Orally active prodrugs of gemcitabine

Abstract

The present disclosure includes compounds according to formula (I) or formula (II) (wherein R1, R2, and R3 are defined herein) and methods of making those compounds. The disclosure extends to those compounds for the treatment of neoplastic disease or methods for treating neoplastic disease using those compounds.

Description

[Technical field]

[0001] The present invention relates to a novel class of orally active prodrugs of gemcitabine, their preparation, and uses thereof. [Background technology]

[0002] Gemcitabine, as described below, is a pyrimidine nucleoside analogue that has been shown to be active against multiple solid tumor types.After FDA approval in 1996, gemcitabine has become the standard treatment for the treatment of pancreatic cancer.More recently, the compound has also been approved for the treatment of non-small cell lung cancer, ovarian cancer, bladder cancer, and breast cancer.

[0003] [ka]

[0004] Gemcitabine is administered at approximately 1000-1250 mg / m once weekly for up to 7 weeks. 2Gemcitabine is administered by intravenous infusion over 30 minutes at a dose of 100 mg / kg, followed by a 1-week break from treatment. The use of oral gemcitabine is limited by its poor oral bioavailability, a result of first-pass metabolism. Shipley LA. et al., "Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs." Drug Metabolism & Disposition. 20(6):849-55, 1992. In addition, gemcitabine, when administered orally, has been implicated in causing dose-limiting adverse intestinal lesions characterized by moderate to severe loss of mucosal epithelium along the entire length of the intestine (atrophic enteropathy) in mice receiving a single oral (gavage) dose of 167,333 or 500 mg / kg gemcitabine. Horton ND et al., "Toxicity of single-dose oral gemcitabine in mice," American Association for Cancer Research, Poster Presentation, Orlando, FL, March 27-31, 2004. Similar exposure via intravenous administration in previous mouse studies did not result in mortality or gastrointestinal toxicity.

[0005] In 2009, Bender et al. reported that an orally active prodrug of gemcitabine; LY2334737, was significantly less susceptible to degradation by CDA due to a valproic acid conjugate at its 4-(N)-position. Based on in vivo data in HCT-116 human colon xenografts, LY2334737 was advanced into phase I clinical trials, but its development was discontinued after unexpected hepatotoxicity was observed in a study in Japanese patients in 2013.

[0006] As shown in the gemcitabine chemical structure above, gemcitabine has three functional groups (i.e., -OH, -OH, -NH2) that are suitable for chemical prodrug derivatization. Triple drugs in which all three replaceable moieties are substituted are described in WO2020 / 107013. However, the triple-substituted prodrug compounds are unstable at room temperature. The instability of the active ingredient presented significant problems in formulation development and did not result in a stable drug product. Thus, the triple-substituted compounds are not suitable for advancing as orally active prodrugs for therapeutic use. Summary of the Invention

[0007] Research continues in the art regarding orally active prodrugs of gemcitabine for the development and / or provision of medical product treatments suitable for use in cancer therapy, particularly the treatment of pancreatic, ovarian, and breast cancer.

[0008] The present invention relates to a new class of orally active prodrugs of gemcitabine, including orally active substituted prodrugs, in which a combination of specific functional groups is derivatized with promoieties (chemical functional groups used to modify the structure of the parent drug to improve physicochemical, biopharmaceutical, or pharmacokinetic properties). The promoieties are typically inert and biologically safe. However, one of these groups is typically always H, specifically the group at the R3 position, as shown below.

[0009] Therefore, the present invention provides a compound of formula (I):

[0010] [ka]

[0011] (In the formula, R1 is selected from 2-propylpentanoic acid, 2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid, and 2-amino-3-methylbutanoic acid; R2 is H, and R3 is selected from H, 2-propylpentanoic acid, 2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid, and 2-methylpropanoic acid. or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotope, or prodrug of said compound of formula (I) or an N-oxide thereof.

[0012] The substituted compounds have one free primary alcohol position (not an isobutyric acid moiety), which is advantageous since it exhibits enhanced stability in formulations of drugs suitable for therapeutic use.

[0013] In other embodiments, R1 and R3 are selected in the following respective combinations to obtain the specifically named compounds: Valproic acid (2-propylpentanoic acid) (R1) and valproic acid (R3), the compound of which is (2R,3R,5R)-4,4-difluoro-2(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl 2-propylpentanoate; or Valproic acid and H, an embodiment of the compound is N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-propylpentanamide; or Boc valine (2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid) and H, an embodiment compound of which is tert-butyl (1-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate; or valine (2-amino-3-methylbutanoic acid) and H, the compound of which is 2-amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-3-methylbutanamide hydrochloride; or Boc valine and Boc valine, an embodiment compound of which is (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoate; Valine and valine, an embodiment of the compound is (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate dihydrochloride; or Boc valine and isobutyric acid (2-methylpropionic acid), an embodiment compound of which is (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate; or valine and isobutyric acid, the compound of which embodiment is (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate hydrochloride; or Valproic acid and isobutyric acid, an embodiment compound of which is (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl isobutyrate.

[0014] In some embodiments, the prodrug moiety of R3 is not H. In additional embodiments, the compound has formula (II):

[0015] [ka]

[0016] and / or the compound referred to as (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate hydrochloride. It is.

[0017] The double-substituted compounds have improved stability at room temperature. Moreover, the compounds of the present invention have stability at 2°C to 8°C. Compared to the triple-substituted compounds, the present invention has essential properties and advantages. The compounds of the present invention are sufficiently stable to be useful as active ingredients, particularly as APIs in formulations, allowing both stable storage and transportation, which are important factors in the supply of commercially suitable pharmaceutical products.

[0018] The present invention extends to pharmaceutical compositions, including formulations, that include the compounds disclosed herein. In embodiments, the formulation comprises a powder.The invention also extends to a capsule comprising the formulation.

[0019] The compounds of the present invention may contain one or more asymmetric carbon atoms.Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof.Each of the asymmetric carbon atoms may be in R or S configuration, and both of these configurations are within the scope of the present invention.

[0020] Modified versions of any one of such compounds are also contemplated, including modifications that improve (e.g., enhance, increase) the solubility, stability, bioavailability, and / or therapeutic index of the drug compared to the unmodified compound. Exemplary modifications include (but are not limited to) applicable prodrug derivatives and deuterium-enriched compounds.

[0021] It should be recognized that the compound of the present invention may exist in the form of salt or solvate, and may be optionally administered in the form of salt or solvate.The present invention encompasses any pharma-ceutically acceptable salt and solvate of any one of the above compounds and its modifications.In some embodiments, the preferred salt is hydrochloride.

[0022] Also within the scope of the invention are the compounds and / or pharmaceutical compositions containing one or more of the described compounds and / or salts thereof for use in the treatment of neoplastic diseases, including neoplastic diseases that overexpress pim, including, but not limited to, leukemia, lymphoma, multiple myeloma, prostate cancer, pancreatic cancer, gastric cancer, colon cancer, or hepatic cancer.

[0023] The present invention also extends to the use of said compounds in the manufacture of a medicament for treating such diseases.The present invention also relates to a method of treating a tumor disease that overexpresses Pim, including but not limited to leukemia, lymphoma, multiple myeloma, prostate cancer, pancreatic cancer, gastric cancer, colon cancer, or liver cancer, by administering an effective amount of one or more of the above compounds, modifications thereof, and / or salts, and compositions thereof to a subject in need thereof.

[0024] The present invention provides a method for producing a compound of the invention provided by formula (I) or (II) or any example disclosed herein, comprising the steps of: Selective protection of the primary alcohol of gemcitabine at the R2 position to produce the first intermediate (1); peptide coupling of intermediate 1 at the R1 position to produce a second intermediate (2); esterification of the second intermediate (2) at the R3 position to produce a third intermediate (3); and Deprotection of the third intermediate (3), preferably at room temperature The methodology includes a four-step process:

[0025] In some embodiments, protection of the primary alcohol (R2-group) may be performed using a silylation reactant (TBDMSCl). Furthermore, the peptide coupling step at the amino group (R1-group) may be carried out using EDCI.HCl / HOBt, preferably in the absence of additional base. The absent additional base may be, for example, DIPEA or TEA. Peptide-like esterification at the secondary alcohol (R3-group) may be performed using EDCI.HCl / HOBt as coupling agent and optionally DMAP as catalyst. Finally, the deprotection step may be performed using either 4M HCl / dioxane or AcCl / EtOH.

[0026] In embodiments, the method further comprises a separation step, which may be carried out by carrying out precipitation from the reaction mixture using an anti-solvent. Preferably, TBME is used as the anti-solvent.

[0027] The resulting method / route of the present invention creates novel compounds that unexpectedly allow such production with fewer synthetic steps. In particular, at least the chromatography steps previously assumed to be essential and associated with the production of the prior art triple-substituted and related compounds are eliminated, thereby freeing up the use and waste of large amounts of solvents (environmental improvement). Furthermore, the expected better stability of the final API and formulations, as well as similar biological deprotection of the prodrug in vivo, are achieved.

[0028] The details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will be apparent from the description and claims. It should be understood that all embodiments / features of the invention described herein (compounds, pharmaceutical compositions, methods of making / using, etc.), including any specific features described in the examples and claims as originally filed, can be combined with each other unless inapplicable or expressly disclaimed. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 shows the results of HPLC-MS analysis of the example compounds. [Diagram 2] FIG. 2 shows the results of NMR analysis of the example compounds. [Diagram 3] FIG. 3 shows the results of a stability study of the powder form of the API. [Figure 4] FIG. 4 shows the results of stability testing of the API in aqueous media. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Exemplary compounds described herein include, but are not limited to, the following:

[0031] [ka]

[0032] (2R,3R,5R)-4,4-Difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate hydrochloride Includes.

[0033] The compounds of the present invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers, or enantiomers as starting materials or intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures may be separated using the same techniques or other techniques known in the art. The asymmetric carbon atoms may each be in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0034] Modified versions of any one of such compounds are also contemplated, including modifications that improve (e.g., enhance, increase) the solubility, stability, bioavailability, and / or therapeutic index of the drug compared to the unmodified compound. Examples of modifications include, but are not limited to, prodrug derivatives and deuterium-enriched compounds. - Prodrug derivatives: Prodrugs are those that, upon administration to a subject, are converted in vivo to the active compounds of the invention [Nature Reviews of Drug Discovery, 2008, vol. 7, p. 255]. It should be noted that in many cases, prodrugs themselves are also within the scope of the compounds described in the present invention. Prodrugs of the compounds of the present invention can be prepared by standard organic reactions, such as reacting with a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.) or an acylating agent. Further examples of methods and strategies for making prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, vol. 4, p. 1985. Deuterium-enriched compounds: Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Hydrogen naturally exists as a mixture of the isotopes XH (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art recognize that in all chemicals that have H atoms, the H atoms are in fact a mixture of H and D, with D accounting for approximately 0.015%. Thus, compounds that are enriched with deuterium at levels greater than its natural abundance of 0.015% should be considered non-natural and, as a result, novel relative to their non-enriched counterparts.

[0035] It should be recognized that the compounds of the present invention may exist and may be optionally administered in the form of salts or solvates. For example, it is within the scope of the present invention to convert and use the compounds of the present invention in the form of pharma-ceutically acceptable salts, which can be obtained from various organic and inorganic acids and bases according to procedures known in the art.

[0036] When the compounds of the present invention have a free base form, the compounds can be prepared as pharma- ceutically acceptable acid addition salts by reacting the free base form of the compound with pharma- ceutically acceptable inorganic or organic acids, e.g., halogen salts such as hydrochloride, hydrobromide, hydroiodide, other mineral acids such as sulfates, nitrates, phosphates, alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate, and benzenesulfonate, and other organic acids such as acetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, and ascorbate salts and their corresponding salts. Further acid addition salts of the present invention include, but are not limited to, adipate, alginate, alginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate. These include salts of the following: glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate, and phthalate. It should be recognized that the free base forms will usually differ somewhat from the respective salt forms in physical properties such as solubility in polar solvents, but that otherwise these salts are equivalent to the respective free base forms for purposes of the present invention.

[0037] When the compound of the present invention has a free acid form, pharma- ceutically acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharma-ceutically acceptable inorganic or organic base.Examples of such bases are alkali metal hydroxides, including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, such as potassium ethanolate and sodium propanolate; and various organic bases, such as ammonium hydroxide, piperidine, diethanolamine, and N-methylglutamine.Also included are aluminum salts of the compound of the present invention.Additional base salts of the present invention include, but are not limited to, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Organic base salts include salts of primary, secondary, and tertiary amines which are substituted amines including, but are not limited to, naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris-(hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will usually differ somewhat from their respective salt forms in physical properties such as solubility in polar solvents, but that otherwise the salts are equivalent to their respective free acid forms for purposes of the present invention.

[0038] In some embodiments, the pharma- ceutically acceptable salt is a hydrochloride salt, hi other embodiments, the salt is selected from a hydrobromide, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, tromethamine salt, or mixtures thereof.

[0039] Compounds of the invention that contain tertiary nitrogen-containing groups include halides (C 1~4 Di(C) sulfates such as alkyl, dimethyl, diethyl, and diamyl sulfates 1~4 ) alkyl halides such as alkyl, decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aryl halides such as benzyl chloride and phenethyl bromide (C 1~4 ) alkyl. Such salts allow for the preparation of both water- and oil-soluble compounds of the invention.

[0040] Amine oxides, also known as amine-N-oxides and N-oxides, which are anticancer drugs with a tertiary nitrogen atom, have been developed as prodrugs [Mol Cancer Therapy, March 2004, 3(3):233-44]. Compounds of the invention that contain a tertiary nitrogen atom can be oxidized by agents such as hydrogen peroxide (H2O2), Caro's acid, or peracids such as meta-chloroperbenzoic acid (mCPBA) to form amine oxides.

[0041] The present invention encompasses pharmaceutical compositions comprising the compounds of the present invention and pharmaceutical excipients, as well as other conventional pharma- ceutical inactive agents. Any inactive excipients commonly used as carriers or diluents, such as sugars, polyhydric alcohols, soluble polymers, salts, and lipids, may be used in the compositions of the present invention. The sugars and polyhydric alcohols that may be employed include, but are not limited to, lactose, sucrose, mannitol, and sorbitol. Exemplary soluble polymers that may be employed are polyoxyethylene, poloxamer, polyvinylpyrrolidone, and dextran. Useful salts include, but are not limited to, sodium chloride, magnesium chloride, and calcium chloride. The lipids that may be employed include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.

[0042] Additionally, the pharmaceutical compositions may contain binders (e.g., gum acacia, corn starch, gelatin, carbomer, ethylcellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers of various pH and ionic strength (e.g., tris-HCL, acetate, phosphate), additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizers (e.g., glycerol, polyethylene glycerol, cyclodextrin), glidants (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose), thickeners (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavor), preservatives (e.g., thimerosalin, glyceryl stearate, sorbitol, sorbitol esters ... The composition may further comprise agents such as: rosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose), polymeric coatings (e.g., poloxamers or poloxamines), coatings and film formers (e.g., ethyl cellulose, acrylates, polymethacrylates), and / or adjuvants.

[0043] In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.

[0044] Furthermore, the present invention encompasses pharmaceutical compositions comprising the compounds of the present invention in any solid or liquid physical form. For example, the compounds can be in crystalline and amorphous form and have any particle size. The particles can be micronized or agglomerated, and can be granular granules, powders, oils, oily suspensions, or any other form of solid or liquid physical form. In some embodiments, the particles are powders.

[0045] A wide variety of administration methods may be used in conjunction with the compounds of the present invention. The compounds of the present invention may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, by inhalation, intravaginally, intraocularly, by local delivery (e.g., by catheter or stent), subcutaneously, intraadipose tissue, intraarticularly, or intrathecally, or may be administered in combination. The compounds according to the present invention may also be administered or administered in combination as sustained release dosage forms. The compounds may be in gaseous, liquid, semi-liquid, or solid form, and may be formulated in a manner suitable for the route of administration used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets, and effervescent powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, and the like. For parenteral administration, reconstitution of a lyophilized powder is commonly used. Chemical and Biological Terms As used herein, "acyl" refers to a carbonyl containing a substituent represented by the formula -C(O)-R, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where said alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.

[0046] "Aliphatic" means a moiety characterized by a straight or branched arrangement of constituent carbon atoms, and may be saturated or partially unsaturated with one or more double or triple bonds.

[0047] "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms (e.g., C1-C 10 (alkyl) refers to a straight or branched chain hydrocarbon containing an alkyl group. Examples of alkyl include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Preferably, the alkyl group has 1 to 10 carbon atoms. More preferably, the alkyl group has 1 to 4 carbon atoms.

[0048] "Alkenyl" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 10 ) and refers to a straight or branched chain hydrocarbon containing one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkylene group has 2 to 10 carbon atoms. More preferably, the alkylene group has 2 to 4 carbon atoms.

[0049] "Alkynyl" refers to an alkyl group having 2 to 20 carbon atoms (e.g., C 10) and refers to a straight or branched chain hydrocarbon containing one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl. Preferably, the alkynyl group has 2 to 10 carbon atoms. More preferably, the alkynyl group has 2 to 4 carbon atoms.

[0050] "Alkylamino" refers to -N(R)-alkyl, where R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0051] "Alkoxy" means an oxygen moiety having a further alkyl substituent. "Alkoxycarbonyl" means an alkoxy group attached to a carbonyl group. "Oxoalkyl" refers to an alkyl further substituted with a carbonyl group, which may be an aldehyde, ketone, ester, amide, acid, or acid chloride.

[0052] The term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C 12 , C3-C8, C3-C6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to a saturated hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C 12 ) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0053] "Heterocycloalkyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

[0054] "Heterocycloalkenyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se) and one or more double bonds.

[0055] "Aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.

[0056] The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, aryl, and heteroaryl include both substituted and unsubstituted moieties. Possible substituents for alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl include, but are not limited to, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 20 Cycloalkyl, C3-C 20 Cycloalkenyl, C1-C 20 Heterocycloalkyl, C1-C20 Heterocycloalkenyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, arylamino, hydroxy, halo, oxo (O=), thioxo (S=), thio, silyl, C1-C 10 Alkylthio, arylthio, C1-C 10 Included among the possible substituents on the alkyl, alkenyl, or alkynyl groups are alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanic acid, sulfonamide, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylate. Meanwhile, possible substituents on the alkyl, alkenyl, or alkynyl groups are C1-C 10 All of the substituents listed above except alkyl are included. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl may be fused to each other.

[0057] "Amino" refers to a nitrogen moiety having two further substituents, each of which has a hydrogen or carbon atom alpha-bonded to the nitrogen. Unless otherwise specified, compounds of the invention containing an amino moiety may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

[0058] "Aromatic" means a moiety whose constituent atoms form an unsaturated ring system, in which all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n + 2. An aromatic ring may be such that the ring atoms are only carbon atoms or may contain carbon and non-carbon atoms (see heteroaryl).

[0059] "Carbamoyl" is the free radical -OC(O)NR a R b wherein R a and Rb are each independently two further substituents, where a hydrogen or carbon atom is alpha to the nitrogen. The carbamoyl moiety may include protected derivatives thereof. Examples of suitable protecting groups for the carbamoyl moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Both unprotected and protected derivatives are within the scope of the present invention.

[0060] "Carbonyl" refers to the radical -C(O)-, which may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, and ketones.

[0061] "Carboxy" refers to the radical -C(O)O-. Additionally, compounds of the invention that contain a carboxy moiety may include protected derivatives thereof, i.e., the oxygen is replaced with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.

[0062] "Cyano" refers to the radical -CN. "Formyl" refers to the radical -CH=O. "Formimino" refers to the radical -HC=NH.

[0063] "Halo" means fluoro, chloro, bromo, or iodo. "Halo-substituted alkyl," as an isolated group or part of a larger group, means an "alkyl" substituted with one or more "halo" atoms, as such term is defined in this application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like.

[0064] "Hydroxy" refers to the radical -OH. "Imine derivative" means a derivative containing a -C(=NR)- moiety, where R contains a hydrogen or carbon atom alpha to the nitrogen.

[0065] "Isomers" means any compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four non-identical substituents is called a "chiral center". A compound with one chiral center has two enantiomeric forms that are of opposite chirality. A mixture of the two enantiomeric forms is called a "racemic mixture".

[0066] "Nitro" refers to the radical -NO2. "Protected derivatives" refers to derivatives of compounds in which reactive sites are blocked with protecting groups. Protected derivatives may be useful in the preparation of drugs or may themselves be active as inhibitors. A comprehensive list of suitable protecting groups can be found in TW Greene, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, 1999.

[0067] The term "substituted" means that an atom or group of atoms replaces hydrogen as a substituent attached to another group of atoms. In aryl and heteroaryl groups, the term "substituted" refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. The term "unsubstituted" means that a given moiety may consist only of hydrogen substituents via available (unsubstituted) valences.

[0068] When a functional group is described as "optionally substituted," the functional group can be either (1) unsubstituted or (2) substituted. When a carbon of a functional group is described as optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on that carbon (if present) may be replaced individually and / or together with any independently selected substituents.

[0069] "Sulfide" means -SR, where R is H, alkyl, carbocycle, heterocycle, carbocycloalkyl, or heterocycloalkyl. Particular sulfide groups are mercapto, alkyl sulfides such as, for example, methyl sulfide (-S-Me), aryl sulfides such as, for example, phenyl sulfide, and aralkyl sulfides such as, for example, benzyl sulfide.

[0070] "Sulfinyl" refers to the radical -S(O)-, which may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.

[0071] "Sulfonyl" refers to the radical -S(O)(O)-, which may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfone esters, and sulfones.

[0072] "Thiocarbonyl group" means the radical -C(S)-, which may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.

[0073] "Animal" includes humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.), and non-mammals (e.g., birds, etc.).

[0074] As used herein, "bioavailability" is the fraction or percentage of a dose of a drug or pharmaceutical composition that reaches the systemic circulation unchanged. In general, when a pharmaceutical is administered intravenously, its bioavailability is 100%. However, when a pharmaceutical is administered via other routes (e.g., orally), its bioavailability is reduced (e.g., due to incomplete absorption and first-pass metabolism). Methods for improving this bioavailability include prodrug approaches, salt synthesis, particle size reduction, complexation, physical form modification, solid dispersions, spray drying, and hot melt extrusion.

[0075] "Disease" specifically includes any unhealthy condition of an animal or part thereof, including an unhealthy condition that may result from or accompany a medical or veterinary therapy administered to the animal, i.e., a "side effect" of such therapy.

[0076] "Pharmaceutically acceptable" means something that is useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes something that is acceptable for human pharmaceutical use, as well as veterinary use.

[0077] "Pharmaceutically acceptable salt" refers to an organic or inorganic salt of the compound of the present invention that is pharmaceutically acceptable as defined above and has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharma- ceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharma- ceutically acceptable salt may have more than one charged atom in its structure. If multiple charged atoms are part of the pharma- ceutical acceptable salt, it may have multiple counterions. Thus, a pharma- ceutical acceptable salt may have one or more charged atoms and / or one or more counterions. In one embodiment, the salt selected is a hydrochloride salt.

[0078] "Pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other substance that is mixed with the compounds of the present invention to form a pharmaceutical composition, i.e., a dosage form that can be administered to a patient. Examples of pharmaceutically acceptable carriers include suitable polyethylene glycols (e.g., PEG400), surfactants (e.g., Cremophor), or cyclic polysaccharides (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether β-cyclodextrin), polymers, liposomes, micelles, nanospheres, and the like.

[0079] A "pharmacophore," as defined by the International Union of Pure and Applied Chemistry, is the collection of steric and electronic features necessary to ensure optimal supramolecular interaction with a particular biological target and trigger (or block) its biological response. For example, camptothecin is the pharmacophore of the well-known drugs topotecan and irinotecan. Mechlorethamine is the pharmacophore of a list of widely used nitrogen mustard drugs such as melphalan, cyclophosphamide, bendamustine, etc.

[0080] "Prodrug" means a compound that is metabolically convertible in vivo to an active drug according to the invention. For example, an inhibitor containing a hydroxyl group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxyl compound.

[0081] "Stability" generally refers to the length of time that a drug maintains its properties without losing efficacy. Sometimes this is referred to as shelf life. Factors that affect drug stability include, among others, the chemical structure of the drug, impurities in the formulation, pH, water content, as well as environmental factors such as temperature, oxidation, light, and relative humidity. Stability can be improved by providing appropriate chemical and / or crystal modifications (e.g., surface modifications that can change hydration kinetics, different crystals that can have different properties), excipients (e.g., everything but the active ingredient in the dosage form), packaging conditions, storage conditions, etc.

[0082] A "therapeutically effective amount" of a composition described herein means an amount of the composition that provides a therapeutic effect in the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject indicates or feels an effect). An effective amount of the composition may range from about 0.1 mg / kg to about 500 mg / kg, preferably about 0.2 to about 50 mg / kg. The effective dose will vary depending on the route of administration as well as the possibility of co-usage with other drugs. However, it will be understood that the total daily usage of the composition of the present invention will be determined by the attending physician within the bounds of good medical practice. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the particular compound employed, the particular composition employed, the patient's age, weight, general health, sex, and diet, the time of administration, route of administration, and rate of excretion of the particular compound employed, the duration of treatment, drugs used in combination or concomitantly with the particular compound employed, and similar factors known in the medical arts.

[0083] As used herein, the term "treating" refers to administering a compound to a subject having a neoplastic or immune disorder, or a symptom of or a predisposition to the disorder, for the purpose of curing, healing, alleviating, mitigating, altering, correcting, ameliorating, improving, or affecting the disorder, the symptoms of the disorder, or the predisposition to the disorder. The term "effective amount" refers to the amount of active agent required to produce the intended therapeutic effect in the subject. The effective amount may vary depending on the route of administration, the amount of excipients used, and the possibility of co-use with other drugs, as recognized by those skilled in the art.

[0084] "Subject" refers to humans and non-human animals. Examples of non-human animals include all vertebrates, such as mammals, such as non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and non-mammals, such as birds, amphibians, and reptiles. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an animal suitable as an experimental animal or disease model.

[0085] "Combination therapy" includes administration of the subject compounds of the present invention further combined with other biologically active ingredients (such as, but not limited to, a second different antitumor agent) and non-pharmaceutical therapies (such as, but not limited to, surgery or radiation therapy). By way of example, the compounds of the present invention may be used in combination with other pharmaceutically active compounds or non-pharmaceutical therapies, preferably compounds that can enhance the effect of the compounds of the present invention. The compounds of the present invention may be administered simultaneously with the other therapy (as a single preparation or separate preparations) or sequentially to the other therapy. In general, combination therapy envisages the administration of two or more drugs / treatments during one cycle or course of therapy.

[0086] In an embodiment, the compound of the present invention is administered in combination with one or more of conventional chemotherapeutic agents.Conventional chemotherapeutic agents include a wide range of therapeutic treatments in the field of oncology.These agents are administered at various stages of disease to shrink tumors, destroy residual cancer cells remaining after surgery, bring about remission, maintain remission, and / or relieve the symptoms associated with cancer or its treatment.Examples of such agents include, but are not limited to, nitrogen mustards (e.g., bendamustine, cyclophosphamide, melphalan, chlorambucil, isophosphamide), nitrosoureas (e.g., carmustine, lomustine, and streptozocin), ethylenimines (e.g., thiotepa, hexamethylmelanine), alkylsulfonates (e.g., busulfan), hydrazines and triazines (e.g., altretamine, procarbazine, dacarbazine, and alkylating agents, such as temozolomide; platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin); plant alkaloids, such as podophyllotoxins (e.g., etoposide and tenisopide), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine); chromomycins (e.g., dactinomycin and plicamycin), anthracyclines (e.g., doxorubicin, daunorubicin, antitumor antibiotics such as epirubicin, mitoxantrone, and idarubicin, as well as a wide variety of antibiotics such as mitomycin and bleomycin; folate antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, foxuridine, cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nelarabine, , and pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors (topotecan, irinotecan), topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide), and a wide variety of antineoplastic agents such as ribonucleotide reductase inhibitors (hydroxyurea), corticosteroid inhibitors (mitotane), anti-microtubule agents (estramustine), and retinoids (bexarotene, isotretinoin, tretinoin (ATRA)).

[0087] The compounds of the present invention may be administered in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states. Examples of such kinases include, but are not limited to, ABL1, ABL2 / ARG, ACK1, AKT1, AKT2, AKT3, ALK, ALK1 / ACVRL1, ALK2 / ACVR1, ALK4 / ACVR1B, ALK5 / TGFBR1, ALK6 / BMPR1B, AMPK(A1 / B1 / G1), AMPK(A1 / B1 / G2), AMPK(A1 / B1 / G3), AMPK(A1 / B2 / G1), AMPK(A2 / B1 / G1), AMPK(A2 / B2 / G1), AMPK(A2 / B2 / G2), ARAF, A RK5 / NUAK1, ASK1 / MAP3K5, ATM, Aurora A, Aurora B, Aurora C, AXL, BLK, BMPR2, BMX / ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMK1a, CAMK1b, CAMK1d, CAMK1g, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDK1-cyclin A, CDK1-cyclin B, CDK1-cyclin E, CDK2-cyclin A, CDK2- Cyclin A1, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin D1, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin T1, CHK1, CHK2, CK1a1, CK1d, CK1 epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3, CLK4, c-MER, c-M ET, COT1 / MAP3K8, CSK, c-SRC, CTK / MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK / MAP3K12, DMPK, DMPK2 / CDC42BPG, DNA-PK, DRAK1 / STK17A, DYRK1 / DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4 / GCN2, EPHA1, EPHA2, EPHA3, EPHA4,EPHA5、EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、ERBB2 / HER2、ERBB4 / HER4、ERK1 / MAPK3、ERK2 / MAPK1、ERK5 / MAPK7、FAK / PTK2、FER、FES / FPS、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1 / VEGFR1、FLT3、FLT4 / VEGFR3、FMS、FRK / PTK5、FYN、GCK / MAP4K2、GRK1、GRK2、GRK3、GRK4、GRK5、GRK6、GRK7、GSK3a、GSK3b、ハスピン、HCK、HGK / MAP4K4、HIPK1、HIPK2、HIPK3、HIPK4、HPK1 / MAP4K1、IGF1R、IKKa / CHUK、IKKb / IKBKB、IKKe / IKBKE、IR、IRAK1、IRAK4、IRR / INSRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR / VEGFR2、KHS / MAP4K5、LATS1、LATS2、LCK、LCK2 / ICK、LKB1、LIMK1、LOK / STK10、LRRK2、LYN、LYNB、MAPKAPK2、MAPKAPK3、MAPKAPK5 / PRAK、MARK1、MARK2 / PAR-1Ba、MARK3、MARK4、MEK1、MEK2、MEKK1、MEKK2、MEKK3、MELK、MINK / MINK1、MKK4、MKK6、MLCK / MYLK、MLCK2 / MYLK2、MLK1 / MAP3K9、MLK2 / MAP3K10、MLK3 / MAP3K11、MNK1、MNK2、MRCKa / 、CDC42BPA、MRCKb / 、CDC42BPB、MSK1 / RPS6KA5、MSK2 / RPS6KA4、MSSK1 / STK23、MST1 / STK4、MST2 / STK3、MST3 / STK24、MST4、mTOR / FRAP1、MUSK、MYLK3、MYO3b、NEK1、NEK2、NEK3、NEK4、NEK6、NEK7、NEK9、NEK11、NIK / MAP3K14、NLK、OSR1 / OXSR1、P38a / MAPK14、P38b / MAPK11、P38d / MAPK13、P38g / MAPK12、P70S6K / RPS6KB1、p70S6Kb / 、RPS6KB2、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PASK、PBK / TOPK、PDGFRa、PDGFRb、PDK1 / PDPK1、PDK1 / PDHK1、PDK2 / PDHK2、PDK3 / P DHK3, PDK4 / PDHK4, PHKg1, PHKg2, PI3Ka (p110a / p85a), PI3Kb (p110b / p85). a) PI3Kd (p110d / p85a), PI3Kg (p120g), PIM1, PIM2, PIM3, PKA, PKAcb, PK Acg, PKCa, PKCb1, PKCb2, PKCd, PKC, PKC, PKCg, PKC, PKC, PKC / PR KD1, PKCニ / PRKD3, PKC, PKC, PKD2 / PRKD2, PKG1a, PKG1b, PKG2 / PRK G2, PKN1 / PRK1, PKN2 / PRK2, PKN3 / PRK3, PLK1, PLK2, PLK3, PLK4 / SAK, PRKX YK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON / MST1R, ROS / ROS1 RSK1、RSK2、RSK3、RSK4、SGK1、SGK2、SGK3 / SGKL、SIK1、SIK2、SLK / STK2、SNAR K / NUAK2、SRMS、SSTK / TSSK6、STK16、STK22D / TSSK1、STK25 / YSK1、STK32b / Y ANK2, STK32c / YANK3, STK33, STK38 / NDR1, STK38L / NDR2, STK39 / STLK3, SRPK 1, SRPK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TBK1, TEC, TESK1, and TGF BR2, TIE2 / TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7 / CHAK1, TSS K2、TSSK3 / STK22C、TTBK1、TTBK2、TTK、TXK、TYK1 / LTK、TYK2、TYRO3 / SKY、UL K1、ULK2、ULK3、VRK1、VRK2、WEE1、WNK1、WNK2、WNK3、YES / YES1、ZAK / MLTK、ZA P70, ZIPK / DAPK3, KINASE, MUTANTS, ABL1(E255K), ABL1(F317I), ABL1(G250). E) ABL1(H396P), ABL1(M351T), ABL1(Q252H), ABL1(T315I), ABL1(Y253F).ALK (C1156Y), ALK (L1196M), ALK (F1174L), ALK (R1275Q), BRAF(V599E), BTK(E41K), CHK2(I157T), c-Kit(A829P), c-KIT(D816H), c-KIT(D81). 6V) c-Kit(D820E) c-Kit(N822K) c-Kit(T670I) c-Kit(V559D) c-Kit(V559D / V654A) c-K it(V559D / T670I)、C-Kit(V560G)、c-KIT(V654A)、C-MET(D1228H)、C-MET(D1228N)、C-MET(F1). 200I, c-MET(M1250T), C-MET(Y1230A), C-MET(Y1230C), C-MET(Y1230D), C-MET(Y1230H), c- Src(T341M), EGFR(G719C), EGFR(G719S), EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR (L 858R,T790M, EGFR(d746-750 / T790M), EGFR(d746-750), EGFR(d747-749 / A750P), EGFR(d747). -752 / P753S) EGFR(d752-759) FGFR1(V561M) FGFR2(N549H) FGFR3(G697C) FGFR3(K650E) FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2 (V617F), LRRK2 (G2019S), LRRK2 (I2020T), LRRK2 (R1441C), p38a(T106M), PDGFRa(D842V), PDGFRa(T674I), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T), RET( R749T) RET(R813Q) RET(V804L) RET(V804M) RET(Y791F) Refer to TIF2(R849W), TIF2(Y897S), and TIF2(Y1108F).

[0088] The compounds disclosed herein may be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathways, or processes.Such target pathways or processes include, but are not limited to, heat shock proteins (e.g., HSP90), poly-ADP (adenosine diphosphate)-ribose polymerase (PARP), hypoxia-inducible factor (HIF), proteosome, Wnt / hedgehog / notch signaling proteins, TNF-α, matrix metalloproteinase, farnesyltransferase, apoptosis pathways (e.g., Bcl-xL, Bcl-2, Bcl-w), histone deacetylase (HDAC), histone acetyltransferase (HAT), and methyltransferase (e.g., histone lysine methyltransferase, histone arginine methyltransferase, DNA methyltransferase, etc.).

[0089] The compounds of the present invention may be administered in combination with one or more of other anti-cancer agents, including, but not limited to, gene therapy, RNAi cancer therapy, chemoprotectants (e.g., amfostine, mesna, and dexrazoxane), antibody conjugates (e.g., brentuximab vedotin, ibritumomab tiuxetan), cancer immunotherapy such as interleukin-2, cancer vaccines (e.g., sipuleucel-T), or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab, trastuzumab, etc.).

[0090] The compound of the present invention may be administered in combination with radiation therapy or surgery.Radiation is generally delivered internally (implantation of radioactive material near cancer site) or externally by machine using photon (X-ray or gamma-ray) or particle beam.When combination therapy further comprises radiation therapy, this radiation therapy may be carried out for any suitable period as long as the beneficial effect from the interaction of the combination of therapeutic agent and radiation therapy can be obtained.For example, in appropriate cases, when radiation therapy is temporarily separated from the administration of therapeutic agent, perhaps even for several days or weeks, this beneficial effect can still be obtained.

[0091] In certain embodiments, the compounds of the present invention are administered in combination with one or more of radiation therapy, surgery, or anti-cancer agents including, but not limited to, DNA damaging agents, antimetabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, and the like.

[0092] In certain embodiments, the compounds of the invention are selected from the group consisting of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezomib, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomiphene, crizotinib, ciclovir, cyclosporine ... Clophosphamide, dasatinib, liposomal daunorubicin, decitabine, degarelix, denileukin diftitox, denileukin diftitox, denosumab, docetaxel, doxorubicin, liposomal doxorubicin, epirubicin, eribulin mesylate, erlotinib, estramustine, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hirubicin Strelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, ipilimumab, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine, nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particles, pami It is administered in combination with one or more of the following: prasugrel hydrochloride, panitumumab, pegaspargase, peginterferon alfa-2b, pemetrexed disodium, pentostatin, raloxifene, rituximab, sorafenib, streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate, radiation therapy, or surgery.

[0093] The present invention further provides a method for preventing or treating a neoplastic disease or an autoimmune disease.In one embodiment, the present invention provides a method for treating a neoplastic disease or an autoimmune disease in a subject in need of treatment, comprising administering to said subject a therapeutically effective amount of a compound of the present invention.In one embodiment, the present invention further provides the use of a compound of the present invention in the manufacture of a medicament for stopping or slowing the progression of a neoplastic disease or an autoimmune disease.

[0094] In certain embodiments, the neoplastic disease is lung cancer, head and neck cancer, cancer of the central nervous system, prostate cancer, testicular cancer, colorectal cancer, pancreatic cancer, liver cancer, gastric cancer, biliary tract cancer, esophageal cancer, gastrointestinal stromal tumor, breast cancer, cervical cancer, ovarian cancer, uterine cancer, leukemia, lymphoma, multiple myeloma, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, renal cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, or myeloproliferative disease.

[0095] Autoimmune diseases that may be affected by the use of the compounds and compositions described in the present invention include, but are not limited to, allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic conditions, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), Churg-Strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (as well as associated glomerulonephritis and pulmonary hemorrhage). ), Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, localized scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjäggren's disease, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitis), vitiligo, and Wegener's granulomatosis.

[0096] Detailed Description of the Invention To synthesize a compound according to the invention or an embodiment thereof, such as formula (I) or (II), from the starting material (gemcitabine), the general scheme shown below is followed. The necessary starting materials may be obtained by standard procedures of organic chemistry. The present process is an improved route and has been invented by the applicant to establish a more efficient route to existing processes for producing derivative compounds. It is to be understood that the invention is not limited to the specific embodiments shown and described herein. The compounds and processes of the invention will be better understood in connection with the following representative examples, which are not intended to limit the scope of the invention.

[0097] Chemical Examples: EXAMPLES Example 1: Synthesis of Doubly Substituted Gemcitabine Product or LR-06-B.HCL, chemically known as: (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate hydrochloride Note that due to variability in the polarity of products / intermediates / by-products during the process, three LCMS methods are used: - ESI+_std_75V, detected at 254nm - ESI+_non-polarized_75V, detected at 254nm - ESI+_Non-polar_75V_1200Da, detected at 254nm

[0098] Example of the four-step manufacturing process: 1. The first step is the selective protection of the primary alcohol of gemcitabine at the R2 position using the silyl derivative: TBDMSCL or (-)-deoxyephedrine, N-(tert-butyldimethylsilyl)-

[0099] [ka]

[0100] [Table 1]

[0101] [Table 2]

[0102] 2. The second step is the peptide coupling of intermediate 1 at the R1 position with valproic acid (peptide coupling).

[0103] [ka]

[0104] [Table 3]

[0105] [Table 4]

[0106] 3. The third step is the esterification of intermediate 2 at the R3 position with Boc-valine.

[0107] [ka]

[0108] [Table 5]

[0109] [Table 6]

[0110] 4. The fourth step involves deprotection of intermediate 3 to form a compound according to an embodiment of the present invention - Formula II (known as LR-06-B.HCL) compound.

[0111] [Table 7]

[0112] The resulting doubly substituted gemcitabine example compound, defined by Formula II and known as LR-06-B.HCL, was easily isolated as a white powder in good yield and with the expected purity.

[0113] Spectral analysis HPLC-MS was performed using the following parameters: Column: Acquity UPLC® Peptide BEH C18-130Å, 1.7 μm-2.1 mm×100 mm Solvent A: 0.1% HCOOH in water Solvent B: 0.1% HCOOH in ACN

[0114] [Table 8]

[0115] Detected at 254 nm: Room temperature = 6.1 min - m / z = 489.2 [M+H]+ A graph of the results can be seen in Figure 1. The NMR graph is presented in Figure 2 with the following raw peak data: NMR 1H (DMSO-d6, 400 MHz): 11.12 (s, 1H, NH), 8.70 (br s, 3H, NH3+), 8.23 ​​(d, J=7.7 Hz, 1H, CHar), 7.38 (d, J=7.7 Hz, 1H, CHar), 6.33 (t, J=8.4 Hz, 1H, CH), 5.53 (m, 1H, CH), 4.35 (dd, J=7.4 and 3.3 Hz, CH), 4.10 (d, J=4.9 Hz, CH), 3.78 (ddd, J=35, 12.7 and 2.9 Hz, CH2), 2.66 (m, 1H, CH), 2.25 (m, 1H, CH), 1.53 (m, 2H, CH2), 1.35 (m, 2H, CH2), 1.24 (m, 4H, 2 x CH2), 1.01 (m, 6H, 2 x CH3), 0.86 (m, 6H, 2 x CH3). Its melting point was determined to be 203-205°C. Melting point measurements were performed on an MP50 melting point apparatus (Mettler Toledo).

[0116] [Table 9]

[0117] recrystallization Isolation of the preferred example compounds made by this procedure (by simple filtration, dilution, addition of anti-solvent, and cooling) was additionally explored.

[0118] A first set of recrystallisation trials (2010-P, scale 350 mg, purity 97.5%) was carried out and the first set looked promising as the product was always recovered as a fine powder. In each case the initial suspension was heated to reflux with the aim of complete dissolution of the solids. After 10 minutes of heating, the solution or remaining suspension was cooled to room temperature with stirring for 1 hour before filtration.

[0119] [Table 10]

[0120] The best yield / purity combination was obtained with acetone, and the high purification effect of ethanol is impressive, since the deprotection step may also be performed with this particular choice of solvent, streamlining the entire purification process.

[0121] A second set of recrystallization trials was performed (2010-R, scale 250 mg, purity 93.5%) as described in the table below.

[0122] [Table 11]

[0123] This second recrystallization highlights the possibility of producing an acceptable quality pharmaceutical product from the raw API. Processing Efficiency These results supported the hypothesis that column chromatography may not be essential to the process and could identify more direct methods of preparation that would have advantages.

[0124] To this end, a set of deprotection tests involving two available processes and various reaction work-up procedures was carried out on the raw intermediate 3 bearing both TBDMS and Boc protecting groups (2010-Q, scale 350 mg, SM purity 90%).

[0125] [Table 12]

[0126] It was also found that the new compounds produced via this method were much easier to isolate (in both the dioxane and ethanol routes) as they crystallized in the reaction mixture during deprotection.

[0127] In conclusion, applicants have determined that it is possible to directly isolate the doubly substituted compound with acceptable purity without column chromatography immediately after deprotection of the raw intermediate 3. The yields, although rather lower, remain relatively comparable, in the same range, or even higher than the much more laborious chromatography / deprotection procedures previously used in prior art processes to produce different compounds.

[0128] The process developed to produce the example products of the present invention involves a shorter synthetic route than previously provided to produce potentially useful gemcitabine products. Specifically, in the new method developed by the applicant, the final Boc-deprotection step can now be carried out at room temperature, which is a great advantage; in the longer 6-step process described in the art, much lower temperatures are required to avoid hydrolysis of the isobutyric acid moiety. Solubility Data The solubility of the example monohydrochloride salt (LR-06-B.HCl) was measured in standard water and buffers at pH 1.2, 4.5, and 6.9. In each example, a first estimation was performed by adding a small amount of solvent until the solid (50 mg) was dissolved, followed by a second estimation by adding a small amount of solid to a given amount of solvent until saturation was reached (suspension observed after 15 minutes). This second estimation was performed twice for each solution.

[0129] [Table 13]

[0130] In comparison, the art-described solubility of triple-substituted gemcitabine in the HCL salt form is typically measured to be only 170 mg / mL in water, which is significantly different from the embodiment of this example, suggesting that selecting the same salt (HCL) would not be a safe choice.

[0131] This study demonstrates that methods for solubilizing the compound while avoiding the addition of significant amounts of excipients that may be required for the triple prodrug may be unnecessary or limited. Stability Data Stability studies of powder and aqueous solutions of the example compound (LR-06-B.HCL) were conducted to determine its potential use in formulation development: First, powder forms of the API were tested after 3 months of storage at either RT or 2-4° C., as shown in FIG. 3; in all cases, no significant changes were measured, suggesting a stable and versatile product that may be more useful in further pharmaceutical formulations than those found thus far.

[0132] The stability of LR-06-B.HCl in aqueous media at RT was also evaluated:

[0133] [Table 14]

[0134] Significant short-term degradation of the API in aqueous media was observed, see FIG. Regarding the MS profile, the majority of the observed impurities are related to cleavage of the valproic acid moiety and / or rearrangement / cleavage of the valine moiety. The UV profile suggests that the core of the molecule is not affected by the degradation. In agreement with earlier observations, a less acidic medium could result in a higher rate of valine hydrolysis.

[0135] The physical and chemical properties of the two salts (this example and the triply substituted prior art example) are surprisingly different: based on the poor stability of the same salts selected, compared to the three functional groups of the API, the salt selection has less impact, but rather option 2.

[0136] Additional Example Compounds Additional examples of substituted gemcitabine HCL (where R2 remains H) were generated and identified during these process investigations. The example compounds are defined by the combination of two groups selected at each of R1 and R3: Valproic acid (2-propylpentanoic acid) (R1) and valproic acid (R3), the compound of which is (2R,3R,5R)-4,4-difluoro-2(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl 2-propylpentanoate; or Valproic acid and H, an embodiment of the compound is N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-propylpentanamide; or Boc valine (2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid) and H, an embodiment compound of which is tert-butyl (1-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate; or valine (2-amino-3-methylbutanoic acid) and H, the compound of which is 2-amino-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-3-methylbutanamide hydrochloride; or Boc valine and Boc valine, an embodiment compound of which is (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoate; Valine and valine, an embodiment of the compound is (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate dihydrochloride; or Boc valine and isobutyric acid (2-methylpropionic acid), an embodiment compound of which is (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate; or valine and isobutyric acid, the compound of which embodiment is (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate hydrochloride; or Valproic acid and isobutyric acid, an embodiment compound of which is (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl isobutyrate.

[0137] LC-MS and NMR were performed to confirm the formation and a 100 mg sample was saved.

[0138] Bioavailability The three most promising LR06 formulations in a novel dog PK study to evaluate oral bioavailability versus intravenous gemcitabine (LR06b will be administered orally, blood gemcitabine will be measured systemically, and percent bioavailability of gemcitabine will be determined by comparison to intravenous gemcitabine; data not yet available).

[0139] The formulation of LR06b for oral administration in dogs was observed to have oral bioavailability (triple substitution) that was at least as good as the reference (greater than 50% as assessed by intravenous gemcitabine comparison).

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is selected from 2-propylpentanoic acid, 2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid, and 2-amino-3-methylbutanoic acid; R ２ is H; and R ３ is selected from 2-propylpentanoic acid, 2-(tert-butoxycarbonyl)-amino-3-methylbutanoic acid, and 2-methylpropionic acid. or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotope, or prodrug of said compound of formula (I) or an N-oxide thereof.

2. The compound according to claim 1, (2R,3R,5R)-4,4-difluoro-2(hydroxymethyl)-5-(2-oxo4-(2propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl 2-propylpentanoate; (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoate; (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate dihydrochloride; (2R,3R,5R)-5-(4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate; (2R,3R,5R)-5-(4-(2-amino-3-methylbutanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl isobutyrate hydrochloride; and (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl isobutyrate A compound selected from:

3. 2. The compound of claim 1, wherein the salt is the hydrochloride salt.

4. Formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 3】 5. The compound of claim 4, represented by: or a pharmaceutically acceptable salt thereof.

6. (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate.

7. (2R,3R,5R)-4,4-difluoro-2-(hydroxymethyl)-5-(2-oxo-4-(2-propylpentanamido)-1,2-dihydropyrimidin-1-yl)oxolan-3-yl(2S)-2-amino-3-methylbutanoate hydrochloride.

8. 10. A pharmaceutical composition comprising a formulation comprising one or more pharmaceutically acceptable excipients and a compound according to any one of claims 1 to 7, optionally wherein the formulation is a powder.

9. 9. A pharmaceutical composition according to claim 8 for use as a medicament.

10. 9. The pharmaceutical composition of claim 8, for use in the treatment of an autoimmune condition or a neoplastic disease, optionally a tumor disease that overexpresses pim, including but not limited to leukemia, lymphoma, multiple myeloma, prostate cancer, pancreatic cancer, gastric cancer, colon cancer, or liver cancer.

11. Use of a compound described in any one of claims 1 to 7 in the manufacture of a medicament for treating an autoimmune condition or a neoplastic disease, including, but not limited to, a pim-overexpressing neoplastic disease, including leukemia, lymphoma, multiple myeloma, prostate cancer, pancreatic cancer, gastric cancer, colon cancer, or liver cancer.

12. 8. A compound according to claim 1, having the following formula (I): 【Chemistry 4】 1. A method for producing a compound according to claim 1, wherein the compound is R ２ selectively protecting the primary alcohol group in R １ coupling a peptide to the amino group of the first intermediate in order to produce a second intermediate (2); R ３ peptidomimetic esterification of the second intermediate (2) to produce a third intermediate (3); and Deprotecting the third intermediate (3) A method comprising:

13. 13. A method of producing the compound of claim 12, wherein the protecting step is carried out with a silylation reactant (TBDMSCl).

14. 13. A method for producing a compound of claim 12, wherein the coupling step is carried out using EDCI.HCl / HOBt, and optionally the coupling step is carried out in the absence of an additional base, preferably in the absence of DIPEA or TEA.

15. 13. A method for producing the compound of claim 12, wherein the esterifying step is carried out using EDCI.HCl / HOBt as a coupling agent and / or DMAP as a catalyst.

16. 13. A method of producing the compound of claim 12, wherein the deprotecting step is carried out using 4M HCl / dioxane or AcCl / EtOH.

17. 13. A method for producing the compound of claim 12, further comprising an isolation step comprising a precipitation step using an anti-solvent, optionally TBME.

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