S1P1 modulator compounds and methods for preparing these compounds

Abstract

The present embodiments are directed, in part, to methods and compositions that can be used, for example, to prepare compounds of formula (I) or pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 937,485, filed November 19, 2019, which is incorporated herein by reference in its entirety.

[0002] field Embodiments disclosed herein relate to compounds and methods for preparing compounds or pharmaceutically acceptable salts thereof, which can be used, for example, to modulate S1P1 receptor activity. [Background technology]

[0003] [ka] Compounds of formula (I) are reported in Patent Document 1, which is incorporated herein by reference in its entirety. In addition to methods for producing such compounds or pharmaceutically acceptable salts thereof, other synthetic methods may still be needed. This disclosure addresses such needs, among others. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Patent Application Publication No. WO2018 / 231745 [Overview of the project]

[0005] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method is [ka] Equation (II) under suitable conditions, [ka] Contact with formula (III) to obtain the following structure

Chemical formula

[0006] In some embodiments, the method comprises (a) adding a coupling reagent and optionally an additive to a solution of a compound of formula (II) in a first organic solvent to form a mixture and stirring the mixture for at least about 5 minutes;

Chemical formula

Chemical formula

Chemical formula

[0007] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide [ka] Add the compound of formula (II) to the solution to form a mixture, and stir the mixture for at least about 1 hour. (b) the mixture from step (a) [ka] Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of approximately 95°C and stir the mixture at that temperature for at least approximately 5 hours. (d) Cool the mixture from step (c) to about 15-20°C, add water to form a slurry, (e) Stir the slurry from step (d) at approximately 15-20°C for about 1 hour, (f) Filtering the slurry from step (e) to form a solid (from), (g) Wash the solid from step (f) with water and methyl tert-butyl ether, (h) Dry the solid from step (g) under vacuum at approximately 55°C. [ka] The present invention also provides a method comprising forming a compound of formula (I), wherein the variables in the formula are as defined herein.

[0008] In some embodiments, [ka] A method for preparing a compound having the structure or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide [ka] Add to the solution to form a mixture, and stir the mixture for at least about 1 hour. (b) the mixture from step (a) [ka] Stir together for about 1 hour, (c) Heat the mixture from step (b) to a temperature of approximately 95°C and stir the mixture at that temperature for at least approximately 5 hours. (d) Cool the mixture from step (c) to about 15-20°C, add water to the mixture to form a slurry, (e) Stir the slurry from step (d) at approximately 15-20°C for about 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl tert-butyl ether, (h) Dry the solid from step (g) under vacuum at at least about 55°C. [ka] The present invention also provides a method that includes forming [a certain object].

[0009] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] This includes bringing equation (V) into contact with R2R3C=O under suitable conditions. [ka] The present invention further provides a method for preparing a compound of formula (II), wherein the variables in the formula are as defined herein.

[0010] In some embodiments, [ka] A method for preparing the compound of formula (II), comprising the following steps: (a) In the compound R2R3C=O [ka] Adding pyrrolidine to a solution of the compound of formula (V) to form a mixture, (b) Heat the mixture from step (a) under reflux, stir the mixture at that temperature for about 19.5 hours, cool the mixture to about 15-20°C, and add water to the mixture. (c) Adjust the pH of the mixture from step (b) to approximately 2 with HCl, (d) The mixture from step (c) is stirred with n-heptane to form a slurry, the slurry is stirred at approximately 15-20°C for about 1 hour, and the slurry is filtered to form a solid. (e) Wash the solid from step (d) with water and n-heptane, (g) Dry the solid from step (e) under vacuum at approximately 50°C. [ka] This includes forming a compound of formula (II), wherein, A, B, and E are each independently N or CR6. X and Y are independently O, S, or NR7. The present invention also provides a method in which R2, R3, R4, R5, R6, and R7 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0011] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula R1CN with ammonium hydroxide, [ka] The present invention further provides a method for preparing a compound of formula (III), wherein R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl.

[0012] In some embodiments, [ka] A method for preparing the compound of formula (III), comprising the following steps: (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture, (b) Heat the mixture from step (a) to a temperature of approximately 75°C and stir the mixture at that temperature for approximately 4 hours to form a slurry. (c) Cool the slurry from step (b) to ambient temperature and stir it at ambient temperature for approximately 16 hours. (d) Filtering the slurry from step (c) to form a solid, (e) Wash the solid from step (d) with alcohol, and dry the washed solid at approximately 50°C under vacuum. [ka] The present invention also provides a method comprising forming a compound of formula (III), wherein R1 is as defined herein.

[0013] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] The compound of formula (II) is brought into contact with a coupling reagent with or without an additive, [ka] The present invention provides a method for forming an intermediate having the structure of formula (XIII), wherein R8 is an optionally substituted C1-C6 alkyl, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, the intermediate of formula (XIII) is [ka] It is a compound having the following structure.

[0014] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] An intermediate having the structure of formula (XIII) [ka] Further contact with the compound of formula (III), [ka] A method is provided for forming an intermediate having the structure of formula (XVI), wherein the variables in the formula are as defined herein. In some embodiments, the intermediate of formula (XVI) is [ka] It is a compound having the following structure.

[0015] In some embodiments, [ka] The present invention provides a compound of formula (XIII) or a pharmaceutically acceptable salt thereof, wherein R8 is optionally substituted with a C1-C6 alkyl group, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, [ka] The present invention provides a compound having the structure of formula (XIII) or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, [ka] The present invention provides a compound having the structure of formula (XVI) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In some embodiments, [ka] The present invention provides compounds having the structure or pharmaceutically acceptable salts thereof.

[0017] In some embodiments, a method for forming a compound of formula I, [ka] A compound having formula (XVI) is reacted under thermal dehydration cyclization conditions. [ka] The method involves forming a compound of formula I.

[0018] In some embodiments, the formula [ka] The present invention provides a crystalline form of a compound having [a certain characteristic]. In some embodiments, the crystalline form is form I. [Brief explanation of the drawing]

[0019] [Figure 1] The high-performance liquid chromatography (HPLC) chromatogram of N-hydroxy-1H-pyrazole-4-carboxyimidoamide (compound 2-2) is shown. [Figure 2] The high-performance liquid chromatography (HPLC) chromatogram of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2) is shown. [Figure 3] The high-performance liquid chromatography (HPLC) chromatogram of 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1) is shown. [Figure 4] The polarized light microscopy (PLM) analysis results (10 μm scale) of 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1) are shown. [Figure 5] The differential thermal analysis (DSC) results for 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1) are shown. [Figure 6] The X-ray powder diffraction (XRPD) results for 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1) are shown. [Modes for carrying out the invention]

[0020] Unless otherwise defined, all technical and scientific terms have the same meaning as those commonly understood by those skilled in the art in the field to which the disclosed embodiments pertain. If there are multiple definitions of a term referenced herein, the definition in this section shall prevail unless otherwise specified. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety.

[0021] As used herein, the terms "a" or "an" mean "at least one" or "one or more" unless otherwise explicitly indicated by the context.

[0022] As used herein, the term “approximately” means that a number is an approximation and that small variations are not expected to significantly affect the implementation of the embodiments of this disclosure. Where numerical limitations are used, unless otherwise indicated by the context, “approximately” means that the number may vary by ±10%, but will remain within the scope of the embodiments of this disclosure.

[0023] As used herein, the terms “additive” or “coupling additive” mean a reagent suitable for combination with a coupling reagent in a coupling reaction to suppress side reactions and reduce or eliminate racemization. In some embodiments, additives may include, but are not limited to, ethylcyanohydroxyiminoacetate, N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), aza derivatives of 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhat), 4-(N,N-dimethylamino)pyridine (DMAP), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), or any combination thereof.

[0024] As used herein, the term “alcohol” means any organic compound in which a hydroxyl group (-OH) is bonded to a carbon atom, and this carbon atom is bonded to other hydrogen atoms and / or carbon atoms. For example, the term “alcohol” means a linear or branched alkyl-OH group with 1 to 20 carbon atoms, and includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, t-butanol, etc. In some embodiments, the alkyl-OH chain is 1 to 10 carbon atoms long, 1 to 8 carbon atoms long, 1 to 6 carbon atoms long, 1 to 4 carbon atoms long, 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0025] As used herein, the terms “alkoxy,” “phenyloxy,” “benzoxy,” and “pyrimidinyloxy” each mean an alkyl group, phenyl group, benzyl group, or pyrimidinyl group that is optionally substituted and bonded via an oxygen atom. For example, the term “alkoxy” means a linear or branched -O-alkyl group having 1 to 20 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, etc. In some embodiments, the alkoxy chain is 1 to 10 carbon atoms long, 1 to 8 carbon atoms long, 1 to 6 carbon atoms long, 1 to 4 carbon atoms long, 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0026] As used herein, the term "alkyl" means a linear or branched saturated hydrocarbon group. Alkyl groups may contain 1 to 20, 2 to 20, 1 to 10, 2 to 10, 1 to 8, 2 to 8, 1 to 6, 2 to 6, 1 to 4, 2 to 4, 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups, but not limited to, include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl- Examples include 1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, and 2-ethyl-1-butyl.

[0027] As used herein, the terms "alkylene" or "alkylenyl" refer to a divalent alkyl group. Examples of alkylenes (or alkylenyls) include methylene or methyleneyl (-CH2-).

[0028] As used herein, the term "alkynyl" means a linear or branched alkyl group having one or more carbon-carbon triple bonds and 2 to 20 carbon atoms, and includes, but is not limited to, acetylene, 1-propylene, and 2-propylene. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0029] As used herein, the terms “ambient temperature” and “room temperature” or “RT” are understood in the art and generally refer to a temperature similar to the temperature of the room in which the reaction takes place (e.g., reaction temperature), e.g., about 20°C to about 30°C, e.g., 25°C or about 25°C.

[0030] As used herein, the term "amide" means any compound containing a functional group comprising a carbonyl group bonded to a nitrogen atom, or an amide functional group. For example, amides are derived from carboxylic acids and amines.

[0031] As used herein, the term "aryl" means a monocyclic, bicyclic, or polycyclic (e.g., having two, three, or four fused rings) aromatic hydrocarbon. In some embodiments, the aryl group has 6 to 20 carbon atoms or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, indenyl, and tetrahydronaphthyl. Examples of aryl groups include, but are not limited to, the following: [ka] [ka]

[0032] As used herein, the term "carbocyclic ring" means a saturated or unsaturated cyclic ring having five, six, or seven members, which optionally includes an O, S, or N atom as part of the ring. Examples of carbocyclic rings, but not limited to, include cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocyclic rings listed above.

[0033] As used herein, the term “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0034] As used herein, “comprising” (and any form of “comprising,” e.g., “comprise,” “comprises,” and “comprised”), “having” (and any form of “having,” e.g., “have” and “has”), “including” (and any form of “including,” e.g., “includes” and “include”), or “containing” (and any form of “containing,” e.g., “contians” and “contain”) are inclusive or unrestricted and do not exclude any additional unenumerated elements or method steps.

[0035] As used herein, the term “contact” means bringing two compounds / atoms together to form at least one covalent bond between the compounds or atoms.

[0036] As used herein, the terms “coupling reagent” or “peptide coupling reagent” mean, but are not limited to, reagents that facilitate the formation of amide bonds between amines and carboxylic acids, and include carbodiimides, aminium / uronium and phosphonium salts, and propanephosphonic anhydrides. For example, coupling reagents include diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and hexafluorophosphate benzotriazole These include tetramethyluronium (HBTU), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), propanephosphonic anhydride (PPAA, T3P), or any combination thereof.

[0037] As used herein, the term "cyano" means -CN.

[0038] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon containing a cycloalkyl, alkenyl, or alkynyl group with up to 20 ring-forming carbon atoms. Examples of cycloalkyl groups include monocyclic or polycyclic ring systems such as fused ring systems, bridging ring systems, and spiro-ring systems. In some embodiments, polycyclic ring systems include two, three, or four fused rings. Cycloalkyl groups may contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted with oxo or sulfide groups. Examples of cycloalkyl groups, though not limited to them, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. In addition, moieties in which one or more aromatic rings are condensed (share a common bond) to a cycloalkyl ring, such as benzo or thienyl derivatives of pentane, pentene, hexane (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-on-1-yl), are also included in the definition of cycloalkyl groups.

[0039] As used herein, the term “cycloheteroalkyl” means a 5-membered, 6-membered, or 7-membered saturated or partially unsaturated ring containing 1 to 2 heteroatoms (e.g., nitrogen, oxygen, and / or sulfur) bonded, either alone or as part of another group, via a carbon atom or heteroatom, and optionally, via a linker (CH2)n (where n is 0, 1, 2, or 3). The above groups may contain 1 to 4 substituents (e.g., alkyl, halo, oxo, and / or any alkyl or aryl substituent as defined herein). In addition, any cycloheteroalkyl ring may be condensed with a cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl ring.

[0040] As used herein, the terms "for example" and "such as" and their grammatical equivalents.

[0041] As used herein, the term "halo" means a halogen group, and is not limited to, fluoro, chloro, bromo, and iodine.

[0042] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0043] As used herein, the term "haloalkyl" refers to a C having one or more halogen substituents. 1~6 This refers to alkyl groups. Examples of haloalkyl groups, though not limited to them, include CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, and CH2CF3.

[0044] As used herein, the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and at least one heteroatomic ring member (ring-forming atom) (e.g., sulfur, oxygen, or nitrogen). In some embodiments, the heteroaryl group has at least one heteroatomic ring-forming atom, each of which is independently sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having two, three, or four fused rings) systems. Examples of heteroaryl groups, though not limited to them, include pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (e.g., indole-3-yl), pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, prinyl, carbazolyl, and benzimi Examples include dazolyl, indolinyl, pyranil, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, indolidinyl, isoindolyl, isobenzofuranil, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinazolinyl, phenanthiazolyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanil, and phenoxazinyl groups.Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

[0045] As used herein, the terms “heterocyclic” or “heterocyclic formula” mean monocyclic or bicyclic or bicyclic heterocyclic systems of 5 to 7 members or 7 to 10 members (any of these rings may be saturated or unsaturated, and consist of a carbon atom and 1 to 3 heteroatoms selected from N, O, and S (the N and S heteroatoms may be optionally oxidized, and the N heteroatom may be optionally quaternized)), and include bicyclic groups in which any of the above-defined heterocyclic rings are fused with a benzene ring. Particularly useful are rings containing one oxygen or sulfur atom, rings containing 1 to 3 nitrogen atoms, or rings combining one oxygen or sulfur atom with 1 to 2 nitrogen atoms. Heterocyclic rings can be bonded with any heteroatom or carbon atom, which results in a stable structure. Examples of heterocyclic groups are not limited to piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, oxazolyl, oxazolidinyl, isoxazolidinyl Examples include isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranil, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranil, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholinol is the same as morpholinyl.

[0046] As used herein, the term "heterocycloalkyl" means a non-aromatic heterocycle having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more of the ring-forming carbon atoms are substituted by a heteroatom (e.g., O, N, or S atom). Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., condensed, cross-linked, or spiro-based). In some embodiments, the heterocycloalkyl group has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, and pyrrolidine-2-on-3-yl. In addition, the ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may be optionally substituted with oxos or sulfides. For example, the ring-forming sulfur atom may be substituted with one or two oxos (forming S(O) or S(O)2). As another example, the ring-forming carbon atom may be substituted with an oxo (forming a carbonyl group).Furthermore, the definition of heterocycloalkyl includes, but is not limited to, moieties having one or more aromatic rings fused (sharing a common bond) with a non-aromatic heterocyclic ring, such as pyridinyl, thiophenyl, phthaliumidyl, naphthaliumidyl, and heterocyclic benzo derivatives (e.g., indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridine-7(4H)-on-5-yl, isoindorin-1-on-3-yl, and 3,4-dihydroisoquinorin-1(2H)-on-3-yl groups). The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted with oxo or sulfide.

[0047] As used herein, the term "heterocycloalkylalkyl" means C substituted by heterocycloalkyl. 1~6 It means alkyl.

[0048] As used herein, the terms "hydroxyl" or "hydroxy" mean the -OH group.

[0049] As used herein, the terms "hydroxyalkyl" or "hydroxylalkyl" mean alkyl groups substituted with a hydroxyl group. Examples of hydroxylalkyls include, but are not limited to, -CH2OH and -CH2CH2OH.

[0050] As used herein, the term “patient” means any animal, including mammals (e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates (e.g., humans)).

[0051] As used herein, the term “isolate” means separating a compound described herein from other components of a synthetic organic chemical reaction mixture by conventional techniques (e.g., filtration).

[0052] As used herein, the term “mammal” means rodents (i.e., mice, rats, or guinea pigs), monkeys, cats, dogs, cattle, horses, pigs, or humans. In some embodiments, the mammal is a human.

[0053] As used herein, the term "nitro" means -NO2.

[0054] As used herein, the term “n-membered” (where n is an integer) typically describes the number of ring-forming atoms in a part, in this case, the number of ring-forming atoms is n. For example, pyridine is an example of a six-membered heteroaryl ring, and thiophene is an example of a five-membered heteroaryl ring.

[0055] As used herein, the expression "optionally substituted" means that the substitution is optional, and therefore includes both unsubstituted and substituted atoms and parts. "Substituted" atom or part indicates that any hydrogen atom or part may be substituted with a substituent selected from the indicated substituents, provided that the substitution does not exceed the normal valence of the specified atom or part and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, three hydrogen atoms on the carbon atom may be substituted with substituents.

[0056] As used herein, the expression “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that is suitable, to the extent of reasonable medical judgment, for use in contact with human and animal tissues. In some embodiments, “pharmaceutically acceptable” means being approved by a federal or state government regulatory agency, or being listed in the United States Pharmacopeia or other widely recognized pharmacopoeia for use in animals, and more specifically for use in humans.

[0057] In some embodiments, the salts of the compounds described herein are pharmaceutically acceptable salts. As used herein, the expression “pharmaceutically acceptable salts” includes, but is not limited to, salts of an acidic or basic group. Compounds that are inherently basic can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, but is not limited to, salts containing pharmaceutically acceptable anions such as sulfuric acid, thiosulfuric acid, citric acid, maleic acid, acetic acid, oxalic acid, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acidic phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acidic citrate, tartrate, oleate, tannate, pantothenate, tartrate, and ascorbyl. These are acids that form salts, succinates, maleates, gentisates, fumarates, glucons, glucarons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, bicarbonates, malons, mesylates, esylates, napsydisylates, tosylates, besylates, orthophosphates, trifluoroacetates, and pamoates (including 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds that are inherently acidic can form base salts with various pharmacologically acceptable cations. Examples of such salts, but not limited to, are alkali metal or alkaline earth metal salts, specifically salts of calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron. This embodiment also includes quaternary ammonium salts of the compounds described herein, in which case the compounds have one or more tertiary amine moieties.

[0058] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two, or three preferred substituents.

[0059] As used herein, the term “purified” means that, when isolated, the isolate contains at least 90% by weight, at least 95% by weight, at least 98% by weight, or at least 99% by weight of the compound described herein, relative to the weight of the isolate.

[0060] As used herein, the term "quaternary ammonium salt" means that at least one of the tertiary amine moieties of the parent compound is modified by converting the tertiary amine moiety to a quaternary ammonium cation via alkylation (e.g., methylation or ethylation) (and the cation is Cl - CH3COO - , and CF3COO - This means derivatives of the compounds of this disclosure having one or more tertiary amine moieties (balanced by anions such as the above).

[0061] As used herein, the term "solution / suspension" means a liquid composition in which a first portion of the active agent is dissolved and a second portion of the active agent is suspended in a liquid matrix in particulate form.

[0062] As used herein, the term “solvent” means a normally liquid substance capable of dissolving or dispersing one or more other substances, and includes water, inorganic non-aqueous solvents, and organic solvents. The term “inorganic non-aqueous solvent” means a solvent other than water that is not an organic compound. Examples of “inorganic non-aqueous solvents” include, but are not limited to, liquid ammonia, liquid sulfur dioxide, sulfuryl chloride and sulfuryl fluoride chloride, phosphoryl chloride, dinitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, pure sulfuric acid, and other inorganic acids. The term “organic solvent” means a carbon-based solvent. Examples of “organic solvents” include, but are not limited to, aromatic compounds (e.g., benzene and toluene), alcohols (e.g., methanol, ethanol, and propanol), esters, ethers, ketones (e.g., acetone), amines, and nitrified and halogenated hydrocarbons. “Organic solvents” include both polar and non-polar organic solvents. A "polar organic solvent" refers to an organic solvent that has a large dipole moment (also known as a "partial charge"). Generally, organic solvents with a dielectric constant of approximately 5 or more are considered "polar organic solvents," while those with a dielectric constant of less than 5 are considered "non-polar organic solvents." Examples of "polar organic solvents," but not limited to, include acetic acid, methanol, acetone, acetonitrile, DMSO, and DMF. Examples of non-polar organic solvents, but not limited to, include benzene, carbon tetrachloride, and n-hexane. "Organic solvents" include both protic and aprotic organic solvents. A "protic organic solvent" refers to an organic solvent that has a hydrogen atom (acidic hydrogen atom) bonded to oxygen or nitrogen. Examples of "protic organic solvents," but not limited to, include methanol, ethanol, propanol, isopropanol, butanol, hexanol, phenol, acetic acid, benzoic acid, and their partially fluorinated compounds.Examples of "aprotic organic solvents" include, but are not limited to, ethylene glycol dimethyl ether, ethylene glycol methyl ethyl ether, diethylene glycol dimethyl ether, diethylene glycol methyl ethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, 1,3-dimethoxypropane, 1,2-dimethoxypropane, propylene glycol dimethyl ether, dipropylene glycol dimethyl ether, dioxane, dimethyl carbonate, ethyl methyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 2,3-dimethylethylene carbonate, butylene carbonate, acetonitrile, methoxyacetonitrile, propionitrile, butyrolactone, valerolactone, dimethoxyethane, sulfolane, methylsulfolane, sulfone, dimethyl sulfone, ethyl methyl sulfone, and isopropyl methyl sulfone.

[0063] As used herein, the expression “substantially isolated” means a compound that has been at least partially or substantially isolated from the environment in which the compound was formed or detected.

[0064] As used herein, the terms "preferred substituent" or "substituent" mean a group that does not impair the synthesis or pharmaceutically usefulness of the compounds described herein or intermediates useful for preparing them. Examples of preferred substituents include, but are not limited to, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C5-C6 aryl, C1-C6 alkoxy, C3-C5 heteroaryl, C3-C6 cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -NH(C6 aryl), -N(C5-C6 aryl)2, -CHO, -CO(C1-C6 alkyl), -CO((C5-C6)aryl), -CO2((C1-C6)alkyl), and -CO2((C5-C6)aryl). Those skilled in the art can easily select suitable substituents based on the stability, pharmacological activity, and synthetic activity of the compounds described herein.

[0065] As used herein, the term “not limited to” should be understood to mean the same thing unless otherwise specified.

[0066] In various places in this specification, substituents of compounds may be disclosed as groups or ranges. Embodiments are expressly intended to include any individual partial combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is expressly intended to disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0067] In compounds where a variable appears more than once, each variable can be a different part selected from the Markouche group that defines that variable. For example, if a structure is described having two R groups present simultaneously on the same compound, the two R groups can represent different parts selected from the Markouche group defined for R. In another example, multiple substituents can be of arbitrary choice, for example. [ka] When specified in this format, the substituent R can appear s times on the ring, and it should be understood that R may be a different part in each appearance. In the example above, the variable T 1 If it is defined to contain hydrogen (for example, T 1 If the molecule is CH2, NH, etc., any H can be replaced by a substituent.

[0068] Furthermore, it should be understood that certain features described herein, which are described in the context of separate embodiments for clarity, may be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for brevity may be provided separately or in any preferred partial combination.

[0069] It should be understood that this embodiment, where applicable, encompasses processes for stereoisomers, diastereomers, and optical stereoisomers of compounds, as well as mixtures thereof. Furthermore, it should be understood that stereoisomers, diastereomers, and optical stereoisomers of compounds, as well as mixtures thereof, are within the scope of this embodiment. In non-limiting examples, the mixture may be a racemate, or the mixture may contain one particular stereoisomer in an unequal proportion to the other. In addition, the compound may be provided as a substantially pure stereoisomer, diastereomer, and optical stereoisomer (e.g., epimer).

[0070] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers (e.g., enantiomers and diastereomers) are intended to be included within the scope of the embodiments unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by the separation or stereoselective synthesis of racemic mixtures. Many geometric isomers, such as olefins and C=N double bonds, can also exist in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of compounds are also included in these embodiments, and these can be isolated as mixtures of isomers or as separate isomeric forms. When a compound capable of stereoisomerism or geometric isomerism is referred to by its structure or name without mentioning a specific R / S or cis / trans configuration, all such isomers are intended to be considered.

[0071] In some embodiments, the composition comprises a compound or a pharmaceutically acceptable salt thereof having an enantiomer purity of at least 90%, at least 95%, at least 98%, or at least 99%, or 100%, meaning that the ratio of one enantiomer to the other enantiomer in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or that the other is entirely in the form of one enantiomer.

[0072] The separation of a racemic mixture of compounds can be carried out by any of the many methods known in the art (e.g., including chiral HPLC and fractional recrystallization using chiral splitting acids (optically active salt-forming organic acids)). Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids (e.g., D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids (e.g., β-camphorsulfonic acid)). Other suitable resolving agents for fractional crystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norphedrine, ephedrine, N-methylfedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. Separation of racemic mixtures can also be performed by elution using a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0073] Compounds may also include tautomers. Tautomers arise when a single bond is replaced by an adjacent double bond, accompanied by the simultaneous movement of a proton. Tautomers include prototropic tautomers, which are isomer-protonated states with the same empirical formula and total charge. Examples of prototropic tautomers, but not limited to, include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms. Cyclic forms can have protons occupying two or more positions in the heterocyclic system and include, but not limited to, 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomers exist in equilibrium or are sterically locked into a single form by appropriate substitution.

[0074] The compounds include hydrates and solvates, as well as anhydrous and non-solvated forms.

[0075] Compounds may include isotopes of all atoms that appear in the intermediate or final compound. Isotopes are atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deutherium.

[0076] In some embodiments, the compound or a salt thereof is substantially isolated. Partial isolation may include, for example, a composition in which the compound is concentrated. Substantial isolation may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or a salt thereof. Methods for isolating compounds and salts thereof are routinely practiced in the art.

[0077] While the compounds of this disclosure are suitable, similar results can be expected by incorporating other functional groups into the compounds. In particular, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometric pattern of the compound, and this distance can be altered by incorporating aliphatic chains of various lengths, which may be optically substituted or may contain amino acids, dicarboxylic acids, or diamines. The distances and relative orientations between monomers within the compound can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacing a carbonyl group with a dicarbonyl changes the distance between monomers and alters the periodicity of the compound due to the property of the dicarbonyl unit to incorporate the inverse arrangement of two carbonyl moieties. Pyromellitic anhydrides represent yet another alternative to simple amide bonds, which can alter the stereostructure and physical properties of the compound. Using the latest methods in solid-phase organic chemistry (E. Atherton and RCSheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford 1989), it is now possible to synthesize homodisperse compounds with molecular weights close to 5,000 daltons. Other substitution patterns are equally effective.

[0078] Embodiments of various methods for preparing compounds of formula (I) and salts thereof are provided. Unless otherwise specified or indicated by context, variables may be any of the options described herein.

[0079] In some embodiments, methods for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof are as described in the appended exemplary and non-limiting claims.

[0080] In some embodiments, a process or method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method is provided for preparing a compound of formula (II). [ka] Formula (II) The compound of formula (III) [ka] Formula (III) The following structure is brought into contact with the following under suitable conditions: [ka] This includes forming a compound having formula (I), During the ceremony, A, B, and E are each independently N or CR6. X and Y are independently O, S, or NR7. R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. R2, R3, R4, R5, R6, and R7 are each independently H, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 hydroxyalkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted cycloalkyl, or an optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or an optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or an optionally substituted cycloheteroalkyl.

[0081] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the contact is a reaction. In some embodiments, the contact is condensation. In some embodiments, the contact is coupling. In some embodiments, the contact is cyclization.

[0082] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is N or CR6. In some embodiments, A is N. In some embodiments, A is CR6.

[0083] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein B is N or CR6. In some embodiments, B is N. In some embodiments, B is CR6.

[0084] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein E is N or CR6. In some embodiments, E is N. In some embodiments, E is CR6.

[0085] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is O, S, or NR7. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR7.

[0086] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is O, S, or NR7. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NR7.

[0087] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is H, OH, NH2, NO2, optionally substituted carbocyclic compounds, optionally substituted aryl groups, optionally substituted heteroaryl groups, branched or unbranched alkyl alcohols, halos, branched or unbranched alkyls, amides, cyanos, alkoxys, haloalkyls, acrylsulfonyls, nitrites, or alkylsulfanyls. In some embodiments, R1 is H. In some embodiments, R1 is OH. In some embodiments, R1 is NH2. In some embodiments, R1 is -NO2. In some embodiments, R1 is optionally substituted carbocyclic compounds. In some embodiments, R1 is optionally substituted aryl groups. In some embodiments, R1 is optionally substituted heteroaryl groups. In some embodiments, R1 is branched or unbranched alkyl alcohols. In some embodiments, R1 is halos. In some embodiments, R1 is a branched or unbranched alkyl group. In some embodiments, R1 is an amide group. In some embodiments, R1 is a cyano group. In some embodiments, R1 is an alkoxy group. In some embodiments, R1 is a haloalkyl group. In some embodiments, R1 is an alkylsulfonyl group. In some embodiments, R1 is a nitrite group. In some embodiments, R1 is an alkylsulfanyl group.

[0088] In some embodiments, R2 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R2 is H. In some embodiments, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R2 is optionally substituted C1-C6 alkoxy. In some embodiments, R2 is optionally substituted cycloalkyl. In some embodiments, R2 is optionally substituted cycloheteroalkyl.

[0089] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R3 is H. In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R3 is optionally substituted C1-C6 alkoxy. In some embodiments, R3 is optionally substituted cycloalkyl. In some embodiments, R3 is optionally substituted cycloheteroalkyl.

[0090] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R4 is H. In some embodiments, R4 is optionally substituted C1-C6 alkyl. In some embodiments, R4 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R4 is optionally substituted C1-C6 alkoxy. In some embodiments, R4 is optionally substituted cycloalkyl. In some embodiments, R4 is optionally substituted cycloheteroalkyl.

[0091] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R5 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R5 is H. In some embodiments, R5 is optionally substituted C1-C6 alkyl. In some embodiments, R5 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R5 is optionally substituted C1-C6 alkoxy. In some embodiments, R5 is optionally substituted cycloalkyl. In some embodiments, R5 is optionally substituted cycloheteroalkyl.

[0092] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R6 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R6 is H. In some embodiments, R6 is optionally substituted C1-C6 alkyl. In some embodiments, R6 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R6 is optionally substituted C1-C6 alkoxy. In some embodiments, R6 is optionally substituted cycloalkyl. In some embodiments, R6 is optionally substituted cycloheteroalkyl.

[0093] In some embodiments, R7 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R7 is H. In some embodiments, R7 is optionally substituted C1-C6 alkyl. In some embodiments, R7 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R7 is optionally substituted C1-C6 alkoxy. In some embodiments, R7 is optionally substituted cycloalkyl. In some embodiments, R7 is optionally substituted cycloheteroalkyl.

[0094] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are both optionally substituted cycloalkyls or optionally substituted cycloheteroalkyls. In some embodiments, R2 and R3 are both optionally substituted cycloalkyls. In some embodiments, R2 and R3 are both optionally substituted cycloheteroalkyls.

[0095] In some embodiments, R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0096] In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof further includes: [ka] The compound of formula (II) [ka] By coupling it with the compound of formula (III), [ka] This includes forming a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the coupling comprises reacting compounds of formula (II) and formula (III) for at least about 5 minutes. In some embodiments, the reaction comprises heating the reactants at a temperature of at least about 40°C for at least about 1, 2, 3, 4, or 5 minutes.

[0098] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof further involves quenching the reaction product of a compound of formula (II) and a compound of formula (III), [ka] The process involves forming a slurry containing the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, quenching involves cooling the reaction product of the compound of formula (II) and the compound of formula (III), and / or adding water to quench the reaction product to form a slurry.

[0099] In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof further includes: [ka] This involves isolating a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is achieved by filtering, washing, and / or drying the slurry. [ka] This involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, isolation is achieved by filtering the slurry. [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by washing the slurry, [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by drying the slurry. [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by filtering and drying the slurry. [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by filtering and washing the slurry. [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by washing and drying the slurry. [ka] The process involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, isolation is performed by filtering, washing, and drying the slurry. [ka] This involves obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is: [ka] The process involves washing to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the washing includes washing with water and / or an organic solvent. In some embodiments, the washing includes washing with a solvent to remove impurities (e.g., unreacted or excess compounds of the compound of formula (II) or formula (III), by-products derived from coupling reagents and / or additives, and any combination thereof). In some embodiments, the washing includes washing with water. In some embodiments, the washing includes washing with an organic solvent. In some embodiments, the washing includes washing with water and an organic solvent. In some embodiments, the washing does not include washing with water. In some embodiments, the washing does not include washing with an organic solvent.

[0102] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Coupling reagent and optionally additive in the first organic solvent [ka] Add the compound of formula (II) to the solution to form a mixture, and stir the mixture for at least about 5 minutes. (b) the mixture from step (a) [ka] Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of at least about 40°C and stir the mixture at that temperature. (d) Cool the mixture from step (c), add water to the mixture to form a slurry, (e) Stirring the slurry from step (d), (f) Filtering the slurry from step (e) to obtain a solid, (g) Wash the solid from step (f) with water and / or a second organic solvent, (h) Dry the solid from step (g) under vacuum at a temperature of at least about 30°C. [ka] The present invention provides a method comprising forming a compound of formula (I), wherein the variables are as defined herein.

[0103] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the coupling reagent is carbodiimide. In some embodiments, the carbodiimide is DCC, DIC, or EDC hydrochloride. In some embodiments, the carbodiimide is DCC. In some embodiments, the carbodiimide is DIC. In some embodiments, the coupling reagent is EDC hydrochloride.

[0104] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the additive is HOBt, HOAt, or ethyl cyanohydroxyiminoacetate. In some embodiments, the additive is HOBt. In some embodiments, the additive is HOAt. In some embodiments, the additive is ethyl cyanohydroxyiminoacetate.

[0105] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the first organic solvent is a polar organic solvent. In some embodiments, the polar organic solvent is a polar aprotic organic solvent. In some embodiments, the polar aprotic organic solvent is dimethylformamide or diethylformamide. In some embodiments, the polar aprotic organic solvent is diethylformamide. In some embodiments, the polar aprotic organic solvent is dimethylformamide.

[0106] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the amount of the coupling reagent is at least about 1.0 equivalent in molar ratio to the amount of the compound of formula (II). In some embodiments, the amount of the coupling reagent is about 1.2 equivalents in molar ratio to the amount of the compound of formula (II). In some embodiments, the amount of the additive is at least about 1.0 equivalent in molar ratio to the amount of the compound of formula (II). In some embodiments, the amount of the additive is about 1.0 equivalent in molar ratio to the amount of the compound of formula (II).

[0107] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound of formula (II) in a first organic solvent is at least about 0.1 mol / L. In some embodiments, the concentration of the compound of formula (II) in the first organic solvent is about 0.8 mol / L.

[0108] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein in step (a), the mixture is stirred for at least about 5 minutes. In some embodiments, in step (a), the mixture is stirred for about 1 hour.

[0109] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the amount of compound of formula (III) is at least about 1.0 equivalent in molar ratio to the amount of compound of formula (II). In some embodiments, the amount of compound of formula (III) is about 1.2 equivalents in molar ratio to the amount of compound of formula (II).

[0110] In some embodiments, in step (b), the mixture is stirred for at least 5 minutes. In some embodiments, in step (b), the mixture is stirred for at least about 1 hour.

[0111] In some embodiments, in step (c), the temperature is at least about 60°C. In some embodiments, in step (c), the temperature is at least about 75°C. In some embodiments, in step (c), the temperature is about 95°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 90°C to about 95°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 85°C to about 95°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 80°C to about 95°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 75°C to about 95°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 95°C to about 100°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 95°C to about 105°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 95°C to about 110°C. In some embodiments, in step (c), the mixture from step (a) is heated to about 90°C to about 115°C.

[0112] In some embodiments, in a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in step (c), the mixture is stirred at its temperature for at least about 1, 2, 3, 4, or 5 minutes. In some embodiments, in step (c), the mixture is stirred at its temperature for at least about 1 hour. In some embodiments, in step (c), the mixture is stirred at its temperature for at least 5 hours. In some embodiments, in step (c), the mixture is stirred at its temperature for at least 18 hours.

[0113] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein in step (d), the mixture is cooled to about 5 to 25°C. I. In some embodiments, in step (d), the mixture is cooled to about 15 to 20°C.

[0114] In some embodiments, in step (d), the volume ratio of water to the first organic solvent is at least about 1. In some embodiments, in step (d), the volume ratio of water to the first organic solvent is about 2.

[0115] In some embodiments, in step (e), the mixture is stirred at approximately 5–25°C. I. In some embodiments, in step (e), the mixture is stirred at approximately 15–20°C.

[0116] In some embodiments, in step (e), the slurry is stirred for at least about 5 minutes. In some embodiments, in step (e), the slurry is stirred for about 1 hour.

[0117] In some embodiments, a method is provided for preparing a compound of formula (I), wherein in step (g), the volume ratio of water to the first organic solvent in each washing cycle is at least about 0.5. In some embodiments, in step (g), the volume ratio of water to the first organic solvent in each washing cycle is about 0.5.

[0118] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the solid is washed at least once with water. In some embodiments, the solid is washed twice with water.

[0119] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is at least about 0.5. In some embodiments, the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is about 0.5.

[0120] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the solid is washed at least once with a second organic solvent. In some embodiments, the solid is washed twice with the second organic solvent.

[0121] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the second organic solvent is an ether. In some embodiments, the ether is a dialkyl ether. In some embodiments, the ether is a methyl tert-butyl ether.

[0122] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the solid is dried at about 55°C. In some embodiments, the solid is dried at about 45°C to about 55°C. In some embodiments, the solid is dried at about 55°C to about 65°C. In some embodiments, the solid is dried at about 50°C to about 60°C.

[0123] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide [ka] Add the compound of formula (II) to the solution to form a mixture, and stir the mixture for at least about 1 hour. (b) the mixture from step (a) [ka] Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of approximately 95°C and stir the mixture at that temperature for at least approximately 5 hours. (d) Cool the mixture from step (c) to about 15-20°C, add water to form a slurry, (e) Stir the slurry from step (d) at approximately 15-20°C for about 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl tert-butyl ether, (h) Dry the solid from step (g) under vacuum at approximately 55°C. [ka] The present invention also provides a method comprising forming a compound of formula (I), wherein the variables in the formula are as defined herein.

[0124] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein in step (c), the mixture of step (b) is heated under reflux or near reflux. In some embodiments, in step (c), the mixture of step (b) is heated to about 95°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 90°C to about 95°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 85°C to about 95°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 80°C to about 95°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 75°C to about 95°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 95°C to about 100°C. In some embodiments, in step (c), the mixture of step (b) is heated to about 95°C to about 105°C. In some embodiments, the mixture from step (b) is heated to about 95°C to about 110°C. In some embodiments, the mixture from step (b) is heated to about 90°C to about 115°C.

[0125] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises recrystallizing the solid of step (h) from a solvent. In some embodiments, the solvent for recrystallization is water, dimethylformamide, ethanol, or methyl tert-butyl ether. In some embodiments, the solvent for recrystallization is ethanol. In some embodiments, when the solvent for recrystallization is ethanol or methyl tert-butyl ether, the mixture forms a slurry.

[0126] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the slurry is heated to a temperature of at least about 50°C when the solvent for recrystallization is ethanol. In some embodiments, when the solvent is ethanol, the slurry is heated to a temperature of about 75°C. In some embodiments, the slurry is stirred at about 75°C for about 15 hours.

[0127] In some embodiments, when the solvent is methyl tert-butyl ether, the slurry is heated to a temperature of at least about 30°C. In some embodiments, when the solvent is methyl tert-butyl ether, the slurry is heated to a temperature of about 45°C. In some embodiments, the slurry is stirred at about 45°C for about 15 hours.

[0128] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the purity of the recrystallized solid is at least about 95%. In some embodiments, the purity of the recrystallized solid is at least about 99%. In some embodiments, the purity of the recrystallized solid is about 99.5%.

[0129] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the recrystallized solid is white to off-white in color.

[0130] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the solid is dried at about 55°C. In some embodiments, the solid is dried at about 45°C to about 55°C. In some embodiments, the solid is dried at about 55°C to about 65°C. In some embodiments, the solid is dried at about 50°C to about 60°C.

[0131] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is O.

[0132] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is O.

[0133] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound to be prepared or produced is [ka] Equation (VI), [ka] Formula (VII), [ka] Formula (VIII), or [ka] The compound has the formula (IX), wherein the variables are as defined in claim 1. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] The compound has the formula (VI), wherein the variables are as defined in claim 1. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound produced is [ka] The compound has the formula (VII), wherein the variables are as defined in claim 1. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound produced is [ka] The compound has the formula (VIII), wherein the variables are as defined in claim 1. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound produced is [ka] The formula has the expression (IX), where the variables are as defined in claim 1.

[0134] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently H or an optionally substituted C1-C6 alkyl group.

[0135] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein either R4 or R5 is H.

[0136] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The present invention provides a method having the formula (X), wherein the variables in the formula are as defined in claim 1.

[0137] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is

Chemical formula

[0138] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H or optionally substituted C1-C6 alkyl, and provides a method.

[0139] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are optionally substituted C1-C6 alkyl, and provides a method.

[0140] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are methyl or ethyl. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are methyl. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are ethyl.

[0141] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is

Chemical formula

[0142] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein either R2 or R3 is H.

[0143] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0144] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are both optionally substituted 5-, 6-, or 7-membered cycloalkyl or cycloheteroalkyl.

[0145] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted C1-C6 alkyl, optionally substituted carbocycle, optionally substituted aryl group, or optionally substituted heteroaryl group.

[0146] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl group or optionally substituted heteroaryl group.

[0147] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heteroaryl group.

[0148] In some embodiments, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted nitrogen-containing heteroaryl group.

[0149] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is [ka] It provides a method to achieve this.

[0150] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [ka] It provides a method to achieve this.

[0151] In some embodiments, [Chemical Formula] A method for preparing a compound having the structure of or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Adding EDC hydrochloride and ethyl cyano hydroxyiminoacetate to a solution of [Chemical Formula] in dimethylformamide to form a mixture, and stirring the mixture for at least about 1 hour; (b) Stirring the mixture of step (a) with [Chemical Formula] for about 1 hour; (c) Heating the mixture of step (b) to a temperature of about 95 °C and stirring the mixture at that temperature for at least about 5 hours; (d) Cooling the mixture of step (c) to about 15 - 20 °C, adding water to the mixture to form a slurry; (e) Stirring the slurry of step (d) at about 15 - 20 °C for about 1 hour; (f) Filtering the slurry of step (e) to form a solid; (g) Washing the solid of step (f) with water and methyl - tert - butyl ether; (h) Drying the solid of step (g) under vacuum at at least about 55 °C to form [Chemical Formula] also provides a method.

[0152] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising [Chemical Formula] contacting formula (V) with R2R3C=O under suitable conditions, [ka] The present invention provides a method for preparing a compound of formula (II), wherein the variables are as defined herein. In some embodiments, contact is a reaction. In some embodiments, contact is a condensation. In some embodiments, contact is a coupling. In some embodiments, contact is a cyclization.

[0153] In some embodiments, [ka] A method for preparing the compound of formula (II), comprising the following steps: (a) In the compound R2R3C=O [ka] Adding pyrrolidine to a solution of the compound of formula (V) to form a mixture, (b) Heat the mixture from step (a) under reflux, stir the refluxed mixture at that temperature for about 19.5 hours, cool the mixture to about 15-20°C, and add water to the mixture. (c) Adjust the pH of the mixture from step (b) to approximately 2 with HCl, (d) The mixture from step (c) is stirred with n-heptane to form a slurry, the slurry is stirred at approximately 15-20°C for about 1 hour, and the slurry is filtered to form a solid. (e) Wash the solid from step (d) with water and n-heptane, (g) Dry the solid from step (e) under vacuum at approximately 50°C. [ka] This includes forming a compound of formula (II), wherein, A, B, and E are each independently N or CR6. X and Y are independently O, S, or NR7. The present invention also provides a method in which R4, R5, R6, and R7 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or in which case R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0154] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein in step (b), the mixture from step (a) is heated under reflux to or near the boiling point of the compound R2R3C=O. In some embodiments, in step (b), the mixture from step (a) is heated to about 95°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 90°C to about 95°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 85°C to about 95°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 80°C to about 95°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 75°C to about 95°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 95°C to about 100°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 95°C to about 105°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 95°C to about 110°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 90°C to about 115°C.

[0155] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein A is N or CR6. In some embodiments, A is N. In some embodiments, A is CR6.

[0156] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein B is N or CR6. In some embodiments, B is N. In some embodiments, B is CR6.

[0157] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein E is N or CR6. In some embodiments, E is N. In some embodiments, E is CR6.

[0158] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein X is O, S, or NR7. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR7.

[0159] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Y is O, S, or NR7. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NR7.

[0160] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R2 is H. In some embodiments, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R2 is optionally substituted C1-C6 alkoxy. In some embodiments, R2 is optionally substituted cycloalkyl. In some embodiments, R2 is optionally substituted cycloheteroalkyl.

[0161] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R3 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R3 is H. In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R3 is optionally substituted C1-C6 alkoxy. In some embodiments, R3 is optionally substituted cycloalkyl. In some embodiments, R3 is optionally substituted cycloheteroalkyl.

[0162] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R4 is H. In some embodiments, R4 is optionally substituted C1-C6 alkyl. In some embodiments, R4 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R4 is optionally substituted C1-C6 alkoxy. In some embodiments, R4 is optionally substituted cycloalkyl. In some embodiments, R4 is optionally substituted cycloheteroalkyl.

[0163] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R5 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R5 is H. In some embodiments, R5 is optionally substituted C1-C6 alkyl. In some embodiments, R5 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R5 is optionally substituted C1-C6 alkoxy. In some embodiments, R5 is optionally substituted cycloalkyl. In some embodiments, R5 is optionally substituted cycloheteroalkyl.

[0164] In some embodiments, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R6 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R6 is H. In some embodiments, R6 is optionally substituted C1-C6 alkyl. In some embodiments, R6 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R6 is optionally substituted C1-C6 alkoxy. In some embodiments, R6 is optionally substituted cycloalkyl. In some embodiments, R6 is optionally substituted cycloheteroalkyl.

[0165] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R7 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl. In some embodiments, R7 is H. In some embodiments, R7 is optionally substituted C1-C6 alkyl. In some embodiments, R7 is optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R7 is optionally substituted C1-C6 alkoxy. In some embodiments, R7 is optionally substituted cycloalkyl. In some embodiments, R7 is optionally substituted cycloheteroalkyl.

[0166] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are both optionally substituted cycloalkyls or optionally substituted cycloheteroalkyls. In some embodiments, R2 and R3 are both optionally substituted cycloalkyls. In some embodiments, R2 and R3 are both optionally substituted cycloheteroalkyls.

[0167] In some embodiments, a method is provided for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are both optionally substituted cycloalkyls or optionally substituted cycloheteroalkyls. In some embodiments, R4 and R5 are both optionally substituted cycloalkyls. In some embodiments, R4 and R5 are both optionally substituted cycloheteroalkyls.

[0168] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, by contacting a compound of formula R1CN with ammonium hydroxide. [ka] The present invention further provides a method for preparing a compound of formula (III), wherein R1 is H, OH, NH2, NO2, optionally substituted carbocyclic compounds, optionally substituted aryl groups, optionally substituted heteroaryl groups, branched or unbranched alkyl alcohols, halos, branched or unbranched alkyls, amides, cyanos, alkoxys, haloalkyls, acrylsulfonyls, nitrites, or alkylsulfanyls. In some embodiments, the contact is a reaction. In some embodiments, the contact is a condensation. In some embodiments, the contact is a coupling. In some embodiments, the contact is a cyclization.

[0169] In some embodiments, [ka] A method for preparing the compound of formula (III), comprising the following steps: (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture, (b) Heat the mixture from step (a) to a temperature of approximately 75°C and stir the mixture at that temperature for approximately 4 hours to form a slurry. (c) Cool the slurry from step (b) to ambient temperature and stir it at ambient temperature for approximately 16 hours. (d) Filtering the slurry from step (c) to form a solid, (e) Wash the solid from step (d) with alcohol, and dry the washed solid at approximately 50°C under vacuum. [ka] The present invention also provides a method comprising forming a compound of formula (III), wherein R1 is as defined herein.

[0170] In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. In some embodiments, R1 is H. In some embodiments, R1 is OH. In some embodiments, R1 is -NH2. In some embodiments, R1 is -NO2. In some embodiments, R1 is optionally substituted carbocyclic. In some embodiments, R1 is optionally substituted aryl group. In some embodiments, R1 is optionally substituted heteroaryl group. In some embodiments, R1 is branched or unbranched alkyl alcohol. In some embodiments, R1 is halo. In some embodiments, R1 is a branched or unbranched alkyl group. In some embodiments, R1 is an amide group. In some embodiments, R1 is a cyano group. In some embodiments, R1 is an alkoxy group. In some embodiments, R1 is a haloalkyl group. In some embodiments, R1 is an alkylsulfonyl group. In some embodiments, R1 is a nitrite group. In some embodiments, R1 is an alkylsulfanyl group.

[0171] In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the alcohol is an optionally substituted C1-C6 alkyl alcohol. In some embodiments, the alcohol is methanol, ethanol, propanol, or butanol. In some embodiments, the alcohol is ethanol. In some embodiments, the alcohol is methanol. In some embodiments, the alcohol is propanol. In some embodiments, the alcohol is butanol.

[0172] In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the hydroxylamine is hydroxylamine hydrochloride. In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein an organic base is added when the hydroxylamine is hydroxylamine hydrochloride. In some embodiments, the organic base is diisopropylethylamine. In some embodiments, the amount of the organic base is at least about 1.5 equivalents in molar ratio to the amount of hydroxylamine hydrochloride.

[0173] In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein in step (a), the amount of hydroxylamine is at least about 1.5 equivalents in molar ratio to the amount of R1CN.

[0174] In some embodiments, a method is provided for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein in step (b), the mixture from step (a) is heated under reflux to or near the boiling point of the alcohol. In some embodiments, the mixture from step (a) is heated to about 75°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 70°C to about 75°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 65°C to about 75°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 60°C to about 75°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 75°C to about 75°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 75°C to about 80°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 75°C to about 85°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 75°C to about 90°C. In some embodiments, in step (b), the mixture from step (a) is heated to about 90°C to about 95°C.

[0175] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] The compound of formula (II) is brought into contact with a coupling reagent with or without an additive. [ka] The present invention provides a method for forming an intermediate having the structure of formula (XIII), wherein R8 is an optionally substituted C1-C6 alkyl, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, the compound of formula (II) reacts with a coupling reagent with or without an additive to form the intermediate of formula (XIII). In some embodiments, the compound of formula (II) is coupled with a coupling reagent with or without an additive to form the intermediate of formula (XIII).

[0176] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the intermediate of formula (XIII) is [ka] The present invention provides a compound having the structure of formula (XIV). In some embodiments, the intermediate of formula (XIII) is [ka] Equation (XIV-I), [ka] Formula (XIV-II), [ka] Formula (XIV-III), or [ka] It is a compound having the structure of formula (XIV-IV). In some embodiments, the intermediate of formula (XIII) is [ka] It is a compound having the structure of formula (XIV-I). In some embodiments, the intermediate of formula (XIII) is [ka] It is a compound having the structure of formula (XIV-V). In some embodiments, the intermediate of formula (XIII) is [ka] The compound has the structure of formula (XIV-VI). In some embodiments, the intermediate of formula (XIII) is [ka] It is a compound having the following structure.

[0177] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] An intermediate having the structure of formula (XIII) [ka] Further contact with the compound of formula (III), [ka] A method is provided for forming an intermediate having the structure of formula (XVI). In some embodiments, the intermediate of formula (XIII) further reacts with the compound of formula (III) to form the intermediate of formula (XVI). In some embodiments, the intermediate of formula (XIII) further couples with the compound of formula (III) to form the intermediate of formula (XVI).

[0178] In some embodiments, the intermediate of formula (XVI) is [ka] Formula (XVII), [ka] Formula (XVIII), [ka] Formula (XIX), or [ka] It is a compound having the structure of formula (XX). In some embodiments, the intermediate of formula (XVI) is [ka] It is a compound having the structure of formula (XVII). In some embodiments, the intermediate of formula (XVI) is [ka] It is a compound having the structure of formula (XVII-I). In some embodiments, the intermediate of formula (XVI) is [ka] It is a compound having the structure of formula (XVII-II). In some embodiments, the intermediate of formula (XVI) is [ka] It is a compound having the following structure.

[0179] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] An intermediate having the structure of formula (XVI) under thermal dehydration cyclization conditions [ka] A method is provided for further forming the compound of formula (I). In some embodiments, the intermediate of formula (XVI) is further condensed under thermal dehydration cyclization conditions to form the compound of formula (I). In some embodiments, the intermediate of formula (XVI) is further cyclized under thermal dehydration cyclization conditions to form the compound of formula (I). In some embodiments, [ka] The compound of formula (I) is [ka] That is the case.

[0180] In some embodiments, isolated from the method described herein [ka] The compound of formula (XIII) or a pharmaceutically acceptable salt thereof is also provided.

[0181] In some embodiments, [ka] The present invention also provides compositions comprising one or more compounds of formula (XIII) or pharmaceutically acceptable salts thereof.

[0182] In some embodiments, [ka] The present invention also provides a solution containing one or more compounds of formula (XIII) or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, isolated from the method described herein [ka] The compound of formula (XVI) or a pharmaceutically acceptable salt thereof is also provided.

[0184] In some embodiments, [ka] The present invention also provides compositions comprising one or more compounds of formula (XVI) or pharmaceutically acceptable salts thereof.

[0185] In some embodiments, [ka] The present invention also provides solutions containing one or more compounds of formula (XVI) or pharmaceutically acceptable salts thereof.

[0186] In some embodiments, a method for forming a compound of formula I, [ka] A compound having the structure of formula (XVI) is reacted under thermal dehydration cyclization conditions. [ka] The present invention also provides a method that includes forming a compound of formula I.

[0187] In some embodiments, the structure [ka] The present invention provides a crystalline form of a compound having [a certain characteristic]. In some embodiments, the crystalline form is form I. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including peaks at approximately 8.9±0.5°²θ, approximately 9.4±0.5°²θ, 15.7±0.5°²θ, approximately 17.7±0.5°²θ, approximately 18.9±0.5°²θ, 24.3±0.5°²θ, approximately 26.0±0.5°²θ, and approximately 26.7±0.5°²θ. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including one or more peaks shown in Figure 6. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern including one or more peaks shown in Table 14. Crystal morphology I according to claim 142, characterized in some embodiments by an X-ray powder diffraction pattern including one or more interplanar spacing values ​​at approximately 10.0 ± 0.5 degrees angstroms, approximately 9.4 ± 0.5 degrees angstroms, approximately 5.6 ± 0.5 degrees angstroms, approximately 5.0 ± 0.5 degrees angstroms, approximately 4.7 ± 0.5 degrees angstroms, approximately 3.7 ± 0.5 degrees angstroms, approximately 3.4 ± 0.5 degrees angstroms, and approximately 3.3 ± 0.5 degrees angstroms.

[0188] The compounds described herein may be shown in a specific stereochemistry (e.g., cis or trans) around a particular atom, but compounds can also be prepared in the opposite direction or as racemic mixtures. Such isomers or racemic mixtures are included in this disclosure. In addition, although the compounds are shown collectively in a table, any compound or a pharmaceutically acceptable salt thereof can be selected from the table and used in the embodiments provided herein.

[0189] In some embodiments, pharmaceutical compositions comprising any compound described herein or a pharmaceutically acceptable salt thereof are provided.

[0190] The compounds described herein can be prepared according to the methods described herein and in the examples. The methods described herein can be adapted based on the compounds described herein as desired. In some embodiments, the methods can be used to prepare one or more compounds described herein, and it will be obvious to those skilled in the art which compounds can be prepared according to the methods described herein.

[0191] The conditions and temperature can be varied as shown in the examples described herein. These schemes are non-limiting synthesis schemes, and the synthesis routes can be modified, as will be apparent to those skilled in the art who have read this specification. Compounds can also be prepared according to the schemes described in the examples.

[0192] The compounds can be used to modulate the S1P1 receptor. Therefore, in some embodiments, the compounds may be referred to as S1P1 receptor modulating compounds.

[0193] The compounds in the above table and examples section may be shown with a specific stereochemistry (e.g., cis or trans) around a particular atom, but the compounds can also be prepared in the opposite direction or as racemic mixtures.

[0194] In some embodiments, this embodiment provides a pharmaceutical composition comprising any compound described herein or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the compounds are prepared according to the schemes described in the examples. These schemes can be used to prepare the compounds and compositions described herein. The synthesis may be carried out according to the examples described herein, with variations in conditions and temperature, or with modifications that are readily apparent based on the compound being synthesized.

[0196] The conditions and temperatures can be varied as shown in the examples described herein. These schemes are non-limiting synthesis schemes, and the synthesis routes can be modified, as will be apparent to those skilled in the art who have read this specification.

[0197] This disclosure also provides the following non-limiting embodiments.

[0198] Examples are provided below to help you better understand the embodiments disclosed herein. Please understand that these examples are illustrative only and should not be construed as limiting the embodiments in any way.

[0199] The following examples are illustrative of, but not limiting, the methods described herein. Other suitable modifications and adaptations to various conditions and parameters commonly encountered in the treatments, synthesis, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

[0200] The following embodiments are provided.

[0201] 1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The compound of formula (II) under suitable conditions [ka] When brought into contact with the compound of formula (III), [ka] This includes generating a compound having the above formula (I), During the ceremony, A, B, and E are each independently N or CR6. X and Y are independently O, S, or NR7. R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. The method wherein R2, R3, R4, R5, R6, and R7 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0202] 2. The above method, [ka] The compound of formula (II) above [ka] By coupling it with the compound of formula (III), [ka] The method according to Embodiment 1, further comprising generating the compound of formula (I).

[0203] 3. The method according to Embodiment 2, wherein the coupling comprises contacting the compounds of formula (II) and formula (III) with a coupling reagent and optionally an additive in a solution containing the compounds of formula (II) and formula (III).

[0204] 4. The method according to Embodiment 2 or 3, wherein the coupling comprises reacting the compounds of formula (II) and formula (III) for at least about 5 minutes.

[0205] 5. The method according to Embodiment 4, wherein the reaction comprises heating the reactants to a temperature of at least about 40°C for at least about 1, 2, 3, 4, or 5 minutes.

[0206] 6. Quench the reaction mixture, [ka] The method according to Embodiment 5, further comprising forming a slurry containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0207] 7. The method according to Embodiment 6, wherein the quench includes cooling the reactants and / or adding water to the reactants in order to quench the reactants and form a slurry.

[0208] 8. [ka] The method according to Embodiment 6 or 7, further comprising isolating a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0209] 9. [ka] The isolation of the compound of formula (I) or a pharmaceutically acceptable salt thereof is performed by filtering, washing, and / or drying the slurry. [ka] The method according to Embodiment 8, comprising obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0210] 10. The slurry is filtered, [ka] The method according to Embodiment 9, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is obtained.

[0211] 11. [ka] The method according to Embodiment 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is washed with water and / or an organic solvent.

[0212] 12. The slurry or [ka] The method according to Embodiments 9, 10, or 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is dried.

[0213] 13. The above method involves the following steps: (a) Coupling reagent and optionally additive in the first organic solvent [ka] Add the compound of formula (II) to the solution to form a mixture, and stir the mixture for at least about 5 minutes. (b) The mixture from step (a) [ka] Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of at least about 40°C and stir the mixture at the said temperature, (d) Cool the mixture from step (c), add water to the mixture to form a slurry, (e) Stirring the slurry from step (d), (f) Filtering the slurry from step (e) to obtain a solid, (g) Wash the solid from step (f) with water and / or a second organic solvent, (h) Dry the solid from step (g) under vacuum at a temperature of at least about 30°C. [ka] The method according to Embodiment 1, comprising forming a compound of formula (I), wherein the variables are as defined in Embodiment 1.

[0214] 14. The method according to Embodiment 13, wherein the coupling reagent is carbodiimide.

[0215] 15. The method according to Embodiment 14, wherein the carbodiimide is DCC, DIC, or EDC hydrochloride.

[0216] 16. The method according to Embodiment 13, wherein the coupling reagent is EDC hydrochloride.

[0217] 17. The method according to any one of Embodiments 13 to 16, wherein the additive is HOBt, HOAt, or ethyl cyanohydroxyiminoacetate.

[0218] 18. The method according to any one of Embodiments 13 to 16, wherein the additive is ethyl cyanohydroxyiminoacetate.

[0219] 19. The method according to any one of embodiments 13 to 18, wherein the first organic solvent is a polar organic solvent.

[0220] 20. The method according to Embodiment 19, wherein the polar organic solvent is a polar aprotic organic solvent.

[0221] 21. The method according to Embodiment 20, wherein the polar aprotic organic solvent is dimethylformamide or diethylformamide.

[0222] 22. The method according to Embodiment 20, wherein the polar aprotic solvent is dimethylformamide.

[0223] 23. The method according to any one of Embodiments 13 to 22, wherein the amount of the coupling reagent is at least about 1.0 equivalent in molar ratio to the amount of the compound of formula (II).

[0224] 24. The method according to any one of Embodiments 13 to 22, wherein the amount of the coupling reagent is approximately 1.2 equivalents in molar ratio to the amount of the compound of formula (II).

[0225] 25. The method according to any one of Embodiments 13 to 24, wherein the amount of the additive is at least about 1.0 equivalent in molar ratio to the amount of the compound of formula (II).

[0226] 26. The method according to any one of Embodiments 13 to 24, wherein the amount of the additive is about 1.0 equivalent in molar ratio to the amount of the compound of formula (II).

[0227] 27. The method according to any one of Embodiments 13 to 26, wherein the concentration of the compound of formula (II) in the first organic solvent is at least about 0.1 mol / L.

[0228] 28. The method according to any one of Embodiments 13 to 26, wherein the concentration of the compound of formula (II) in the first organic solvent is about 0.8 mol / L.

[0229] 29. The method according to any one of embodiments 13 to 28, wherein in step (a), the mixture is stirred for at least about 5 minutes.

[0230] 30. The method according to any one of Embodiments 13 to 28, wherein in step (a), the mixture is stirred for about 1 hour.

[0231] 31. The method according to any one of Embodiments 13 to 30, wherein the amount of the compound of formula (III) is at least about 1.0 equivalent in molar ratio to the amount of the compound of formula (II).

[0232] 32. The method according to any one of Embodiments 13 to 30, wherein the amount of the compound of formula (III) is approximately 1.2 equivalents in molar ratio to the amount of the compound of formula (II).

[0233] 33. The method according to any one of embodiments 13 to 32, wherein in step (b), the mixture is stirred for at least 5 minutes.

[0234] 34. The method according to any one of embodiments 13 to 32, wherein in step (b), the mixture is stirred for at least about 1 hour.

[0235] 35. The method according to any one of embodiments 13 to 34, wherein in step (c), the temperature is at least about 60°C.

[0236] 36. The method according to any one of embodiments 13 to 34, wherein in step (c), the temperature is at least about 75°C.

[0237] 37. The method according to any one of embodiments 13 to 34, wherein in step (c), the temperature is approximately 95°C.

[0238] 38. The method according to any one of embodiments 13 to 37, wherein in step (c), the mixture is stirred at the temperature for at least about 1, 2, 3, 4, or 5 minutes.

[0239] 39. The method according to any one of embodiments 13 to 37, wherein in step (c), the mixture is stirred at the temperature for at least about 1 hour.

[0240] 40. The method according to any one of embodiments 13 to 37, wherein in step (c), the mixture is stirred at the temperature for about 5 hours.

[0241] 41. The method according to any one of embodiments 13 to 37, wherein in step (c), the mixture is stirred at the temperature for about 18 hours.

[0242] 42. The method according to any one of Embodiments 13 to 41, wherein in step (d), the mixture is cooled to about 5 to 25°C.

[0243] 43. The method according to any one of embodiments 13 to 41, wherein in step (d), the mixture is cooled to about 15 to 20°C.

[0244] 44. The method according to any one of Embodiments 13 to 43, wherein in step (d), the volume ratio of water to the first organic solvent is at least about 1.

[0245] 45. The method according to any one of Embodiments 13 to 43, wherein in step (d), the volume ratio of water to the first organic solvent is about 2.

[0246] 46. ​​The method according to any one of Embodiments 13 to 45, wherein in step (e), the mixture is stirred at approximately 5 to 25°C.

[0247] 47. The method according to any one of Embodiments 13 to 45, wherein in step (e), the mixture is stirred at approximately 15 to 20°C.

[0248] 48. The method according to any one of embodiments 13 to 47, wherein in step (e), the slurry is stirred for at least about 5 minutes.

[0249] 49. The method according to any one of embodiments 13 to 47, wherein in step (e), the slurry is stirred for about 1 hour.

[0250] 50. The method according to any one of Embodiments 13 to 49, wherein in step (g), the volume ratio of water to the first organic solvent in each washing cycle is at least about 0.5.

[0251] 51. The method according to any one of Embodiments 13 to 49, wherein in step (g), the volume ratio of water to the first organic solvent in each washing cycle is about 0.5.

[0252] 52. The method according to any one of embodiments 13 to 51, wherein the solid is washed at least once with water.

[0253] 53. The method according to any one of embodiments 13 to 51, wherein the solid is washed twice with water.

[0254] 54. The method according to any one of embodiments 13 to 53, wherein the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is at least about 0.5.

[0255] 55. The method according to any one of Embodiments 13 to 53, wherein the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is about 0.5.

[0256] 56. The method according to any one of embodiments 13 to 55, wherein the solid is washed at least once with the second organic solvent.

[0257] 57. The method according to any one of embodiments 13 to 55, wherein the solid is washed twice with the second organic solvent.

[0258] 58. The method according to any one of embodiments 13 to 57, wherein the second organic solvent is an ether.

[0259] 59. The method according to embodiment 58, wherein the ether is a dialkyl ether.

[0260] 60. The method according to Embodiment 58, wherein the ether is methyl-tert-butyl ether.

[0261] 61. The method according to any one of embodiments 13 to 60, wherein the solid is dried at approximately 55°C.

[0262] 62. The above method includes the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide [ka] Adding the compound of formula (II) to the solution to form a mixture, and stirring the mixture for at least about 1 hour, (b) The mixture from step (a) [ka] Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of about 95°C and stir the mixture at that temperature for at least about 5 hours. (d) Cool the mixture from step (c) to about 15-20°C, add water to form a slurry, (e) Stirring the slurry from step (d) at approximately 15-20°C for approximately 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl tert-butyl ether, (h) The solid from step (g) is dried under vacuum at approximately 55°C. [ka] The method according to Embodiment 1, comprising forming a compound of formula (I), wherein the variables are as defined in Embodiment 1.

[0263] 63. The method according to any one of embodiments 13 to 62, further comprising recrystallizing the solid of step (h) from the solvent.

[0264] 64. The method according to Embodiment 63, wherein the solvent is water, dimethylformamide, ethanol, or methyl tert-butyl ether.

[0265] 65. The method according to Embodiment 63, wherein the solvent is ethanol.

[0266] 66. The method according to Embodiment 63, wherein the mixture forms a slurry when the solvent is ethanol or methyl tert-butyl ether.

[0267] 67. The method according to Embodiment 66, wherein the solvent is ethanol, and the slurry is heated to a temperature of at least about 50°C.

[0268] 68. The method according to Embodiment 66, wherein the solvent is ethanol and the slurry is heated to a temperature of about 75°C.

[0269] 69. The method according to Embodiment 68, wherein the slurry is stirred at approximately 75°C for approximately 15 hours.

[0270] 70. The method according to Embodiment 66, wherein the solvent is methyl-tert-butyl ether, and the slurry is heated to a temperature of at least about 30°C.

[0271] 71. The method according to Embodiment 66, wherein the solvent is methyl-tert-butyl ether and the slurry is heated to a temperature of about 45°C.

[0272] 72. The method according to Embodiment 71, wherein the slurry is stirred at approximately 45°C for approximately 15 hours.

[0273] 73. The method according to any one of embodiments 63 to 72, wherein the purity of the recrystallized solid is at least about 95%.

[0274] 74. The method according to any one of embodiments 63 to 72, wherein the purity of the recrystallized solid is at least about 99%.

[0275] 75. The method according to any one of embodiments 63 to 72, wherein the purity of the recrystallized solid is approximately 99.5%.

[0276] 76. The method according to any one of embodiments 63 to 75, wherein the color of the recrystallized solid is white to off-white.

[0277] 77. The method according to any one of Embodiments 1 to 76, wherein X is O.

[0278] 78. The method according to any one of Embodiments 1 to 77, wherein Y is O.

[0279] 79. The compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] Equation (VI), [ka] Formula (VII), [ka] Formula (VIII), or [ka] The method according to any one of Embodiments 1 to 78, having the formula (IX), wherein the variables are as defined in Embodiment 1.

[0280] 80. The compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The method according to any one of Embodiments 1 to 78, having the formula (VI), wherein the variables are as defined in Embodiment 1.

[0281] 81. The method according to any one of Embodiments 1 to 80, wherein R4 and R5 are each independently H or a C1-C6 alkyl group substituted with an optional component.

[0282] 82. The method according to any one of Embodiments 1 to 80, wherein either R4 or R5 is H.

[0283] 83. The compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The method according to any one of Embodiments 1 to 80, having the formula (X), wherein the variables in the formula are as defined in Embodiment 1.

[0284] 84. The compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The method according to Embodiment 83, wherein the formula is (XI), and the variables are as defined in Embodiment 1.

[0285] 85. The method according to any one of Embodiments 1 to 84, wherein R2 and R3 are each independently H or a C1-C6 alkyl group substituted with an optional component.

[0286] 86. The method according to any one of Embodiments 1 to 84, wherein both R2 and R3 are optionally substituted C1-C6 alkyl groups.

[0287] 87. The method according to any one of Embodiments 1 to 84, wherein both R2 and R3 are methyl or ethyl.

[0288] 88. The method according to any one of Embodiments 1 to 84, wherein either R2 or R3 is H.

[0289] 89. The method according to any one of Embodiments 1 to 84, wherein R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteralkyl.

[0290] 90. The method according to any one of Embodiments 1 to 84, wherein R2 and R3 are both optionally substituted 5-membered, 6-membered, or 7-membered cycloalkyl or cycloheteroalkyl groups.

[0291] 91. The compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The method according to any one of Embodiments 1 to 84, having the structure of formula (XII) and where R1 is as defined in Embodiment 1.

[0292] 92. The method according to any one of Embodiments 1 to 91, wherein R1 is an optionally substituted C1-C6 alkyl group, an optionally substituted carbon ring, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

[0293] 93. The method according to any one of Embodiments 1 to 91, wherein R1 is an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0294] The method according to any one of Embodiments 1 to 91, wherein 94.R1 is an optionally substituted heteroaryl group.

[0295] The method according to any one of Embodiments 1 to 91, wherein 95.R1 is an optionally substituted nitrogen-containing heteroaryl group.

[0296] 96.R1 is, [ka] The method according to any one of embodiments 1 to 91.

[0297] 97.R1 [ka] The method according to any one of embodiments 1 to 91.

[0298] 98. The compound of formula (I) above [ka] The method according to Embodiment 1.

[0299] 99. The above method, formula [ka] The compound of formula under suitable conditions [ka] When the compound is brought into contact with the compound having the following structure, [ka] The method according to Embodiment 1, comprising forming a pharmaceutically acceptable salt thereof.

[0300] 100. The above method involves the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide [ka] Add to the solution to form a mixture, and stir the mixture for at least about 1 hour. (b) The mixture from step (a) [ka] Stir with the compound of formula (III) for about 1 hour, (c) Heat the mixture from step (b) to a temperature of about 95°C and stir the mixture at that temperature for at least about 5 hours. (d) Cool the mixture from step (c) to about 15-20°C, add water to the mixture to form a slurry, (e) Stirring the slurry from step (d) at approximately 15-20°C for approximately 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl tert-butyl ether, (h) Dry the solid from step (g) under vacuum at at least about 55°C. [ka] The method according to Embodiment 99, which includes forming a

[0301] 101. [ka] By bringing equation (V) into contact with R2R3C=O under suitable conditions, [ka] The method further includes a method for preparing the compound of formula (II), wherein, A, B, and E are each independently N or CR6. X and Y are independently O, S, or NR7. The method according to any one of Embodiments 1 to 100, wherein R4, R5, R6, and R7 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0302] 102. The above method includes the following steps: (a) In the compound R2R3C=O [ka] Adding pyrrolidine to a solution of the compound of formula (V) to form a mixture, (b) Heat the mixture from step (a) under reflux, stir the mixture at the temperature for about 19.5 hours, cool the mixture to about 15-20°C, and add water to the mixture. (c) Adjust the pH of the mixture from step (b) to approximately 2 with HCl, (d) The mixture from step (c) is stirred with n-heptane to form a slurry, the slurry is stirred at approximately 15-20°C for approximately 1 hour, and the slurry is filtered to form a solid. (e) Wash the solid from step (d) with water and n-heptane, (g) Dry the solid from step (e) under vacuum at approximately 50°C. [ka] The method according to Embodiment 101, comprising forming a compound of formula (II), wherein the variables are as defined in Embodiment 1.

[0303] 103. By contacting the compound of formula R1CN with ammonium hydroxide [ka] The method according to any one of Embodiments 1 to 102, further comprising a method for preparing a compound of formula (III), wherein R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. 104. The above method includes the following steps: (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture, (b) Heat the mixture from step (a) to a temperature of about 75°C, and stir the mixture at that temperature for about 4 hours to form a slurry. (c) Cool the slurry from step (b) to ambient temperature and stir it at the ambient temperature for about 16 hours. (d) Filtering the slurry from step (c) to form a solid, (e) Wash the solid from step (d) with alcohol, and dry the washed solid at approximately 50°C under vacuum. [ka] The method according to Embodiment 103, comprising forming a compound of formula (III).

[0304] 105. The method according to Embodiment 104, wherein the alcohol is an optionally substituted C1-C6 alkyl alcohol.

[0305] 106. The method according to Embodiment 104, wherein the alcohol is methanol, ethanol, propanol, or butanol.

[0306] 107. The method according to Embodiment 104, wherein the alcohol is ethanol.

[0307] 108. The method according to any one of Embodiments 104 to 107, wherein the hydroxylamine is a hydroxylamine hydrochloride salt.

[0308] 109. The method according to Embodiment 108, wherein an organic base is added.

[0309] 110. The method according to Embodiment 109, wherein the organic base is diisopropylethylamine.

[0310] 111. The method according to Embodiment 108 or 109, wherein the amount of the organic base is at least about 1.5 equivalents in molar ratio to the amount of hydroxylamine hydrochloride.

[0311] 112. The method according to any one of Embodiments 104 to 111, wherein in step (a), the amount of hydroxylamine is at least about 1.5 equivalents in molar ratio to the amount of R1CN.

[0312] 113. [ka] When the compound of formula (II) comes into contact with a coupling reagent with or without an additive, [ka] The method according to any one of Embodiments 1 to 76, wherein an intermediate having the formula (XIII) is formed, in which R2, R3, R4, and R5 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, and R8 is optionally substituted C1-C6 alkyl.

[0313] 114. The intermediate product is [ka] The method according to Embodiment 113, wherein the compound has the structure of formula (XIV).

[0314] 115. The intermediate product is [ka] Equation (XIV-I), [ka] Formula (XIV-II), [ka] Formula (XIV-III), or [ka] The method according to Embodiment 114, wherein the compound has the structure of formula (XIV-IV).

[0315] 116. The intermediate product is [ka] The method according to Embodiment 114, wherein the compound has the structure of formula (XIV-I).

[0316] 117. The intermediate is [ka] The method according to Embodiment 114, wherein the compound has the structure of formula (XIV-V).

[0317] 118. The aforementioned intermediate is [ka] The method according to Embodiment 114, wherein the compound has the structure of formula (XIV-VI).

[0318] 119. The intermediate product is [ka] The method according to Embodiment 114, wherein the compound has the structure.

[0319] 120. [ka] An intermediate having the structure of formula (XIII) is [ka] Further contact with the compound of formula (III), [ka] The method according to Embodiment 113, which forms an intermediate having the structure of formula (XVI).

[0320] 121. The intermediate is [ka] The method according to Embodiment 120, wherein the compound has the structure.

[0321] 122. The aforementioned intermediate is [ka] The method according to Embodiment 120, wherein the compound has the structure of formula (XVII).

[0322] 123. The aforementioned intermediate is [ka] The method according to Embodiment 120, wherein the compound has the structure of formula (XVII-I).

[0323] 124. The intermediate product is [ka] The method according to Embodiment 120, wherein the compound has the structure of formula (XVII-II).

[0324] 125. The intermediate product is [ka] The method according to Embodiment 120, wherein the compound has the structure.

[0325] 126. [ka] An intermediate having the structure of formula (XVI) is subjected to thermal dehydration cyclization conditions. [ka] The method according to Embodiment 120, further forming the compound of formula (I).

[0326] 127. [ka] The compound of formula (I) [ka] The method according to Embodiment 120.

[0327] 128. Compounds having the following structure: [ka] Formula (XIII), or a pharmaceutically acceptable salt thereof, In the formula, X is O, S, or NR7, and R2, R3, R4, R5, and R7 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, and R8 is optionally substituted C1-C6 alkyl, the compound or a pharmaceutically acceptable salt thereof.

[0328] 129. The above compound has the following structure: [ka] Having formula (XIV), The compound according to Embodiment 128, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, and R5 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, and R8 is optionally substituted C1-C6 alkyl.

[0329] 130. The above compound has the following structure: [ka] Equation (XIV-I), [ka] Formula (XIV-II), [ka] Formula (XIV-III), or [ka] The formula (XIV-IV) is given by, The compound according to Embodiment 129, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, and R6 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0330] 131. The above compound has the following structure: [ka] Having formula (XIV-VI), The compound according to Embodiment 129, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0331] 132. The above compound has the following structure: [ka] A compound according to Embodiment 129, or a pharmaceutically acceptable salt thereof, having the above.

[0332] 133. The compound according to any one of Embodiments 128 to 132, wherein the compound is isolated by any one of Embodiments 1 to 76.

[0333] 134. Compounds having the following structure: [ka] Formula (XVI), or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. The compound, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, and R5 are each independently H, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 hydroxyalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted cycloalkyl group, or an optionally substituted cycloheteroalkyl group, and R2 and R3 are both optionally substituted cycloalkyl groups or optionally substituted cycloheteroalkyl groups, or R4 and R5 are both optionally substituted cycloalkyl groups or optionally substituted cycloheteroalkyl groups.

[0334] 135. The above compound has the following structure: [ka] Formula (XVII), [ka] Formula (XVIII), [ka] Formula (XIX), or [ka] Having formula (XX), During the ceremony, R1 is H, OH, NH2, NO2, optionally substituted carbocyclic, optionally substituted aryl group, optionally substituted heteroaryl group, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl. The compound according to Embodiment 134, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, and R6 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, and R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R4 and R5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0335] 136. The above compound has the following structure: [ka] Equation (XVII-I) or [ka] Having formula (XVII-II), The compound according to Embodiment 134, or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R6 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, or R2 and R3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.

[0336] 137. The above compound has the following structure: [ka] A compound according to Embodiment 134, or a pharmaceutically acceptable salt thereof, having the above.

[0337] 138. The compound according to any one of Embodiments 134 to 137, wherein the compound is isolated by any one of Embodiments 1 to 76.

[0338] 139. A composition comprising the compound described in any one of Embodiments 128 to 138.

[0339] 140. A solution comprising the compound described in any one of Embodiments 128 to 138.

[0340] 141. A method for forming a compound of formula I, [ka] The compound having the structure of formula (XVI) is reacted under thermal dehydration cyclization conditions, [ka] The method comprising forming a compound of formula I.

[0341] 142. [ka] A crystalline form of a compound having the formula, wherein the form is form I of the compound.

[0342] Crystal morphology I according to Embodiment 142, characterized by an X-ray powder diffraction pattern including peaks at approximately 8.9±0.5°²θ, 9.4±0.5°²θ, 15.7±0.5°²θ, 17.7±0.5°²θ, 18.9±0.5°²θ, 24.3±0.5°²θ, 26.0±0.5°²θ, and 26.7±0.5°²θ.

[0343] 144. Crystal morphology I according to Embodiment 142, characterized by an X-ray powder diffraction pattern including one or more peaks shown in Figure 6.

[0344] 145. Crystal morphology I according to Embodiment 143, characterized by an X-ray powder diffraction pattern containing one or more peaks shown in Table 14.

[0345] Crystal morphology I according to Embodiment 142, characterized by an X-ray powder diffraction pattern including one or more interplanar spacing values ​​at approximately 10.0 ± 0.5 degrees angstroms, approximately 9.4 ± 0.5 degrees angstroms, approximately 5.6 ± 0.5 degrees angstroms, approximately 5.0 ± 0.5 degrees angstroms, approximately 4.7 ± 0.5 degrees angstroms, approximately 3.7 ± 0.5 degrees angstroms, approximately 3.4 ± 0.5 degrees angstroms, and approximately 3.3 ± 0.5 degrees angstroms. [Examples]

[0346] Example 1: Method for preparing the compound of formula (I) This specification provides both general and specific synthesis schemes. The compounds disclosed herein can be prepared according to the methods described herein, or intermediates leading to the compounds disclosed herein can be prepared according to the methods described herein. Substituents can be varied depending on the compounds or intermediates prepared based on the following examples and other modifications known to those skilled in the art.

[0347] The compounds of the following examples were prepared using the methods disclosed herein, or the examples were modified according to those skilled in the art to prepare the compounds.

[0348] General procedure A: Scheme 1 [ka]

[0349] Synthesis of Compound 2-2: N-hydroxy-1H-pyrazole-4-carboxyimidoamide 2-2 Scheme 2 [ka]

[0350] Synthesis of compound 2-2: N-hydroxy-1H-pyrazole-4-carboxyimidoamide. Based on the results shown in Table 1, it was found that EtOH is a preferred solvent for the synthesis of N-hydroxy-1H-pyrazole-4-carboxyimidoamide (compound 2-2). [Table 1]

[0351] Next, the volume of ethanol (EtOH) was used to isolate N-hydroxy-1H-pyrazole-4-carboximidoamide (compound 2-2) (Table 2). First, the volume of EtOH was reduced to 25 volumes (25 vol) of compound 2-1 in scheme 2. By carrying out the reaction in a smaller volume of solvent, it was observed that the product precipitated from the reaction mixture upon completion of the reaction. The desired product was isolated as a white solid using direct filtration (purity 99.9%, yield 84.9%). Next, different volumes of EtOH were tested. In compound 2-1 in scheme 2, the yields were similar for 5, 10, and 20 volumes of EtOH. However, a decrease in yield was observed for 15 volumes of EtOH. The purity of the product was consistent. This suggests that the quality of the product was independent of the solvent load. To investigate the effect of yield on a larger scale, the reaction with compound 2-1 was performed on a 25g scale using EtOH in 5, 10, and 25 volumes of compound 2-1 (Table 3). It was observed that the yield increased as the volume of EtOH decreased. The volume of EtOH that yielded the highest yield in the synthesis of N-hydroxy-1H-pyrazole-4-carboxyimidoamide (compound 2-2) was found to be 5 volumes (5 vol) of compound 2-1. This result was unexpected. [Table 2] [Table 3]

[0352] Experiment on the synthesis of compound 2-2: N-hydroxy-1H-pyrazole-4-carboxyimidoamide A stirred solution of 4-cyanopyrazole (2-1, 25 g) in ethanol (125 mL) was treated with hydroxylamine hydrochloride (28 g) and N,N-diisopropylethylamine (DIPEA) (93.8 mL). The reaction mixture was heated to 75 °C and stirred for 4 h. During the 4 h stirring period, the reaction mixture became a white slurry. The slurry was cooled to ambient temperature and stirred for 16 h. The slurry was filtered to afford a solid, which was washed with EtOH (50 mL×2). The recovered solid was dried under vacuum at 50 °C to afford N-hydroxy-1H-pyrazole-4-carboximidamide (Compound 2-2) as a white solid (22.8 g, 67.3% yield). UPLC-qDa (C4H6N4O) Calcd 127.05 [M + H] + , found 127.03. 1 H NMR (500 MHz, DMSO-d6) δ ppm 5.63 (s, 2H), 7.67 (bs, 1H), 7.96 (bs, 1H), 9.11 (s, 1H), 12.87 (bs, 1H).

[0353] General procedure B: Scheme 3

Chem.

[0354] Compound 4-2: Synthesis of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid Scheme 4

Chem.

[0355] Compound 4-2: Synthesis of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid The synthesis route of Scheme 4 involved the reaction of 3-acetyl-4-hydroxybenzoic acid compound 4-1 with 3-pentanone in the presence of pyrrolidine to obtain 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 2-2). Screening of the reaction solvent was initiated by carrying out the reaction in toluene (Table 4). The first experimental run followed the procedure outlined in Patent WO2000 / 03681, adding pyrrolidine (0.5 equivalents) and 3-pentanone (1.0 equivalent) to 15 volumes (15 vol) of compound 4-1 in hot toluene, followed by the addition of 3-acetyl-4-hydroxybenzoic acid (compound 4-1). The reaction mixture was stirred at 80°C for 24 hours, resulting in a low conversion rate of 3.0%. Next, the order of addition was changed, and pyrrolidine and 3-pentanone were added to 3-acetyl-4-hydroxybenzoic acid (compound 4-1) in toluene. To further complete the reaction, the equivalent amounts of pyrrolidine and 3-pentanone were increased. The reaction in toluene was slow and did not show a high conversion rate to the desired product. Since the reaction kinetics were slow in nonpolar solvents such as toluene, polar solvents were screened. The reaction carried out in EtOH showed a conversion rate of 80.6% after 48 hours. Next, acetic acid was incorporated as an additive to enhance the progress of the reaction by assisting the mechanistically occurring proton transfer. The addition of acetic acid did not show a significant increase in the conversion rate. The reaction in isopropanol (IPA) showed similar results to the reaction in EtOH. 1-propanol was included because it has a higher boiling point and allows the reaction to be carried out at higher temperatures. The reaction in 1-propanol showed almost the same conversion rate as the reactions carried out in EtOH and IPA, except for the shorter reaction time. 3-pentanone was incorporated as a solvent that played both the role of solvent and reagent in the reaction. The reaction of compound 4-1 in 10 volumes (10 vol) of 3-pentanone showed the highest conversion rate and shortest reaction time at 95°C. [Table 4]

[0356] Encouraged by the results showing that 3-pentanone acted as both a solvent and a reagent, we investigated the optimal volume of 3-pentanone (Table 5). When the reaction was carried out with 2.5 volumes (2.5 vol) of compound 4-1, a conversion rate of 71.9% was observed after 16 hours. Adding an additional 1.25 vol of 3-pentanone to the reactants increased the conversion rate to 90.6% after 21 hours. When the reaction was carried out with 5 vol of 3-pentanone, a conversion rate of 73.2% was observed after 16 hours. Adding another 1.25 vol of 3-pentanone to the reactants increased the conversion rate to 92.6% after 21 hours. Based on the results obtained in Run 2, when the reaction was carried out with 6.25 vol of 3-pentanone, a conversion rate of 100% was observed after 19 hours. During the reaction, it was found that using an excess of 6.25 vol of 3-pentanone initially resulted in a faster reaction rate leading to completion. The volume of 3-pentanone that yielded the highest yield as a solvent was found to be 6.25 volumes of compound 4-1. [Table 5]

[0357] Crystallization conditions were developed for the isolation of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid, compound 4-2 (Table 6). The initial isolation of the product involved acid-base extraction, yielding compound 4-2 as a yellow solid. The reaction mixture was diluted with ethyl acetate (siRNA), and the pH was adjusted to 2 using 0.5 M HCl. Phase separation was performed, and the pH of the organic layer was adjusted to 5 with 5 M NaOH. The organic layer was concentrated under pressure to obtain the desired product as a crystalline yellow solid. Next, direct crystallization from the reaction mixture was tested. Crystallization was found to occur by first adding H2O, and then adjusting the pH of the reaction mixture to 2 using 5 M hydrochloric acid to form a slurry. The slurry was filtered to obtain compound 4 as a yellow solid in 59.8% yield. Various solvents were screened to improve the yield. When acetone and IPA were used as poor solvents, the solid was not isolated. After pH adjustment, adding n-heptane at 20°C resulted in a slight increase in yield. Next, when n-heptane was added to the slurry at 10-15°C, the yield increased to 77.4%. These conditions were found to enhance the crystallization of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2). [Table 6]

[0358] Experiment on the synthesis of compound 4-2: 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid To a stirred solution of 3-acetyl-4-hydroxybenzoic acid (compound 4-1, 20 g) in 3-pentanone (125 mL), pyrrolidine (18.5 mL) was added. The reaction mixture was heated to 95 °C and stirred for 19.5 hours. The reaction mixture was cooled to 15-20 °C, and H₂O (60 mL) was added to form a slurry. The pH of the slurry was adjusted to 2 by adding 5M aqueous HCl (55 mL). n-heptane (60 mL) was added, and the slurry was stirred at 15-20 °C for approximately 1 hour. The slurry was filtered, and the solid was washed with water (20 mL x 2) and n-heptane (20 mL x 2). The collected solid was dried under vacuum at 50°C to obtain 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid, compound 4-2, as a yellow solid (17.8 g, yield 64.5%). UPLC-qDa (C 14 H 16 O4) Calculated value: 249.11 [M + H] + , measured value 249.19. 1 H NMR (500 MHz, CDCl3) δ ppm 0.95 - 0.98 (t, J =7.44Hz,6H),1.74- 1.87 (m, 4H), 2.79 (s, 2H), 7.03 -7.05 (d, J =8.78Hz,1H),8.19- 8.21 (dd, J =8.78,2.20Hz,1H),8.65(d,J = 2.2 Hz, 1H).

[0359] Figure 4 shows the results of polarized light microscopy (PLM) analysis (10 μm scale) of 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1). Those skilled in the art will understand that these results were produced by conventional polarized light microscopy, which is known and understood by those skilled in the art.

[0360] Figure 5 shows the differential thermal analysis (DSC) results of 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1). Those skilled in the art will understand that these results were produced by conventional polarized light microscopy, which is known and understood by those skilled in the art.

[0361] Figure 6 and the table show the results of X-ray powder diffraction (XRPD) of 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1). Those skilled in the art will understand that these results were produced by conventional polarized light microscopy, which is known and understood by those skilled in the art. [Table 7-1] [Table 7-2] [Table 7-3]

[0362] General procedure C: Scheme 5 [ka]

[0363] Example 2: Synthesis of Compound 6-1: 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one Scheme 6 [ka]

[0364] Synthesis of compound 6-1:6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one 2-methyltetrahydrofuran (MeTHF) was screened as a promising solvent for the synthesis of compound 6-1 (Table 7). Since purging of DMF can be difficult due to its slow evaporation rate, alternative solvents were tested. The reaction was carried out at 75°C in MeTHF (10 vol) with 10 volumes of compound 4-2. During the reaction, the reaction mixture became very viscous, making product isolation difficult. This reaction yielded compound 4-2 in 21.9% yield. For comparison, the reaction was carried out in parallel at 95°C in DMF (10 vol) with 10 volumes of compound 4-2. Compound 6-1 was isolated via crystallization in 64.3% yield. DMF was found to be a suitable solvent for the synthesis of compound 6-1. [Table 8]

[0365] The volume of DMF was screened to determine the concentrations for the reaction and crystallization (Table 8). When the reaction was carried out with 15 volumes of compound 4-2 in DMF (15 vol), the yield was low, which is thought to be due to the solubility of the product in DMF. When the reaction was carried out with 2.5 volumes of compound 4-2 in DMF (2.5 vol), the mixture was found to be very viscous, making product isolation difficult. Although the yield was good in this reaction, the purity of compound 6-1 was found to be low. When the reaction was carried out with 5 and 10 volumes of compound 4-2 in DMF (5 vol and 10 vol), the yields were nearly identical, showing promising results. It was found that the volume of DMF in one embodiment of the reaction was 5 volumes of compound 4-2. [Table 9]

[0366] The initial isolation technique for compound 6-1 involved column chromatography. Isolation of the desired compound 6-1 by column chromatography resulted in a low yield of 34.6%. Crystallization conditions were screened to eliminate chromatography (Table 9). Direct crystallization from the reaction mixture was considered for the isolation of compound 6-1. Crystallization of the desired compound 6-1 was initiated by adding water to the reaction mixture. Patent application publication WO2018 / 231745 reports the appearance of compound 6-1 as a white solid. However, the solid isolated from crystallization was yellowish-brown. Adding a poor solvent was considered to improve the appearance and yield. Adding 5M NaOH at 20°C after adding H2O slightly improved the appearance, but the yield remained low at 64.3%. Next, adding H2O and 5M NaOH at 5°C showed a slight increase in yield. After adding H2O, adding 5M HCl at 20°C slightly improved the appearance, but the yield was low at 63.5%. Incorporating MeOH as a poor solvent significantly reduced the yield. Adding water to the reaction mixture at 5°C resulted in almost the same yield as when added at 20°C. Increasing the volume of water was also investigated, but it was found that increasing the volume of water did not significantly increase the yield. Based on the yield and appearance, crystallization by adding H2O (10 vol) to 10 volumes of compound 4-2 at 20°C was found to be the best condition for isolating compound 6-1. [Table 10]

[0367] When compound 6-1 was crystallized, a yellowish-brown solid was obtained as crystals. Since the presence of oxyma in the product may be a contributing factor to the product's color, the oxyma load was screened (Table 10). Low oxyma loads significantly reduced the reaction's progress. Low oxyma loads did not improve the appearance of compound 6-1, and the yield decreased significantly. [Table 11]

[0368] Various color-improvement conditions were screened to improve the appearance of compound 6-1. The purity and potency (%w / w) of the active pharmaceutical ingredient were analyzed simultaneously. The potency was calculated based on input materials normalized to 100%. First, recrystallization of the yellowish-brown compound 6-1 was considered as a color-improvement method to improve the appearance of compound 6-1 (Table 11). Based on the fact that compound 6-1 dissolves in DMF and dimethyl sulfoxide (DMSO), these two solvents were selected. Compound 6-1 was dissolved in the described solvent at the desired temperature and stirred for 4 hours. Crystallization occurred when water was added at 15-20°C, and a solid was obtained by filtration. Recrystallization in DMSO at 20°C resulted in improved appearance, purity, and potency. Various temperatures for recrystallization in DMF were screened. Higher temperatures in DMF resulted in decreased potency and recovery rate of the final compound 6-1. [Table 12]

[0369] Next, charcoal treatment was used as an approach to improve the color tone (Table 12). DMF and DMSO were used as solvents depending on the solubility of compound 6-1. The charcoal treatment consisted of adding activated carbon (5 wt%) to a solution of yellowish-brown compound 6-1 in the solvent and stirring at 20°C for 5 hours. After filtering off the charcoal, crystallization occurred when water was added at 15-20°C, and a solid was obtained by filtration. As a result of charcoal treatment in DMF, both purity and potency improved, and the recovery rate was 63.4%. Compared to DMF, charcoal treatment in DMSO showed a slight decrease in purity and potency, but a high recovery rate of 70.4% was observed. [Table 13]

[0370] Another approach to improving the color involved reslurrying the yellowish-brown compound 6-1 in different solvents exhibiting low solubility. Various solvents for reslurrying were screened (Table 13). The reslurrying procedure involved stirring compound 6-1 in the desired solvent at the specified temperature for 15 hours. The final compound 6-1 was isolated by filtration. Solids isolated from reslurries in MeOH, SiO, and acetone showed visible color improvement. However, due to the low recovery rate of the reslurries in these solvents, purity and titer were not analyzed. Reslurrying in MTBE at 45°C yielded a white to off-white solid with a purity of 97.2%, a titer of 101.8%, and a recovery rate of 81.2%. Different solvent volumes and temperatures for reslurrying in EtOH were screened. Solids isolated from reslurrying in EtOH (10 vol) with 10 volumes of compound 6-1 at 45°C showed visible color improvement. However, due to the low recovery rate of the reslurry, purity and titer were not analyzed. The final compound 6-1 obtained from the reslurry in EtOH (10 vol) at 20°C yielded a purity of 98.7%, a potency of 101.7%, and a recovery rate of 75.7%. The final compound 6-1 obtained from the reslurry in EtOH (5 vol) at 75°C using 5 volumes of compound 6-1 yielded a purity of 99.8%, a potency of 105.6%, and a recovery rate of 66.0%.

[0371] Recrystallization in DMSO and DMF, as well as charcoal treatment, were not selected as color improvement procedures. These solvents yielded favorable improvements for compound 6-1. However, purging was difficult due to the high boiling points of each solvent. The reslurry of compound 6-1 in EtOH (5 vol) at 75°C showed the most promising results and was selected as the method for improving the color of the yellowish-brown compound 6-1. [Table 14]

[0372] Experiment on the synthesis of compound 6-1:6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one To a stirred solution of 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2, 70 g) in N,N-dimethylformamide (DMF, 350 mL), EDCI (64.9 g) and ethylcyanohydroiminoacetate (Oxyma, 40.1 g) were added. The reaction mixture was stirred at ambient temperature for 1 hour. N-hydroxy-1H-pyrazole-4-carboximidoamide (compound 2-2, 42.7 g) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was heated to 95°C and stirred for 5 hours. The reaction mixture was cooled to 15-20°C, and H2O (700 mL) was added to form a slurry. The slurry was stirred at 15-20°C for approximately 1 hour. The slurry was filtered to obtain a solid, which was washed with water (175 mL x 2) and methyl-t-butyl ether ("MTBE") (175 mL x 2). The collected solid was dried under vacuum at 55°C to obtain yellowish-brown compound 6-1 as a yellowish-brown solid (75.2 g).

[0373] The yellowish-brown compound 6-1 was stirred with EtOH (375 mL) to form a slurry, and the slurry was heated to 75°C. The slurry was held at 75°C for 16 hours. The slurry was cooled to 15-20°C and stirred for approximately 1 hour. The slurry was filtered, and the solid was washed with EtOH (100 mL x 3). The collected solid was dried under vacuum at 55°C to obtain 6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one (compound 6-1) as a white to off-white solid (63.2 g, yield 66.2%). UPLC-qDa (C 18 H 18 N4O3) Calculated value: 339.15 [M + H] + , measured value 339.14. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.88 - 0.91 (t, J =7.44Hz,6H),1.70- 1.81 (m, 4H), 2.92 (s, 2H), 7.26 - 7.28 (d, J =8.78Hz,1H),8.06(s,1H),8.25- 8.28 (dd, J =8.66,2.32Hz,1H),8.43-8.44(d,J = 2.20 Hz, 1H), 8.48 (s, 1H), 13.48 (bs, 1H).

[0374] Synthesis of the ester intermediate of compound 6-1:6-(3-(1H-pyrazole-4-yl)-1,2,4-oxadiazole-5-yl)-2,2-diethylchroman-4-one The one-pot process of Scheme 7 consisted of two different chemical bond formation transformations. First, 2,2-diethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2) was esterified by activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and ethylcyanohydroxyacetate (Oxyma) to obtain intermediate 7-1. Next, intermediate 7-2 was obtained by esterification of intermediate 7-1 in the presence of N-hydroxy-1H-pyrazole-4-carboxyimidoamide (compound 2-2). Compound 6-1 was obtained by thermal dehydration cyclization after esterification of compound 4-2 and compound 2-2. The two transient intermediates were isolated and characterized by conventional methods that would be known to those skilled in the art and used for in-process analysis.

[0375] Scheme 7 [ka]

[0376] Intermediate 7-1: Ethyl(Z)-2-cyano-2-(((2,2-diethyl-4-oxochroman-6-carbonyl)oxy)imino)acetate Oxyma ester intermediate 7-1 1 H-NMR: 1H NMR (500 MHz, CDCl3) δ ppm 0.95 - 0.98 (t, J = 7.44 Hz, 6H), 1.44 - 1.47 (t, J = 7.08 Hz, 3H), 1.74-1.88 (m, 4H), 2.80(s, 2H), 4.50 - 4.54(q, J = 7.16 Hz, 2H), 7.09 - 7.10(d, J = 8.78 Hz, 1H), 8.22 - 8.25(dd, J = 8.78, 2.22 Hz, 1H), 8.69- 8.70(d, J = 2.20 Hz, 1H).

[0377] Intermediate 7-2: N-((2,2-diethyl-4-oxochroman-6-carbonyl)oxy)-1H-pyrazole-4-carboxyimidoamide Oxyma ester intermediate 7-2 1 H-NMR: 1 H NMR (400 MHz, CDCl3) δ ppm 0.85 - 0.88 (t, J = 7.22 Hz, 6H), 1.61-1.78 (m, 4H), 2.67 (s, 2H), 5.93 (bs, 2H), 6.86 - 6.88 (d, J = 8.59 Hz, 1H), 7.85 (s, 2H), 8.05 - 8.08 (dd, J = 8.78, 1.95 Hz, 1H), 8.39 - 8.40 (d, J =1.95 Hz, 1H).

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the method is: 【Chemistry 1】 Compound of formula (II) under suitable conditions 【Chemistry 2】 When brought into contact with the compound of formula (III), 【Transformation 3】 The process includes generating the compound having formula (I), During the ceremony, A, B, and E are each independent of N or CR 6 And, X and Y are, independently, O, S, or NR 7 And, R 1 However, H, OH, NH 2 NO 2 , optionally substituted carbon rings, optionally substituted aryl groups, optionally substituted heteroaryl groups, branched or unbranched alkyl groups is a lower alcohol, halo, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, acrylsulfonyl, nitrite, or alkylsulfanyl, R 2 、R 3 、R 4 、R 5 、R 6 、and R 7 are each independently H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 1 ~C 6 hydroxyalkyl, optionally substituted C 1 ~C 6 alkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, R 2 and R 3 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R 4 and R 5 are both optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, The aforementioned method involves the following steps: (a) The coupling reagent and additive in the first organic solvent 【Chemistry 4】 Add the compound of formula (II) to the solution to form a mixture, and stir the mixture for at least 5 minutes. (b) The mixture from step (a) 【Transformation 5】 Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of at least 40°C and stir the mixture at the said temperature, (d) Cooling the mixture from step (c), adding water to the mixture to form a slurry, (e) Stirring the slurry from step (d), (f) Filtering the slurry from step (e) to obtain a solid, (g) Wash the solid from step (f) with water and / or a second organic solvent, (h) The solid from step (g) is dried under vacuum at a temperature of at least 30°C. 【Transformation 6】 This includes forming the compound of formula (I), The method wherein the additive is ethyl cyanohydroxyiminoacetate.

2. The method according to claim 1, wherein the coupling reagent is carbodiimide.

3. The method according to claim 1, wherein the coupling reagent is EDC hydrochloride.

4. The method according to any one of claims 1 to 3, wherein the first organic solvent is a polar organic solvent. 。

5. The method according to claim 4, wherein the polar organic solvent is dimethylformamide.

6. The method according to any one of claims 1 to 5, wherein in step (a), the mixture is stirred for at least 5 minutes.

7. The method according to any one of claims 1 to 6, wherein in step (b), the mixture is stirred for at least 5 minutes.

8. The method according to any one of claims 1 to 7, wherein in step (c), the temperature is 95°C.

9. The method according to any one of claims 1 to 8, wherein in step (c), the mixture is stirred at the temperature for at least 1, 2, 3, 4, or 5 minutes.

10. The method according to any one of claims 1 to 9, wherein the solid is washed at least once with the second organic solvent.

11. The method according to any one of claims 1 to 10, wherein the second organic solvent is an ether.

12. The method according to claim 11, wherein the ether is methyl tert-butyl ether.

13. The method according to any one of claims 1 to 12, wherein the solid is dried at 55°C.

14. The aforementioned method involves the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide 【Transformation 7】 Adding the compound of formula (II) to the solution to form a mixture, and stirring the mixture for at least one hour, (b) The mixture from step (a) 【Transformation 8】 Stirring with the compound of formula (III), (c) Heat the mixture from step (b) to a temperature of 95°C and stir the mixture at that temperature for at least 5 hours. (d) Cool the mixture from step (c) to 15-20°C and add water to form a slurry, (e) Stirring the slurry from step (d) at 15-20°C for 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl-tert-butyl ether, (h) The solid from step (g) is dried at 55°C under vacuum. 【Chemistry 9】 This includes forming a compound of formula (I), wherein A, B, E, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 The method according to claim 1, wherein the property is as defined in claim 1.

15. The method according to claim 14, further comprising recrystallizing the solid of step (h) from the solvent.

16. The method according to claim 15, wherein the solvent is water, dimethylformamide, ethanol, or methyl-tert-butyl ether.

17. The method according to claim 15, wherein when the solvent is ethanol or methyl-tert-butyl ether, the mixture from the recrystallization forms a slurry.

18. The method according to claim 17, wherein when the solvent is ethanol, the slurry is heated to a temperature of at least 50°C.

19. The method according to claim 17, wherein when the solvent is ethanol, the slurry is heated to a temperature of 75°C.

20. The method according to any one of claims 15 to 19, wherein the purity of the recrystallized solid is at least 95%.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 10】 Equation (VI), 【Chemistry 11】 Formula (VII), 【Chemistry 12】 Formula (VIII), 【Chemistry 13】 Formula (IX), 【Chemistry 14】 Formula (X), or 【Chemistry 15】 The formula has the equation (XI), where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The method according to any one of claims 1 to 20, wherein is as defined in claim 1.

22. R 2 and R 3 However, each is independently substituted with hydrogen or optionally substituted C 1 ~C 6 The method according to any one of claims 1 to 21, wherein the alkyl group is alkyl.

23. The compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 16】 It has the structure of formula (XII), R 1 The method according to any one of claims 1 to 21, wherein is as defined in claim 1.

24. R 1 However, C was replaced by an arbitrary choice. 1 ~C 6 It is an alkyl group, an optionally substituted carbon ring, an optionally substituted aryl group, or an optionally substituted heteroaryl group. The method described in any one of the requests 1 to 23.

25. R 1 but, 【Chemistry 17】 The method according to any one of claims 1 to 23.

26. The compound of formula (I) [Chemistry 18] The method according to any one of claims 1 to 25.

27. The method described above is formula 【Chemistry 19】 The compound of formula under suitable conditions 【Chemistry 20】 When the compound is brought into contact with the compound having the following structure, 【Chemistry 21】 The method according to claim 1, comprising forming a pharmaceutically acceptable salt thereof.

28. The aforementioned method involves the following steps: (a) EDC hydrochloride and ethylcyanohydroxyiminoacetate in dimethylformamide 【Chemistry 22】 Add to the solution to form a mixture, and stir the mixture for at least one hour. (b) The mixture from step (a) 【Chemistry 23】 Stirring with the compound of formula (III) for 1 hour, (c) Heat the mixture from step (b) to a temperature of 95°C and stir the mixture at that temperature for at least 5 hours. (d) Cool the mixture from step (c) to 15-20°C, add water to the mixture to form a slurry, (e) Stirring the slurry from step (d) at 15-20°C for 1 hour, (f) Filtering the slurry from step (e) to form a solid, (g) Wash the solid from step (f) with water and methyl-tert-butyl ether, (h) Dry the solid from step (g) under vacuum at at least 55°C. 【Chemistry 24】 The method according to claim 27, comprising forming 【Request Item 29】 【Chemistry 25】 Equation (V) under suitable conditions R 2 R 3 By bringing it into contact with C=O, 【Chemistry 26】 The method further includes a method for preparing a compound of formula (II), wherein A, B, E, X, Y, R 2 , R 3 , R 4 and R 5 The method according to any one of claims 1 to 28, wherein is as defined in claim 1.

30. The method described above is (a) R 2 R 3 C=O 【Chemistry 27】 Adding pyrrolidine to a solution of the compound of formula (V) to form a mixture, (b) Heat the mixture from step (a) under reflux, stir the mixture at the temperature for 19.5 hours, cool the mixture to 15-20°C, and add water to the mixture; (c) Adjust the pH of the mixture from step (b) to 2 with HCl. (d) The mixture from step (c) is stirred with n-heptane to form a slurry, the slurry is stirred at 15-20°C for 1 hour, and the slurry is filtered to form a solid. (e) Wash the solid from step (d) with water and n-heptane, (g) The solid from step (e) is dried at 50°C under vacuum. 【Chemistry 28】 This includes forming the compound of formula (II), wherein A, B, E, X, Y, R 2 , R 3 , R 4 and R 5 The method according to claim 29, wherein the property is as defined in claim 1.

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