Preparation method of compound and compound S1P1 modulator

Abstract

The present embodiments relate, in part, to methods and compositions that may be used, for example, for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 937,485, filed November 19, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The embodiments disclosed herein relate to compounds that can, for example, be used to modulate the activity of the S1P1 receptor, and methods for preparing the compounds or pharmaceutically acceptable salts thereof. Background Technology

[0004] The compound of formula (I) is reported in international application publication number WO2018 / 231745. Its entire contents are incorporated herein by reference. In addition to methods for preparing such compounds or their pharmaceutically acceptable salts, other synthetic methods may be required. This disclosure addresses these and other needs. Summary of the Invention

[0005] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In some embodiments, the method includes:

[0006] Under suitable conditions, make Compound Contact Compounds,

[0007] To produce with Compounds with the structure of

[0008] A, B, E, X, Y, R1, R2, R3, R4 and R5 are as provided herein and may be selected, for example, from the group of the corresponding chemical sections described herein.

[0009] In some embodiments, the method includes:

[0010] (a) Add the coupling agent and optional additives to The compound is placed in a solution in a first organic solvent to form a mixture, and the mixture is stirred for at least about 5 minutes;

[0011] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0012] (c) Heat the mixture from step (b) to a temperature of at least about 40°C and stir the mixture at that temperature;

[0013] (d) Cool the mixture from step (c) and add water to the mixture to form a slurry;

[0014] (e) The slurry from step (d) of mixing;

[0015] (f) Filter the slurry from step (e) to obtain solids;

[0016] (g) Wash the solids from step (f) with water and / or a second organic solvent; and

[0017] (h) Dry the solid from step (g) in a vacuum at a temperature of at least about 30°C to form Compounds, where the variables are provided in this paper.

[0018] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, comprising the following steps:

[0019] (a) To The compound was added to a solution of dimethylformamide with EDC hydrochloride and ethyl cyanohydroxyimino to form a mixture, and the mixture was stirred for at least about 1 hour.

[0020] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0021] (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;

[0022] (d) Cool the mixture from step (c) to about 15-20°C and add water to form a slurry;

[0023] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0024] (f) Filter the slurry from step (e) to form a solid;

[0025] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0026] (h) Dry the solid from step (g) in a vacuum at approximately 55°C to form Compounds, where variables are as defined herein.

[0027] In some implementation schemes, it is also provided that has A method for preparing a compound with a specific structure or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0028] (a) To Add EDC hydrochloride and ethyl cyanohydroxyimino to a solution of dimethylformamide to form a mixture, and stir the mixture for at least about 1 hour;

[0029] (b) Combine the mixture from step (a) with... Stir together for about 1 hour;

[0030] (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;

[0031] (d) Cool the mixture from step (c) to about 15-20°C and add water to the mixture to form a slurry;

[0032] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0033] (f) Filter the slurry from step (e) to form a solid;

[0034] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0035] (h) Dry the solid from step (g) in a vacuum at at least about 55°C to form

[0036] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, further comprising... A method for preparing a compound, the method comprising, under suitable conditions... The compound is in contact with R2R3C=O, where the variables are as defined herein.

[0037] In some implementation schemes, it is also provided The method for preparing the compound includes the following steps:

[0038] (a) To The compound is mixed by adding pyrrolidine to a solution of compound R2R3C=O;

[0039] (b) Heat the mixture from step (a) under reflux, stir the mixture at that temperature for about 19.5 hours, cool the mixture to a temperature of about 15-20°C, and add water to the mixture;

[0040] (c) Adjust the pH of the mixture from step (b) to approximately 2 using HCl;

[0041] (d) Stir the mixture from step (c) with n-heptane to form a slurry, stir the slurry at about 15-20°C for about 1 hour, and filter the slurry to form a solid; and

[0042] (e) Wash the solid from step (d) with water and n-heptane; and

[0043] (g) Dry the solid from step (e) in a vacuum at approximately 50°C to form Compounds, wherein:

[0044] A, B, and E are each independently N or CR6;

[0045] X and Y are each independently O, S, or NR7.

[0046] 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0047] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, including... A method for preparing a compound comprising contacting a compound of formula R1CN with ammonium hydroxide, wherein R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group.

[0048] In some implementation schemes, it is also provided The method for preparing the compound includes the following steps:

[0049] (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture;

[0050] (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;

[0051] (c) Cool the slurry from step (b) to ambient temperature and stir it at ambient temperature for about 16 hours;

[0052] (d) Filter the slurry from step (c) to form a solid; and

[0053] (e) Wash the solid from step (d) with alcohol and dry the washed solid in a vacuum at about 50°C to form Compound, R1 as defined herein.

[0054] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, making The compound is contacted with a coupling agent, with or without additives, to form a compound with... The intermediate of the structure, wherein R8 is an optionally substituted C1-C6 alkyl group, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, the intermediate of formula (XIII) is a […]. Compounds with a specific structure.

[0055] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, having The intermediate of the structure further contacts Compounds to form with The intermediate of the structure, wherein the variables are as defined herein. In some implementations, the intermediate of equation (XVI) is a structure having Compounds with a specific structure.

[0056] In some implementation schemes, the following are provided A compound or a pharmaceutically acceptable salt thereof, wherein R8 is an optionally substituted C1-C6 alkyl group, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, a compound having Compounds of a certain structure or their pharmaceutically acceptable salts.

[0057] In some implementations, a method is provided that has Compounds with a structure or pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In some embodiments, a structure having Compounds of a certain structure or their pharmaceutically acceptable salts.

[0058] In some embodiments, a method for forming a compound of formula I includes making a compound having Compounds of the formula react under thermal cyclization and dehydration conditions to form Compounds.

[0059] In some implementations, a formula is provided. The crystalline form of the compound. In some embodiments, the crystalline form is form I. Attached Figure Description

[0060] Figure 1 HPLC chromatogram of N-hydroxy-1H-pyrazole-4-formamidinium (compound 2-2)

[0061] Figure 2 High performance liquid chromatography (HPLC) chromatogram of 2,2-diethyl-4-oxonyl-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2).

[0062] Figure 3High performance liquid chromatography (HPLC) chromatogram of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchromatin-4-one (compound 6-1).

[0063] Figure 4 Polarizing microscopy (PLM) analysis results of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1) (10 μm scale).

[0064] Figure 5 Differential thermal analysis (DSC) results of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1).

[0065] Figure 6 X-ray powder diffraction (XRPD) results of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1). Detailed Implementation

[0066] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments pertain. Where multiple definitions exist for a term cited herein, those definitions in this section shall prevail unless otherwise stated. All patents, applications, published applications, and other publications cited herein are incorporated herein by reference in their entirety.

[0067] As used herein, unless the context clearly indicates otherwise, the term "a" means "at least one" or "one or more".

[0068] As used herein, the term “about” means that a value is approximate and that small variations will not significantly affect the practice of the disclosed embodiments. When numerical limits are used, unless the context otherwise requires, “about” means that a value may vary by ±10% and remain within the range of the disclosed embodiments.

[0069] As used herein, the term “additive” or “coupling additive” refers to an agent suitable for combination with a coupling agent in a coupling reaction to suppress side reactions and reduce or eliminate racemization. In some embodiments, the additive is, but is not limited to, ethyl cyanohydroxyimino, 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 aza derivatives of 3-hydroxy-4-oxomethylene-3,4-dihydro-1,2,3-benzotriazine (HODhbt), 3-hydroxy-4-oxomethylene-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.

[0070] As used herein, the term "alcohol" refers to any organic compound in which a hydroxyl group (-OH) is bonded to a carbon atom, which in turn is bonded to other hydrogen and / or carbon atoms. For example, the term "alcohol" refers to a straight-chain or branched alkyl-OH group of 1 to 20 carbon atoms, including but not limited to methanol, ethanol, n-propanol, isopropanol, tert-butanol, etc. In some embodiments, the alkyl-OH chain has a length of 1 to 10 carbon atoms, a length of 1 to 8 carbon atoms, a length of 1 to 6 carbon atoms, a length of 1 to 4 carbon atoms, a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0071] As used herein, the terms "alkoxy," "phenoxy," "phenoxy," and "pyrimidinoxy" refer to optionally substituted alkyl, phenyl, benzyl, or pyrimidinyl groups bonded by an oxygen atom. For example, the term "alkoxy" refers to a straight-chain or branched -O-alkyl group of 1 to 20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, etc. In some embodiments, the alkoxy chain has a length of 1 to 10 carbon atoms, a length of 1 to 8 carbon atoms, a length of 1 to 6 carbon atoms, a length of 1 to 4 carbon atoms, a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0072] As used herein, the term "alkyl" refers to a straight-chain 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 include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, tert-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-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, 2-ethyl-1-butyl, etc.

[0073] As used herein, the term "alkylene" or "olefinic" refers to a divalent alkyl linking group. An example of an alkylene (or olefinic) group is a methylene or methanyl (-CH2-).

[0074] As used herein, the term "alkynyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds and 2 to 20 carbon atoms, including but not limited to acetylene, 1-propene, 2-propene, etc. In some embodiments, the alkynyl chain has a length of 2 to 10 carbon atoms, a length of 2 to 8 carbon atoms, a length of 2 to 6 carbon atoms, or a length of 2 to 4 carbon atoms.

[0075] As used herein, the terms “ambient temperature” and “room temperature” or “RT” are understood in the art and generally refer to the approximate temperature of the room in which the reaction takes place, such as the reaction temperature, for example, a temperature from about 20°C to about 30°C, for example at or about 25°C.

[0076] As used herein, the term "amide" refers to any compound containing a carbonyl group bonded to a nitrogen atom or containing an amide functional group. For example, amides are derived from carboxylic acids and amines.

[0077] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings). 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, anthracene, phenanthryl, indenyl, indenyl, tetrahydronaphthyl, etc. Examples of aryl groups include, but are not limited to:

[0078]

[0079]

[0080] As used herein, the term "carbocyclic ring" refers to a 5-, 6-, or 7-membered saturated or unsaturated cyclic ring, optionally containing an O, S, or N atom as part of the ring. Examples of carbocyclic rings include, but are not limited to, cyclopentyl, cyclohexyl, cyclopent-1,3-diene, phenyl, and any of the above heterocycles.

[0081] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0082] As used herein, the terms “comprise” (and any form of inclusion, such as “comprise”, “comprises” and “comprised”), “have” (and any form of having, such as “have” and “has”), “include” (and any form of inclusion, such as “includes” and “include”) or “contains” (and any form of containment, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps.

[0083] As used in this article, the term "contact" refers to the bonding of two compounds / atoms together to form at least one covalent bond between the compounds or atoms.

[0084] As used herein, the term "coupling agent" or "peptide coupling agent" refers to an agent that promotes the formation of an amide bond between an amine and a carboxylic acid, including but not limited to carbodiimides, ammonium / ureonium and phosphonium salts, and propanephosphonic anhydride. Examples of coupling agents 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, azirbenzotriazole tetramethylurea hexafluorophosphate (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, benzotriazole tetramethylurea hexafluorophosphate, etc. Methylurea hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyAOP), propanephosphonic anhydride (PPAA, T3P) or any combination thereof.

[0085] As used in this article, the term "cyano" refers to -CN.

[0086] As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cycloalkyl, alkenyl, and ynyl groups containing up to 20 cyclic carbon atoms. Cycloalkyl groups can comprise monocyclic or polycyclic systems, such as fused-ring, bridged-ring, and spirocyclic systems. In some embodiments, the polycyclic system comprises 2, 3, or 4 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 cyclic carbon atoms. The cyclic carbon atoms of a cycloalkyl group may optionally be substituted with an oxydiyl group or a thio group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc. The definition of cycloalkyl also includes portions having one or more aromatic rings fused to the cycloalkyl ring (having a common bond), such as benzo or thiophene derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-one-1-yl).

[0087] As used herein, the term "cyclohexaalkyl" as used alone or as part of another group refers to a 5-, 6-, or 7-membered saturated or partially unsaturated ring comprising one or two heteroatoms, such as nitrogen, oxygen, and / or sulfur, linked by a carbon atom or heteroatom where possible, optionally linked by a linking group (CH2)n (where n is 0, 1, 2, or 3). The aforementioned group may include one to four substituents, such as alkyl, halogen, oxonyl, and / or any substituent of the alkyl or aryl groups listed herein. Furthermore, any cyclohexaalkyl ring may be fused to a cycloalkyl, aryl, heteroaryl, or cyclohexaalkyl ring.

[0088] As used in this article, the terms “for example” and “such as” and their grammatical equivalents are used.

[0089] As used herein, the term "halogen" refers to a halogen group, including but not limited to fluorine, chlorine, bromine, and iodine.

[0090] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0091] As used herein, the term "haloalkyl" refers to a C-shaped alkyl group having one or more halogen substituents. 1-6 Alkyl groups. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, etc.

[0092] As used herein, the term "heteroaryl" refers to an aromatic heterocycle having up to 20 cyclic atoms (e.g., C) and at least one heteroatom ring member (cyclic atom), such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl has at least one or more heteroatom ring atoms, each heteroatom being independently sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl has 3 to 20 cyclic atoms, 3 to 10 cyclic atoms, 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms. In some embodiments, the heteroaryl comprises 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryls include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indoleyl (e.g., indole-3-yl), pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiapheneyl, purineyl, and carbazole. The following are listed: α-methyl, benzimidazolyl, indololinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thiaanthryl, indolazinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthaneyl, 2H-pyrroleyl, pyrroleyl, 3H-indolyl, 4H-quinazinyl, phthalazinyl, naphthidyl, quinazolinyl, phenanthridineyl, acridineyl, pteridineyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenothiazinyl, etc. 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.

[0093] As used herein, the term "heterocycle" refers to a 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic system, wherein any ring may be saturated or unsaturated and consists of a carbon atom and one to three heteroatoms selected from N, O, and S, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and includes any bicyclic group formed by the fusion of a heterocycle as defined above with a benzene ring. Particularly useful are rings containing one oxygen or sulfur atom, one to three nitrogen atoms, or one oxygen or sulfur atom bonded to one or two nitrogen atoms. Heterocycles can be attached to any heteroatom or carbon atom, resulting in a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxomylidenepiperazinyl, 2-oxomylidenepiperazinyl, 2-oxomylidenepyrrolyl, 2-oxomylideneazonyl, azaphenyl, pyrroleyl, 4-piperidinoneyl, pyrroleyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolinyl, imidazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, morpholinyl, thiazolyl, thiazolinyl, isothiazolyl, quininecycloyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl, benzothiaphenyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiophenyl sulfone, and oxadiazolyl. The morpholino group is the same as the morpholino group.

[0094] As used herein, the term "heterocyclic alkyl" refers to a non-aromatic heterocycle having up to 20 cyclic atoms, including cyclic alkyl, alkenyl, and alkynyl groups, wherein one or more cyclic carbon atoms are substituted with heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic systems). In some embodiments, the heterocyclic alkyl group has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, the heterocyclic alkyl group comprises 3 to 14 cyclic atoms, 3 to 7 cyclic atoms, or 5 or 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocyclic alkyl group comprises 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group comprises 0 to 2 triple bonds. Examples of heterocyclic alkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazino, tetrahydrofurano, tetrahydrothiopheno, 2,3-dihydrobenzofurano, 1,3-benzodioxolane, benzo-1,4-dioxane, piperidino, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, pyrazolyl, thiazolyl, imidazolyl, pyrrolidine-2-one-3-yl, etc. Furthermore, the cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with an oxonium or thioyl group. For example, the cyclic S atom may be substituted with one or two oxonium groups (forming S(O) or S(O)2). In another example, the cyclic C atom may be substituted with an oxonium group (forming a carbonyl group). The definition of heterocyclic alkyl also includes portions having one or more aromatic rings fused with a non-aromatic heterocycle (sharing a common bond), including but not limited to pyridinyl, thiopheneyl, phthalimide, naphthimide, and heterocyclic benzo[a] derivatives such as indole, isoindole, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3-yl. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with an oxy subunit or a thio group.

[0095] As used herein, the term "heterocyclic alkyl alkyl" refers to a C-shaped alkyl group substituted with a heterocyclic alkyl group. 1-6 alkyl.

[0096] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0097] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH and -CH2CH2OH.

[0098] As used herein, the term “patient” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates such as humans.

[0099] As used herein, the term "separation" refers to the separation of the compound described herein from other components of the synthetic organic chemical reaction mixture using conventional techniques such as filtration.

[0100] As used herein, the term "mammal" refers to rodents (i.e., mice, rats, or guinea pigs), monkeys, cats, dogs, cattle, horses, pigs, or humans. In some embodiments, the mammal is a human.

[0101] As used in this article, the term "nitro" refers to -NO2.

[0102] As used herein, the term "n-membered," where n is an integer, typically describes the number of cyclic atoms in a portion, where the number of cyclic atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl ring.

[0103] As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and parts. A “substituted” atom or part means that any hydrogen atom or part can be substituted with a substituent selected from the specified 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 the methyl group is optionally substituted, then the three hydrogen atoms on the carbon atom can be substituted with substituents.

[0104] As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues, within the bounds of reasonable medical judgment. In some embodiments, “pharmaceutically acceptable” means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more specifically for human use.

[0105] In some embodiments, the salts of the compounds described herein are pharmaceutically acceptable salts. As used herein, the phrase "pharmaceutically acceptable salt" includes, but is not limited to, salts with acidic or basic groups. Basic compounds are capable of forming a variety of salts with a wide range of inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including, but not limited to, sulfuric acid, thiosulfate, citric acid, maleic acid, acetic acid, oxalic acid, hydrochloride, hydrobromide, hydroiodate, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactic acid, salicylate, citrate, acid citrate, tartrate, oleate, tannin, pantothenate, etc. Salts such as acid salts, tartrate salts, ascorbate salts, succinate salts, maleate salts, gentianate salts, fumarate salts, gluconate salts, glucuronates, glycoside salts, formate salts, benzoate salts, glutamate salts, methanesulfonate salts, ethanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, bicarbonate salts, malonate salts, methanesulfonate salts, ethanesulfonate salts, naphthalenedisulfonate salts, toluenesulfonate salts, benzenesulfonate salts, orthophosphates, trifluoroacetates, and bis(hydroxynaphthalate) salts (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthalenecarboxylate)). In addition to the acids mentioned above, compounds including the amino moiety can form pharmaceutically acceptable salts with various amino acids. Acidic compounds can form basic salts with various pharmaceutically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts, particularly calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. This embodiment also includes quaternary ammonium salts of the compounds described herein, wherein the compounds have one or more tertiary amine moieties.

[0106] As used herein, the term "phenyl" refers to -C6H5. Phenyls may be unsubstituted or substituted with one, two, or three suitable substituents.

[0107] As used herein, the term "purified" means that, when isolated, the isolate contains at least 90%, at least 95%, at least 98%, or at least 99% by weight of the compound described herein.

[0108] As used herein, the phrase "quaternary ammonium salt" refers to a derivative of the disclosed compound having one or more tertiary amine moieties, wherein the derivative is formed by alkylation (cation via anion such as OCl). - CH3COO - and CF3COO - (Equilibrium), such as methylation or ethylation, modifies at least one tertiary amine moiety in the parent compound by converting the tertiary amine moiety into a quaternary ammonium cation.

[0109] As used herein, the term "solution / suspension" refers to a liquid composition in which a first portion of the active agent is present in a solution and a second portion of the active agent is present in a suspension in particulate form within a liquid matrix.

[0110] As used herein, the term "solvent" refers to a liquid substance capable of dissolving or dispersing one or more other substances, including water, inorganic non-aqueous solvents, and organic solvents. The term "inorganic non-aqueous solvent" refers to a solvent other than water that is not an organic compound. Examples of "inorganic non-aqueous solvents" include, but are not limited to, inorganic acids such as liquid ammonia, liquid sulfur dioxide, sulfuryl chloride and sulfuryl chloride fluorides, phosphoryl chloride, nitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, and pure sulfuric acid. The term "organic solvent" refers to a carbon-based solvent. Examples of "organic solvents" include, but are not limited to, aromatic compounds such as benzene and toluene; alcohols such as methanol, ethanol, and propanol; esters; ethers; ketones such as acetone; amines; and nitrated and halogenated hydrocarbons. "Organic solvents" include both polar and non-polar organic solvents. "Polar organic solvents" are organic solvents with a large dipole moment (also known as "partial charge"). Generally, organic solvents with a dielectric constant greater than about 5 are considered "polar organic solvents," while organic solvents with a dielectric constant less than about 5 are considered "non-polar organic solvents." Examples of “polar organic solvents” include, but are not limited to, acetic acid, methanol, acetone and acetonitrile, DMSO and DMF. Examples of nonpolar organic solvents include, but are not limited to, benzene, carbon tetrachloride and n-hexane. “Organic solvents” include proton and aproton organic solvents. The term “proton organic solvent” refers to an organic solvent having a hydrogen atom bonded to oxygen or nitrogen (acidic hydrogen atom). Examples of “proton organic solvents” include, but are not limited to, 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, 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, methyl ethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 2,3-dimethyl ethylene carbonate, butyl carbonate, acetonitrile, methoxyacetonitrile, propionitrile, butyrolactone, valerate, dimethoxyethane, sulfolane, methyl sulfolane, sulfolane cyclobutene, dimethyl sulfone, ethyl methyl sulfone, and isopropyl methyl sulfone.

[0111] As used in this article, the phrase “substantially separated” refers to a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

[0112] As used herein, the phrase “suitable substituent” or “substituent” means a group that does not render the compounds described herein or the synthesis or pharmaceutical efficacy of intermediates used to prepare them ineffective. Examples of suitable 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, oxydiyl, halogen, 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 readily select suitable substituents based on the stability, pharmacological and synthetic activity of the compounds described herein.

[0113] As used herein, unless otherwise expressly stated, it should be understood to follow the term "and not limited to".

[0114] Throughout this specification, substituents of the compounds may be disclosed as groups or ranges. Specifically, embodiments include each individual sub-combination of members of these groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl, respectively.

[0115] For compounds in which a variable appears more than once, each variable can be a different part selected from the Markush group that defines the variable. For example, when the described structure has two R groups present on the same compound, the two R groups can represent different parts selected from the Markush group defined for R. In another example, when in, for example When multiple optional substituents are specified in the form of , it can be understood that the substituent R can appear s times on the ring, and R can be a different part each time it appears. In the example above, variable T 1 Defined as including hydrogen, such as when T 1 When it is CH2, NH, etc., any H can be substituted by substituents.

[0116] It should also be understood that, for clarity, certain features described herein in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0117] It should be understood that, where applicable, this embodiment includes methods for processing stereoisomers, diastereomers, and optical stereoisomers of compounds, and mixtures thereof. Furthermore, it should be understood that stereoisomers, diastereomers, and optical stereoisomers of compounds, and mixtures thereof, are within the scope of this embodiment. As a non-limiting example, the mixture may be a racemic mixture, or the mixture may contain one particular stereoisomer in a different proportion relative to another. Additionally, the compound may be provided as substantially pure stereoisomers, diastereomers, and optical stereoisomers (e.g., epimers).

[0118] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of many alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included in the embodiments and can be isolated as mixtures of isomers or as separate isomers. When a compound capable of stereoisomerism or geometric isomerism is specified in its structure or name without mentioning a specific R / S or cis / trans configuration, all such isomers are intended to be considered.

[0119] In some embodiments, the composition comprises at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure of the compound or a pharmaceutically acceptable salt thereof, which means that the ratio of one enantiomer to another in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is present entirely in one enantiomer without the other enantiomer.

[0120] Resolution of racemic mixtures of compounds can be performed by any of the numerous methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolving acid (which is an optically active salt-forming organic acid). Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids, such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on 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.

[0121] Compounds may also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, including, but not limited to, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0122] The compounds also include hydrates and solvates, as well as anhydrous and nonsolvent forms.

[0123] Compounds can also include all atomic isotopes present in intermediates or the final compound. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0124] In some embodiments, the compound or its salt is substantially isolated. Partial isolation may include, for example, a composition rich in the compound. Substantial isolation may include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the compound or its salt by weight. Methods for separating the compound and its salt are conventional in the art.

[0125] While the disclosed compounds are suitable, other functional groups can be included in the compounds to anticipate similar results. In particular, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometry of the compound, and this distance can be altered by including aliphatic chains of different lengths, which can optionally be substituted or may include amino acids, dicarboxylic acids, or diamines. The distance and relative orientation between monomers within the compound can also be altered by replacing the amide bond with a substitute having additional atoms. Thus, replacing the carbonyl group with a dicarbonyl group changes the distance between monomers and the tendency of the dicarbonyl unit to adopt an anti-arrangement of two carbonyl moieties and alter the periodicity of the compound. Pyromellitic anhydride represents another alternative to the simple amide bond, which can alter the conformation and physical properties of the compound. Modern methods of solid-phase organic chemistry (E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis, Practical Approach, IRL Press, Oxford, 1989) now allow the synthesis of homodispersed compounds with molecular weights approaching 5,000 Daltons. Other alternatives are equally effective.

[0126] Embodiments of various methods for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof are provided. Unless otherwise specified or contextually provided, a variable may be any option described herein.

[0127] In some embodiments, the preparation method of the compound of formula (I) or a pharmaceutically acceptable salt thereof is as described in the appended exemplary non-limiting claims.

[0128] In some embodiments, a process or method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In some embodiments, the method includes, under suitable conditions, causing a compound of formula (II) to...

[0129]

[0130] Contact (III) compounds

[0131]

[0132] To form compounds having the following structures

[0133]

[0134] in:

[0135] A, B, and E are each independently N or CR6;

[0136] X and Y are each independently O, S, or NR7;

[0137] R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group.

[0138] 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0139] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein 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.

[0140] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein A is N or CR6. In some embodiments, A is N. In some embodiments, A is CR6.

[0141] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein B is N or CR6. In some embodiments, A is N. In some embodiments, A is CR6.

[0142] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein E is N or CR6. In some embodiments, E is N. In some embodiments, E is CR6.

[0143] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0144] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0145] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group. 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 an optionally substituted carbocyclic ring. In some embodiments, R1 is an optionally substituted aryl group. In some embodiments, R1 is an optionally substituted heteroaryl group. In some embodiments, R1 is a branched or unbranched alkyl alcohol. In some embodiments, R1 is a halogen. In some embodiments, R1 is a branched or unbranched alkyl group. In some embodiments, R1 is an amide. 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 alkylthio group.

[0146] In some embodiments, R2 is 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 heteroalkyl. In some embodiments, R2 is H. In some embodiments, R2 is an optionally substituted C1-C6 alkyl. In some embodiments, R2 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R2 is an optionally substituted C1-C6 alkoxy. In some embodiments, R2 is an optionally substituted cycloalkyl. In some embodiments, R2 is an optionally substituted heteroalkyl.

[0147] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is 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 heteroalkyl. In some embodiments, R3 is H. In some embodiments, R3 is an optionally substituted C1-C6 alkyl. In some embodiments, R3 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R3 is an optionally substituted C1-C6 alkoxy. In some embodiments, R3 is an optionally substituted cycloalkyl. In some embodiments, R3 is an optionally substituted heteroalkyl.

[0148] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R4 is 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 heteroalkyl. In some embodiments, R4 is H. In some embodiments, R4 is an optionally substituted C1-C6 alkyl. In some embodiments, R4 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R4 is an optionally substituted C1-C6 alkoxy. In some embodiments, R4 is an optionally substituted cycloalkyl. In some embodiments, R4 is an optionally substituted heteroalkyl.

[0149] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R5 is 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 heteroalkyl. In some embodiments, R5 is H. In some embodiments, R5 is an optionally substituted C1-C6 alkyl. In some embodiments, R5 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R5 is an optionally substituted C1-C6 alkoxy. In some embodiments, R5 is an optionally substituted cycloalkyl. In some embodiments, R5 is an optionally substituted heteroalkyl.

[0150] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R6 is 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 heteroalkyl. In some embodiments, R6 is H. In some embodiments, R6 is an optionally substituted C1-C6 alkyl. In some embodiments, R6 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R6 is an optionally substituted C1-C6 alkoxy. In some embodiments, R6 is an optionally substituted cycloalkyl. In some embodiments, R6 is an optionally substituted heteroalkyl.

[0151] In some embodiments, R7 is 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 heteroalkyl. In some embodiments, R7 is H. In some embodiments, R7 is an optionally substituted C1-C6 alkyl. In some embodiments, R7 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R7 is an optionally substituted C1-C6 alkoxy. In some embodiments, R7 is an optionally substituted cycloalkyl. In some embodiments, R7 is an optionally substituted heteroalkyl.

[0152] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl. In some embodiments, R2 and R3 together are optionally substituted cycloalkyl. In some embodiments, R2 and R3 together are optionally substituted heteroalkyl.

[0153] In some embodiments, R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl. In some embodiments, R4 and R5 together are optionally substituted cycloalkyl. In some embodiments, R4 and R5 together are optionally substituted heteroalkyl.

[0154] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof further includes... Compounds and Compound coupling to form A compound or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein coupling comprises reacting a compound of formula (II) and a compound of formula (III) for at least about 5 minutes. In some embodiments, the reaction comprises heating the reaction to a temperature of at least about 40°C for at least about 1, 2, 3, 4, or 5 minutes.

[0156] In some embodiments, the method for preparing compound (I) or a pharmaceutically acceptable salt thereof further includes quenching the reactions of compounds (II) and (III) to form a compound containing... A slurry of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, quenching includes cooling and / or adding water to the reaction of the compounds of formula (II) and (III) to quench the reaction, forming a slurry.

[0157] In some embodiments, the method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof further includes isolating... The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes filtration, washing, and / or drying of the slurry to obtain... A compound or a pharmaceutically acceptable salt thereof.

[0158] In some implementations, separation includes filtering the slurry to obtain The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes washing the slurry to obtain... The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes drying the slurry to obtain... The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes filtering and drying the slurry to obtain... The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes filtering and washing the slurry to obtain... The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes washing and drying the slurry to obtain... A compound or a pharmaceutically acceptable salt thereof. In some embodiments, the separation includes filtering, washing, and drying the slurry to obtain... A compound or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, including washing to obtain The compound or a pharmaceutically acceptable salt thereof, wherein washing includes washing with water and / or an organic solvent. In some embodiments, washing includes washing with a solvent to remove impurities such as unreacted or excess compounds of formula (II) or (III), byproducts derived from coupling agents and / or additives, and any combination thereof. In some embodiments, washing includes washing with water. In some embodiments, washing includes washing with an organic solvent. In some embodiments, washing includes washing with both water and an organic solvent. In some embodiments, washing does not include washing with water. In some embodiments, washing does not include washing with an organic solvent.

[0160] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, comprising the following steps:

[0161] (a) Add the coupling agent and optional additives to The compound is placed in a solution in a first organic solvent to form a mixture, and the mixture is stirred for at least about 5 minutes;

[0162] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0163] (c) Heat the mixture from step (b) to a temperature of at least about 40°C and stir the mixture at that temperature;

[0164] (d) Cool the mixture from step (c) and add water to the mixture to form a slurry;

[0165] (e) The slurry from step (d) of mixing;

[0166] (f) Filter the slurry from step (e) to obtain solids;

[0167] (g) Wash the solids from step (f) with water and / or a second organic solvent; and

[0168] (h) Dry the solid from step (g) in a vacuum at a temperature of at least about 30°C to form Compounds, where the variables are provided in this paper.

[0169] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the coupling agent is a 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 agent is EDC hydrochloride.

[0170] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0171] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0172] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the molar ratio of the amount of coupling agent to the amount of compound (II) is at least about 1.0 equivalent. In some embodiments, the molar ratio of the amount of coupling agent to the amount of compound (II) is about 1.2 equivalent. In some embodiments, the molar ratio of the amount of additive to the amount of compound (II) is at least about 1.0 equivalent. In some embodiments, the molar ratio of the amount of additive to the amount of compound (II) is about 1.0 equivalent.

[0173] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the concentration of compound (II) in a first organic solvent is at least about 0.1 mol / L. In some embodiments, the concentration of compound (II) in a first organic solvent is about 0.8 mol / L.

[0174] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0175] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the molar ratio of the amount of compound (III) to the amount of compound (II) is at least about 1.0 equivalents. In some embodiments, the molar ratio of the amount of compound (III) to the amount of compound (II) is about 1.2 equivalents.

[0176] In some embodiments, in step (b), the mixture is stirred for at least about 5 minutes. In some embodiments, in step (b), the mixture is stirred for at least about 1 hour.

[0177] 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.

[0178] In some embodiments, the preparation method of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein in step (c), the mixture is stirred at the temperature for at least about 1, 2, 3, 4, or 5 minutes. In some embodiments, in step (c), the mixture is stirred at the temperature for at least about 1 hour. In some embodiments, in step (c), the mixture is stirred at the temperature for about 5 hours. In some embodiments, in step (c), the mixture is stirred at the temperature for about 18 hours.

[0179] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, in step (d), the mixture is cooled to about 5-25°C. In some embodiments, in step (d), the mixture is cooled to about 15-20°C.

[0180] 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.

[0181] In some embodiments, in step (e), the mixture is stirred at about 5-25°C. In some embodiments, in step (e), the mixture is stirred at about 15-20°C.

[0182] In some embodiments, in step (e), the slurry is stirred for at least about 5 minutes. In some embodiments, in step (e), the mixture is stirred for about 1 hour.

[0183] In some embodiments, a method for preparing the compound of formula (I) is provided, 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.

[0184] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the solid is washed with water at least once. In some embodiments, the solid is washed with water twice.

[0185] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0186] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the solid is washed with a second organic solvent at least once. In some embodiments, the solid is washed with a second organic solvent twice.

[0187] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0188] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0189] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, comprising the following steps:

[0190] (a) To The compound was added to a solution of dimethylformamide with EDC hydrochloride and ethyl cyanohydroxyimino to form a mixture, and the mixture was stirred for at least about 1 hour.

[0191] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0192] (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;

[0193] (d) Cool the mixture from step (c) to about 15-20°C and add water to form a slurry;

[0194] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0195] (f) Filter the slurry from step (e) to form a solid;

[0196] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0197] (h) Dry the solid from step (g) in a vacuum at approximately 55°C to form Compounds, where variables are as defined herein.

[0198] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, in step (c), the mixture of step (b) is heated to 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 of step (b) is heated to about 95°C to about 110°C. In some embodiments, the mixture of step (b) is heated to about 90°C to about 115°C.

[0199] In some embodiments, the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof further includes recrystallizing the solid from step (h) from the solvent. In some embodiments, the solvent used for recrystallization is water, dimethylformamide, ethanol, or methyl tert-butyl ether. In some embodiments, the solvent used for recrystallization is ethanol. In some embodiments, when the solvent used for recrystallization is ethanol or methyl tert-butyl ether, the mixture forms a slurry.

[0200] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein when the solvent used for recrystallization is ethanol, the slurry is heated to a temperature of at least about 50°C. 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.

[0201] 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.

[0202] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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 at least about 99.5%.

[0203] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the recrystallized solid is white to off-white in color.

[0204] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, 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.

[0205] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein X is O.

[0206] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein Y is O.

[0207] In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound prepared or produced has The variables are as defined in claim 1. In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has The variables are as defined in claim 1. In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the resulting compound has The formula (I) is used, wherein the variables are as defined in claim 1. In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the resulting compound has... The formula (I) is used, wherein the variables are as defined in claim 1. In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has... The expression, wherein the variables are defined as in claim 1.

[0208] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R4 and R5 are each independently H, or optionally substituted C1-C6 alkyl groups.

[0209] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R4 or R5 is H.

[0210] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The expression, wherein the variables are defined as in claim 1.

[0211] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The expression, wherein the variables are defined as in claim 1.

[0212] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 are each independently H, or optionally substituted C1-C6 alkyl groups.

[0213] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 are both optionally substituted C1-C6 alkyl groups.

[0214] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 are both methyl or ethyl. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 are both methyl. In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 are both ethyl.

[0215] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The formula is as defined in claim 1.

[0216] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 or R3 is H.

[0217] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0218] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 together are optionally substituted 5, 6 or 7-membered cycloalkyl or heteroalkyl groups.

[0219] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is an optionally substituted C1-C6 alkyl group, an optionally substituted carbocyclic ring, an optionally substituted aryl group, or an optionally substituted heteroaryl group.

[0220] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is an optionally substituted aryl group or an optionally substituted heteroaryl group.

[0221] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is an optionally substituted heteroaryl group.

[0222] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is an optionally substituted nitrogen-containing heteroaryl group.

[0223] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is

[0224] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula (I) is

[0225] In some implementation schemes, it is also provided that has A method for preparing a compound with a specific structure or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0226] (a) To Add EDC hydrochloride and ethyl cyanohydroxyimino to a solution of dimethylformamide to form a mixture, and stir the mixture for at least about 1 hour;

[0227] (b) Combine the mixture from step (a) with... Stir together for about 1 hour;

[0228] (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;

[0229] (d) Cool the mixture from step (c) to about 15-20°C and add water to the mixture to form a slurry;

[0230] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0231] (f) Filter the slurry from step (e) to form a solid;

[0232] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0233] (h) Dry the solid from step (g) in a vacuum at at least about 55°C to form

[0234] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, further comprising... The method for preparing the compound involves, under suitable conditions... The compound contacts R₂R₃C=O, where the variables are as defined herein. 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.

[0235] In some implementation schemes, it is also provided The method for preparing the compound includes the following steps:

[0236] (a) To The compound is mixed by adding pyrrolidine to a solution of compound R2R3C=O;

[0237] (b) Heat the mixture from step (a) under reflux and 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;

[0238] (c) Adjust the pH of the mixture from step (b) to approximately 2 using HCl;

[0239] (d) Stir the mixture from step (c) with n-heptane to form a slurry, stir the slurry at about 15-20°C for about 1 hour, and filter the slurry to form a solid; and

[0240] (e) Wash the solid from step (d) with water and n-heptane; and

[0241] (g) Dry the solid from step (e) in a vacuum at approximately 50°C to form Compounds, wherein:

[0242] A, B, and E are each independently N or CR6;

[0243] X and Y are each independently O, S, or NR7.

[0244] 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 heteroalkyl, or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0245] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein, in step (b), the mixture of step (a) is heated under reflux at or near the boiling point of compound R2R3C=O. In some embodiments, in step (b), the mixture of step (a) is heated to about 95°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 90°C to about 95°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 85°C to about 95°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 80°C and about 95°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 75°C to about 95°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 95°C to about 100°C. In some embodiments, in step (b), the mixture of 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.

[0246] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein A is N or CR6. In some embodiments, A is N. In some embodiments, A is CR6.

[0247] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein B is N or CR6. In some embodiments, B is N. In some embodiments, B is CR6.

[0248] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein E is N or CR6. In some embodiments, E is N. In some embodiments, E is CR6.

[0249] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, 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.

[0250] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, 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.

[0251] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R2 is 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 heteroalkyl. In some embodiments, R2 is H. In some embodiments, R2 is an optionally substituted C1-C6 alkyl. In some embodiments, R2 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R2 is an optionally substituted C1-C6 alkoxy. In some embodiments, R2 is an optionally substituted cycloalkyl. In some embodiments, R2 is an optionally substituted heteroalkyl.

[0252] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R3 is 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 heteroalkyl. In some embodiments, R3 is H. In some embodiments, R3 is an optionally substituted C1-C6 alkyl. In some embodiments, R3 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R3 is an optionally substituted C1-C6 alkoxy. In some embodiments, R3 is an optionally substituted cycloalkyl. In some embodiments, R3 is an optionally substituted heteroalkyl.

[0253] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R4 is 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 heteroalkyl. In some embodiments, R4 is H. In some embodiments, R4 is an optionally substituted C1-C6 alkyl. In some embodiments, R4 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R4 is an optionally substituted C1-C6 alkoxy. In some embodiments, R4 is an optionally substituted cycloalkyl. In some embodiments, R4 is an optionally substituted heteroalkyl.

[0254] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R5 is 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 heteroalkyl. In some embodiments, R5 is H. In some embodiments, R5 is an optionally substituted C1-C6 alkyl. In some embodiments, R5 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R5 is an optionally substituted C1-C6 alkoxy. In some embodiments, R5 is an optionally substituted cycloalkyl. In some embodiments, R5 is an optionally substituted heteroalkyl.

[0255] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R6 is 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 heteroalkyl. In some embodiments, R6 is H. In some embodiments, R6 is an optionally substituted C1-C6 alkyl. In some embodiments, R6 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R6 is an optionally substituted C1-C6 alkoxy. In some embodiments, R6 is an optionally substituted cycloalkyl. In some embodiments, R6 is an optionally substituted heteroalkyl.

[0256] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R7 is 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 heteroalkyl. In some embodiments, R7 is H. In some embodiments, R7 is an optionally substituted C1-C6 alkyl. In some embodiments, R7 is an optionally substituted C1-C6 hydroxyalkyl. In some embodiments, R7 is an optionally substituted C1-C6 alkoxy. In some embodiments, R7 is an optionally substituted cycloalkyl. In some embodiments, R7 is an optionally substituted heteroalkyl.

[0257] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl. In some embodiments, R2 and R3 together are optionally substituted cycloalkyl. In some embodiments, R2 and R3 together are optionally substituted heteroalkyl.

[0258] In some embodiments, a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided, wherein R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl. In some embodiments, R4 and R5 together are optionally substituted cycloalkyl. In some embodiments, R4 and R5 together are optionally substituted heteroalkyl.

[0259] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, further comprising contacting a compound of formula R1CN with ammonium hydroxide to prepare the compound. A method for producing a compound, wherein R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group. 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.

[0260] In some implementation schemes, it is also provided The method for preparing the compound includes the following steps:

[0261] (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture;

[0262] (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;

[0263] (c) Cool the slurry from step (b) to ambient temperature and stir it at ambient temperature for about 16 hours;

[0264] (d) Filter the slurry from step (c) to form a solid; and

[0265] (e) Wash the solid from step (d) with alcohol and dry the washed solid in a vacuum at about 50°C to form Compound, R1 as defined herein.

[0266] In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group. 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 an optionally substituted carbocyclic ring. In some embodiments, R1 is an optionally substituted aryl group. In some embodiments, R1 is an optionally substituted heteroaryl group. In some embodiments, R1 is a branched or unbranched alkyl alcohol. In some embodiments, R1 is a halogen. In some embodiments, R1 is a branched or unbranched alkyl group. In some embodiments, R1 is an amide. 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 alkylthio group.

[0267] In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, 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.

[0268] In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein the hydroxylamine is hydroxylamine hydrochloride. In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein, when the hydroxylamine is hydroxylamine hydrochloride, an organic base is added. In some embodiments, the organic base is diisopropylethylamine. In some embodiments, the molar ratio of the organic base to the amount of hydroxylamine hydrochloride is at least about 1.5 equivalents.

[0269] In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein in step (a), the molar ratio of the amount of hydroxylamine to the amount of R1CN is at least about 1.5 equivalents.

[0270] In some embodiments, a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof is provided, wherein, in step (b), the mixture of step (a) is heated under reflux at or near the boiling point of the alcohol. In some embodiments, the mixture of step (a) is heated to about 75°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 70°C to about 75°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 65°C to about 75°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 60°C to about 75°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 75°C to about 75°C. In some embodiments, in step (b), the mixture of step (a) is heated to about 75°C to about 80°C. In some embodiments, in step (b), the mixture of 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.

[0271] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, making The compound is contacted with a coupling agent, with or without additives, to form a compound with... The intermediate of the structure, wherein R8 is an optionally substituted C1-C6 alkyl group, and R2, R3, R4, R5, R6, and R7 are as defined herein. In some embodiments, the compound of formula (II) is reacted with a coupling agent with or without additives to form intermediate of formula (XIII). In some embodiments, the compound of formula (II) is coupled with a coupling agent with or without additives to form intermediate of formula (XIII).

[0272] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the intermediate of formula (XIII) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XIII) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XIII) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XIII) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XIII) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XIII) is a compound having... Compounds with a specific structure.

[0273] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, having The intermediate of the structure further contacts Compounds, to form compounds with The intermediate of formula (XIII). In some embodiments, the intermediate of formula (XIII) is further reacted with a compound of formula (III) to form the intermediate of formula (XVI). In some embodiments, the intermediate of formula (XIII) is further coupled with a compound of formula (III) to form the intermediate of formula (XVI).

[0274] In some implementations, the intermediate of formula (XVI) is having Compounds with a structure. In some embodiments, the intermediate of formula (XVI) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XVI) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XVI) is a compound having... Compounds with a structure. In some embodiments, the intermediate of formula (XVI) is a compound having... Compounds with a specific structure.

[0275] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein, having The intermediate of the structure is further formed under thermal cyclization and dehydration conditions. Compound. In some embodiments, the intermediate of formula (XVI) further condenses under thermal cyclization and dehydration conditions to form compound (I). In some embodiments, the intermediate of formula (XVI) further cyclizes under thermal cyclization and dehydration conditions to form compound (I). In some embodiments, wherein... Compounds are

[0276] In some implementation schemes, it is also provided Compounds or pharmaceutically acceptable salts thereof, isolated from the methods described herein.

[0277] In some implementations, it is also provided that includes one or more A composition of a compound or a pharmaceutically acceptable salt thereof.

[0278] In some implementations, it is also provided that includes one or more A solution of a compound or a pharmaceutically acceptable salt thereof.

[0279] In some implementation schemes, it is also provided Compounds or pharmaceutically acceptable salts thereof, isolated from the methods described herein.

[0280] In some implementations, it is also provided that includes one or more A composition of a compound or a pharmaceutically acceptable salt thereof.

[0281] In some implementations, it is also provided that includes one or more A solution of a compound or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, a method for forming a compound of formula I is also provided, the method comprising making a compound having Compounds with the structure react under thermal cyclization and dehydration conditions to form Compounds.

[0283] In some implementations, a method is provided that has The crystalline form of the compound. In some embodiments, the crystalline form is type I. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern containing peaks at the following locations: approximately 8.9 ± 0.5 degrees 2θ, approximately 9.4 ± 0.5 degrees 2θ, 15.7 ± 0.5 degrees 2θ, approximately 17.7 ± 0.5 degrees 2θ, approximately 18.9 ± 0.5 degrees 2θ, 24.3 ± 0.5 degrees 2θ, approximately 26.0 ± 0.5 degrees 2θ, and approximately 26.7 ± 0.5 degrees 2θ. In some embodiments, crystalline form I is characterized by containing the following... Figure 6 The X-ray powder diffraction pattern of one or more peaks shown. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern comprising one or more peaks as shown in Table 14. In some embodiments, crystalline form I of claim 142 is characterized by an X-ray powder diffraction pattern comprising one or more d-spacing values ​​at: about 10.0 ± 0.5 Å, about 9.4 ± 0.5 Å, about 5.6 ± 0.5 Å, about 5.0 ± 0.5 Å, about 4.7 ± 0.5 Å, about 3.7 ± 0.5 Å, about 3.4 ± 0.5 Å, and about 3.3 ± 0.5 Å.

[0284] Although the compounds described herein may exhibit specific stereochemical properties around certain atoms, such as cis or trans, they may also be prepared in opposite conformations or racemic mixtures. Such isomers or racemic mixtures are included in this disclosure. Furthermore, while compounds are uniformly represented in the table, any compound or its pharmaceutically acceptable salt may be selected from the table and used in the embodiments provided herein.

[0285] In some embodiments, a pharmaceutical composition is provided comprising a compound described herein or a pharmaceutical salt of any compound described herein.

[0286] The compounds described herein can be prepared according to the methods described herein and in the examples. The methods described herein may be adapted based on the needs and compounds described herein. In some embodiments, the method can be used to prepare one or more compounds as described herein, and it will be obvious to those skilled in the art which compounds can be prepared according to the methods described herein.

[0287] Conditions and temperatures can be varied, as shown in the examples described herein. These schemes are non-limiting synthetic schemes, and the synthetic routes can be modified, as will be apparent to those skilled in the art upon reading this specification. These compounds can also be prepared according to the schemes described in the examples.

[0288] These compounds can be used to modulate the S1P1 receptor. Therefore, in some embodiments, these compounds may be referred to as S1P1 receptor modulating compounds.

[0289] Although the compounds in the table or examples above are shown to have specific stereochemical properties around certain atoms, such as cis or trans, the compounds can also be prepared in opposite conformations or racemic mixtures.

[0290] In some embodiments, this embodiment provides a pharmaceutical composition comprising a compound described herein or a pharmaceutical salt of any compound described herein.

[0291] In some embodiments, the compounds are prepared according to the methods described in the examples. These methods can be used to prepare the compounds and compositions described herein. Conditions and temperatures can be varied, or the synthesis can be performed with obvious modifications based on the synthesized compounds, according to the examples described herein.

[0292] Conditions and temperatures can be varied, as illustrated in the embodiments described herein. These schemes are non-limiting synthetic methods, and the synthetic routes can be modified, as will be apparent to those skilled in the art upon reading this specification.

[0293] This disclosure also provides the following non-limiting embodiments:

[0294] To better understand the embodiments disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the embodiments in any way.

[0295] The following examples are illustrative and not restrictive of the methods described herein. Other appropriate modifications and adjustments to the various conditions and parameters commonly encountered in the therapeutic, synthetic, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

[0296] The following implementation plan is provided:

[0297] 1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, said method comprising:

[0298] Under suitable conditions compound contact

[0299] Compounds, to produce compounds having the following formula

[0300]

[0301] in:

[0302] A, B, and E are each independently N or CR6;

[0303] X and Y are each independently O, S, or NR7;

[0304] R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group.

[0305] 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0306] 2. The method as described in embodiment 1, wherein the method further includes... Compounds and Compound coupling to produce Compounds.

[0307] 3. The method of embodiment 2, wherein the coupling comprises contacting the compounds of formula (II) and (III) with a coupling agent and optionally with an additive to a solution containing the compounds of formula (II) and (III).

[0308] 4. The method as described in embodiment 2 or 3, wherein the coupling comprises reacting the compound of formula (II) and the compound of formula (III) for at least about 5 minutes.

[0309] 5. The method of embodiment 4, wherein the reaction comprises heating the reaction to a temperature of at least about 40°C for at least about 1, 2, 3, 4 or 5 minutes.

[0310] 6. The method of embodiment 5, wherein the method further comprises a quenching reaction to form a mixture containing... A slurry of a compound or a pharmaceutically acceptable salt thereof.

[0311] 7. The method of embodiment 6, wherein the quenching includes cooling and / or adding water to the reaction to quench the reaction to form a slurry.

[0312] 8. The method as described in embodiment 6 or 7 further includes separating A compound or a pharmaceutically acceptable salt thereof.

[0313] 9. The method as described in embodiment 8, wherein the separation The compound or its pharmaceutically acceptable salt includes filtering, washing, and / or drying the slurry to obtain A compound or a pharmaceutically acceptable salt thereof.

[0314] 10. The method as described in embodiment 9, wherein the slurry is filtered to obtain A compound or a pharmaceutically acceptable salt thereof.

[0315] 11. The method as described in embodiment 10, wherein washing is performed with water and / or an organic solvent. A compound or a pharmaceutically acceptable salt thereof.

[0316] 12. The method as described in embodiments 9, 10, or 11, wherein the dried slurry or A compound or a pharmaceutically acceptable salt thereof.

[0317] 13. The method as described in implementation scheme 1, wherein the method includes the following steps:

[0318] (a) Add the coupling agent and optional additives to The compound is placed in a solution in a first organic solvent to form a mixture, and the mixture is stirred for at least about 5 minutes;

[0319] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0320] (c) Heat the mixture from step (b) to a temperature of at least about 40°C and stir the mixture at that temperature;

[0321] (d) Cool the mixture from step (c) and add water to the mixture to form a slurry;

[0322] (e) The slurry from step (d) of mixing;

[0323] (f) Filter the slurry from step (e) to obtain solids;

[0324] (g) Wash the solids from step (f) with water and / or a second organic solvent; and

[0325] (h) Dry the solid from step (g) in a vacuum at a temperature of at least about 30°C to form Compounds, wherein the variables are as defined in Implementation Scheme 1.

[0326] 14. The method as described in embodiment 13, wherein the coupling agent is carbodiimide.

[0327] 15. The method as described in embodiment 14, wherein the carbodiimide is DCC, DIC, or EDC hydrochloride.

[0328] 16. The method as described in embodiment 13, wherein the coupling agent is EDC hydrochloride.

[0329] 17. The method as described in any one of embodiments 13-16, wherein the additive is HOBt, HOAt or ethyl cyanohydroxyimino.

[0330] 18. The method of any one of embodiments 13-16, wherein the additive is ethyl cyanohydroxyimino.

[0331] 19. The method as described in any one of embodiments 13-18, wherein the first organic solvent is a polar organic solvent.

[0332] 20. The method as described in embodiment 19, wherein the polar organic solvent is a polar aprotic organic solvent.

[0333] 21. The method of embodiment 20, wherein the polar aprotic organic solvent is dimethylformamide or diethylformamide.

[0334] 22. The method as described in embodiment 20, wherein the polar aprotic organic solvent is dimethylformamide.

[0335] 23. The method as described in any one of embodiments 13-22, wherein the molar ratio of the amount of coupling agent to the amount of compound of formula (II) is at least about 1.0 equivalent.

[0336] 24. The method as described in any one of embodiments 13-22, wherein the molar ratio of the amount of coupling agent to the amount of compound of formula (II) is about 1.2 equivalents.

[0337] 25. The method as described in any one of embodiments 13-24, wherein the molar ratio of the amount of additive to the amount of compound of formula (II) is at least about 1.0 equivalent.

[0338] 26. The method as described in any one of embodiments 13-24, wherein the molar ratio of the amount of additive to the amount of compound of formula (II) is about 1.0 equivalent.

[0339] 27. The method as described in any one of embodiments 13-26, wherein the concentration of the compound of formula (II) in the first organic solvent is at least about 0.1 mol / L.

[0340] 28. The method as described in any one of embodiments 13-26, wherein the concentration of compound (II) in the first organic solvent is about 0.8 mol / L.

[0341] 29. The method as described in any one of embodiments 13-28, wherein in step (a), the mixture is stirred for at least about 5 minutes.

[0342] 30. The method as described in any one of embodiments 13-28, wherein in step (a), the mixture is stirred for about 1 hour.

[0343] 31. The method as described in any one of embodiments 13-30, wherein the molar ratio of the amount of compound (III) to the amount of compound (II) is at least about 1.0 equivalent.

[0344] 32. The method as described in any one of embodiments 13-30, wherein the molar ratio of the amount of compound (III) to the amount of compound (II) is about 1.2 equivalents.

[0345] 33. The method as described in any one of embodiments 13-32, wherein in step (b), the mixture is stirred for at least about 5 minutes.

[0346] 34. The method as described in any one of embodiments 13-32, wherein in step (b), the mixture is stirred for at least about 1 hour.

[0347] 35. The method as described in any one of embodiments 13-34, wherein in step (c), the temperature is at least about 60°C.

[0348] 36. The method as described in any one of embodiments 13-34, wherein in step (c), the temperature is at least about 75°C.

[0349] 37. The method as described in any one of embodiments 13-34, wherein in step (c), the temperature is about 95°C.

[0350] 38. The method as described in any one of embodiments 13-37, wherein, in step (c), the mixture is stirred at the temperature for at least about 1, 2, 3, 4 or 5 minutes.

[0351] 39. The method as described in any one of embodiments 13-37, wherein in step (c), the mixture is stirred at the temperature for at least about 1 hour.

[0352] 40. The method as described in any one of embodiments 13-37, wherein in step (c), the mixture is stirred at the temperature for about 5 hours.

[0353] 41. The method as described in any one of embodiments 13-37, wherein in step (c), the mixture is stirred at the temperature for about 18 hours.

[0354] 42. The method as described in any one of embodiments 13-41, wherein in step (d), the mixture is cooled to about 5-25°C.

[0355] 43. The method as described in any one of embodiments 13-41, wherein in step (d), the mixture is cooled to about 15-20°C.

[0356] 44. The method as described in any one of embodiments 13-43, wherein, in step (d), the volume ratio of water to the first organic solvent is at least about 1.

[0357] 45. The method as described in any one of embodiments 13-43, wherein, in step (d), the volume ratio of water to the first organic solvent is about 2.

[0358] 46. ​​The method as described in any one of embodiments 13-45, wherein in step (e), the mixture is stirred at about 5-25°C.

[0359] 47. The method as described in any one of embodiments 13-45, wherein, in step (e), the mixture is stirred at about 15-20°C.

[0360] 48. The method as described in any one of embodiments 13-47, wherein in step (e), the slurry is stirred for at least about 5 minutes.

[0361] 49. The method as described in any one of embodiments 13-47, wherein in step (e), the slurry is stirred for about 1 hour.

[0362] 50. The method as described in any one of embodiments 13-49, wherein, in step (g), the volume ratio of water to the first organic solvent in each washing cycle is at least about 0.5.

[0363] 51. The method as described in any one of embodiments 13-49, wherein, in step (g), the volume ratio of water to the first organic solvent in each washing cycle is about 0.5.

[0364] 52. The method as described in any one of embodiments 13-51, wherein the solid is washed with water at least once.

[0365] 53. The method as described in any one of embodiments 13-51, wherein the solid is washed twice with water.

[0366] 54. The method as described in any one of embodiments 13-53, wherein the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is at least about 0.5.

[0367] 55. The method as described in any one of embodiments 13-53, wherein the volume ratio of the second organic solvent to the first organic solvent in each washing cycle is about 0.5.

[0368] 56. The method as described in any one of embodiments 13-55, wherein the solid is washed at least once with a second organic solvent.

[0369] 57. The method as described in any one of embodiments 13-55, wherein the solid is washed twice with a second organic solvent.

[0370] 58. The method as described in any one of embodiments 13-57, wherein the second organic solvent is an ether.

[0371] 59. The method as described in embodiment 58, wherein the ether is a dialkyl ether.

[0372] 60. The method of embodiment 58, wherein the ether is a methyl tert-butyl ether.

[0373] 61. The method as described in any one of embodiments 13-60, wherein the solid is dried at about 55°C.

[0374] 62. The method as described in implementation scheme 1, wherein the method includes the following steps:

[0375] (a) To The compound was added to a solution of dimethylformamide with EDC hydrochloride and ethyl cyanohydroxyimino to form a mixture, and the mixture was stirred for at least about 1 hour.

[0376] (b) Combine the mixture from step (a) with... The compounds are stirred together;

[0377] (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;

[0378] (d) Cool the mixture from step (c) to about 15-20°C and add water to form a slurry;

[0379] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0380] (f) Filter the slurry from step (e) to form a solid;

[0381] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0382] (h) Dry the solid from step (g) in a vacuum at approximately 55°C to form Compounds, wherein the variables are as defined in Implementation Scheme 1.

[0383] 63. The method as described in any one of embodiments 13-62 further includes the solid from step (h) of recrystallization from the solvent.

[0384] 64. The method as described in embodiment 63, wherein the solvent is water, dimethylformamide, ethanol or methyl tert-butyl ether.

[0385] 65. The method as described in embodiment 63, wherein the solvent is ethanol.

[0386] 66. The method of embodiment 63, wherein when the solvent is ethanol or methyl tert-butyl ether, the mixture forms a slurry.

[0387] 67. The method of embodiment 66, wherein when the solvent is ethanol, the slurry is heated to a temperature of at least about 50°C.

[0388] 68. The method of embodiment 66, wherein when the solvent is ethanol, the slurry is heated to a temperature of approximately 75°C.

[0389] 69. The method as described in embodiment 68, wherein the slurry is stirred at about 75°C for about 15 hours.

[0390] 70. The method of embodiment 66, wherein when the solvent is methyl tert-butyl ether, the slurry is heated to a temperature of at least about 30°C.

[0391] 71. The method of embodiment 66, wherein when the solvent is methyl tert-butyl ether, the slurry is heated to a temperature of at least about 45°C.

[0392] 72. The method as described in embodiment 71, wherein the slurry is stirred at about 45°C for about 15 hours.

[0393] 73. The method as described in any one of embodiments 63-72, wherein the purity of the recrystallized solid is at least about 95%.

[0394] 74. The method as described in any one of embodiments 63-72, wherein the purity of the recrystallized solid is at least about 99%.

[0395] 75. The method as described in any one of embodiments 63-72, wherein the purity of the recrystallized solid is about 99.5%.

[0396] 76. The method as described in any one of embodiments 63-75, wherein the color of the recrystallized solid is white to off-white.

[0397] 77. The method as described in any one of embodiments 1-76, wherein X is O.

[0398] 78. The method as described in any one of embodiments 1-77, wherein Y is O.

[0399] 79. The method as described in any one of embodiments 1-78, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The formula is given by the variables as defined in Implementation Scheme 1.

[0400] 80. The method as described in any one of embodiments 1-78, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The formula is given by the variables as defined in Implementation Scheme 1.

[0401] 81. The method as described in any one of embodiments 1-80, wherein R4 or R5 is each independently H or an optionally substituted C1-C6 alkyl group.

[0402] 82. The method as described in any one of embodiments 1-80, wherein R4 or R5 is H.

[0403] 83. The method as described in any one of embodiments 1-80, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The formula is given by the variables as defined in Implementation Scheme 1.

[0404] 84. The method as described in embodiment 83, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The formula is given by the variables as defined in Implementation Scheme 1.

[0405] 85. The method as described in any one of embodiments 1-84, wherein R2 or R3 is each independently H or an optionally substituted C1-C6 alkyl group.

[0406] 86. The method as described in any one of embodiments 1-84, wherein R2 and R3 are both optionally substituted C1-C6 alkyl groups.

[0407] 87. The method as described in any one of embodiments 1-84, wherein R2 and R3 are both methyl or ethyl.

[0408] 88. The method as described in any one of embodiments 1-84, wherein R2 or R3 is H.

[0409] 89. The method as described in any one of embodiments 1-84, wherein R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0410] 90. The method as described in any one of embodiments 1-84, wherein R2 and R3 together are optionally substituted 5, 6 or 7-membered cycloalkyl or heterocycloalkyl.

[0411] 91. The method as described in any one of embodiments 1-84, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has The structure is as defined in Implementation 1.

[0412] 92. The method as described in any one of embodiments 1-91, wherein R1 is an optionally substituted C1-C6 alkyl, an optionally substituted carbocyclic, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0413] 93. The method as described in any one of embodiments 1-91, wherein R1 is an optionally substituted aryl or an optionally substituted heteroaryl.

[0414] 94. The method as described in any one of embodiments 1-91, wherein R1 is an optionally substituted heteroaryl group.

[0415] 95. The method as described in any one of embodiments 1-91, wherein R1 is an optionally substituted nitrogen-containing heteroaryl group.

[0416] 96. The method as described in any one of embodiments 1-91, wherein R1 is

[0417] 97. The method as described in any one of embodiments 1-91, wherein R1 is a specific formula.

[0418] 98. The method as described in embodiment 1, wherein the compound of formula (I) is

[0419] 99. The method as described in Implementation Scheme 1, wherein the method comprises the following steps:

[0420] Under suitable conditions, make the formula Compound contact type Compounds,

[0421] To form with Compounds of a certain structure or their pharmaceutically acceptable salts.

[0422] 100. The method of embodiment 99, wherein the method includes the following steps:

[0423] (a) To Add EDC hydrochloride and ethyl cyanohydroxyimino to a solution of dimethylformamide to form a mixture, and stir the mixture for at least about 1 hour;

[0424] (b) Combine the mixture from step (a) with... The compounds were stirred together for about 1 hour;

[0425] (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;

[0426] (d) Cool the mixture from step (c) to about 15-20°C and add water to the mixture to form a slurry;

[0427] (e) Stir the slurry from step (d) at about 15-20°C for about 1 hour;

[0428] (f) Filter the slurry from step (e) to form a solid;

[0429] (g) Wash the solid from step (f) with water and methyl tert-butyl ether; and

[0430] (h) Dry the solid from step (g) in a vacuum at at least about 55°C to form

[0431] 101. The method as described in any one of embodiments 1-100, further comprising by causing Prepared by contacting R2R3C=O under suitable conditions The method of compounding, and

[0432] in:

[0433] A, B, and E are each independently N or CR6;

[0434] X and Y are each independently O, S, or NR7.

[0435] 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 heteroalkyl, or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0436] 102. The method as described in embodiment 101, wherein the method includes the following steps:

[0437] (a) To The compound is mixed by adding pyrrolidine to a solution of compound R2R3C=O;

[0438] (b) Heat the mixture from step (a) under reflux, stir the mixture at that temperature for about 19.5 hours, cool the mixture to a temperature of about 15-20°C, and add water to the mixture;

[0439] (c) Adjust the pH of the mixture from step (b) to approximately 2 using HCl;

[0440] (d) Stir the mixture from step (c) with n-heptane to form a slurry, stir the slurry at about 15-20°C for about 1 hour, and filter the slurry to form a solid; and

[0441] (e) Wash the solid from step (d) with water and n-heptane; and

[0442] (g) Dry the solid from step (e) in a vacuum at approximately 50°C to form Compound of formula (II), wherein the variables are as defined in implementation scheme 1.

[0443] 103. The method as described in any one of embodiments 1-102, further comprising preparing by contacting a compound of formula R1CN with ammonium hydroxide. A method for a compound, wherein R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group.

[0444] 104. The method as described in embodiment 103, wherein the method includes the following steps:

[0445] (a) Adding hydroxylamine to a solution of the R1CN compound in alcohol to form a mixture;

[0446] (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;

[0447] (c) Cool the slurry from step (b) to ambient temperature and stir it at ambient temperature for about 16 hours;

[0448] (d) Filter the slurry from step (c) to form a solid; and

[0449] (e) Wash the solid from step (d) with alcohol and dry the washed solid in a vacuum at about 50°C to form Compounds.

[0450] 105. The method as described in embodiment 104, wherein the alcohol is an optionally substituted C1-C6 alkyl alcohol.

[0451] 106. The method as described in embodiment 104, wherein the alcohol is methanol, ethanol, propanol or butanol.

[0452] 107. The method as described in embodiment 104, wherein the alcohol is ethanol.

[0453] 108. The method as described in any one of embodiments 104-107, wherein the hydroxylamine is hydroxylamine hydrochloride.

[0454] 109. The method as described in embodiment 108, wherein an organic base is added.

[0455] 110. The method as described in embodiment 109, wherein the organic base is diisopropylethylamine.

[0456] 111. The method as described in embodiment 108 or 109, wherein the molar ratio of the amount of organic base to the amount of hydroxylamine hydrochloride is at least about 1.5 equivalents.

[0457] 112. The method as described in any one of embodiments 104-111, wherein in step (a), the molar ratio of the amount of hydroxylamine to the amount of R1CN is at least about 1.5 equivalents.

[0458] 113. The method as described in any one of embodiments 1-76, wherein The compound is contacted with a coupling agent, with or without additives, to form a compound with... The intermediate, 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl, and wherein R8 is optionally substituted C1-C6 alkyl.

[0459] 114. The method as described in embodiment 113, wherein the intermediate is having Compounds with a specific structure.

[0460] 115. The method as described in embodiment 114, wherein the intermediate is having Compounds with the structure of .

[0461] 116. The method as described in embodiment 114, wherein the intermediate is having Compounds with a specific structure.

[0462] 117. The method as described in embodiment 114, wherein the intermediate is having Compounds with a specific structure.

[0463] 118. The method as described in embodiment 114, wherein the intermediate is having Compounds with a specific structure.

[0464] 119. The method as described in embodiment 114, wherein the intermediate is having Compounds with a specific structure.

[0465] 120. The method as described in embodiment 113, wherein, having The intermediate of the structure further contacts Compounds, to form compounds with The intermediate part of the structure.

[0466] 121. The method as described in embodiment 120, wherein the intermediate is having Compounds with the structure of .

[0467] 122. The method as described in embodiment 120, wherein the intermediate is having Compounds with a specific structure.

[0468] 123. The method as described in embodiment 120, wherein the intermediate is having Compounds with a specific structure.

[0469] 124. The method as described in embodiment 120, wherein the intermediate is having Compounds with a specific structure.

[0470] 125. The method as described in embodiment 120, wherein the intermediate is having Compounds with a specific structure.

[0471] 126. The method as described in embodiment 120, wherein, having The intermediate of the structure is further formed under thermal cyclization and dehydration conditions. Compounds.

[0472] 127. The method as described in implementation scheme 120, wherein, Compounds are

[0473] 128. Compounds having the following structures:

[0474] Or its pharmaceutically acceptable salt.

[0475] Wherein, X is O, S or NR7; 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl, and wherein R8 is optionally substituted C1-C6 alkyl.

[0476] 129. The compound as described in embodiment 128, wherein the compound has the following structure:

[0477] Or its pharmaceutically acceptable salt.

[0478] 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl, and wherein R8 is optionally substituted C1-C6 alkyl.

[0479] 130. The compound as described in embodiment 129, wherein the compound has the following structure: Or its pharmaceutically acceptable salt.

[0480] 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0481] 131. The compound as described in embodiment 129, wherein the compound has the following structure:

[0482] Or its pharmaceutically acceptable salt.

[0483] 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 heteroalkyl, or R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0484] 132. The compound as described in embodiment 129, wherein the compound has the following structure:

[0485] Formula, or its pharmaceutically acceptable salt,

[0486] 133. The compound as described in any one of embodiments 128-132, wherein the compound is isolated from any of the methods described in embodiments 1-76.

[0487] 134. Compounds having the following structures:

[0488] Or its pharmaceutically acceptable salt.

[0489] in:

[0490] R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group.

[0491] R2, R3, R4, and R5 are each independently H, an optional substituted C1-C6 alkyl, an optional substituted C1-C6 hydroxyalkyl, an optional substituted C1-C6 alkoxy, an optional substituted cycloalkyl, or an optional substituted heteroalkyl; R2 and R3 together are optional substituted cycloalkyl or optional substituted heteroalkyl; or R4 and R5 together are optional substituted cycloalkyl or optional substituted heteroalkyl.

[0492] 135. The compound as described in embodiment 134, wherein the compound has the following structure:

[0493] Or its pharmaceutically acceptable salt.

[0494] in:

[0495] R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group; and

[0496] R2, R3, R4, R5, and R6 are each independently H, an optional substituted C1-C6 alkyl, an optional substituted C1-C6 hydroxyalkyl, an optional substituted C1-C6 alkoxy, an optional substituted cycloalkyl, or an optional substituted heteroalkyl; R2 and R3 together are optional substituted cycloalkyl or optional substituted heteroalkyl; or R4 and R5 together are optional substituted cycloalkyl or optional substituted heteroalkyl.

[0497] 136. The compound as described in embodiment 134, wherein the compound has the following structure:

[0498] Or its pharmaceutically acceptable salt.

[0499] 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 heteroalkyl, or R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

[0500] 137. The compound as described in embodiment 134, wherein the compound has the following structure:

[0501] Formula, or its pharmaceutically acceptable salt,

[0502] 138. The compound as described in any one of embodiments 134-137, wherein the compound is isolated from any of the methods described in embodiments 1-76.

[0503] 139. A composition comprising the compound of any one of embodiments 128-138.

[0504] 140. A solution comprising the compound of any one of embodiments 128-138.

[0505] 141. A method for forming a compound of formula I, the method comprising making a compound having Compounds of the formula react under thermal cyclization and dehydration conditions to form Compounds.

[0506] 142. A kind of formula The crystalline form of the compound, wherein the crystalline form is crystal form I of the compound.

[0507] 143. Crystalline form I as described in embodiment 142, characterized in that the X-ray powder diffraction pattern includes peaks at approximately 8.9 ± 0.5 degrees 2θ, approximately 9.4 ± 0.5 degrees 2θ, 15.7 ± 0.5 degrees 2θ, approximately 17.7 ± 0.5 degrees 2θ, approximately 18.9 ± 0.5 degrees 2θ, 24.3 ± 0.5 degrees 2θ, approximately 26.0 ± 0.5 degrees 2θ, and approximately 26.7 ± 0.5 degrees 2θ.

[0508] 144. The crystalline form I as described in embodiment 142, characterized in that it comprises as follows: Figure 6 The X-ray powder diffraction pattern of one or more peaks is shown.

[0509] 145. Crystalline form I as described in embodiment 143, characterized in that it comprises an X-ray powder diffraction pattern of one or more peaks as shown in Table 14.

[0510] 146. The crystalline form I as described in embodiment 142, characterized in that it comprises one or more X-ray powder diffraction patterns with d-spacing values ​​of approximately 10.0 ± 0.5 Å, approximately 9.4 ± 0.5 Å, approximately 5.6 ± 0.5 Å, approximately 5.0 ± 0.5 Å, approximately 4.7 ± 0.5 Å, approximately 3.7 ± 0.5 Å, approximately 3.4 ± 0.5 Å, and approximately 3.3 ± 0.5 Å.

[0511] Example

[0512] Example 1: Method for preparing compound (I)

[0513] This document provides certain synthetic methods, including general and specific methods. The compounds disclosed herein can be prepared according to the methods described herein, or intermediates that produce the compounds disclosed herein can be prepared according to the methods described herein. Substitutions may vary depending on the compound or intermediate prepared, based on the examples below and other modifications known to those skilled in the art.

[0514] The methods disclosed herein are used to prepare the following compounds in the examples below, or, according to those skilled in the art, to modify the examples to prepare compounds.

[0515] General Step A:

[0516] Option 1

[0517]

[0518] Synthesis of compound 2-2: N-hydroxy-1H-pyrazole-4-formamidin 2-2

[0519] Option 2

[0520]

[0521] Synthesis of compound 2-2: N-hydroxy-1H-pyrazole-4-formamidinium.

[0522] Based on the results in Table 1, EtOH was found to be the preferred solvent for the synthesis of N-hydroxy-1H-pyrazole-4-formamidin (compound 2-2).

[0523] Table 1 Screening of reaction conditions for the synthesis of compound 2-2.

[0524]

[0525] *Note: Compound 2-2 (%) = AUC (%), determined by HPLC.

[0526] Next, a specific volume of ethanol (EtOH) was used to separate N-hydroxy-1H-pyrazole-4-formamidinium (compound 2-2) (Table 2). First, the volume of EtOH was reduced to 25 times (25 vol) the volume of compound 2-1 in Scheme 2. It was observed that by reacting with a lower volume of solvent, the product precipitated from the reaction mixture after the reaction was complete. The desired product was separated by direct filtration as a white solid (99.9% purity, 84.9% yield). Next, different volumes of ethanol were investigated. The yields were similar for 5, 10, and 20 times the volume of EtOH for compound 2-1 in Scheme 2. However, a decrease in yield was observed when using 15 times the volume of EtOH. The purity of the product was consistent, indicating that the quality of the product is not dependent on the solvent loading. The effect on the yield on a larger scale was investigated by reacting compound 2-1 at a scale of 25 g with 5, 10, and 25 times the volume of EtOH for compound 2-1 (Table 3). An increase in yield was observed as the volume of EtOH decreased. It was found that the volume of EtOH required to provide the optimal yield for the synthesis of N-hydroxy-1H-pyrazole-4-formamidin (compound 2-2) was 5 times that of compound 2-1 (5 vol). This result was unexpected.

[0527] Table 2 Screening of isolation conditions for the synthesis of compound 2-2.

[0528]

[0529]

[0530] *Note: Compound 2-2 (%) = AUC (%), determined by HPLC.

[0531] Table 3. EtOH volume screening for the synthesis of compound 2-2 at a scale of 25 g.

[0532]

[0533] *Note: Compound 2-2 (%) = AUC (%), determined by HPLC.

[0534] Synthesis of compound 2-2: N-hydroxy-1H-pyrazole-4-formamidin

[0535] Hydroxylamine hydrochloride (28 g) and N,N-diisopropylethylamine (DIPEA) (93.8 mL) were added to a stirred solution of 4-cyanopyrazole (2-1, 25 g) in ethanol (125 mL). The reaction mixture was heated to 75 °C and stirred for 4 hours. During the 4 hours of stirring, the reaction mixture turned into a white slurry. The slurry was cooled to ambient temperature and stirred for 16 hours. The slurry was filtered to obtain a solid, which was washed with EtOH (50 mL x 2). The collected solid was dried under vacuum at 50 °C to give N-hydroxy-1H-pyrazole-4-methylamidine (compound 2-2) (22.8 g, 67.3% yield) as a white solid.

[0536] The calculated value of UPLC-qDa(C4H6N4O) is 127.05 [M+H]. + The measured value is 127.03.

[0537] 1 H NMR (500MHz, DMSO-d6) δppm 5.63 (s, 2H), 7.67 (bs, 1H), 7.96 (bs, 1H), 9.11 (s, 1H), 12.87 (bs, 1H).

[0538] General Step B:

[0539] Option 3

[0540]

[0541] Synthesis of compound 4-2: 2,2-Diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid scheme 4

[0542]

[0543] Synthesis of compound 4-2: 2,2-Diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid

[0544] The synthetic route in Scheme 4 involves reacting 3-acetyl-4-hydroxybenzoic acid compound 4-1 with 3-pentanone in the presence of pyrrolidine to generate 2,2-diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 2-2). The reaction solvent was screened by starting the reaction in toluene (Table 4). The initial laboratory run followed the steps outlined in patent WO 2000 / 03681, in which pyrrolidine (0.5 equivalents) and 3-pentanone (1.0 equivalents) were added to 15 times their volume (15 vol) of 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 h, showing a low conversion of 3.0%. Subsequently, the order of addition was changed, with pyrrolidine and 3-pentanone added to 3-acetyl-4-hydroxybenzoic acid (compound 4-1) in toluene. The equivalents of pyrrolidine and 3-pentanone were also increased in an attempt to further advance the reaction. The reaction in toluene was slow and did not show high conversion to the desired product. Polar solvents were screened due to the slow reaction kinetics in nonpolar solvents such as toluene. The reaction in EtOH showed an 80.6% conversion after 48 hours. Next, acetic acid was added as an additive in an attempt to accelerate the reaction by aiding the mechanically occurring proton transfer. The addition of acetic acid did not show a significant increase in conversion. The reaction in isopropanol (IPA) showed similar results to that in EtOH. 1-Propanol was included because of its higher boiling point, which would allow the reaction to proceed at a higher temperature. The reaction in 1-propanol showed similar conversions to those in EtOH and IPA, only with a shorter reaction time. 3-Pentanone was added as a solvent, serving a dual role as both a solvent and a reagent in the reaction. The reaction in 10 times the volume (10 vol) of 3-pentanone in compound 4-1, carried out at 95 °C, showed the highest conversion and the shortest reaction time.

[0545] Table 4. Screening of reaction conditions for the synthesis of compound 4-2.

[0546]

[0547] *Note: Compound 4-2 (%) = AUC (%), determined by HPLC.

[0548] **0.5 equivalents of acetic acid used as an additive**

[0549] The volume of 3-pentanone was examined as a result of its dual role as both solvent and reagent (Table 5). The reaction was carried out in 2.5 times the volume (2.5 vol) of compound 4-1, showing a conversion of 71.9% at 16 hours. Adding an additional 3-pentanone (1.25 vol) to the reaction increased the conversion to 90.6% at 21 hours. The reaction was carried out in 3-pentanone (5 vol), with a conversion of 73.2% at 16 hours. Adding an additional 3-pentanone (1.25 vol) to the reaction increased the conversion to 92.6% at 21 hours. Based on the results seen in round 2, the reaction was carried out in 3-pentanone (6.25 vol), with 100% conversion observed at 19 hours. It was found that the reaction proceeded and completed more rapidly when an excess of 3-pentanone (6.25 vol) was initially used during the reaction process. It was found that the volume of 3-pentanone as a solvent that provided the best yield was 6.25 times that of compound 4-1.

[0550] Table 5. Volume screening of 3-pentanone used for the synthesis of compound 4-2.

[0551]

[0552] *Note: Compound 4-2 (%) = AUC (%), determined by HPLC.

[0553] **Add an additional 3-pentanone (1.25 vol) to promote the reaction to the reported conversion.

[0554] Crystallization conditions were developed for the separation of compound 4-2, 4,2-diethyl-4-oxonyl-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (Table 6). Initial separation of the product involved acid-base extraction, yielding compound 4-2 as a yellow solid. The reaction mixture was diluted with ethyl acetate (EtOAc) 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 using 5 M NaOH. The organic layer was concentrated under pressure to obtain the desired product as a yellow crystalline solid. Next, direct crystallization from the reaction mixture was investigated. It was found that crystallization occurred by first adding H₂O and then adjusting the pH of the reaction mixture to 2 using 5 M HCl to form a slurry. The slurry was filtered to produce compound 4 as a yellow solid in 59.8% yield. Different solvents were screened in an attempt to improve the yield. No solid was separated when acetone and isopropanol (IPA) were used as antisolvents. After pH adjustment, the addition of n-heptane to the slurry at 20 °C resulted in a slight increase in yield. Next, adding n-heptane to the slurry at 10-15°C increased the yield by 77.4%. These conditions were found to enhance the crystallization of 2,2-diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2).

[0555] Table 6. Screening of isolation conditions for the synthesis of compound 4-2.

[0556]

[0557]

[0558] *Note: Compound 4-2 (%) = AUC (%), determined by HPLC.

[0559] Synthesis of compound 4-2: 2,2-Diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid

[0560] Pyrrolidine (18.5 mL) was added to a stirred solution of 3-acetyl-4-hydroxybenzoic acid (compound 4-1, 20 g) in 3-pentanone (125 mL). The reaction was heated to 95 °C and stirred for 19.5 h. The reaction 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 5 M HCl solution (55 mL). n-Heptane (60 mL) was added and the slurry was stirred at 15–20 °C for about 1 h. 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 give compound 4-2 (17.8 g, yield 64.5%), a yellow solid.

[0561] UPLC-qDa(C 14 H 16 O4) Calculated value: 249.11 [M+H] + The measured value was 249.19. 1 H NMR (500MHz, CDCl3) δppm 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=2.2Hz,1H).

[0562] Figure 4 The results of polarized light microscopy (PLM) analysis of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1) (10 μm scale) are shown. Those skilled in the art will understand that the results were produced using conventional polarized light microscopy methods known and understood by those skilled in the art.

[0563] Figure 5 The results of differential thermal analysis (DSC) of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1) are shown. Those skilled in the art will understand that these results were produced using conventional polarized light microscopy methods known and understood by those skilled in the art.

[0564] Figure 6 The table shows the X-ray powder diffraction (XRPD) results for 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1), which, as will be understood by those skilled in the art, were produced using conventional polarized light microscopy methods known and understood by those skilled in the art.

[0565] Table 14. X-ray powder diffraction (XRPD) results of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1). Figure 6 The XRPD peaks in this paper are indexed and listed.

[0566]

[0567]

[0568] General step C:

[0569] Option 5

[0570]

[0571] Example 2: Synthesis of compound 6-1: 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethyltryptane-4-one

[0572] Option 6

[0573] Route 1

[0574]

[0575] Route 2

[0576]

[0577] Synthesis of Compound 6-1: 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethyltryptane-4-one

[0578] 2-Methyltetrahydrofuran (MeTHF) was screened as a potential solvent for the synthesis of compound 6-1 (Table 7). An alternative solvent was investigated because DMF is difficult to remove due to its low evaporation rate. The reaction was carried out at 75 °C in 10 vol of MeTHF, the same volume as compound 4-2. During the reaction, the reaction mixture became very viscous, and separation of the product proved difficult. The reaction produced compound 4-2 in 21.9% yield. For comparative purposes, the reaction was carried out in parallel at 95 °C in 10 vol of DMF, the same volume as compound 4-2. Separation of compound 6-1 was obtained by crystallization in 64.3% yield. DMF was found to be a suitable solvent for the synthesis of compound 6-1.

[0579] Table 7. Solvent screening for the synthesis of compound 6-1.

[0580]

[0581] The volume of DMF was screened to determine the concentration used for the reaction and crystallization (Table 8). The reaction, carried out in 15 times the volume of DMF (15 vol) of compound 4-2, resulted in a low yield, likely due to the solubility of the product in DMF. The reaction, carried out in 2.5 times the volume of DMF (2.5 vol) of compound 4-2, became very viscous, and separation of the product proved difficult. Although the reaction produced a good yield, the purity of compound 6-1 was found to be low. Reactions carried out in 5 times and 10 times the volume of DMF (5 vol and 10 vol) of compound 4-2 showed favorable results with similar yields. In one embodiment of the reaction, the volume of DMF was found to be 5 times that of compound 4-2.

[0582] Table 8. DMF volume screening used for the synthesis of compound 6-1.

[0583]

[0584] *Note: Compound 6-1 (%) = AUC (%), determined by HPLC.

[0585] The initial separation technique for compound 6-1 involved column chromatography. Separation of the desired compound 6-1 by column chromatography resulted in a low yield of 34.6%. Crystallization conditions were screened to exclude chromatographic methods (Table 9). Direct crystallization from the reaction mixture was explored to separate compound 6-1. Water was added to the reaction mixture to initiate crystallization of the desired compound 6-1. Compound 6-1 was reported as a white solid in patent application publication WO 2018 / 231745. However, the solid separated from the crystals was a brownish-red solid. To improve the appearance of the solid and the yield, the addition of an antisolvent was explored. Addition of H₂O at 20°C, followed by 5M NaOH, resulted in a slight improvement in appearance, but a low yield of 64.3%. Next, addition of H₂O and 5M NaOH at 5°C showed a slight increase in yield. Addition of H₂O at 20°C, followed by 5M HCl, resulted in a slightly improved appearance and a low yield of 63.5%. Addition of MeOH as an antisolvent resulted in a significant decrease in yield. Adding water to the reaction mixture at 5°C resulted in similar yields compared to addition at 20°C. Further investigation with larger volumes of water revealed that the yield did not increase significantly with increasing water volume. Based on yield and appearance, the optimal conditions for isolating compound 6-1 were found to be crystallization at 20°C with 10 times the volume of H₂O (10 vol) of compound 4-2.

[0586] Table 9. Screening of isolation conditions for compound 6-1.

[0587]

[0588]

[0589] The crystallization of compound 6-1 yielded a crystalline brownish-red solid. The presence of Oxyma in the product was a potential factor influencing its color; therefore, the Oxyma loading was screened (Table 10). The reaction progress decreased significantly with decreasing Oxyma loading. Lower Oxyma loading did not improve the appearance of compound 6-1 and led to a significant decrease in yield.

[0590] Table 10. Reagent loading screening for the synthesis of compound 6-1.

[0591]

[0592] Different color-restoring conditions were screened to improve the appearance of compound 6-1. Simultaneously, the purity and potency (%w / w) of the drug were analyzed. Potency was tabulated based on input materials and normalized relative to 100%. First, recrystallization of the brown compound 6-1 was explored as a color-restoring method to improve its appearance (Table 11). DMF and dimethyl sulfoxide (DMSO) were chosen because compound 6-1 is soluble in both solvents. The brown compound 6-1 was dissolved in the solvents at the desired temperature and stirred for 4 hours. Crystallization occurred upon addition of water at 15–20 °C, and the solid was obtained by filtration. Recrystallization in DMSO at 20 °C improved appearance, purity, and potency. Different temperatures for recrystallization in DMF were screened. Higher temperatures in DMF resulted in a decrease in both the final potency and recovery of compound 6-1.

[0593] Table 11. Color restoration screening for recrystallization of brown compound 6-1

[0594]

[0595]

[0596] *Note: Purity (%) = AUC (%), determined by HPLC.

[0597] Next, char treatment was used as a color restoration method (Table 12). Due to the solubility of compound 6-1, DMF and DMSO were used as solvents. The char treatment involved adding activated charcoal (5 wt%) to a solution of the brown compound 6-1 in the solvent and stirring at 20°C for 5 hours. The charcoal was filtered off, and crystallization occurred upon addition of water at 15-20°C, followed by filtration to obtain a solid. Charcoal treatment in DMF resulted in increased purity and potency, with a recovery rate of 63.4%. Compared to DMF, charcoal treatment in DMSO showed slightly lower purity and potency, but a higher recovery rate of 70.4%.

[0598] Table 12. Color Restoration Screening: Carbon Treatment

[0599]

[0600] *Note: Purity (%) = AUC (%), determined by HPLC.

[0601] Another color restoration method involved reslurrying the brownish compound 6-1 in various solvents where it exhibited low solubility. Various solvents were screened for reslurrying (Table 13). The reslurrying procedure involved stirring compound 6-1 in the desired solvent at a specified temperature for 15 hours. The final compound 6-1 was then separated by filtration. Solids separated from reslurries in MeOH, EtOAc, and acetone showed visual improvement in color. However, reslurrying in these solvents resulted in very low recoveries, making it impossible to analyze purity and potency. Reslurrying in MTBE at 45°C yielded white to off-white solids with a purity of 97.2%, a potency of 101.8%, and a recovery of 81.2%. Different solvent volumes and temperatures were screened for reslurrying in EtOH. Solids separated from a reslurry in 10 times the volume of compound 6-1 in EtOH (10 vol) at 45°C showed visual improvement in color. However, the recovery of the reslurry was so low that it was impossible to analyze purity and potency. The final compound 6-1 obtained from the reslurry in EtOH (10 vol) at 20 °C yielded 98.7% purity, 101.7% potency, and 75.7% recovery. The final compound 6-1 obtained from the reslurry in five times the volume of EtOH (5 vol) at 75 °C yielded 99.8% purity, 105.6% potency, and 66.0% recovery.

[0602] Recrystallization and char treatment in DMSO and DMF were not selected as color restoration steps. While they did produce favorable improvements in compound 6-1, both solvents were difficult to remove due to their respective high boiling points. Reslurrying in EtOH (5 vol) at 75 °C showed the most favorable results and was selected as the method for restoring the brown color of compound 6-1.

[0603] Table 13. Color restoration screening: Resin

[0604]

[0605] *Note: Purity (%) = AUC (%), determined by HPLC.

[0606] Synthetic Experiment of Compound 6-1: 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

[0607] To a stirred solution of 2,2-diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2, 70 g), EDCI (64.9 g) and ethyl cyanohydroxyiminoacetate (Oxyma, 40.1 g) were added to N,N-dimethylformamide (DMF, 350 mL). The reaction was stirred at ambient temperature for 1 hour. N-hydroxy-1H-pyrazole-4-formamidinium (compound 2-2, 42.7 g) was added, and the reaction was stirred at ambient temperature for 1 hour. The reaction was heated to 95 °C and stirred for 5 hours. The reaction 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 about 1 hour. The slurry was filtered to obtain a solid, which was washed with water (175 mL x 2) and methyl tert-butyl ether (“MTBE”) (175 mL x 2). The collected solid was dried under vacuum at 55°C to obtain a brownish-brown compound 6-1 (75.2 g) that was a brownish-brown solid.

[0608] The brown compound 6-1 was stirred with EtOH (375 mL) to form a slurry, which was then heated to 75 °C. The slurry was maintained at 75 °C for 16 hours. The slurry was then cooled to 15-20 °C and stirred for about 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 give 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one (compound 6-1) (63.2 g, 66.2% yield) as a white to off-white solid.

[0609] UPLC-qDa(C 18 H 18 Calculated value of N4O3: 339.15 [M+H] + The measured value is 339.14.

[0610] 1 H NMR(500MHz,DMSO-d6)δppm 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=2.20Hz, 1H), 8.48 (s, 1H), 13.48 (bs, 1H).

[0611] Compound 6-1: An ester intermediate for the synthesis of 6-(3-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)-2,2-diethylchroman-4-one

[0612] Scheme 7's one-pot process consists of two different chemical bond-forming transformations. First, esterification of 2,2-diethyl-4-oxoylide-3,4-dihydro-2H-1-benzopyran-6-carboxylic acid (compound 4-2) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and ethyl cyanohydroxyiminoacetate (Oxyma) yields intermediate 7-1. Next, esterification of intermediate 7-1 is carried out in the presence of N-hydroxy-1H-pyrazole-4-formamidinium (compound 2-2) to yield intermediate 7-2. Then, thermal cyclization dehydration is performed following the esterification between compounds 4-2 and 2-2 to produce compound 6-1. The two transition intermediates are separated and characterized using conventional methods known to those skilled in the art and used for in-process analytical purposes.

[0613] Option 7

[0614]

[0615] Intermediate 7-1: (Z)-2-cyano-2-(((2,2-diethyl-4-oxomylidene-6-carbonyl)oxy)imino)ethyl acetate

[0616] Oxyma ester intermediate 7-1 1 H-NMR: 1 H NMR (500MHz, CDCl3) δppm 0.95-0.98 (t, J=7.44Hz, 6H), 1.44-1.47 (t, J=7.08Hz, 3H), 1.74-1.88

[0617] (m,4H),2.80(s,2H),4.50-4.54(q,J=7.16Hz,2H),7.09-7.10(d,J=8.78H z, 1H), 8.22-8.25 (dd, J = 8.78, 2.22Hz, 1H), 8.69-8.70 (d, J = 2.20Hz, 1H).

[0618] Intermediate 7-2: N-((2,2-diethyl-4-oxomylidene-6-carbonyl)oxy)-1H-pyrazole-4-formamidin

[0619] Oxyma ester intermediate 7-2 1 H-NMR: 1H NMR(400MHz,CDCl3)δppm 0.85-0.88(t,J=7.22Hz,6H),1.61-1.78(m,4H),2.67(s,2H),5.93(bs,2H),6.86-6.88(d,J=8.59Hz,1H),7.85(s,2H),8.05-8.08(dd,J=8.78,1.95Hz,1H),8.39-8.40(d,J=1.95Hz,1H)。

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, said method comprising: Under suitable conditions compound contact Compounds, to produce compounds having the following formula in: A, B, and E are each independently N or CR6; X and Y are each independently O, S, or NR7; R1 is H, OH, NH2, NO2, an optionally substituted carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group, a branched or unbranched alkyl alcohol, a halogen, a branched or unbranched alkyl group, an amide, a cyano group, an alkoxy group, a haloalkyl group, an alkylsulfonyl group, a nitrite group, or an alkylthio group. 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 heteroalkyl; R2 and R3 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl; or R4 and R5 together are optionally substituted cycloalkyl or optionally substituted heteroalkyl.

2. The method as described in claim 1, wherein, The method further includes... Compounds and Compound coupling to produce The compound, wherein the variable is defined as in claim 1.

3. The method as described in claim 2, wherein, The coupling involves contacting compounds of formula (II) and (III) with a coupling agent and optionally with an additive to a solution containing compounds of formula (II) and (III).

4. The method of claim 3, further comprising a quenching reaction to form a mixture containing... A slurry of a compound or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, further comprising separating A compound or a pharmaceutically acceptable salt thereof, wherein the variable is as defined in claim 1.

6. The method of claim 1, wherein, The method includes the following steps: (a) Add the coupling agent and optional additives to The compound is placed in a solution in a first organic solvent to form a mixture, and the mixture is stirred for at least about 5 minutes; (b) Combine the mixture from step (a) with... The compounds are stirred together; (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) and add water to the mixture to form a slurry; (e) The slurry from step (d); (f) Filter the slurry from step (e) to obtain a solid; (g) Wash the solids from step (f) with water and / or a second organic solvent; and (h) Dry the solid from step (g) in a vacuum at a temperature of at least about 30°C to form A compound, wherein the variable is as defined in claim 1.

7. The method of claim 6, wherein, The coupling agent is carbodiimide.

8. The method of claim 6, wherein, The coupling agent is EDC hydrochloride.

9. The method according to any one of claims 6-8, wherein the additive is HOBt, HOAt, or ethyl cyanohydroxyimino.

10. The method according to any one of claims 6-8, wherein the additive is ethyl cyanohydroxyimino.

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