a neilotinib-resistant AML cell. In certain embodiments, the cell is a conservinib-resistant AML cell. In certain embodiments, the cell is a cytarabine-resistant AML cell.

In certain embodiments, the cell is a chronic leukemia cell. In certain embodiments, the cell is a recurrent chronic leukemia cell. In certain embodiments, the cell is a refractory chronic leukemia cell. In certain embodiments, the cell is a drug-resistant chronic leukemia cell. In certain embodiments, the cell is a multiple drug-resistant chronic leukemia cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant chronic leukemia cell. In certain embodiments, the cell is an imatinib-resistant chronic leukemia cell. In certain embodiments, the cell is a dasatinib-resistant chronic leukemia cell. In certain embodiments, the cell is a neilotinib-resistant chronic leukemia cell. In certain embodiments, the cell is a conservedinib-resistant chronic leukemia cell. In certain embodiments, the cell is a cytarabine-resistant chronic leukemia cell.

In certain embodiments, the cell is a CLL cell. In certain embodiments, the cell is a recurrent CLL cell. In certain embodiments, the cell is a refractory CLL cell. In certain embodiments, the cell is a drug-resistant CLL cell. In certain embodiments, the cell is a multiple drug-resistant CLL cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant CLL cell. In certain embodiments, the cell is an imatinib-resistant CLL cell. In certain embodiments, the cell is a multiditinib-resistant CLL cell. In certain embodiments, the cell is a neilotinib-resistant CLL cell. In certain embodiments, the cell is a conservinib-resistant CLL cell. In certain embodiments, the cell is a cytarabine-resistant CLL cell.

In certain embodiments, the cell is a CML cell. In certain embodiments, the cell is a recurrent CML cell. In certain embodiments, the cell is a refractory CML cell. In certain embodiments, the cell is a drug-resistant CML cell. In certain embodiments, the cell is a multiple drug-resistant CML cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant CML cell. In certain embodiments, the cell is an imatinib-resistant CML cell. In certain embodiments, the cell is a dasatinib-resistant CML cell. In certain embodiments, the cell is a neilotinib-resistant CML cell. In certain embodiments, the cell is a conservinib-resistant CML cell. In certain embodiments, the cell is a cytarabine-resistant CML cell.

In certain embodiments, the cell is a Philadelphia positive leukemia cell. In one embodiment, the cell is a Philadelphia positive ALL cell. In another embodiment, the cell is a Philadelphia positive AML cell. In another embodiment, the cell is a Philadelphia positive CLL cell. In another embodiment, the cell is a Philadelphia positive CML cell.

Inhibition of cell growth may be determined, for example, by counting the number of cells contacted with a compound of interest, by comparing cell proliferation with the same cell that is otherwise not in contact with the compound, or by determining the size of the tumor Lt; / RTI &gt; The number of cells as well as the size of the cells can be determined using any method known in the art (e.g., trypan blue exclusion and cell counting to determine the incorporation of ³ H-thymidine into intracellular neonatal DNA) Can be easily evaluated.

Black method

Patient samples were obtained from non-interventional and prospective studies. The study included samples from adult patients over 18 years of age diagnosed with acute myelogenous leukemia (AML).

In one embodiment, the data acquisition method was performed as follows: On the first day, a patient sample of bone marrow (BM) or peripheral blood (PB) was received. Most of the sample was diluted with the culture medium and the target compound and compound combination, for example, a compound or combination of compounds as described herein, Lt; / RTI &gt; well plate. The number of live leukemic cells seeded into each well was fixed at 8000-32000 according to the percentage of white blood cells per sample. These plates were incubated for 72 hours and analyzed on the fourth day. To identify leukemic cells, gating strategies based on FSC / SSC and lack of expression or expression of different surface markers were added. Monoclonal antibody selection was performed to optimize the identification of leukemic cells in each sample.

In one embodiment, non-limiting examples of biomarkers are biomarkers CD34, CD45, CD117, and HLADR (van Dongen, JJ and A. Orfao, EuroFlow: Resetting leukemia and lymphoma immunophenotyping . Basis for companion diagnostics and personalized medicine, Leukemia, 2012, 26, 1899-907) were included in the combination.

In one embodiment, antibody combinations such as CD117 / CD45, CD34 / CD45, and HLADR / CD45 were used. Live leukemic cells were identified by their light scattering properties (FSC ^{int / hi} / SSC ^int ) in the absence of Annexin-V-FITC staining. FSC / SSC selection was performed to exclude debris. The average percentage of cell survival at the time of sample acceptance was 80%, and the sample was processed only if the survival rate exceeded 50%.

In one embodiment, sample validation was performed as follows: BM and PB samples were extracted under sterile conditions and housed in the lab within 24 hours of extraction. Initial analysis assessed the number of pathologic cells and their survival rate. Different volumes of samples (1 [mu] L, 3 [mu] L, 5 [mu] L and 7 [mu] L) were aliquoted into 96-well plates. To dissolve red blood cells, 180 μL of ammonium chloride lysis solution was added to each well (2 g KHCO ₃ , 16.58 g NH ₄ Cl, 0.074 g Na ₂ EDTA · 2H ₂ O, 1 L H ₂ O). After a 10 minute incubation period at 4 DEG C, the plate was centrifuged at 1200 rpm for 5 minutes and the supernatant was removed. The dissolution step was performed twice. (BB, 2.4 g HEPES, 8.19 g NaCl, 0.37 g Cl ₂ Ca, H ₂ O 1 L), and the following monoclonal antibodies to the following monoclonal antibodies: Anexin V-FITC (Immunostep, Salamanca, Spain) (Clone 104D2) -PE (Becton Dickinson, San Jose, CA), CD34 (Clone 581) -PerCP (BioLegend (BioLegend)) was added to each well. ), HLADR (Clone L243) -PB (Bio Legend) and CD45 (HI30) -PO (Life Technologies, Carlsbad, CA) (van Dongen, JJ, et al. Euroflow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes, Leukemia, 2012, 26, 1908-75). After an incubation in the dark room for 15 minutes at room temperature, a washing step was performed using a binding buffer solution. For analysis, the pellet was resuspended in 30 μL BB in Vivia's ExviTech ® platform. Upon arrival, cell counts and survival rates were computerized and the optimal volume of sample for use per well was determined.

In one embodiment, assays were performed according to the following method: The entire sample was resuspended in 20% (v / v) FBS (Thermo Scientific, Waltham, Mass.), 2% HEPES, 1% (Zell Shield, Labclinics, Barcelona, Spain) and RPMI 1640 supplemented with 1% L-glutamine 200 mM (Lonza, Hopkinton, Mass., USA) to a final volume of 60 μL per well Lt; / RTI &gt; The mixture was dispensed into a Multidrop Combi Smart (Thermosynthetic, Waltham, Mass., USA) in 96-well plates containing the compounds described herein. The drug plate was previously prepared using an Echo 550 liquid handler (LabCyte, Sunnyvale, Calif., USA). Five or eight concentrations were used for each compound tested and adjusted to cover the range of activity across the patients. The compounds tested were also tested as controls for the corresponding blasts. The plate was incubated for 5% CO ₂ humidified air at 48 hours or 72 hours at 37 ℃ containing.

In one embodiment, data analysis was performed with Summit software (Beckman Coulter). Identification of pathological cells was performed using a gating strategy based on FSC / SSC and a lack of expression or expression of different mAb markers. Depletion was measured as the difference in the number of living cells in the control well without the well vs compound containing the compounds described herein. Subsequently, annexin V was used to exclude dead cells, and only the number of living cells in the drug and control wells was measured. Cells without annexin V staining and appropriate FSC / SSC were considered as living cells (Koopman, G., et al., Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis, Blood, 1994, 84, 1415 -20). Using these parameters, an FCS analyzer was used to determine the effect of each individual compound. For final analysis, data was transferred to ActivityBase (IDBS, Guildford, UK).

The disclosure will be further understood by the following non-limiting examples.

The in vitro effects of compounds on AML samples when the plates were incubated for 72 hours are illustrated in Table 2:

The in vitro effects of compounds on AML samples when plates were incubated for 48 hours are illustrated in Table 3:

The EC ₅₀ value Is provided as follows:

A ≤ 1 μM, 1 <B ≤ 10 μM, 10 <C <20 μM, D ≥ 20 μM;

The Emax values are provided as follows:

A = 0-10%; B = 10-20%; C> 20%

In vitro inhibition

matter

Cells were grown in RPMI-1640 supplemented with L-glutamine and 10% FBS in the following cancer cell lines:

CCRF-CEM; CCRF-CEM-cytarabine resistance; HL-60;

Way

18, 96 well plates of each cell line were seeded with a total volume of 50 μL per well using an optimized number of cells per well. The plates were allowed to stand overnight. The plate wells were seeded with 100 [mu] L of medium for the control group. The following day, the cells were exposed to test compounds as described below. At the same time as the drug exposure, a CTG assay was performed on the 18th plate for a 0 hour count.

Compounds were added to cells and media already on the plate to obtain the desired final concentration. 50 [mu] L of the medium was added to the cell control wells, and 50 [mu] L of the mix was added to the vehicle control wells. 10 [mu] M doxorubicin was added to the appropriate wells as a control. Cells exposed to the test compound were incubated at 37 占 폚 for 72 hours, followed by CTG assays.

Cellator-glow (CTG)

At the end of the 72 hour exposure period, the plates were removed from a 5% CO ₂ incubator at 37 ° C for a caterator-glow (CTG) assay and left on the bench at room temperature for 30 minutes. 100 μL of the celator-gel reagent was added, mixed for 2 minutes, and then incubated for an additional 10 minutes at room temperature. The luminescence was recorded using Synergy 4.0.

All exemplified compounds were tested according to this method and were found to have an IC ₅₀ value of less than 100 μM in each cell line. The results for the compounds are provided in Table 4.

<Table 4> CCRF-CEM; CCRF-CEM-cytarabine resistance; And in vitro inhibition of HL-60.

The IC ₅₀ values in Table 1 are as follows:

A = < 1 [mu] M

B =? 1 and 10?? M

C => 10 and ≤ 25 μM

D = > 25 and &lt; 100 [mu] M

The embodiments described above are intended for illustrative purposes only, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are intended to be encompassed by the appended claims.

Modifications are intended to be limited only by the scope of the appended claims, since such modifications will be apparent to one of ordinary skill in the art.

Claims (30)

A compound of formula I or a pharmaceutically acceptable salt thereof.
(I)

here
Y is

ego;
X is

ego;
R is

ego;
R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;
W is NH _2, halo, OMe, or OH;
T is NH _2, F, Cl, or halogen;
R ¹ is hydrogen, halo, OH, protected OH, cyano, or alkynyl;
Q is OR < ³ &gt;;
E is CR ⁴ R ⁵ ;
L is H, p-Me, p-OMe, p-Cl, or 3,4-Cl;
n is 1;
m is 1 or 2;
p is absent or O;
R ^y is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each of which is independently optionally substituted;
R &lt; ² &gt; is hydrogen or alkyl;
R ³ is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl or aralkyl;
R ⁴ and R ⁵ are
i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Optionally substituted; or
ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.
&Lt; / RTI &gt;
R ⁶ is hydrogen,

Or
Items 1 R ⁶ and X and Y are combined together with the atom to which they are attached to form a 6-membered heterocyclic ring, where R ^6, and X and Y are one of the single divalent -O- with Or; or
R 1 out of ⁶ and X and Y dogs in combination with the atoms to which they are attached to form a 7-12- membered heterocyclic ring;
Where R is

, And both X and Y are

, At least one R ^y is other than alkyl. The compound according to claim 1, wherein R &lt; ¹ &gt; is OH or F. 3. A compound according to claim 1 or 2, wherein X is -NHCH ₂ Ph and Y is

&Lt; / RTI &gt; 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
<Formula IId>

3. The compound according to claim 1 or 2, wherein the compound has the formula IIe or a pharmaceutically acceptable salt thereof.
<Formula IIe>

here
R ² is hydrogen; R &lt; ³ &gt; is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
(IIf)

here
R ² is hydrogen; R < ³ > is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen. 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
<Formula IIg>

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
<Formula IIh>

here
R ² is hydrogen; R &lt; ³ &gt; is alkyl; R ⁴ is hydrogen, R ⁵ is alkyl, or R ⁴ is alkyl and R ⁵ is hydrogen. 3. The compound according to claim 1 or 2, having one of the following formulas.

3. The compound according to claim 1 or 2, having one of the following formulas.

3. The compound according to claim 1 or 2, having one of the following formulas.

3. The compound according to claim 1 or 2, having one of the following formulas.

3. The compound according to claim 1 or 2, having one of the following formulas.

3. A compound according to claim 1 or 2,

A compound of formula (IIa) or a pharmaceutically acceptable salt thereof.
<Formula IIa>

here
Y is OH,

, Or OR &lt; ⁷ &gt;;
R is

ego;
R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;
W is NH _2, Cl, or OMe, and;
T is NH _2, F, or Cl, and;
R &lt; ¹ &gt; is hydrogen, OH, or F;
R &lt; ² &gt; is hydrogen or alkyl;
Q is OR &lt; ³ &gt;;
E is CR ⁴ R ⁵ ;
n is 1;
R ³ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁴ and R ⁵ are
i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Optionally substituted; or
ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.
&Lt; / RTI &gt;
R ⁷ is alkyl, alkenyl, or alkynyl, each independently optionally substituted. 16. The compound of claim 15 having the formula: EMI58.1 or a pharmaceutically acceptable salt thereof.

here
R ² is hydrogen; R &lt; ³ &gt; is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen. 17. The compound according to claim 15 or 16, having one of the following formulas.

17. The compound according to claim 15 or 16, having one of the following formulas.

A compound of formula (IIb) or a pharmaceutically acceptable salt thereof.
<Formula IIb>

here
Y is OH,

, Or OR &lt; ⁷ &gt;;
R is

ego;
R ^z is H or C (O) Z, wherein Z is a fatty acid chain selected from palmitoleic acid, oleic acid, linoleic acid, or arachidonic acid;
R &lt; ² &gt; is hydrogen or alkyl;
Q is OR &lt; ³ &gt;;
E is CR ⁴ R ⁵ ;
n is 1;
R ³ is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R ⁴ and R ⁵ are
i) R ⁴ and R ⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, Substituted; or
ii) R ⁴ and R ⁵ together with the carbon atoms to which they are attached form a 3-7 membered cycloalkyl ring.
&Lt; / RTI &gt;
R ⁷ is alkyl, alkenyl, or alkynyl, each independently optionally substituted. 20. A compound according to claim 19 having the formula: EMI2.1 or a pharmaceutically acceptable salt thereof.

here
R ² is hydrogen; R &lt; ³ &gt; is alkyl; R &lt; ⁴ &gt; is hydrogen and R &lt; ⁵ &gt; is alkyl or cycloalkyl; Or R &lt; ⁴ &gt; is alkyl or cycloalkyl and R &lt; ⁵ &gt; is hydrogen. 21. A compound according to claim 19 or 20,

A compound selected from:
Fluoro-2-oxydotetrahydro-4H-furo [3, &lt; RTI ID = 0.0 &gt; 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
Fluoro-2-oxydotetrahydro-4H-furo [3, &lt; RTI ID = 0.0 &gt; 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
Yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) - methyl) -methanone hydrochloride (2R, 3R, 0.0 &gt; benzene &lt; / RTI &gt; phosphoramidate,
Yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyldi (2R, 3R, 4S, 5R) (((3-hydroxy-2,2-dimethylpropanoyl) thio) ethyl) phosphate,
S- (2 - ((((2R, 3R, 4S, 5R) -5- (6-Amino-2-chloro-9H- purin- Furan-2-yl) methoxy) (benzylamino) phosphoryloxy) ethyl) 3-hydroxy-2,2-dimethylpropanethioate,
S- (2 - ((((2R, 3R, 4S, 5R) -5- (6-Amino-2-chloro-9H- purin- Furan-2-yl) methoxy) (benzylamino) phosphoryloxy) ethyl) 3-hydroxy-2,2-dimethylpropanethioate,
2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl ) Methoxy) (2-methoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl ) Methoxy) (2-methoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
(2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- 1 (2H) -yl) -3,4-dihydroxytetrahydrofuran- 0.0 &gt; benzene &lt; / RTI &gt; phosphoramidate,
((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- (1-methyl-2-nitro-1H-imidazol-5-yl) methyl) benzyl phosphoramidate,
((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- (1-methyl-2-nitro-1H-imidazol-5-yl) methyl) benzyl phosphoramidate,
Methyl (((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- 1 (2H) -yl) -3,4-dihydroxytetrahydrofuran- ) Methoxy) (2-methoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
Ethyl (((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- 1 (2H) -yl) -3,4-dihydroxytetrahydrofuran- ) Methoxy) (2-ethoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
Ethyl (((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- ) Methoxy) (2-ethoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
S- (2 - ((((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- 1 (2H) -yl) -3,4-dihydroxytetrahydro Furan-2-yl) methoxy) (benzylamino) phosphoryloxy) ethyl) 3-hydroxy-2,2-dimethylpropanethioate,
Methyl (2S) - (((2R, 3S, 4S, 5R) -3,4-dihydroxy-5- (4- Methoxy-4-methyl-1-oxopentan-2-yl) amino) phospholyl) thiophene- -L-leucinate,
Yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylhydrogenol (2R, 3S, 4S, 5R) Benzyl phosphoramidate,
((2R, 3S, 4S, 5R) -5- (4-Amino-2-oxopyrimidin- (1-methyl-2-nitro-1H-imidazol-5-yl) methyl) benzyl phosphoramidate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (6-Amino-2-fluoro-9H- purin-9- yl) -7- hydroxy-2-oxydotetrahydro-4H- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-leucinate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (6-Amino-2-fluoro-9H- purin-9- yl) -7- hydroxy-2-oxydotetrahydro-4H- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-leucinate,
Isopropyl (((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9- ) Methoxy) (phenoxy) phosphoryl) -L-alaninate,
S- (2 - ((((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran Yl) methoxy) (benzylamino) phospholyl) oxy) ethyl) 3-hydroxy-2,2-dimethylpropanethioate,
(((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9-yl) -3,4-dihydroxytetrahydrofuran- Methoxy) (2- ((3-hydroxy-2,2-dimethylpropanoyl) thio) ethoxy) phosphoryl) -L-
(6-amino-2-fluoro-9H-purin-9-yl) 2-d] [l, 3,2] dioxaphosphinine 2-oxide,
(6-amino-2-fluoro-9H-purin-9-yl) 2-d] [l, 3,2] dioxaphosphinine 2-oxide,
(((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9-yl) -3,4-dihydroxytetrahydrofuran- Methoxy) (hydroxy) phosphoryl) -L-leucinate,
(((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9-yl) -3,4-dihydroxytetrahydrofuran- Methoxy) (2-ethoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
Methyl (((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9- yl) -3,4-dihydroxytetrahydrofuran- Methoxy) (2S-1-methoxy-1-oxo-4-methylpent-2-ylamino) phosphoryl) -L-
(((2R, 3R, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9- Yl) methoxy) (2-methoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
Methyl (((2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-9H- purin-9- yl) -3,4-dihydroxytetrahydrofuran- Methoxy) (2-methoxy-2-oxoethoxy) phosphoryl) -L-leucinate,
(6-amino-2-fluoro-9H-purin-9-yl) -7-hydroxy-2-oxydotetrahydro -4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl) amino) propyl propionate,
(6-amino-2-fluoro-9H-purin-9-yl) -7-hydroxy-2-oxydotetrahydro -4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl) amino) propyl propionate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (6-Amino-2-fluoro-9H- purin-9- yl) -7- hydroxy-2-oxydotetrahydro-4H- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (6-Amino-2-fluoro-9H- purin-9- yl) -7- hydroxy-2-oxydotetrahydro-4H- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (2-Amino-6-methoxy-9H- purin-9- yl) -7- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
Ethyl ((4aR, 6R, 7S, 7aS) -6- (2-Amino-6-methoxy-9H- purin-9- yl) -7- , 2-d] [1,3,2] dioxaphosphinin-2-yl) -L-alaninate,
6-methoxy-9H-purin-9-yl) -7-hydroxy-2-oxydotetrahydro (2S) -4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl) amino) propyl propionate,
S- (2 - ((((2R, 3S, 4S, 5R) -5- (2-Amino-6-methoxy-9H- purin-9-yl) -3,4-dihydroxytetrahydrofuran Yl) methoxy) (benzylamino) phospholyl) oxy) ethyl) 3-hydroxy-2,2-dimethylpropanethioate, or
(2R, 3S, 4S, 5R) -5- (2-Amino-6-methoxy-9H- purin-9-yl) -3,4- dihydroxytetrahydrofuran- 2- yl) methylhydrogen Benzyl phosphoramidate,
Or a pharmaceutically acceptable salt thereof. A compound selected from:
6-chloro-purin-9-yl) -7-fluoro-2-oxo-4a, 6a, 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate (diastereoisomers 1 and 2);
[(2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-purin-9- yl) -3,4- dihydroxy- tetrahydrofuran-2-yl] methoxy- - benzyl-phosphonamidic acid;
[(Benzylamino) - [(3-methyl-2-nitro-imidazol-4-yl) methoxy] phospholyl] oxy Methyl] -3,4-dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one (diastereoisomers 1 and 2);
[(2R, 3S, 4S, 5R) -5- (4-Amino-2-oxo-pyrimidin- 1 -yl) -3,4-dihydroxy-tetrahydrofuran- 2-nitrothiazol-5-yl) methyl] phosphate;
Yl] methyl (3- (4-amino-2-oxo-pyrimidin-1 -yl) -3,4-dihydroxy-tetrahydrofuran- Methyl-2-nitro-imidazol-4-yl) methyl (2-nitrothiazol-5-yl) methyl phosphate;
[(2R, 3S, 4S, 5R) -5 - [[(benzylamino) - [(5-nitro-2- thienyl) methoxy] phospholyl] oxymethyl] -Dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one (diastereoisomers 1 and 2);
[(2R, 3S, 4S, 5R) -5- (4-Amino-2-oxo-pyrimidin- 1 -yl) -3,4-dihydroxy-tetrahydrofuran- 5-nitro-2-furyl) methyl] phosphate;
Benzyl (2S) -2 - [[[(2R, 3S, 4S, 5R) -5- 2-yl] methoxy - [(5-nitro-2-thienyl) methoxy] phosphoryl] amino] propanoate (diastereoisomers 1 and 2);
[(2R, 3S, 4S, 5R) -5 - [[(Benzylamino) - [(5-nitro- 2- furyl) methoxy] phospholyl] oxymethyl] Dihydroxy-tetrahydrofuran-2-yl] pyrimidin-2-one (diastereoisomers 1 and 2);
Benzyl (2S) -2 - [[(4aR, 6R, 7S, 7aR) -6- 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate (diastereoisomers 1 and 2);
6-amino-2-fluoro-purin-9-yl) -7-hydroxy-2-oxo-4a, 6 , 7,7a-tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphinin-2-yl] amino] propanoate (diastereoisomers 1 and 2); And
Methyl (2S) -2 - [[[(2R, 3S, 4S, 5R) -5- (6-Amino-2-fluoro-purin-9-yl) -3,4-dihydroxy-tetrahydrofuran Yl] methoxy- (2-methoxy-2-oxo-ethoxy) phospholyl] amino] -4-methyl-pentanoate;
Or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. 25. The pharmaceutical composition according to claim 24, wherein the composition is an oral preparation. A method of treating a blood cancer comprising administering an effective therapeutic amount of a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or a composition of claim 24 or 25. 27. The method of claim 26, wherein the blood cancer is leukemia cancer. 28. The method of claim 27, wherein the leukemia is acute myelogenous leukemia (AML). 27. The method of claim 26, wherein said compound or composition is administered in combination with or alternatively with a second chemotherapeutic agent. 24. A combination comprising a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and one, two, three or more other therapeutic agents.