Preparation process for PI3K inhibitors

Abstract

This disclosure provides a process for preparing compounds of formula (I), such as (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (compound 1), and salts and / or solvates thereof, which inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα).

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 532,695, filed on 15 August 2023, which is incorporated herein by reference in its entirety.

[0002] (Field of invention) This disclosure provides a process for preparing compounds of formula (I), such as (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (compound 1), and salts and / or solvates thereof, which inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). [Background technology]

[0003] The phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene, is part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several researchers have demonstrated the role of PI3K / AKT signaling in physiological and pathophysiological functions that drive tumor progression, including metabolism, cell growth, proliferation, angiogenesis, and metastasis. (See Fruman, DA The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018, 15, 273-291) Suppression of PI3K / AKT / TOR signaling (e.g., pharmacological or genetic) can lead to cancer cell death and regression of tumor growth.

[0004] The specific compounds of formula (I) are described in International Publication No. 2022 / 265993, which is incorporated herein by reference in its entirety. Alternative synthetic procedures for the preparation of compounds of formula (I) are needed. Such alternative synthetic procedures are disclosed herein. [Overview of the project]

[0005] Some embodiments are based on formula (I): [ka] A process for preparing a compound, or a salt and / or solvate thereof, Formula (Ii): [ka] The compound, (i) Carbonyl equivalents, and (ii) Equation (I-ii) [ka] By bringing it into contact with the compound, This includes forming a compound of formula (I), wherein, Z is O or NR x And, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 However, they are independently selected from halogens, hydroxyls, cyanos, optionally substituted with hydroxyls, C1-C6 alkyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R 2 These are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoropolymers. R 3is C1~C6 alkyl, C1~C6 haloalkyl, or C3~C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1~C6 alkyl, Ring A is 6-10 membered aryl, C3~C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, each R 4 is independently (i) halogen, (ii) C1~C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NR A R B , (iii) C1~C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3~C6 cycloalkyl, (iv) C1~C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii) -SO2(C1~C6 alkyl), (xiii) -S(=O)(=NH)(C1~C6 alkyl), (xiv) -C(=O)(C1~C6 alkyl), (xv) -CO2(C1~C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1~C6 alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G , and (xviii) 3-9 membered cycloalkyl optionally substituted with 1 or 2 independently selected R GSelected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1~C6 alkyl), (vi)-C(=O)O(C1~C6 alkyl), (vii)-SO2(C1~C6 alkyl), (viii) 3-6 member cycloalkyls optionally substituted with hydroxyl, (ix) Optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl group substituted with one or two substituents independently selected from 5-6 member heteroaryl groups, 3-6 member cycloalkyl groups, -SO2(C1-C6 alkyl groups), -CO2H, and -SO2(NH2), or R C and R D However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR compounds. B1 R C1 , -SO2(C1~C6 alkyl), -CO2H, C1~C6 alkyl, C1~C6 alkoxy, and C1~C6 haloalkoxy are optionally substituted with hydroxyl to form 4~10 membered heterocyclines, Each R A2 , R B2 , and R C2 These are independently hydrogen or C1-C6 alkyl groups. Each R GHowever, independently, fluoro, cyano, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and -NR compounds exist. A1 R B1 ,=NR A2 -C(=O)NR C1 R D1 The present invention provides a process selected from the group consisting of -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, C1~C6 haloalkoxy, -SO2(C1~C6 alkyl), and -CO2H.

[0006] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, [ka] of, (i) Carbonyl equivalents, and (ii) Structure [ka] By contacting it with pyrimidine-2,5-diamine having, The present invention provides a process that includes forming compound 1.

[0007] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, [ka] The present invention provides a process that includes reacting to form compound 1.

[0008] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, [ka] Make contact with it, [ka] The formation of a formula in which R'' is a C1-C6 alkyl, and [ka] The present invention provides a process that includes reacting to form compound 1.

[0009] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) [ka] Make contact with it, [ka] The process involves forming a compound such that R'' is a C1-C6 alkyl compound. (b) [ka] Contact it with a trifluoromethylation reagent, [ka] To form, (c) [ka] Bring it into contact with HCl, [ka] To form, and (d) [ka] (i) carbonyl equivalent, and (ii) structure [ka] By contacting it with pyrimidine-2,5-diamine having, A process for forming compound 1 is provided.

[0010] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) [ka] Make contact with it, [ka] To form a formula in which LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl, (b) [ka] When brought into contact with acid, [ka] To form, (c) [ka] Make contact with it, [ka] The process involves forming a compound such that R'' is a C1-C6 alkyl compound. (d) [ka] Contact it with a trifluoromethylation reagent, [ka] To form, (e) [ka] Bring it into contact with HCl, [ka] To form, and (f) [ka] (i) carbonyl equivalent, and (ii) structure [ka] By contacting it with pyrimidine-2,5-diamine having, A process for forming compound 1 is provided.

[0011] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) [ka] Make contact with it, [ka] The formation of a formula in which Hal is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. (b) [ka] When brought into contact with acid, [ka] To form, (c) [ka] Make contact with it, [ka] The process involves forming a compound such that R'' is a C1-C6 alkyl compound. (d) [ka] Contact it with a trifluoromethylation reagent, [ka] To form, (e) [ka] Bring it into contact with HCl, [ka] To form, and (f) [ka] (i) R'OC(O)Cl (wherein R' is selected from C1-C6 alkyls and C6-C10 aryls substituted with 1-3 independently selected C1-C6 alkyls or C1-C6 alkoxys), and (ii) structure [ka] By contacting it with pyrimidine-2,5-diamine having, A process for forming compound 1 is provided.

[0012] Other embodiments include those described in the detailed description and / or claims.

[0013] Additional definitions To facilitate understanding of the disclosures contained herein, several additional terms are defined below. In general, the nomenclature used herein, as well as the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications referenced throughout this specification and its appendices is incorporated herein by reference in their entirety.

[0014] When referring to a number or numerical range, the term "approximately" means that the number or numerical range referred to is an approximation within, for example, experimental variability and / or statistical experimental error, and therefore the number or numerical range may vary by up to ±10% of the stated number or numerical range.

[0015] "API" refers to active pharmaceutical ingredients.

[0016] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with other components of a pharmaceutical formulation, suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0017] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic compounds described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other methods previously determined. Pharmacologically acceptable salts are not particularly limited as long as they can be used pharmacopoeia. Examples of salts formed by the compounds described herein with bases include: salts having inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts having organic bases such as methylamine, ethylamine, and ethanolamine; salts having basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, which specifically include: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0018] The term "pharmaceutically acceptable solvate" refers to a solvate of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. A solvate is a crystalline solid that contains molecules of the solvent within its crystal lattice. In some cases, the solvate form of a compound may be advantageous in altering the properties of the compound, such as solubility, stability, dissolution rate, and mechanical behavior. An exemplary solvate is a hydrate, which is a water solvate. If the average number of water molecules present in each repeating unit (i.e., unit cell) of the hydrate's crystal lattice is known, the hydrate is prefixed with the average number of water molecules in each unit cell. For example, a monohydrate contains an average of one water molecule per unit cell, a dihydrate contains an average of two water molecules per unit cell, and a hemihydrate contains an average of half a water molecule per unit cell. For more detailed information, see, for example, KRMorris, Polymorphism in Pharmaceutical Solids 1999, pages 125-181; Jeffrey, GAAcc. Chem. Res. 1969, 344-352; Rev. Pure Appl. Chem., 1963, 50-90; Encyclopedia of Pharm. Tech., 1993, 7, pages 393-441 (each of which is incorporated herein in its entirety).

[0019] As used herein, the term “carbonyl equivalent” refers to a reagent that, upon contact with an amino group, reacts to form a nucleophilic acyl-substituted substrate that can further react with a nucleophile, such as an amine, to form urea. In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyl groups and C6-C10 aryl groups optionally substituted with 1-3 independently selected C1-C6 alkyl, nitro, or C1-C6 alkoxy groups. In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0020] As used herein, the term “isocyanate-forming reagent” refers to a reagent that, upon contact with an amino group, reacts to form an isocyanate. The isocyanate may further react with an amine to form urea. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters.

[0021] The term "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I).

[0022] The term "oxo" refers to a divalent double bond oxygen atom (i.e., "=O"). As used herein, the oxo group is bonded to a carbon atom to form a carbonyl group.

[0023] The term "hydroxyl" refers to the -OH radical.

[0024] The term "cyano" refers to the -CN radical.

[0025] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that contains the indicated number of carbon atoms and may be linear or branched. For example, C 1-10 This indicates that the group may have 1 to 10 carbon atoms (including both ends) within it. Alkyl groups may be either unsubstituted or substituted with one or more substituents. Non-restrictive examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term “saturated” means that only single bonds exist between the constituent carbon atoms and other available valencies occupied by hydrogen and / or other substituents as defined herein.

[0026] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halos.

[0027] The term "alkoxy" refers to -O-alkyl radicals (e.g., -OCH3).

[0028] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbon atoms, in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0029] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may include multiple condensed and / or crosslinked rings. Non-limiting examples of condensed / crosslinked cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Other examples of cycloalkyls include spiro rings (for example, spiro dirings in which two rings are linked by only one atom). Non-exclusive examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane. In this context, the term "saturated" refers only to single bonds present between the constituent carbon atoms.

[0030] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is aromatic (however, the ring containing the heteroatoms does not have to be, e.g., tetrahydroisoquinolinyl). The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolylbenzothienyl, benzooxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, prinyl, thienopyridinyl, pyrido[2,3 Examples include -d]pyrimidinyl, pyrrolo[2,3-b]pyrimidinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyrimidinyl, pyrazolo[3,4-b]pyrimidinyl, pyrazolo[3,4-c]pyrimidinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyrimidinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, and the like. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. To clarify, heteroaryls also include aromatic lactams, aromatic cyclic ureas, or their vinyl analogs, where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), for example, one or more pyridones (e.g., [ka] ), pyrimidone (for example) [ka] ), pyridazinon (for example) [ka] ), pyrazinon (for example) [ka] ), and imidazolone (for example) [ka] ) and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group (i.e., "=O") as used herein is a component of a heteroaryl ring).

[0031] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated cyclic system having 3 to 16 ring atoms (e.g., 5-8 member monocyclic, 8-12 member bicyclic, or 11-14 member tricyclic ring systems) with 1 to 3 heteroatoms in the case of monocyclic, 1 to 6 heteroatoms in the case of bicyclic, or 1 to 9 heteroatoms in the case of tricyclic or polycyclic, where the heteroatoms are O, N, or S (e.g., carbon atoms and monocyclic, bicyclic, or tricyclic rings). In the formula, each is selected from 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, or S, and if the valence allows, one or more ring atoms may be substituted with 1 to 3 oxos (e.g., forming a lactam), one or more N or S atoms may be substituted with 1 to 2 oxides (e.g., forming an N-oxide, S-oxide, or S,S-dioxide), and 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazine, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. Multiple condensed and crosslinked rings may also be included as heterocyclyls.Non-limiting examples of condensed / crosslinked heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo Examples include [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3-oxabicyclo[3.2.1]octane. Other heterocyclines include spiro rings (for example, spiro dirings in which two rings are linked by only one atom).Non-restrictive examples of spirocyclic heterocyclines include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, and 2-oxaspiro[2. Examples include 2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane.

[0032] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, and isothiazole.

[0033] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself, for example, one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene.

[0034] To avoid misunderstanding, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher-order cyclic system (e.g., tricyclic, polycyclic cyclic system), such rings and cyclic groups have condensation points where (i) adjacent ring atoms (e.g., [xx0] ring system, where 0 is a zero atomic bridge (e.g., [ka] (ii) monocyclic atoms (spiro-condensed ring systems) (for example, [ka] (iii) a continuous arrangement of ring atoms (a bridged ring system having all bridge lengths > 0) (for example) [ka] It is understood that this includes those having a fused ring that is located at ).

[0035] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. When used herein, isotopes include atoms that have the same atomic number but different mass numbers. Common examples include tritium and deuterium as isotopes of hydrogen, and carbon as isotopes. 13 C and 14 This includes, but is not limited to, C.

[0036] In addition, the compounds disclosed herein, either generally or specifically, are intended to include all tautomer forms. Therefore, as an example, partial: [ka] Compounds containing: [ka] This includes tautomer forms. Similarly, pyridinyl or pyrimidinyl moieties described as being optionally substituted with hydroxyl include pyridone or pyrimidone tautomer forms.

[0037] The compounds provided herein may include a variety of stereochemical forms. The compounds also include enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers resulting from structural asymmetry in particular compounds. Unless otherwise indicated, if a disclosed compound is named or described by its structure (e.g., a "flat" structure) without specifying its stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, if a disclosed compound is named or described by a structure that specifies its stereochemistry (e.g., a structure with "wedge" and / or "dashed" bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0038] Details of one or more embodiments of this disclosure are described in the accompanying drawings and the following description. Other features and advantages of this disclosure will be apparent from the description and drawings, as well as from the claims. [Brief explanation of the drawing]

[0039] [Figure 1] The XRPD diffractogram of compound 1, form 1 hemihydrate is shown. [Figure 2] The TG / DSC thermogram of form 1 is shown. [Figure 3] This shows the DSC thermogram of form 1 (first thermal cycle). [Figure 4] This shows the DSC thermogram of Form 1 (first cooling cycle). [Modes for carrying out the invention]

[0040] This disclosure provides a process for preparing compounds of formula (I), such as (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (compound 1), and salts and / or solvates thereof, which inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα).

[0041] Some embodiments are based on formula (I): [ka] A process for preparing a compound, or a salt and / or solvate thereof, Formula (Ii): [ka] The compound, (i) Carbonyl equivalent or isocyanate forming reagent, and (ii) Equation (I-ii) [ka] By bringing it into contact with the compound, This includes forming a compound of formula (I), wherein, Z is O or NR x And, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 However, they are independently selected from halogens, hydroxyls, cyanos, optionally substituted with hydroxyls, C1-C6 alkyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R 2 These are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoropolymers. R 3However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R 4 However, they became independent, (i) halogen, (ii) Optionally, one or two hydroxyls or -NR A R B C1-C6 alkyl groups that are substituted with (iii) C1-C6 alkoxys that are optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. (iv) C1-C6 haloalkyl, (v) Hydroxyl, (vi) Cyano, (vii)-CO2H, (viii)-NR A R B , (ix=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii)-SO2(C1~C6 alkyl), (xiii)-S(=O)(=NH)(C1~C6 alkyl), (xiv)-C(=O)(C1~C6 alkyl), (xv)-CO2(C1~C6 alkyl), (xvi) 5-6 member heteroaryls that are optionally substituted with C1-C6 alkyl groups. (xvii) One or two independently selected R G A 3- to 9-membered heterocycline that is substituted by, and (xviii) One or two independently selected R GSelected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1~C6 alkyl), (vi)-C(=O)O(C1~C6 alkyl), (vii)-SO2(C1~C6 alkyl), (viii) 3-6 member cycloalkyls optionally substituted with hydroxyl, (ix) Optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl group substituted with one or two substituents independently selected from 5-6 member heteroaryl groups, 3-6 member cycloalkyl groups, -SO2(C1-C6 alkyl groups), -CO2H, and -SO2(NH2), or R C and R D However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR compounds. B1 R C1 , -SO2(C1~C6 alkyl), -CO2H, C1~C6 alkyl, C1~C6 alkoxy, and C1~C6 haloalkoxy are optionally substituted with hydroxyl to form 4~10 membered heterocyclines, Each R A2 , R B2 , and R C2 These are independently hydrogen or C1-C6 alkyl groups. Each R Gis independently selected from the group consisting of fluoro, cyano, hydroxyl, C1~C6 alkyl optionally substituted with hydroxyl, C1~C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, C1~C6 haloalkoxy, -SO2(C1~C6 alkyl), and -CO2H. A process is provided.

[0042] Some embodiments provide a process for preparing a compound of formula (I):

化

化

化

[0043] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0044] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an isocyanate-forming reagent. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl ester.

[0045] Some embodiments involve compounds of formula (I). [ka] A compound of, or a salt and / or solvate thereof, Formula (Ii): [ka] The compound, (i) Carbonyl equivalent or isocyanate forming reagent, and (ii) Equation (I-ii) [ka] By bringing it into contact with the compound, Prepared by a process involving the formation of a compound of formula (I), Z is O or NR x And, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 However, they are independently selected from halogens, hydroxyls, cyanos, optionally substituted with hydroxyls, C1-C6 alkyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R 2These are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoropolymers. R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R 4 However, they became independent, (i) halogen, (ii) Optionally, one or two hydroxyls or -NR A R B C1-C6 alkyl groups that are substituted with (iii) C1-C6 alkoxys that are optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. (iv) C1-C6 haloalkyl, (v) Hydroxyl, (vi) Cyano, (vii)-CO2H, (viii)-NR A R B , (ix=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii)-SO2(C1~C6 alkyl), (xiii)-S(=O)(=NH)(C1~C6 alkyl), (xiv)-C(=O)(C1~C6 alkyl), (xv)-CO2(C1~C6 alkyl), (xvi) 5-6 member heteroaryls that are optionally substituted with C1-C6 alkyl groups. (xvii) One or two independently selected R G A 3- to 9-membered heterocycline that is substituted by, and (xviii) One or two independently selected R G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1~C6 alkyl), (vi)-C(=O)O(C1~C6 alkyl), (vii)-SO2(C1~C6 alkyl), (viii) 3-6 member cycloalkyls optionally substituted with hydroxyl, (ix) Optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl group substituted with one or two substituents independently selected from 5-6 member heteroaryl groups, 3-6 member cycloalkyl groups, -SO2(C1-C6 alkyl groups), -CO2H, and -SO2(NH2), or R C and R D However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR compounds. B1 R C1, -SO2(C1~C6 alkyl), -CO2H, C1~C6 alkyl, C1~C6 alkoxy, and C1~C6 haloalkoxy are optionally substituted with hydroxyl to form 4~10 membered heterocyclines, Each R A2 , R B2 , and R C2 These are independently hydrogen or C1-C6 alkyl groups. Each R G However, independently, fluoro, cyano, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and -NR compounds exist. A1 R B1 ,=NR A2 -C(=O)NR C1 R D1 The group is selected from -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, C1~C6 haloalkoxy, -SO2(C1~C6 alkyl), and -CO2H.

[0046] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0047] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an isocyanate-forming reagent. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl ester.

[0048] Some embodiments involve compounds of formula (I). [ka] A compound of, or a salt and / or solvate thereof, Formula (Ii): [ka] The compound, (i) Carbonyl equivalents, and (ii) Equation (I-ii) [ka] By bringing it into contact with the compound, Prepared by a process involving the formation of a compound of formula (I), Z is O or NR x And, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 However, they are independently selected from halogens, hydroxyls, cyanos, optionally substituted with hydroxyls, C1-C6 alkyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R 2These are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoropolymers. R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R 4 However, they became independent, (i) halogen, (ii) Optionally, one or two hydroxyls or -NR A R B C1-C6 alkyl groups that are substituted with (iii) C1-C6 alkoxys that are optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. (iv) C1-C6 haloalkyl, (v) Hydroxyl, (vi) Cyano, (vii)-CO2H, (viii)-NR A R B , (ix=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii)-SO2(C1~C6 alkyl), (xiii)-S(=O)(=NH)(C1~C6 alkyl), (xiv)-C(=O)(C1~C6 alkyl), (xv)-CO2(C1~C6 alkyl), (xvi) 5-6 member heteroaryls that are optionally substituted with C1-C6 alkyl groups. (xvii) One or two independently selected R G A 3- to 9-membered heterocycline that is substituted by, and (xviii) One or two independently selected R G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1~C6 alkyl), (vi)-C(=O)O(C1~C6 alkyl), (vii)-SO2(C1~C6 alkyl), (viii) 3-6 member cycloalkyls optionally substituted with hydroxyl, (ix) Optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl group substituted with one or two substituents independently selected from 5-6 member heteroaryl groups, 3-6 member cycloalkyl groups, -SO2(C1-C6 alkyl groups), -CO2H, and -SO2(NH2), or R C and R D However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR compounds. B1 R C1, -SO2(C1~C6 alkyl), -CO2H, C1~C6 alkyl, C1~C6 alkoxy, and C1~C6 haloalkoxy are optionally substituted with hydroxyl to form 4~10 membered heterocyclines, Each R A2 , R B2 , and R C2 These are independently hydrogen or C1-C6 alkyl groups. Each R G However, independently, fluoro, cyano, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and -NR compounds exist. A1 R B1 ,=NR A2 -C(=O)NR C1 R D1 The present invention provides compounds, or salts and / or solvates thereof, selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H.

[0049] Some embodiments are based on formula (I): [ka] A process for preparing a compound, or a salt and / or solvate thereof, Formula (Ii): [ka] The compound, (i) Carbonyl equivalents, and (ii) Equation (I-ii) [ka] By bringing it into contact with the compound, This includes forming a compound of formula (I), Z is O or NR x And, R xThese are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 However, they are independently selected from halogens, hydroxyls, cyanos, optionally substituted with hydroxyls, C1-C6 alkyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R 2 These are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoropolymers. R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R 4 However, they became independent, (i) halogen, (ii) Optionally, one or two hydroxyls or -NR A R B C1-C6 alkyl groups that are substituted with (iii) C1-C6 alkoxys that are optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. (iv) C1-C6 haloalkyl, (v) Hydroxyl, (vi) Cyano, (vii)-CO2H, (viii)-NR A R B , (ix=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii)-SO2(C1~C6 alkyl), (xiii)-S(=O)(=NH)(C1~C6 alkyl), (xiv)-C(=O)(C1~C6 alkyl), (xv)-CO2(C1~C6 alkyl), (xvi) 5-6 member heteroaryls that are optionally substituted with C1-C6 alkyl groups. (xvii) One or two independently selected R G A 3- to 9-membered heterocycline that is substituted by, and (xviii) One or two independently selected R G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1~C6 alkyl), (vi)-C(=O)O(C1~C6 alkyl), (vii)-SO2(C1~C6 alkyl), (viii) 3-6 member cycloalkyls optionally substituted with hydroxyl, (ix) Optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl group substituted with one or two substituents independently selected from 5-6 member heteroaryl groups, 3-6 member cycloalkyl groups, -SO2(C1-C6 alkyl groups), -CO2H, and -SO2(NH2), or R C and RD However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR compounds. B1 R C1 , -SO2(C1~C6 alkyl), -CO2H, C1~C6 alkyl, C1~C6 alkoxy, and C1~C6 haloalkoxy are optionally substituted with hydroxyl to form 4~10 membered heterocyclines, Each R A2 , R B2 , and R C2 These are independently hydrogen or C1-C6 alkyl groups. Each R G However, independently, fluoro, cyano, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and -NR compounds exist. A1 R B1 ,=NR A2 -C(=O)NR C1 R D1 The present invention provides a process selected from the group consisting of -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, C1~C6 haloalkoxy, -SO2(C1~C6 alkyl), and -CO2H.

[0050] In some embodiments, forming a compound of formula (I) by contacting a compound of formula (Ii) with a carbonyl equivalent and a compound of formula (I-ii) includes adding the carbonyl equivalent to the compound of formula (Ii) and a base to form mixture 1, and then adding the compound of formula (I-ii) to mixture 1 to form mixture 2.

[0051] In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.0 to about 4.0 (e.g., about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3). In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.3.

[0052] In some embodiments, the molar ratio of the base to the compound of formula (Ii) is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.5.

[0053] In some embodiments, the addition of a carbonyl equivalent to the compound of formula (Ii) and a base to form mixture 1 is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0054] In some embodiments, the addition of a carbonyl equivalent to the compound of formula (Ii) and a base to form mixture 1 is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0055] In some embodiments, the addition of the carbonyl equivalent to the compound of formula (Ii) and the base is carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C). In some embodiments, the addition of the carbonyl equivalent to the compound of formula (Ii) is carried out at about 0°C to about 5°C. In some embodiments, the addition of the carbonyl equivalent to the compound of formula (Ii) is carried out at about 0°C to about 2°C. In some embodiments, the addition of the carbonyl equivalent to the compound of formula (Ii) is carried out at about 0°C.

[0056] In some embodiments, after adding the carbonyl equivalent to the compound of formula (Ii) and the base, the mixture 1 is stirred for about 1 hour to about 7 days (for example, about 1 hour to about 2 days, about 5 hours to about 1 day, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours).

[0057] In some embodiments, forming mixture 2 by adding the compound of formula (I-ii) to mixture 1 includes adding a second base to mixture 1 and then adding the compound of formula (I-ii) to mixture 1. In some embodiments, forming mixture 2 by adding the compound of formula (I-ii) to mixture 1 includes adding a second base to mixture 1 and then adding the compound of formula (I-ii) to mixture 1. In some embodiments, forming mixture 2 by adding the compound of formula (I-ii) to mixture 1 includes adding the compound of formula (I-ii) to mixture 1 and then adding a second base to mixture 1. In some embodiments, the second base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundec-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

[0058] In some embodiments, the addition of the second base to mixture 1 and the addition of the compound of formula (I-ii) to mixture 1 is carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C). In some embodiments, the addition of the second base to mixture 1 and the addition of the compound of formula (I-ii) to mixture 1 is carried out at about 0°C to about 5°C. In some embodiments, the addition of the second base to mixture 1 and the addition of the compound of formula (I-ii) to mixture 1 is carried out at about 0°C to about 2°C. In some embodiments, the addition of the second base to mixture 1 and the addition of the compound of formula (I-ii) to mixture 1 is carried out at about 0°C.

[0059] In some embodiments, after forming mixture 2, the mixture 2 is heated to about 20°C to about 90°C (for example, about 20°C to about 60°C, about 20°C to about 50°C, about 20°C to about 40°C, about 25°C to about 35°C, or about 30°C) over about 15 minutes to about 5 hours (for example, about 1 hour to about 3 hours, or about 2 hours), and then heated to about 20°C to about 90°C (for example, about 20°C to about 60°C, about The mixture is stirred at 20°C to approximately 50°C, approximately 20°C to approximately 40°C, approximately 25°C to approximately 35°C, or approximately 30°C for approximately 1 hour to approximately 7 days (for example, approximately 1 hour to approximately 2 days, approximately 5 hours to approximately 1 day, approximately 10 hours to approximately 18 hours, approximately 10 hours to approximately 14 hours, approximately 14 hours to approximately 18 hours, approximately 12 hours to approximately 16 hours, approximately 14 hours to approximately 16 hours, or approximately 16 hours) to form the compound of formula (I).

[0060] In some embodiments, heating mixture 2 and then stirring to form the compound of formula (I) includes adding a base aqueous solution and a post-treatment solvent after heating and stirring. In some embodiments, the base aqueous solution is a sodium bicarbonate aqueous solution. In some embodiments, the base aqueous solution is a 5% w / w sodium bicarbonate aqueous solution. In some embodiments, the post-treatment solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.

[0061] In some embodiments, the method involves recrystallizing the compound of formula (I) from a solvent. In some embodiments, the process involves recrystallizing the compound of formula (I) from the solvent after adding an aqueous base solution and a post-treatment solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6:1 to about 1:10 (e.g., about 6:1 to about 4:2, about 1:7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3:1, about 2:7, about 1:1, or about 5:2). In some embodiments, after recrystallizing the compound of formula (I), the compound of formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then with water, and then with a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing the compound of formula (I), the compound of formula (I) is dried. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at a pressure lower than atmospheric pressure. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at ambient temperature.

[0062] In some embodiments, forming a compound of formula (I) by contacting a compound of formula (Ii) with a carbonyl equivalent and a compound of formula (I-ii) includes adding the compound of formula (Ii) to the carbonyl equivalent and a base to form mixture 1', and then adding the compound of formula (I-ii) to mixture 1' to form mixture 2'. In some embodiments, the compound of formula (Ii) is in the form of a salt. In some embodiments, the compound of formula (Ii) is in the form of a salt, and forming a compound of formula (I) by contacting a compound of formula (Ii) with a carbonyl equivalent and a compound of formula (I-ii) includes adding the compound of formula (Ii) to the carbonyl equivalent and a base to form mixture 1', and then adding the compound of formula (I-ii) to mixture 1' to form mixture 2'.

[0063] In some embodiments, the salt of the compound of formula (Ii) is a hydrochloride salt.

[0064] In some embodiments, the addition of the compound of formula (Ii) to the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0065] In some embodiments, the addition of the compound of formula (Ii) to the carbonyl equivalent and the base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the contact is carried out under nitrogen. In some embodiments, the contact is carried out under argon.

[0066] In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0). In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 1.3. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (Ii) is about 2.0.

[0067] In some embodiments, the molar ratio of the base to the compound of formula (Ii) is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.5.

[0068] In some embodiments, the addition of the compound of formula (Ii) to the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0069] In some embodiments, the addition of the compound of formula (Ii) to the carbonyl equivalent and the base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0070] In some embodiments, the addition of the compound of formula (Ii) to the carbonyl equivalent and the base is carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C). In some embodiments, the addition of the carbonyl equivalent to the compound of formula (Ii) is carried out at about 5°C or below.

[0071] In some embodiments, forming mixture 2' by adding the compound of formula (I-ii) to mixture 1' includes adding a third base to mixture 1' and then adding the compound of formula (I-ii) to mixture 1'. In some embodiments, forming mixture 2' by adding the compound of formula (I-ii) to mixture 1' includes adding a third base to mixture 1' and then adding the compound of formula (I-ii) to mixture 1'. In some embodiments, forming mixture 2' by adding the compound of formula (I-ii) to mixture 1' includes adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1' and then adding the compound of formula (I-ii) to mixture 1'. In some embodiments, forming mixture 2' by adding the compound of formula (I-ii) to mixture 1' includes adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1' and then adding the compound of formula (I-ii) to mixture 1'. In some embodiments, the third base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0072] In some embodiments, the molar ratio of the compound of formula (I-ii) to the compound of formula (Ii) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the compound of formula (I-ii) to the compound of formula (Ii) is about 1.15.

[0073] In some embodiments, the molar ratio of the third base to the compound of formula (Ii) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the third base to the compound of formula (Ii) is about 2.0.

[0074] In some embodiments, the addition of an aqueous sodium chloride solution to mixture 1', the addition of a third base to mixture 1', and the addition of the compound of formula (I-ii) are carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C). In some embodiments, the addition of an aqueous sodium chloride solution to mixture 1', the addition of a third base to mixture 1', and the addition of the compound of formula (I-ii) are carried out at about 0°C to about 5°C.

[0075] In some embodiments, after forming mixture 2', the mixture 2' is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 days, about 12 hours to about 3 days, about 1 day to about 3 days, about 24 hours to about 36 hours, about 30 hours to about 40 hours, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours) to form the compound of formula (I).

[0076] In some embodiments, the process includes stirring mixture 2', then adding water and an extraction solvent to mixture 2' to form mixture 3'. In some embodiments, the extraction solvent is ethyl acetate or isopropyl acetate. In some embodiments, the extraction solvent is isopropyl acetate. In some embodiments, the process includes stirring and / or shaking mixture 3'. In some embodiments, the process includes separating the organic liquid from mixture 3'. In some embodiments, the process includes adding an aqueous base solution to the organic liquid to form mixture 4'. In some embodiments, the aqueous base solution is an aqueous sodium bicarbonate solution. In some embodiments, the aqueous sodium bicarbonate solution is a 5% w / w aqueous sodium bicarbonate solution. In some embodiments, the process includes separating the organic liquid from mixture 4'. In some embodiments, the process includes reducing the volume of the organic liquid at a pressure lower than atmospheric pressure. In some embodiments, the process includes adding a poor solvent to the organic liquid to form a slurry. In some embodiments, the poor solvent is hexane or heptane. In some embodiments, the poor solvent is heptane. In some embodiments, the process includes filtering the slurry to obtain a solid. In some embodiments, the process includes dissolving the solid in isopropanol and adding it to a solid containing water to form a slurry. In some embodiments, the slurry is cooled. In some embodiments, the slurry is filtered. In some embodiments, the slurry is dried at a pressure lower than atmospheric pressure to obtain a compound of formula (I).

[0077] In some embodiments, the compound of formula (I) precipitates from tetrahydrofuran and heptane. In some embodiments, the compound of formula (I) precipitates from isopropanol and water. In some embodiments, the compound of formula (I) precipitates from tetrahydrofuran and heptane, and then precipitates from isopropanol and water. In some embodiments, after precipitation of the compound of formula (I), the compound of formula (I) is dried. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at a pressure lower than atmospheric pressure. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at about 25°C to about 70°C (e.g., about 20°C to about 25°C, about 30°C to about 60°C, about 40°C to about 50°C, or about 45°C). In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at about 45°C. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at a pressure lower than atmospheric pressure and at a temperature of about 20°C to about 25°C.

[0078] In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters.

[0079] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0080] In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls optionally substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, R' is phenyl. In some embodiments, R' is para-nitrophenyl.

[0081] In some embodiments, the compound of formula (Ii) is brought into contact with R'OC(O)Cl and the compound of formula (I-ii) to form the compound of formula (I). Combine R'OC(O)Cl with a base. When the compound of formula (Ii) is added to a mixture of R'OC(O)Cl and a base, formula (Iia) is obtained. [ka] This includes forming a compound.

[0082] In some embodiments, contacting the compound of formula (Ii) with R'OC(O)Cl and the compound of formula (I-ii) to form the compound of formula (I) is equivalent to adding the compound of formula (Ii) to a mixture of R'OC(O)Cl and a base to form the compound of formula (Iia). [ka] This includes forming a compound.

[0083] In some embodiments, the compound of formula (Ii) is added as a solution or slurry in a solvent.

[0084] In some embodiments, the mixture of R'OC(O)Cl and the base is a solution or slurry in a solvent.

[0085] In some embodiments, the compound of formula (Ii) is in the form of a salt. In some embodiments, the salt is a hydrochloride salt.

[0086] In some embodiments, the compound of formula (Ii) is brought into contact with R'OC(O)Cl and the compound of formula (I-ii) to form the compound of formula (I). Combine R'OC(O)Cl with a base. When the compound of formula (Ii) is added to a mixture of R'OC(O)Cl and a base, formula (Iia) is obtained. [ka] This includes forming a compound of the following: The compound of formula (Ii) is in salt form.

[0087] In some embodiments, combining R'OC(O)Cl with a base involves combining the base with a solvent and then adding R'OC(O)Cl. In some embodiments, combining the base with a solvent and then adding R'OC(O)Cl involves adding R'OC(O)Cl to the base and solvent at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) and then adding R'OC(O)Cl.

[0088] In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water. In some embodiments, when a base is combined with a solvent and then R'OC(O)Cl is added, (i) water is added to the base to form an aqueous solution of the base, (ii) tetrahydrofuran is added to the aqueous solution of the base, and then (iii) R'OC(O)Cl is added to the aqueous solution of tetrahydrofuran and the aqueous solution of the base.

[0089] In some embodiments, the addition of the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base is carried out at a temperature of about -10°C to about 20°C (e.g., about -5°C to about 5°C, about 0°C to about 10°C, about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C). In some embodiments, the addition of the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base is carried out at a temperature of about -5°C to about 5°C. In some embodiments, the addition of the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base is carried out at a temperature of about 0°C to about 5°C. In some embodiments, the addition of the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base is carried out at a temperature of less than 5°C. In some embodiments, the compound of formula (Ii) is added to the mixture of R'OC(O)Cl and the base as a solution in the solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0090] In some embodiments, the compound of formula (Ii) is added to a mixture of R'OC(O)Cl and a base over a period of about 15 minutes to about 48 hours (for example, about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour).

[0091] In some embodiments, mixture 3 is formed by adding the compound of formula (Ii) to a mixture of R'OC(O)Cl and a base. In some embodiments, mixture 3 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, mixture 3 is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

[0092] In some embodiments, a two-phase mixture containing an organic phase and an aqueous phase is formed by stirring mixture 3. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with an aqueous base solution. In some embodiments, the aqueous base solution is an aqueous sodium bicarbonate solution. In some embodiments, the organic phase is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the organic phase, a poor solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the poor solvent is hexane or heptane. In some embodiments, the poor solvent is heptane.

[0093] In some embodiments, after adding the poor solvent, the mixture 4 is stirred at about 20°C to about 80°C (e.g., about 30°C to about 70°C, about 30°C to about 60°C, about 40°C to about 50°C, about 20°C to about 50°C, about 40°C to about 80°C, about 20°C to about 80°C, about 20°C to about 80°C, about 40°C, or about 50°C). In some embodiments, after adding the poor solvent, the mixture 4 is stirred at about 40°C to about 50°C. In some embodiments, stirring is carried out for about 1 minute to about 24 hours (e.g., about 1 minute to about 60 minutes, about 10 minutes to about 50 minutes, about 15 minutes to about 45 minutes, about 20 minutes to about 40 minutes, about 25 minutes to about 35 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 1 minute to about 2 hours, or about 15 minutes to about 4 hours). In some embodiments, stirring is performed for about 30 minutes.

[0094] In some embodiments, after adding the poor solvent, the mixture 4 is allowed to stand and / or stir for about 10 minutes to about 48 hours (e.g., about 6 hours to about 24 hours, about 12 hours to about 24 hours, about 16 hours to about 20 hours, about 18 hours to about 30 hours, about 24 hours to about 48 hours, or about 18 hours). In some embodiments, the standing and / or stirring is carried out at about -20°C to about 15°C (e.g., about -15°C to about 5°C, about -10°C to about 0°C, about -10°C, about -5°C, or about 0°C).

[0095] In some embodiments, after adding a poor solvent, the mixture 4 is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered to obtain the compound of formula (Iia). In some embodiments, the compound of formula (Iia) is rinsed with hexane or heptane (e.g., heptane). In some embodiments, after rinsing the compound of formula (Iia), the compound of formula (Iia) is dried. In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) at a pressure lower than atmospheric pressure. In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) at about 25°C to about 70°C (e.g., about 30°C to about 60°C, about 40°C to about 50°C, about 40°C to about 45°C, about 45°C to about 50°C, or about 45°C). In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) at about 45°C. In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) at about 40°C to about 45°C. In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) at about 45°C to about 50°C. In some embodiments, drying the compound of formula (Iia) includes drying the compound of formula (Iia) under an inert atmosphere (e.g., under nitrogen).

[0096] In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (Ii) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (Ii) is about 1.05. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (Ii) is about 1.3. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (Ii) is about 2.0. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (Ii) is approximately 3.0.

[0097] In some embodiments, the molar ratio of the base to the compound of formula (Ii) is about 1.0 to about 5.0 (e.g., about 1.0 to about 3.0, about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 2.0, about 2.2, about 3.0, or about 3.5). In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 2.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 2.2. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (Ii) is about 3.5.

[0098] In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, trimethylamine, and citric acid. In some embodiments, the base is sodium bicarbonate.

[0099] In some embodiments, the compound of formula (Ii) is brought into contact with R'OC(O)Cl and the compound of formula (I-ii) to form the compound of formula (I). This includes contacting a compound of formula (Iia) with a compound of formula (I-ii) to form a compound of formula (I).

[0100] In some embodiments, the formation of compound (I) by contacting a compound of formula (Iia) with a compound of formula (I-ii) is carried out in the presence of a third base. In some embodiments, the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0101] In some embodiments, forming compound (I) by contacting compound (Iia) with compound (I-ii) includes adding compound (Iia) to compound (I-ii). In some embodiments, forming compound (I) by contacting compound (Iia) with compound (I-ii) includes adding compound (Iia) to compound (I-ii) in the absence of a base.

[0102] In some embodiments, forming compound (I) by contacting a compound of formula (Iia) with a compound of formula (I-ii) includes adding a compound of formula (Iia) to a compound of formula (Iia). In some embodiments, forming compound (I) by contacting a compound of formula (Iia) with a compound of formula (I-ii) includes adding a compound of formula (Iia) to a compound of formula (Iia), and then adding a solvent to the mixture of the compound of formula (I-ii) and the compound of formula (Iia). In some embodiments, the solvent is N,N-dimethylacetamide.

[0103] In some embodiments, forming compound (I) by contacting compound (I-ii) with compound (I-ii) includes adding compound (I-ii) to compound (Iia) in the absence of a base.

[0104] In some embodiments, the formation of compound (I) by contacting the compound of formula (Iia) with the compound of formula (I-ii) is carried out in N,N-dimethylacetamide. In some embodiments, the formation of compound (I) by contacting the compound of formula (Iia) with the compound of formula (I-ii) is carried out under an inert atmosphere. In some embodiments, the formation of compound (I) by contacting the compound of formula (Iia) with the compound of formula (I-ii) is carried out under nitrogen. In some embodiments, the formation of compound (I) by contacting the compound of formula (Iia) with the compound of formula (I-ii) is carried out under argon. In some embodiments, the NN-dimethylacetamide contains less than 2% by volume of water (e.g., less than 1.5% by volume of water, less than 1% by volume of water, less than 0.5% by volume of water, less than 0.3% by volume of water, less than 0.2% by volume of water, less than 0.1% by volume of water, less than 0.05% by volume of water, or less than 0.02% by volume of water). In some embodiments, the N,N-dimethylacetamide contains less than 0.3% by volume of water.

[0105] In some embodiments, after adding the compound of formula (Iia) to the compound of formula (I-ii), or after adding the compound of formula (I-ii) to the compound of formula (Iia), mixture 5 is formed. In some embodiments, mixture 5 is stirred. In some embodiments, mixture 5 is stirred for about 1 minute to about 48 hours (e.g., 1 minute to about 24 hours, 1 minute to about 12 hours, 1 minute to about 6 hours, 1 minute to about 3 hours, about 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is stirred for about 12 hours to about 13 hours. In some embodiments, mixture 5 is stirred for about 3 hours. In some embodiments, mixture 5 is stirred for about 1 hour. In some embodiments, the mixture 5 is stirred at approximately 10°C to approximately 90°C (for example, approximately 10°C to approximately 90°C, approximately 20°C to approximately 80°C, approximately 30°C to approximately 70°C, approximately 30°C to approximately 60°C, approximately 35°C to approximately 60°C, approximately 40°C to approximately 55°C, approximately 45°C to approximately 50°C, approximately 45°C, approximately 50°C, or approximately 50°C).

[0106] In some embodiments, after stirring mixture 5, the process includes adding water to mixture 5 to form mixture 5'. In some embodiments, the process includes stirring mixture 5'. In some embodiments, the process includes stirring mixture 5' for about 1 minute to about 48 hours (e.g., 1 minute to about 24 hours, 1 minute to about 12 hours, 1 minute to about 6 hours, 1 minute to about 3 hours, about 30 minutes to about 1.5 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, the process includes stirring mixture 5' for about 12 hours to about 13 hours. In some embodiments, the process includes stirring mixture 5' for about 3 hours. In some embodiments, the process includes stirring mixture 5' for about 1 hour.

[0107] In some embodiments, a slurry is formed after stirring the mixture 5'. In some embodiments, the slurry is filtered to obtain the compound of formula (I). In some embodiments, the compound of formula (I) is washed with water. In some embodiments, the compound of formula (I) is dried at a pressure lower than atmospheric pressure.

[0108] In some embodiments, the compound of formula (I) is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl alcohol and water. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl alcohol to water is about 1:3 to about 1:1 (e.g., about 1:2). In some embodiments, the ratio of isopropyl acetate to heptane is about 6:1 to about 4:2 (e.g., about 5:2). In some embodiments, after recrystallizing the compound of formula (I), the compound of formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then with water, and then with a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing the compound of formula (I), the compound of formula (I) is dried. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at a pressure lower than atmospheric pressure. In some embodiments, drying the compound of formula (I) includes drying the compound of formula (I) at ambient temperature.

[0109] In some embodiments, the compound of formula (I) has a purity of at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, about 98%, about 98.5%, about 99%, about 99.5%). In some embodiments, less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount) of the compound of formula (A) is present as an impurity together with the compound of formula (I). [ka]

[0110] In some embodiments, less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount) of the compound of formula (B) is present as an impurity along with the compound of formula (I). [ka]

[0111] In some embodiments, this process is [ka] The process involves contacting with an acid to form a compound of formula (Ii), where R'' is a C1-C6 alkyl, and R 3 These are C1-C6 haloalkyl groups.

[0112] In some embodiments, R'' is isopropyl.

[0113] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-dioxane. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate. In some embodiments, the acid is a 1 mole solution of hydrogen chloride in ethyl acetate.

[0114] In some embodiments, contact includes adding the compound of formula (I-iii) to the acid. In some embodiments, contact includes adding the acid to the compound of formula (I-iii). In some embodiments, the addition is carried out at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, stirring is carried out at a temperature of about 0°C to about 10°C. In some embodiments, stirring is carried out at a temperature of about 5°C to about 15°C. In some embodiments, contact includes stirring the compound of formula (I-iii) with the acid for about 5 minutes to about 24 hours (e.g., about 5 minutes to about 10 hours, about 5 minutes to about 5 hours, about 5 minutes to about 3 hours, about 30 minutes to about 1.5 hours, about 3 hours, or about 1 hour) to form mixture 6. In some embodiments, contact includes stirring the compound of formula (I-iii) with the acid for about 3 hours to form mixture 6. In some embodiments, contact includes stirring the compounds of formula (I-iii) with an acid for about 1 hour to form mixture 6. In some embodiments, contact includes stirring the compounds of formula (I-iii) with an acid for at least 1 hour to form mixture 6. In some embodiments, stirring is carried out at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, stirring is carried out at a temperature of about 5°C to about 15°C. In some embodiments, contact includes adding heptane or hexane (e.g., heptane) to mixture 6. In some embodiments, after adding heptane or hexane (e.g., heptane) to the mixture 6, the mixture is cooled to about -20°C to about 0°C (e.g., about -15°C to about -5°C, or about -10°C (e.g., about -15°C to about -5°C)) over about 5 minutes to about 48 hours (e.g., about 5 minutes to about 24 hours, about 3 hours to about 9 hours, about 24 hours, or about 6 hours (e.g., about 6 hours)), and then stirred or allowed to stand (e.g., stirred) for about 10 hours to about 2 days (e.g., about 12 hours to about 24 hours, about 14 hours to about 22 hours, about 18 hours to about 30 hours, about 22 hours to about 26 hours, about 24 hours, or about 18 hours (e.g., about 24 hours)) to form a solid.In some embodiments, the solid is filtered to obtain compounds of formula (I-iii).

[0115] In some embodiments, this process is expressed by formula (I-iv) [ka] The preparation of the compound of formula (I-iii) is carried out by contacting the compound of formula (I-iii) with a trihaloalkylating reagent to form the compound of formula (I-iii), where R'' is a C1-C6 alkyl group. In some embodiments, contacting the compound of formula (I-iv) with a trihaloalkylating reagent includes contacting the compound of formula (I-iv) with a trihaloalkylating reagent and a phase transfer reagent. In some embodiments, a mixture 7 is formed by contacting the compound of formula (I-iv) with a trihaloalkylating reagent and a phase transfer reagent.

[0116] In some embodiments, the C=N double bond in the compound of formula (I-iv) has an E configuration. In some embodiments, the C=N double bond in the compound of formula (I-iv) has a Z configuration.

[0117] In some embodiments, the molar ratio of the trihaloalkylating reagent to the compounds of formula (I-iv) is about 1.0 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the trihaloalkylating reagent to the compounds of formula (I-iv) is about 3.0.

[0118] In some embodiments, the molar ratio of the phase transfer reagent to the compounds of formula (I-iv) is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the phase transfer reagent to the compounds of formula (I-iv) is about 1.0.

[0119] In some embodiments, contacting the compounds of formula (I-iv) with a trihaloalkylating reagent and a phase transfer reagent involves adding the phase transfer reagent to the compounds of formula (I-iv), and then adding the trihaloalkylating reagent to a mixture of the compounds of formula (I-iv) and the phase transfer reagent.

[0120] In some embodiments, the phase transfer reagent is added to the compound of formula (I-iv) at approximately 5°C to approximately 40°C (e.g., approximately 10°C to approximately 35°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C). In some embodiments, the phase transfer reagent is added to the compound of formula (I-iv) at approximately 15°C to approximately 20°C.

[0121] In some embodiments, after adding the phase transfer reagent to the compound of formula (I-iv), the mixture of the compound of formula (I-iv) and the phase transfer reagent is cooled to about -40°C to about 0°C (e.g., -30°C to about -5°C, -25°C to about -10°C, -20°C to about -15°C). In some embodiments, after adding the phase transfer reagent to the compound of formula (I-iv), the mixture of the compound of formula (I-iv) and the phase transfer reagent is cooled to about -20°C to about -15°C.

[0122] In some embodiments, after cooling the mixture of the compound of formula (I-iv) and the phase transfer reagent, the mixture is stirred for about 5 minutes to about 3 hours (e.g., about 5 minutes to about 2 hours, about 30 minutes to about 1.5 hours, or about 1 hour). In some embodiments, after cooling the mixture of the compound of formula (I-iv) and the phase transfer reagent, the mixture is stirred for about 1 hour.

[0123] In some embodiments, the addition of the trihaloalkylating reagent to the mixture of the compounds of formula (I-iv) and the phase transfer reagent is carried out at approximately -40°C to approximately 0°C (e.g., -30°C to approximately -5°C, -25°C to approximately -10°C, -20°C to approximately -15°C). In some embodiments, the addition of the trihaloalkylating reagent to the mixture of the compounds of formula (I-iv) and the phase transfer reagent is carried out at approximately -20°C to approximately -15°C.

[0124] In some embodiments, the trihaloalkylation reagent is added dropwise to a mixture of the compounds of formula (I-iv) and the phase transfer reagent.

[0125] In some embodiments, contacting a compound of formula (I-iv) with a trihaloalkylating reagent and a phase transfer reagent involves adding the trihaloalkylating reagent to the compound of formula (I-iv), and then adding the phase transfer reagent to a mixture of the compound of formula (I-iv) and the trihaloalkylating reagent.

[0126] In some embodiments, contact of the compounds of formula (I-iv) with the trihaloalkylation reagent and the phase transfer reagent is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent includes toluene, xylene, or benzene. In some embodiments, the solvent includes toluene. In some embodiments, the solvent is toluene.

[0127] In some embodiments, the process involves adding a trihaloalkylating reagent to the compound of formula (I-iv) at a temperature of about -78°C to about 25°C (e.g., about -78°C to about 0°C, about -78°C to about -5°C, about -50°C to about 10°C, about -40°C to about 0°C, about -30°C to about 0°C, about -20°C to about -10°C, about -20°C, or about -10°C). In some embodiments, the trihaloalkylating reagent is added to the compound of formula (I-iv) at a temperature of about -20°C to about -10°C.

[0128] In some embodiments, the process involves adding a trihaloalkylating reagent to a compound of formula (I-iv) over a period of about 1 minute to about 24 hours (for example, about 1 minute to about 12 hours, about 12 hours to about 24 hours, about 6 hours to about 12 hours, about 1 minute to about 12 hours, about 1 minute to about 9 hours, about 1 minute to about 6 hours, about 1 minute to about 4 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, or about 1 hour). In some embodiments, the process involves adding a trihaloalkylating reagent to a compound of formula (I-iv) over a period of about 1 hour.

[0129] In some embodiments, the process involves adding a phase transfer reagent and then stirring the compounds of formula (I-iv), the trihaloalkylating reagent, and the phase transfer reagent. In some embodiments, the process involves stirring the compounds of formula (I-iv), the trihaloalkylating reagent, and the phase transfer reagent at about -78°C to about 25°C (e.g., about -78°C to about 0°C, about -78°C to about -5°C, about -50°C to about 10°C, about -40°C to about 0°C, about -30°C to about 0°C, about -20°C to about -10°C, about -20°C, or about -10°C). In some embodiments, the phase transfer reagent is added to the compounds of formula (I-iv) at about -20°C to about -10°C.

[0130] In some embodiments, adding the phase transfer reagent to the mixture of the compound of formula (I-iv) and the trihaloalkylating reagent involves adding the phase transfer reagent to the mixture of the compound of formula (I-iv) and the trihaloalkylating reagent in several portions. In some embodiments, the number of portions is 7 to 13. In some embodiments, the number of portions is 9 to 11. In some embodiments, the number of portions is 10. In some embodiments, the 10 portions are 10 portions of substantially the same weight.

[0131] In some embodiments, the process includes adding water or an aqueous acid solution to the mixture 7. In some embodiments, the process includes adding the aqueous acid solution to the mixture 7 to form a mixture 8. In some embodiments, the aqueous acid solution is an aqueous ammonium chloride solution (e.g., a 10% by weight aqueous ammonium chloride solution). In some embodiments, the addition of water or an aqueous acid solution to the mixture 7 is carried out at a temperature of about -10°C to about 25°C (e.g., about -5°C to about 5°C).

[0132] In some embodiments, the process involves adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from mixture 9 and concentrated under a pressure lower than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, a residue is obtained by concentrating the organic phase at a pressure lower than atmospheric pressure. In some embodiments, the residue is purified using silica gel to obtain compounds of formula (I-iv).

[0133] In some embodiments, the process includes adding water and / or an aqueous solution of a base to mixture 8 to form mixture 9'. In some embodiments, mixture 9' includes an organic phase and an aqueous phase. In some embodiments, the process includes separating the organic phase from mixture 9'. In some embodiments, the process includes distilling the organic phase to obtain a distillate. In some embodiments, the process includes passing the distillate through carbon (e.g., activated carbon). In some embodiments, after passing the distillate through carbon, the process includes reducing the volume of the distillate under a pressure lower than atmospheric pressure to form a concentrate. In some embodiments, the process includes adding water to the concentrate and then reducing the volume of the mixture of water and concentrate to form mixture 9''. In some embodiments, the process includes adding a poor solvent to mixture 9'' and then reducing the volume of mixture 9'' to form mixture 9''''. In some embodiments, the poor solvent is heptane. In some embodiments, the process includes adding a portion of the compound of formula (I-iii) (e.g., a previously prepared portion) to mixture 9'''' to form a precipitate. In some embodiments, the precipitate is filtered and dried to form compounds of formula (I-iii).

[0134] In some embodiments, the trihaloalkylating reagent is selected from TMSCF3, [(trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate, Et3GeNa / C6H5SCF3, N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)cuplate (1-), (SP-4-1)-tetrakis(trifluoromethyl)argentate (1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoroalkylating reagent is a trifluoromethylating reagent. In some embodiments, the trifluoromethylating reagent is TMSCF3.

[0135] In some embodiments, the phase transfer reagent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, 1,1'-(buta-1,4-diyl)bis[4-aza-1-azoniabicyclo[2.2.2]octane]dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmytilammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

[0136] In some embodiments, this process is expressed by formula (Iv) [ka] The compound [ka] The process involves preparing compounds of formula (I-iv) by contacting with, where R'' is a C1-C6 alkyl group. In some embodiments, Z is O. In some embodiments, the compound of formula (Iv) [ka] Contacting it with the compound of formula (Iv) [ka] and includes contact with a condensation base. In some embodiments, the condensation base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the condensation base is potassium carbonate.

[0137] In some embodiments, contact is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0138] In some embodiments, the molar ratio of the condensation base to the compound of formula (Iv) is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.3 to about 1.7, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the condensed base to the compound of formula (Iv) is approximately 1.5.

[0139] In some embodiments, the molar ratio of the condensed base to the compound of formula (Iv) is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.3 to about 1.7, about 1.0 to about 1.5, about 1.0 to about 1.4, about 0.8 to about The molar ratios are approximately 1.2, 0.9 to 1.1, 1.0 to 1.1, 1.2 to 1.4, 0.95 to 1.05, 1.0 to 1.04, 0.8, 0.9, 0.95, 1.0, 1.02, 1.05, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 2.0, 2.5, 3.0, or 3.5). In some embodiments, the molar ratio of the condensation base to the compound of formula (Iv) is approximately 1.02.

[0140] In some embodiments, the compound of formula (Iv) is used [ka] And contact with the condensed base is carried out at approximately 25°C to approximately 80°C (for example, approximately 25°C to approximately 70°C, approximately 25°C to approximately 60°C, approximately 35°C to approximately 50°C, approximately 35°C to approximately 45°C, approximately 35°C, approximately 40°C, or approximately 45°C). In some embodiments, the compound of formula (Iv) is [ka] The contact with the condensed base is carried out at approximately 35°C to 45°C.

[0141] In some embodiments, the compound of formula (Iv) is used [ka] Contact with the condensed base is carried out at approximately 25°C to 80°C (for example, approximately 25°C to 70°C, approximately 25°C to 60°C, approximately 35°C to 50°C, approximately 35°C to 45°C, approximately 35°C, approximately 40°C, or approximately 45°C).

[0142] In some embodiments, the compound of formula (Iv) is used [ka] And contact with a condensed base produces the compound of formula (Iv) [ka] and includes stirring with a condensed base. In some embodiments, the compound of formula (Iv) is [ka] And stirring with a condensed base produces the compound of formula (Iv). [ka] and stirring with the condensed base for about 1 to 48 hours (for example, about 2 to 36 hours, about 2 to 24 hours, about 2 to 12 hours, about 6 to 24 hours, about 9 to 19 hours, about 11 to 17 hours, about 13 to 15 hours, about 13.5 to 14.5 hours, or about 14 hours). In some embodiments, the compound of formula (Iv) is used [ka] And stirring with a condensed base produces the compound of formula (Iv). [ka] This also includes stirring with the condensed base for about 14 hours.

[0143] In some embodiments, the compound of formula (Iv) is used [ka] And contact with a condensed base, [ka] Add to the compound of formula (Iv), then add the condensed base [ka] This includes adding it to a mixture of the compound of formula (Iv).

[0144] In some embodiments, [ka] The addition of to the compound of formula (Iv) is carried out at temperatures of approximately 5°C to 40°C (e.g., approximately 10°C to 35°C, approximately 15°C to 25°C, and approximately 15°C to 20°C). In some embodiments, [ka] The addition of to the compound of formula (Iv) is carried out at approximately 15°C to 20°C.

[0145] In some embodiments, the condensed base is [ka] Adding to a mixture of the compound of formula (Iv) is carried out at temperatures of approximately 5°C to approximately 40°C (e.g., approximately 10°C to approximately 35°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C). In some embodiments, the condensed base is [ka] The addition of the compound of formula (Iv) to the mixture is carried out at approximately 15°C to 20°C.

[0146] In some embodiments, the compound of formula (Iv) is used [ka] And by contact with a condensation base, mixture 10 is obtained. In some embodiments, mixture 10 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is stirred for about 15 minutes to about 5 hours. In some embodiments, stirring of mixture 10 is carried out at about 25°C to about 110°C (e.g., 40°C to about 80°C, 50°C to about 70°C, 55°C to about 65°C, or about 60°C). In some embodiments, stirring of mixture 10 is carried out at about 60°C.

[0147] In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 5°C to about 35°C (for example, about 10°C to about 30°C, about 15°C to about 25°C, or about 20°C). In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 20°C. In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 15°C to about 25°C.

[0148] In some embodiments, cooling the mixture 10 includes forming a slurry. In some embodiments, the process includes filtering the slurry to provide a solution. In some embodiments, the process includes reducing the volume of the solution under a pressure lower than atmospheric pressure. In some embodiments, the process includes (i) adding a solvent to the solution, (ii) reducing the volume of the solution under a pressure lower than atmospheric pressure, optionally (iii) adding a solvent to the solution, and optionally (iv) reducing the volume of the solution under a pressure lower than atmospheric pressure to form a concentrate. In some embodiments, the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol. In some embodiments, steps (iii) and (iv) are required. In some embodiments, the process includes cooling the concentrate to about 5°C to about 35°C (e.g., about 10°C to about 30°C, about 15°C to about 25°C, or about 20°C). In some embodiments, the process includes cooling the concentrate to about 15°C to about 25°C. In some embodiments, the process includes cooling the concentrate and then adding water to the concentrate to form mixture 10'. In some embodiments, the process includes stirring mixture 10' for about 1 hour to about 48 hours (e.g., about 2 hours to about 36 hours, about 2 hours to about 24 hours, about 2 hours to about 12 hours, about 6 hours to about 24 hours, about 9 hours to about 19 hours, about 11 hours to about 17 hours, about 13 hours to about 15 hours, about 13.5 hours to about 14.5 hours, or about 14 hours). In some embodiments, the process includes stirring mixture 10' for about 14 hours. In some embodiments, after stirring mixture 10', a slurry is formed. In some embodiments, the slurry is filtered to obtain the compound of formula (Iv).

[0149] In some embodiments, the process includes cooling the mixture 10 and then concentrating the mixture 10 at a pressure lower than atmospheric pressure to obtain compounds of formula (I-iv).

[0150] In some embodiments, this process In some embodiments, the compound of formula (Iv) is used [ka] And contact with a condensed base, [ka] Add to the compound of formula (Iv), then add the condensed base [ka] This includes adding it to a mixture of the compound of formula (Iv).

[0151] In some embodiments, this process is expressed by formulas (I-vi) [ka] The method includes preparing the compound of formula (Iv) by contacting the compound with an acid. In some embodiments, Z is O.

[0152] In some embodiments, the acid is a protic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron(III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).

[0153] In some embodiments, the acid is acetic acid.

[0154] In some embodiments, contacting a compound of formula (I-vi) with an acid includes adding a compound of formula (I-vi) to an acid. In some embodiments, contacting a compound of formula (I-vi) with an acid includes contacting a compound of formula (I-vi) with an acid in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, a mixture 11 is formed by adding a compound of formula (I-vi) to an acid. In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is heated to about 80°C to about 160°C (e.g., about 90°C to about 150°C, about 100°C to about 140°C, about 110°C to about 130°C, about 115°C to about 125°C, or about 120°C). In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is heated to about 120°C. In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is stirred for about 15 minutes to about 2 days (e.g., about 30 minutes to about 24 hours, about 2 hours to about 16 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, or about 8 hours). In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is stirred for about 8 hours.

[0155] In some embodiments, after stirring the mixture 11, water is added to the mixture 11. In some embodiments, after adding water to the mixture 11, a solvent is added to the mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base solution. In some embodiments, the aqueous base solution is an aqueous potassium carbonate solution (e.g., a 15% by weight aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous base solution, the organic phase is stirred with water and Na2S2O4. In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 8 hours. In some embodiments, a solid is formed by stirring the organic phase with water and Na2S2O4. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, the pH of which is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10), and then stirred for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a two-phase mixture. In some embodiments, the two-phase mixture comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is concentrated under a pressure lower than atmospheric pressure to obtain a compound of formula (Iv).

[0156] In some embodiments, this process is expressed by formulas (I-vii) [ka] The compound [ka] The process involves preparing compounds of formula (I-vi) by contact with LG, where LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl.

[0157] In some embodiments, the compound of formula (I-vii) is the compound of formula (I-vii-i). [ka]

[0158] In some embodiments, formulas (I-vii) [ka] The compound [ka] Making contact with it is expressed by equation (I-vii) [ka] The compound [ka] and contact with a base. In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the base is potassium carbonate.

[0159] In some embodiments, formulas (I-vii) [ka] The compound [ka] Contact with a base is carried out in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

[0160] In some embodiments, formulas (I-vii) [ka] The compound [ka] And contact with a base will produce compounds of formula (I-vii). [ka] This includes contact with a base and sodium iodide.

[0161] In some embodiments, formulas (I-vii) [ka] The compound [ka] Contact with the base and sodium iodide is carried out at approximately 80°C to 160°C (for example, approximately 90°C to 150°C, approximately 100°C to 140°C, approximately 110°C to 130°C, approximately 115°C to 125°C, or approximately 120°C). In some embodiments, formula (I-vii) [ka] The compound [ka] Contact with the base and sodium iodide is carried out at approximately 120°C.

[0162] In some embodiments, compounds of formula (I-vii) are used. [ka] Mixture 13 is formed by adding a base and sodium iodide. In some embodiments, mixture 13 is stirred for about 15 minutes to about 2 days (e.g., about 30 minutes to about 24 hours, about 2 hours to about 16 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 13 is stirred for about 5 hours.

[0163] In some embodiments, this process is expressed by formula (I-viii) [ka] The preparation of the compound of formula (Iv) involves contacting the compound of with an acid, where Hal is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. In some embodiments, Hal is chloro. In some embodiments, the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.

[0164] In some embodiments, formula (I-viii) [ka] Contacting the compound with an acid is carried out in a solvent. In some embodiments, the solvent includes methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

[0165] In some embodiments, contact of the compounds of formula (I-viii) with an acid is carried out at a temperature of about 10°C to about 60°C (e.g., about 15°C to about 55°C, about 15°C to about 35°C, about 20°C to about 30°C, about 23°C to about 27°C, or about 25°C). In some embodiments, contact of the compounds of formula (I-viii) with an acid is carried out at about 25°C.

[0166] In some embodiments, this process is expressed by formula (I-ix) [ka] The compound [ka] The process involves preparing compounds of formula (I-viii) by contacting them with [a certain substance]. In some embodiments, Z is O. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 It is methyl.

[0167] In some embodiments, compounds of formula (I-ix) are used [ka] Contacting it with the compound of formula (I-ix) [ka] and contact with a base. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the contact is carried out in a solvent.

[0168] In some embodiments, the solvent includes methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

[0169] In some embodiments, compounds of formula (I-ix) are used [ka] And contact with a base is carried out at a temperature of about 10°C to about 60°C (for example, about 15°C to about 55°C, about 15°C to about 35°C, about 20°C to about 30°C, about 23°C to about 27°C, or about 25°C). In some embodiments, the compounds of formula (I-ix) are [ka] The contact with the base is carried out at approximately 25°C.

[0170] In some embodiments, Z is O, m is 2, and each R 1 is fluoro, and R 2 However, it is methyl, and R 2 is trifluoromethyl, and ring A is [ka] And here, * This indicates the binding site to urea. ** is R 4 This shows the connection point to R, where n is 1 and R 4 It is -NH2.

[0171] In some embodiments, R 3 The carbon atoms substituted have the (R) configuration.

[0172] In some embodiments, the compound of formula (I) is [ka] That is the case.

[0173] In some embodiments, the compound of formula (I) is [ka] That is the case.

[0174] In some embodiments, the compound of formula (I) is [ka] That is the case.

[0175] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is not a compound selected from the group consisting of [the specified group].

[0176] In some embodiments, Z is NR x And R 3 If ring A is methyl, then ring A is not phenyl.

[0177] In some embodiments, the compound of formula (I) is of formula (X): [ka] A compound of, or a salt and / or solvate thereof, Z is O or NR x And, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R 1 These are halogens that are selected independently. m is 0, 1, 2, or 3, R 2 These are halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R 4 These are, independently, halogens, optionally one or two hydroxyls, or -NR A R B Substituting C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5-6 member heteroaryls optionally substituted with C1~C6 alkyl, and each optionally 1 or 2 independently selected R G Selected from the group consisting of 3-6 member heterocyclines or 3-6 member cycloalkyls that are substituted with, n is 0, 1, or 2. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are independently hydrogen, 4-6 member heterocyclyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), a 3-6 member cycloalkyl optionally substituted with hydroxyl, or optionally hydroxyl, -C(=O)NR B2 R C2 , a C1-C6 alkyl substituted with 1-2 substituents independently selected from 5-6 member heteroaryl, 3-6 member cycloalkyl, SO2(C1-C6 alkyl), -SO2(NH2), or R C and R DThese, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 Selected from the group consisting of -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, and -CO2H, Here, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is not a compound selected from the group consisting of [the specified group].

[0178] In some embodiments, the compounds described herein are not compounds selected from the group of compounds selected from the group of compounds that are not compounds of formula (I) above (i.e., “excluded compounds”). In some embodiments, the excluded compounds have a planar structure as described above. In some embodiments, the excluded compounds are specific stereoisomers, for example, specific enantiomers or diastereomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

[0179] In some embodiments, the compound of formula (I) is formula (IA): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A1 is a 6-membered heteroaryl, R 4 Independently and optionally, -NR A R B Substituting C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A RB -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5-6 member heteroaryls optionally substituted with C1~C6 alkyl, and 1 or 2 independently selected R G A 3-6 member heterocycline is substituted with, and one or two independently selected R(s) are optionally selected. G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, Here, R 4 It is bonded to the ring A1 position, which is para to the N atom of the urea portion. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F This is independently a C1-C6 alkyl group substituted with hydrogen, a 4-6 member heterocycline, a C1-C6 haloalkyl group, a 3-6 member cycloalkyl group optionally substituted with hydroxyl, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 member cycloalkyl group, -SO2(C1-C6 alkyl), and -SO2(NH2), or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0180] In some embodiments, ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A1 is pyrimidinyl. In some embodiments, ring A1 is pyridyl. In some embodiments, ring A1 is pyrazolyl.

[0181] In some embodiments, ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A1 is 5-pyrimidinyl. In some embodiments, ring A1 is 3-pyridyl. In some embodiments, ring A1 is 4-pyrazolyl.

[0182] In some embodiments of formula (IA), [ka] And in the formula, R 4B -NR A R B , and one nitrogen ring member, and optionally one to two independently selected R G1 Selected from 4-6 member heterocyclines that are substituted with R G1 The elements are selected from fluoro, hydroxyl, and C1-C6 alkyl groups.

[0183] In some embodiments of formula (IA), R A and R B Each of these is hydrogen.

[0184] In some embodiments, the compound of formula (I) is formula (IB): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. R 4 Independently and optionally, -NR A R B Substituting C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5-6 member heteroaryls optionally substituted with C1~C6 alkyl, and 1 or 2 independently selected R G A 3-6 member heterocycline is substituted with, and one or two independently selected R(s) are optionally selected. G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F This is independently a C1-C6 alkyl group substituted with hydrogen, a 4-6 member heterocycline, a C1-C6 haloalkyl group, a 3-6 member cycloalkyl group optionally substituted with hydroxyl, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 member cycloalkyl group, -SO2(C1-C6 alkyl), and -SO2(NH2), or R C and R DThese, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0185] In some embodiments, the compound of formula (I) is of formula (IC): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 Selected from the group consisting of , and -CO2H.

[0186] In some embodiments, the compound of formula I is formula (ID): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NRC R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0187] In some embodiments, the compound of formula (I) is formula (IE): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0188] In some embodiments, the compound of formula (I) is formula (IF): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R DThese, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The compound is selected from the group consisting of -CO2(C1~C6 alkyl), C1~C6 haloalkyl, C3~C6 cycloalkyl, and -CO2H, where the compound is [ka] isn't it.

[0189] In some embodiments, the compound of formula (I) is formula (IG): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0190] In some embodiments, the compound of formula (I) is of formula (IH): [ka] or its salts and / or solvates, in the formula, R 1A It is a halogen, R 1B is halogen, cyano, cyclopropyl, or absent (phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl or C1-C6 haloalkyl, R 4 These are C1-C6 alkoxy, C1-C6 haloalkyl, and -NR compounds, which are independently substituted with 1-2 substituents independently selected from C1-C6 alkyl, optionally hydroxyl, and C3-C6 cycloalkyl groups. A R B , and one or two independently selected R G Independently selected from a group consisting of 3- to 9-membered heterocyclines that are substituted by, Each R A , R B , R C1 , and R D1 These are independently hydrogen, 4-6 member heterocycline, optionally hydroxyl, or -C(=O)NR B2 R C2 These are C1-C6 alkyl groups, -C(=O)O(C1-C6 alkyl groups), or C1-C6 haloalkyl groups that are substituted with [C1-C6 alkyl group]. Each R A2 , R B2 , and R C2 However, independently, they are hydrogen or C1-C6 alkyl, Each R G These are independently fluoro, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and =NR A2 -C(=O)NR C1 R D1 The group is selected from the group consisting of C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H.

[0191] In some embodiments, the compound of formula (I) is formula (IJ): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A1 is a 6-membered heteroaryl, R 4 Independently and optionally, -NR A R B Substituting C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5-6 member heteroaryls optionally substituted with C1~C6 alkyl, and 1 or 2 independently selected R G A 3-6 member heterocycline is substituted with, and one or two independently selected R(s) are optionally selected. G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, Here, R 4 It is bonded to the ring A1 position, which is para to the N atom of the urea portion. Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R FThis is independently a C1-C6 alkyl group substituted with hydrogen, a 4-6 member heterocycline, a C1-C6 haloalkyl group, a 3-6 member cycloalkyl group optionally substituted with hydroxyl, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 member cycloalkyl group, -SO2(C1-C6 alkyl), and -SO2(NH2), or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0192] In some embodiments, the compound of formula (I) is formula (IK): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. R 4 Independently and optionally, -NRA R B Substituting C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5-6 member heteroaryls optionally substituted with C1~C6 alkyl, and 1 or 2 independently selected R G A 3-6 member heterocycline is substituted with, and one or two independently selected R(s) are optionally selected. G Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F This is independently a C1-C6 alkyl group substituted with hydrogen, a 4-6 member heterocycline, a C1-C6 haloalkyl group, a 3-6 member cycloalkyl group optionally substituted with hydroxyl, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 member cycloalkyl group, -SO2(C1-C6 alkyl), and -SO2(NH2), or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0193] In some embodiments, the compound of formula (I) is formula (IL): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , RD1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 Selected from the group consisting of , and -CO2H.

[0194] In some embodiments, the compound of formula (I) is formula (IM): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E RF ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0195] In some embodiments, the compound of formula (I) is of formula (IN): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0196] In some embodiments, the compound of formula (I) is formula (IO): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E R F ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R FThese are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0197] In some embodiments, the compound of formula (I) is formula (IP): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is either a halogen or absent (the phenyl ring is R 1A (It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups optionally substituted with one or two fluoropolymers. R 4 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, and -NR. A R B -C(=O)NR C R D -SO2(NR E RF ), -SO2(C1~C6 alkyl), -S(=O)(=NH)(C1~C6 alkyl), -C(=O)(C1~C6 alkyl), -CO2(C1~C6 alkyl), 5~6 member heteroaryl, and optionally one or two independently selected R G Selected from a group consisting of 3-6 member heterocyclines that are substituted by, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F These are, independently, C1-C6 alkyl or C1-C6 haloalkyl groups substituted with hydrogen or optionally with hydroxyl, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 member heterocycline. Each R G These are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and -NR. A1 R B1 -C(=O)NR C1 R D1 The group is selected from -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0198] In some embodiments, the compound of formula (I) is formula (IQ): [ka] or its salts and / or solvates, in the formula, R x These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, R 1A It is a halogen, R 1B is halogen, cyano, cyclopropyl, or absent (phenyl ring is R 1A(It has been replaced by one), R 2 These are C1-C6 alkyl or C1-C6 haloalkyl, R 3 These are C1-C6 alkyl or C1-C6 haloalkyl, R 4 These are C1-C6 alkoxy, C1-C6 haloalkyl, and -NR compounds, which are independently substituted with 1-2 substituents independently selected from C1-C6 alkyl, optionally hydroxyl, and C3-C6 cycloalkyl groups. A R B , and one or two independently selected R G Independently selected from a group consisting of 3- to 9-membered heterocyclines that are substituted by, Each R A , R B , R C1 , and R D1 These are independently hydrogen, 4-6 member heterocycline, optionally hydroxyl, or -C(=O)NR B2 R C2 These are C1-C6 alkyl groups, -C(=O)O(C1-C6 alkyl groups), or C1-C6 haloalkyl groups that are substituted with [C1-C6 alkyl group]. Each R A2 , R B2 , and R C2 However, independently, they are hydrogen or C1-C6 alkyl, Each R G These are independently fluoro, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, and =NR A2 -C(=O)NR C1 R D1 The group is selected from the group consisting of C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H.

[0199] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0200] Several embodiments, each R 1R is an independently selected halogen. In some embodiments, each R 1 is independently selected from fluoro and chloro. In some embodiments, each R 1 The fluorocarbons are selected independently from bromocarbons. In some embodiments, each R 1 is fluoro. In some embodiments, at least one R 1 is an independently selected halogen. In some embodiments, at least one R 1 The is independently selected from fluoro and chloro. In some embodiments, at least one R 1 It is fluoro.

[0201] In some embodiments, at least one R 1 is cyano. In some embodiments, at least one R 1 is hydroxyl. In some embodiments, at least one R 1 is a C1-C6 alkyl group that is optionally substituted with a hydroxyl group. In some embodiments, at least one R 1 is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, at least one R 1 is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, at least one R 1 is hydroxymethyl. In some embodiments, at least one R 1 is an unsubstituted C1-C6 alkyl group. In some embodiments, at least one R 1 is methyl. In some embodiments, at least one R 1 is a C3-C6 cycloalkyl group. In some embodiments, at least one R 1 It is cyclopropyl.

[0202] In some embodiments, m is 2, and one R 1 R is a halogen, and the other R is a halogen. 1is a C1-C6 alkyl group. In some embodiments, m is 2, and one R is 1 One is fluoro, and the other is R 1 In some embodiments, m is methyl, and R is 2. 1 R is a halogen, and the other R is a halogen. 1 is a C3-C6 cycloalkyl group. In some embodiments, m is 2, and one R is 2. 1 R is a halogen, and the other R is a halogen. 1 is cyclopropyl. In some embodiments, m is 2, and one R is 2. 1 One is fluoro, and the other is R 1 is cyano. In some embodiments, m is 2, and one R is 2. 1 R is a halogen, and the other R is a halogen. 1 is a halogen. In some embodiments, m is 2, and one R is 1 One is fluoro, and the other is R 1 It is fluoro.

[0203] In some embodiments, R 2 R is hydroxyl. In some embodiments, R 2 is a C1-C6 alkyl group that is optionally substituted with a hydroxyl group. In some embodiments, R 2 is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R 2 is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R 2 is hydroxymethyl. In some embodiments, R 2 R is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2 R is an unsubstituted C1-C3 alkyl group. In some embodiments, R 2 It is methyl.

[0204] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C3 haloalkyl. In some embodiments, R2 R is difluoromethyl. In some embodiments, 2 It is trifluoromethyl.

[0205] In some embodiments, R 2 is a halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 That is Chlorophyll.

[0206] In some embodiments, R 2 is a C3-C6 cycloalkyl group that is optionally substituted with one or two fluoropolymers. In some embodiments, R 2 is a C3-C6 cycloalkyl group substituted with one or two fluorocarbons. In some embodiments, R 2 is a C3-C6 cycloalkyl group substituted with one fluoropolymer. In some embodiments, R 2 R is a C3-C6 cycloalkyl group with two fluorosubstituted atoms. In some embodiments, R 2 is a C3-C4 cycloalkyl group substituted with one fluoropolymer. In some embodiments, R 2 is a C3-C4 cycloalkyl group substituted with two fluoropolymers. In some embodiments, R 2 These are unsubstituted C3-C6 cycloalkyl groups.

[0207] In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is a C1-C3 alkyl group. In some embodiments, R 3 is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is isopropyl.

[0208] In some embodiments, R 3 is a C1-C6 haloalkyl. In some embodiments, R 3 is a C1-C3 haloalkyl. In some embodiments, R 3 R is difluoromethyl. In some embodiments, 3 It is trifluoromethyl.

[0209] In some embodiments, R 3 R is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl groups. In some embodiments, R 3 is a C3-C6 cycloalkyl group that is optionally substituted with one or two fluoropolymers. In some embodiments, R 3 is a C3-C6 cycloalkyl group substituted with one or two fluorocarbons. In some embodiments, R 3 is a C3-C6 cycloalkyl group substituted with one fluoropolymer. In some embodiments, R 3 R is a C3-C6 cycloalkyl group that is substituted with one fluoro group at the position of the C3-C6 cycloalkyl group bonded to the methine in formula (I). In some embodiments, R 3 is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 is a C3-C6 cycloalkyl group that is optionally substituted with one or two methyl groups. In some embodiments, R 3 is a C3-C6 cycloalkyl group substituted with one or two methyl groups. In some embodiments, R 3 is a C3-C6 cycloalkyl group substituted with one methyl group. In some embodiments, R 3 R is a C3-C6 cycloalkyl group that is substituted with one methyl group at the C3-C6 cycloalkyl position bonded to methine in formula (I). In some embodiments, R 3 R is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3C3-C6 cycloalkyl groups are cyclopropyl groups. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 It is cyclohexyl.

[0210] In some embodiments, R' is a C1-C6 alkyl group. In some embodiments, R' is a C1-C4 alkyl group. In some embodiments, R' is a C1-C3 alkyl group. In some embodiments, R' is isopropyl. In some embodiments, R' is methyl. In some embodiments, R' is ethyl. In some embodiments, R' is n-propyl.

[0211] In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkyl groups. In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkyl groups. In some embodiments, R' is a C6-C10 aryl that is optionally substituted with 1 to 3 independently selected C1-6 alkoxy groups.

[0212] In some embodiments, R'' is a C1-C6 alkyl group. In some embodiments, R'' is a C1-C4 alkyl group. In some embodiments, R'' is a C1-C3 alkyl group. In some embodiments, R'' is isopropyl. In some embodiments, R'' is methyl. In some embodiments, R'' is ethyl. In some embodiments, R'' is n-propyl.

[0213] In some embodiments, Hal is selected from chloro, bromo, and iodine. In some embodiments, Hal is selected from chloro, bromo, and trifluoromethyl. In some embodiments, Hal is chloro. In some embodiments, Hal is bromo. In some embodiments, Hal is iodine. In some embodiments, Hal is trifluoromethanesulfonyl.

[0214] In some embodiments, the compound of formula (Ii) is: [ka] It is a compound of [the compound].

[0215] In some embodiments, the compound of formula (I-iii) is (I-iii-i) [ka] It is a compound of [the compound].

[0216] In some embodiments, the compound of formula (I-iv) is (I-iv-i) [ka] It is a compound of [the compound].

[0217] In some embodiments, the compound of formula (Iv) is of formula (Ivi) [ka] It is a compound of [the compound].

[0218] In some embodiments, the compound of formula (I-vi) is (I-vi-i) [ka] It is a compound of [the compound].

[0219] In some embodiments, the compound of formula (I-viii) is (I-viii-i) [ka] It is a compound of [the compound].

[0220] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein, and the compound is [ka] It is not a compound selected from the group consisting of [the specified group].

[0221] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein, and the compound is [ka] It is not a compound selected from the group consisting of [the specified group].

[0222] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein, and the compound is [ka] It is not a compound selected from the group consisting of [the specified group].

[0223] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein.

[0224] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein.

[0225] In some embodiments, the compound of formula (I) is [ka] or its salt and / or solvate, where R 3 , R 4 , and ring A are as described herein.

[0226] Some embodiments include compound 1: [ka] or a process for preparing salts and / or solvates thereof, [ka] of, (i) Carbonyl equivalent or isocyanate forming reagent, and (ii) Structure [ka] By contacting it with pyrimidine-2,5-diamine having, The present invention provides a process that includes forming compound 1.

[0227] Some embodiments include compound 1: [ka] or its salts and / or solvates, [ka] of, (i) Carbonyl equivalent or isocyanate forming reagent, and (ii) Structure [ka] The present invention provides compound 1, or a salt and / or solvate thereof, prepared by a process comprising contacting it with a pyrimidine-2,5-diamine having [a specific compound].

[0228] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0229] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an isocyanate-forming reagent. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl ester.

[0230] Some embodiments include compound 1: [ka] or a process for preparing salts and / or solvates thereof, [ka] of, (i) Carbonyl equivalents, and (ii) Structure [ka] By contacting it with pyrimidine-2,5-diamine having, The present invention provides a process that includes forming compound 1.

[0231] Some embodiments include compound 1: [ka] or its salts and / or solvates, [ka] of, (i) Carbonyl equivalents, and (ii) Structure [ka] The present invention provides compound 1, or a salt and / or solvate thereof, prepared by a process comprising contacting it with a pyrimidine-2,5-diamine having [a specific compound].

[0232] In some embodiments, [ka] Contacting the carbonyl equivalent with the pyrimidine-2,5-diamine to form compound 1 means that the carbonyl equivalent [ka] The method includes adding the mixture to a base to form mixture 1, and then adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2.

[0233] In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is about 1.0 to about 4.0 (e.g., about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3). In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.05. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.3.

[0234] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5.

[0235] In some embodiments, the carbonyl equivalent is used [ka] The addition of the base to form mixture 1 is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0236] In some embodiments, the carbonyl equivalent is used [ka] The addition to the base to form mixture 1 is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0237] In some embodiments, the carbonyl equivalent is used [ka] The addition to the base is carried out at approximately 0 to approximately 10°C (for example, approximately 0°C to approximately 5°C, approximately 0°C to approximately 2°C, or approximately 0°C). In some embodiments, the carbonyl equivalent is [ka] The addition is carried out at approximately 0°C to approximately 5°C. In some embodiments, the carbonyl equivalent is added. [ka] The addition is carried out at approximately 0°C to approximately 2°C. In some embodiments, the carbonyl equivalent is added. [ka] The addition is done at approximately 0°C.

[0238] In some embodiments, the carbonyl equivalent is used [ka] After adding the base, mixture 1 is stirred for about 1 hour to about 7 days (for example, about 1 hour to about 2 days, about 5 hours to about 1 day, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours).

[0239] In some embodiments, forming mixture 2 by adding pyrimidine-2,5-diamine to mixture 1 includes adding a second base to mixture 1 and then adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, forming mixture 2 by adding pyrimidine-2,5-diamine to mixture 1 includes adding a second base to mixture 1 and then adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, forming mixture 2 by adding a compound of formula (I-ii) to mixture 1 includes adding a compound of formula (I-ii) to mixture 1 and then adding a second base to mixture 1. In some embodiments, the second base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundec-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

[0240] In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C). In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0°C to about 5°C. In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0°C to about 2°C. In some embodiments, the addition of the second base to mixture 1 and the addition of the compound of formula (I-ii) to mixture 1 is carried out at about 0°C.

[0241] In some embodiments, after forming the mixture 2, the mixture 2 is heated to about 20°C to about 90°C (for example, about 20°C to about 60°C, about 20°C to about 50°C, about 20°C to about 40°C, about 25°C to about 35°C, or about 30°C) over about 15 minutes to about 5 hours (for example, about 1 hour to about 3 hours, or about 2 hours), and then heated to about 20°C to about 90°C (for example, about 20°C to about 60°C) Compound 1 is formed by stirring at approximately 20°C to 50°C, approximately 20°C to 40°C, approximately 25°C to 35°C, or approximately 30°C for approximately 1 hour to approximately 7 days (for example, approximately 1 hour to approximately 2 days, approximately 5 hours to approximately 1 day, approximately 10 hours to approximately 18 hours, approximately 10 hours to approximately 14 hours, approximately 14 hours to approximately 18 hours, approximately 12 hours to approximately 16 hours, approximately 14 hours to approximately 16 hours, or approximately 16 hours).

[0242] In some embodiments, heating mixture 2 and then stirring to form compound 1 includes adding a base aqueous solution and a post-treatment solvent after heating and stirring. In some embodiments, the base aqueous solution is a sodium bicarbonate aqueous solution. In some embodiments, the base aqueous solution is a 5% w / w sodium bicarbonate aqueous solution. In some embodiments, the post-treatment solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.

[0243] In some embodiments, the process includes recrystallizing compound 1 from a solvent. In some embodiments, the process includes compound 1 from the solvent after adding an aqueous base solution and a post-treatment solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6:1 to about 1:10 (e.g., about 6:1 to about 4:2, about 1:7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3:1, about 2:7, about 1:1, or about 5:2). In some embodiments, after recrystallizing compound 1, compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then water, and then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing compound 1, compound 1 is dried. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure. In some embodiments, the step of drying compound 1 includes drying compound 1 at ambient temperature.

[0244] In some embodiments, [ka] Contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 is [ka] This includes adding a carbonyl equivalent and a base to form mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2'. In some embodiments, [ka] This is a form of salt. In some embodiments, [ka] It is a form of salt, [ka] Contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 is [ka] The process involves adding a carbonyl equivalent and a base to form mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2'.

[0245] In some embodiments, [ka] Salt is a hydrochloride salt.

[0246] In some embodiments, [ka] The addition of the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0247] In some embodiments, [ka] The addition of to the carbonyl equivalent and base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the contact is carried out under nitrogen. In some embodiments, the contact is carried out under argon.

[0248] In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0). In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.05. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.3. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 2.0.

[0249] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5. In some embodiments, [ka] The addition of the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0250] In some embodiments, [ka] The addition of to the carbonyl equivalent and base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0251] In some embodiments, [ka] The addition of the carbonyl equivalent and the base is carried out at approximately 0 to approximately 10°C (e.g., approximately 0°C to approximately 5°C, approximately 0°C to approximately 5°C, or approximately 0°C). In some embodiments, the carbonyl equivalent is [ka] The addition should be done at a temperature of approximately 5°C or below.

[0252] In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' involves adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, the third base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0253] In some embodiments, the molar ratio of pyrimidine-2,5-diamine to compound 1 is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of pyrimidine-2,5-diamine to compound 1 is about 1.15.

[0254] In some embodiments, the molar ratio of the third base to compound 1 is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the third base to compound 1 is about 2.0.

[0255] In some embodiments, the addition of an aqueous sodium chloride solution to mixture 1', the addition of a third base to mixture 1', and the addition of pyrimidine-2,5-diamine are carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

[0256] In some embodiments, after forming mixture 2, mixture 2' is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 days, about 12 hours to about 3 days, about 1 day to about 3 days, about 24 hours to about 36 hours, about 30 hours to about 40 hours, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours) to form compound 1.

[0257] In some embodiments, the process includes stirring mixture 2', then adding water and an extraction solvent to mixture 2' to form mixture 3'. In some embodiments, the extraction solvent is ethyl acetate or isopropyl acetate. In some embodiments, the extraction solvent is isopropyl acetate. In some embodiments, the process includes stirring and / or shaking mixture 3'. In some embodiments, the process includes separating the organic liquid from mixture 3'. In some embodiments, the process includes adding an aqueous base solution to the organic liquid to form mixture 4'. In some embodiments, the aqueous base solution is an aqueous sodium bicarbonate solution. In some embodiments, the aqueous sodium bicarbonate solution is a 5% w / w aqueous sodium bicarbonate solution. In some embodiments, the process includes separating the organic liquid from mixture 4'. In some embodiments, the process includes reducing the volume of the organic liquid at a pressure lower than atmospheric pressure. In some embodiments, the process includes adding a poor solvent to the organic liquid to form a slurry. In some embodiments, the poor solvent is hexane or heptane. In some embodiments, the poor solvent is heptane. In some embodiments, the process includes filtering the slurry to obtain a solid. In some embodiments, the process includes dissolving the solid in isopropanol and adding it to a solid in which water is dissolved to form a slurry. In some embodiments, the slurry is cooled. In some embodiments, the slurry is filtered. In some embodiments, the slurry is dried at a pressure lower than atmospheric pressure to obtain compound 1.

[0258] In some embodiments, compound 1 precipitates from tetrahydrofuran and heptane. In some embodiments, compound 1 precipitates from isopropanol and water. In some embodiments, compound 1 precipitates from tetrahydrofuran and heptane, and then precipitates from isopropanol and water. In some embodiments, after precipitation of compound 1, compound 1 is dried. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure. In some embodiments, drying compound 1 includes drying compound 1 at about 25°C to about 70°C (e.g., about 20°C to about 25°C, about 30°C to about 60°C, about 40°C to about 50°C, or about 45°C). In some embodiments, drying compound 1 includes drying compound 1 at about 45°C. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure and at about 20°C to about 25°C.

[0259] In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters.

[0260] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0261] In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls optionally substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, R' is phenyl. In some embodiments, R' is para-nitrophenyl.

[0262] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is Combine R'OC(O)Cl with a base. [ka] Add to a mixture of R'OC(O)Cl and a base. [ka] This includes forming.

[0263] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is [ka] Add to a mixture of R'OC(O)Cl and a base. [ka] This includes forming.

[0264] In some embodiments, [ka] It is added as a solution or slurry in a solvent. In some embodiments, [ka] It is added as a solution in the solvent.

[0265] In some embodiments, the mixture of R'OC(O)Cl and the base is a solution or slurry in a solvent.

[0266] In some embodiments, [ka] This is in the form of a salt. In some embodiments, the salt is a hydrochloride salt.

[0267] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is Combine R'OC(O)Cl with a base. [ka] Add to a mixture of R'OC(O)Cl and a base. [ka] Including forming, [ka] It is a form of salt.

[0268] In some embodiments, combining R'OC(O)Cl with a base involves combining the base with a solvent and then adding R'OC(O)Cl. In some embodiments, combining the base with a solvent and then adding R'OC(O)Cl involves adding R'OC(O)Cl to the base and solvent at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) and then adding R'OC(O)Cl.

[0269] In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water. In some embodiments, when a base is combined with a solvent and then R'OC(O)Cl is added, (i) water is added to the base to form an aqueous solution of the base, (ii) tetrahydrofuran is added to the aqueous solution of the base, and then (iii) R'OC(O)Cl is added to the aqueous solution of tetrahydrofuran and the aqueous solution of the base.

[0270] In some embodiments, [ka] The addition of to the mixture of R'OC(O)Cl and the base is carried out at approximately -10°C to approximately 20°C (e.g., approximately -5°C to approximately 5°C, approximately 0°C to approximately 10°C, approximately 0°C to approximately 5°C, approximately 0°C to approximately 5°C, or approximately 0°C). In some embodiments, the addition of the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base is carried out at approximately -5°C to approximately 5°C. In some embodiments,

[0271] [ka] The addition of R'OC(O)Cl to the mixture of the base is carried out at approximately 0°C to approximately 5°C. In some embodiments, [ka] The addition of R'OC(O)Cl to the mixture of base is carried out at temperatures below 5°C. In some embodiments, [ka] It is added to a mixture of R'OC(O)Cl and a base as a solution in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0272] In some embodiments, [ka] It is added to the mixture of R'OC(O)Cl and the base over a period of approximately 15 minutes to approximately 48 hours (for example, approximately 15 minutes to approximately 2 hours, approximately 18 hours to approximately 30 hours, approximately 18 hours to approximately 24 hours, approximately 15 minutes to approximately 24 hours, approximately 1 hour to approximately 7 hours, approximately 1 hour to approximately 5 hours, approximately 2 hours to approximately 4 hours, approximately 3 hours to approximately 7 hours, approximately 24 hours, approximately 21 hours, approximately 18 hours, approximately 16 hours, approximately 12 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, or approximately 1 hour).

[0273] In some embodiments, [ka] Mixture 3 is formed by adding to a mixture of R'OC(O)Cl and a base. In some embodiments, Mixture 3 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, Mixture 3 is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

[0274] In some embodiments, a two-phase mixture containing an organic phase and an aqueous phase is formed by stirring mixture 3. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with a basic aqueous solution. In some embodiments, the basic aqueous solution is an aqueous solution of sodium bicarbonate. In some embodiments, the organic phase is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the organic phase, a poor solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the poor solvent is hexane or heptane. In some embodiments, the poor solvent is heptane.

[0275] In some embodiments, after adding the poor solvent, the mixture 4 is stirred at about 20°C to about 80°C (e.g., about 30°C to about 70°C, about 30°C to about 60°C, about 40°C to about 50°C, about 20°C to about 50°C, about 40°C to about 80°C, about 20°C to about 80°C, about 20°C to about 80°C, about 40°C, or about 50°C). In some embodiments, after adding the poor solvent, the mixture 4 is stirred at about 40°C to about 50°C. In some embodiments, stirring is carried out for about 1 minute to about 24 hours (e.g., about 1 minute to about 60 minutes, about 10 minutes to about 50 minutes, about 15 minutes to about 45 minutes, about 20 minutes to about 40 minutes, about 25 minutes to about 35 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 1 minute to about 2 hours, or about 15 minutes to about 4 hours). In some embodiments, stirring is performed for about 30 minutes.

[0276] In some embodiments, after adding the poor solvent, the mixture 4 is allowed to stand and / or stir for about 10 minutes to about 48 hours (e.g., about 6 hours to about 24 hours, about 12 hours to about 24 hours, about 16 hours to about 20 hours, about 18 hours to about 30 hours, about 24 hours to about 48 hours, or about 18 hours). In some embodiments, the standing and / or stirring is carried out at about -20°C to about 15°C (e.g., about -15°C to about 5°C, about -10°C to about 0°C, about -10°C, about -5°C, or about 0°C).

[0277] In some embodiments, after adding a poor solvent, the mixture 4 is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered. [ka] In some embodiments, [ka] It is rinsed with hexane or heptane (e.g., heptane). In some embodiments, [ka] After rinsing, [ka] To dry. In some embodiments, [ka] Drying is done at a pressure lower than atmospheric pressure. [ka] This includes drying. In some embodiments, [ka] Drying can be done at a temperature of approximately 25°C to 70°C (for example, approximately 30°C to 60°C, approximately 40°C to 50°C, approximately 40°C to 45°C, approximately 45°C to 50°C, or approximately 45°C). [ka] This includes drying. In some embodiments, [ka] Drying it at approximately 45°C [ka] This includes drying. In some embodiments, [ka] Drying it can be done at approximately 40°C to 45°C. [ka] This includes drying. In some embodiments, [ka] Drying it can be done at approximately 45°C to 50°C. [ka] This includes drying. In some embodiments, [ka] Drying can be done under an inert atmosphere (e.g., under nitrogen). [ka] This includes drying.

[0278] In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.0 to approximately 4.0 (e.g., approximately 1.0 to approximately 3.0, approximately 1.0 to approximately 2.0, approximately 1.0 to approximately 1.5, approximately 1.0 to approximately 1.4, approximately 1.0 to approximately 1.1, approximately 1.2 to approximately 1.4, approximately 1.05, approximately 1.1, approximately 1.2, approximately 1.3, approximately 2.0, or approximately 3.0). In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.05. In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.3. In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 2.0. In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 3.0.

[0279] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 1.0 to about 3.0, about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 2.0, about 2.2, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 2.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 2.2. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5.

[0280] In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, trimethylamine, and citric acid. In some embodiments, the base is sodium bicarbonate.

[0281] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is [ka] This includes contacting with pyrimidine-2,5-diamine to form compound 1.

[0282] In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out in the presence of a third base. In some embodiments, the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0283] In some embodiments, [ka] Contacting with pyrimidine-2,5-diamine to form compound 1 is [ka] This includes adding to pyrimidine-2,5-diamine. In some embodiments, [ka] Forming compound 1 by contacting it with pyrimidine-2,5-diamine is possible in the absence of a base. [ka] This includes adding to pyrimidine-2,5-diamine.

[0284] In some embodiments, [ka] Contacting pyrimidine-2,5-diamine to form compound 1 means that pyrimidine-2,5-diamine [ka] This includes adding to the following: In some embodiments, [ka] Contacting pyrimidine-2,5-diamine to form compound 1 means that pyrimidine-2,5-diamine [ka] Add to the solvent pyrimidine-2,5-diamine and [ka] This includes adding it to a mixture with [another substance]. In some embodiments, the solvent is N,N-dimethylacetamide.

[0285] In some embodiments, [ka] Contacting pyrimidine-2,5-diamine to form compound 1 is performed in the absence of a base, and pyrimidine-2,5-diamine is formed [ka] This includes adding it to.

[0286] In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out in N,N-dimethylacetamide. In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out under an inert atmosphere. In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out under nitrogen. In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out under argon. In some embodiments, NN-dimethylacetamide contains less than 2% by volume of water (e.g., less than 1.5% by volume, less than 1% by volume, less than 0.5% by volume, less than 0.3% by volume, less than 0.2% by volume, less than 0.1% by volume, less than 0.05% by volume, or less than 0.02% by volume). In some embodiments, N,N-dimethylacetamide contains less than 0.3% by volume of water.

[0287] In some embodiments, [ka] After adding to pyrimidine-2,5-diamine, or after adding pyrimidine-2,5-diamine [ka] After being added, mixture 5 is formed. In some embodiments, mixture 5 is stirred. In some embodiments, mixture 5 is stirred for about 1 minute to about 48 hours (e.g., 1 minute to about 24 hours, 1 minute to about 12 hours, 1 minute to about 6 hours, 1 minute to about 3 hours, about 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is stirred for about 12 hours to about 13 hours. In some embodiments, mixture 5 is stirred for about 3 hours. In some embodiments, mixture 5 is stirred for about 1 hour. In some embodiments, the mixture 5 is stirred at a temperature of about 10°C to about 90°C (for example, about 10°C to about 90°C, about 20°C to about 80°C, about 30°C to about 70°C, about 30°C to about 60°C, about 35°C to about 60°C, about 40°C to about 55°C, about 45°C to about 50°C, about 45°C, about 50°C, or about 55°C).

[0288] In some embodiments, after stirring mixture 5, the process includes adding water to mixture 5 to form mixture 5'. In some embodiments, the process includes stirring mixture 5'. In some embodiments, the process includes stirring mixture 5' for about 1 minute to about 48 hours (e.g., 1 minute to about 24 hours, 1 minute to about 12 hours, 1 minute to about 6 hours, 1 minute to about 3 hours, about 30 minutes to about 1.5 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, the process includes stirring mixture 5' for about 12 hours to about 13 hours. In some embodiments, the process includes stirring mixture 5' for about 3 hours. In some embodiments, the process includes stirring mixture 5' for about 1 hour.

[0289] In some embodiments, a slurry is formed after stirring the mixture 5'. In some embodiments, the slurry is filtered to obtain compound 1. In some embodiments, compound 1 is washed with water. In some embodiments, compound 1 is dried at a pressure lower than atmospheric pressure.

[0290] In some embodiments, compound 1 is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl alcohol and water. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl alcohol to water is about 1:3 to about 1:1 (e.g., about 1:2). In some embodiments, the ratio of isopropyl acetate to heptane is about 6:1 to about 4:2 (e.g., about 5:2). In some embodiments, after recrystallizing compound 1, compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then with water, and then with a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing compound 1, compound 1 is dried. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure. In some embodiments, the step of drying compound 1 includes drying compound 1 at ambient temperature.

[0291] In some embodiments, compound 1 has a purity of at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, about 98%, about 98.5%, about 99%, about 99.5%). In some embodiments, impurities 1 are present as impurities together with compound 1 in amounts of less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount). [ka]

[0292] In some embodiments, impurities 2 are present as impurities together with compound 1 in amounts of less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount). [ka]

[0293] In some embodiments, this method (a) Dissolve (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salt and / or solvate, in isopropanol to form a solution. (b) Adding water to the solution to form a mixture, (c) Lower the temperature of the mixture, and then maintain the temperature for a period of 1. (d) Raise the temperature of the mixture and then maintain the temperature for a period of 2. (e) Lowering the temperature of the mixture, and then maintaining the temperature for the period of 3, (f) The process includes preparing crystalline hemihydrate form 1 by a process that includes isolating form 1 from the mixture.

[0294] In some embodiments, Embodiment 1 has one or more of the following features.

[0295] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 6.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.4 ± 0.2 degrees 2θ has the highest relative intensity.

[0296] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 15.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.8 ± 0.2 degrees 2θ has a second relative intensity.

[0297] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 18.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.3 ± 0.2 degrees 2θ has the third highest relative intensity.

[0298] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 22.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.3 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0299] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 20.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.8 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0300] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 19.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.3 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0301] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 24.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 24.0 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0302] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 26.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.9 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0303] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 14.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.6 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0304] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 31.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.3 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0305] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.3 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0306] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 29.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 29.2 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0307] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 22.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.8 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0308] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.0 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0309] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.3 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0310] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.5 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0311] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 19.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.9 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0312] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 27.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.6 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0313] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 20.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.5 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0314] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.8 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0315] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.1 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0316] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.8 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0317] In some embodiments, the XRPD pattern of Embodiment 1 has peaks at 6.4, 15.8, and 18.3 (±0.2 degrees 2θ).

[0318] In some embodiments, the XRPD pattern of form 1 has peaks (±0.2 degrees 2θ) at 6.4, 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, and 31.3.

[0319] In some embodiments, the XRPD pattern of form 1 has peaks (±0.2 degrees 2θ) at 6.4, 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, 31.3, 28.3, 29.2, 22.8, 28.0, 25.3, 21.5, 19.9, 27.6, 20.5, 21.8, 25.1, and 25.8.

[0320] In some embodiments, Embodiment 1 features substantially the same XRPD pattern as that shown in Figure 1.

[0321] Form 1 may also have one or more of the following features:

[0322] In some embodiments, Embodiment 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.3%) at about 70°C to about 140°C (e.g., about 90°C to about 130°C, about 90°C to about 120°C, about 90°C to about 115°C, about 100°C to about 140°C, about 110°C to about 140°C, about 100°C to about 120°C, about 105°C to about 120°C, about 109°C to about 115°C, about 75°C to about 125°C, about 85°C to about 113°C, about 85°C to about 105°C, or about 112°C). In some embodiments, Embodiment 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5°C. In some embodiments, Embodiment 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 2.3% between approximately 85°C and approximately 113°C.

[0323] In some embodiments, Embodiment 1 has a TGA curve characterized by a weight loss of about 5% to about 30% (e.g., about 5% to about 27%, about 5% to about 25%, about 5% to about 22%, about 10% to about 25%, about 20% to about 22%, about 14% to about 20%, or about 17.6%) at about 150°C to about 250°C (e.g., about 230 to about 260°C, about 230 to about 240°C, about 240 to about 260°C, about 240 to about 250°C, about 242 to about 248°C, or about 245°C). In some embodiments, Embodiment 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245°C. In some embodiments, Embodiment 1 has a TGA curve characterized by a weight loss of approximately 17.6% at approximately 162°C to approximately 248°C.

[0324] In some embodiments, Embodiment 1 has substantially the same TGA curve as shown in Figure 2. In some embodiments, the crystalline morphology is Embodiment 1 having substantially the same thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram as shown in Figure 2.

[0325] In some embodiments, Embodiment 1 has a differential scanning calorimetry (DSC) first thermal cycle thermogram having an endothermic event with a start temperature of approximately 105°C and a peak at approximately 129°C, an endothermic event with a start temperature of approximately 158°C and a peak at approximately 162°C, and an endothermic event with a start temperature of approximately 174°C and a peak at approximately 177°C.

[0326] In some embodiments, Embodiment 1 has a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 3.

[0327] In some embodiments, Embodiment 1 has a DSC first cooling cycle thermogram characterized by a single exothermic event at a start temperature of 151°C and a peak temperature of 147°C.

[0328] In some embodiments, Embodiment 1 has substantially the same DSC first cooling cycle thermogram as that shown in Figure 4.

[0329] In some embodiments, form 1 is a hemihydrate.

[0330] In some embodiments, the enantiomer excess (ee) of crystalline form 1 is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%).

[0331] In some embodiments, Embodiment 1 is substantially pure.

[0332] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and / or solvate thereof, contains the free base of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, is the free base of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, comprises amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, is amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, comprises the free base amorphous form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, is the free base amorphous form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salts and / or solvates, is Form 1. * Includes. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and / or solvate thereof, is in Form 1 * That is the case.

[0333] In some embodiments, the dissolution in step (a) is carried out at approximately 40°C to 60°C (for example, approximately 45°C to 55°C, or approximately 50°C). In some embodiments, the dissolution in step (a) is carried out at approximately 50°C.

[0334] In some embodiments, the solution formed in step (a) has a concentration of about 0.08 g / mL to about 1.65 g / mL (for example, about 0.09 g / mL to about 1.55 g / mL, about 0.1 g / mL to about 0.145 g / mL, about 0.1 g / mL to about 0.135 g / mL, about 0.12 g / mL to about 0.13 g / mL, or about 0.125 g / mL). In some embodiments, the solution formed in step (a) has a concentration of about 0.125 g / mL.

[0335] In some embodiments, step (a) includes cooling the solution to about 30°C to 50°C (e.g., about 35°C to about 45°C, or about 40°C). In some embodiments, step (a) includes cooling the solution to about 40°C. In some embodiments, the cooling is carried out at a rate of about 0.1°C / min to about 5°C / min (e.g., about 0.5°C / min to about 2°C / min, or about 1°C / min). In some embodiments, the cooling is carried out at a rate of about 1°C / min.

[0336] In some embodiments, the volume / volume ratio of water added to the solution in step (b) to isopropanol used for dissolution in step (a) is about 2:1 to about 6:1 (e.g., about 3:1 to about 5:1, or about 4:1). In some embodiments, the volume / volume ratio of water added to the solution in step (b) to isopropanol used for dissolution in step (a) is about 4:1.

[0337] In some embodiments, approximately 1 / 8 to 1 / 32 of the water is added to the solution per hour. 1 / 16 of the water is added to the solution per hour. In some embodiments, approximately 1 / 16 of the water is added to the solution per hour.

[0338] In some embodiments, the temperature of the mixture in step (c) decreases to about 1°C to about 15°C (e.g., about 1°C to about 10°C, about 2°C to about 8°C, about 3°C ​​to about 7°C, or about 5°C). In some embodiments, the temperature of the mixture in step (c) decreases to about 5°C. In some embodiments, the first period is about 1 minute to about 24 hours (e.g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 6 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 1 minute to about 30 minutes, about 1 minute to about 5 minutes, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, about 1 minute, or about 1 hour). In some embodiments, the first period is about 1 hour. In some embodiments, the first period is about 1 minute.

[0339] In some embodiments, the temperature of the mixture in step (d) rises to about 25°C to about 60°C (e.g., about 25°C to about 50°C, about 30°C to about 60°C, about 30°C to about 50°C, about 35°C to about 45°C, or about 5°C). In some embodiments, the temperature of the mixture in step (c) rises to about 40°C. In some embodiments, the second period is about 1 minute to about 24 hours (e.g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 6 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 1 minute to about 30 minutes, about 1 minute to about 5 minutes, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, about 1 minute, or about 1 hour). In some embodiments, the second period is about 1 hour. In some embodiments, the second period is about 1 minute.

[0340] In some embodiments, the temperature of the mixture in step (e) decreases to about 1°C to about 15°C (e.g., about 1°C to about 10°C, about 2°C to about 8°C, about 3°C ​​to about 7°C, or about 5°C). In some embodiments, the temperature of the mixture in step (e) decreases to about 5°C. In some embodiments, the third period is approximately 1 minute to approximately 24 hours (for example, approximately 1 minute to approximately 18 hours, approximately 1 minute to approximately 12 hours, approximately 1 minute to approximately 6 hours, approximately 1 minute to approximately 3 hours, approximately 1 minute to approximately 2 hours, approximately 1 minute to approximately 30 minutes, approximately 1 minute to approximately 5 minutes, approximately 30 minutes to approximately 1.5 hours, approximately 45 minutes to approximately 1.25 hours, approximately 6 hours to approximately 18 hours, approximately 6 hours to approximately 24 hours, approximately 9 hours to approximately 15 hours, approximately 9 hours to approximately 14 hours, approximately 10 hours to approximately 12 hours, approximately 10.5 hours to approximately 11.5 hours, approximately 11 hours, approximately 12 hours, approximately 1 hour, or approximately 1 minute). In some embodiments, the third period is approximately 11 hours. In some embodiments, the third period is approximately 11 hours.

[0341] In some embodiments, step (f) includes filtering the mixture to obtain form 1. In some embodiments, step (f) includes filtering the mixture to obtain a solid and rinsing the solid to obtain form 1. In some embodiments, rinsing the solid to provide form 1 includes drying the solid after rinsing to obtain form 1. In some embodiments, rinsing the solid includes rinsing the solid with a solvent. In some embodiments, the solvent includes an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent includes water. In some embodiments, the solvent includes alcohol and water. In some embodiments, the solvent includes methanol and water. In some embodiments, the solvent is methanol and water.

[0342] In some embodiments, step (f) is: The mixture is filtered to obtain a solid. Rinsing the solid with methanol and water, and This includes drying the solid to obtain form 1.

[0343] In some embodiments, drying is carried out for about 1 minute to about 16 hours (e.g., about 1 minute to about 14 hours, about 1 minute to about 12 hours, about 1 minute to about 8 hours, about 1 minute to about 4 hours, about 1 minute to about 2 hours, about 1 minute to about 1 hour, or about 1 minute to about 30 minutes). In some embodiments, drying the solid includes drying the solid at a pressure lower than atmospheric pressure. In some embodiments, drying is carried out at a temperature of about 25°C to about 100°C (e.g., about 25°C to about 80°C, about 35°C to about 80°C, about 45°C to about 70°C, about 45°C to about 60°C).

[0344] In some embodiments, this method (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salt and / or solvate, is dissolved in methanol to form a solution. Adding water to the solution to form the first mixture, Adding form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea to the first mixture to form the second mixture, and The process includes preparing crystalline hemihydrate form 1 by a process that includes isolating a solid from a third mixture to obtain form 1.

[0345] In some embodiments, this method (a) Dissolve (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salt and / or solvate, in methanol to form a solution. (b) Adding water to the solution to form the first mixture, (c)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea form 1 is added to the first mixture to form the second mixture. (d) Stir the second mixture, (e) Adding water to the second mixture to form a third mixture, (f) Stirring the third mixture, and (g) The process includes preparing crystalline hemihydrate form 1 by isolating form 1 from a third mixture.

[0346] In some embodiments, the solution formed in step (a) has a concentration of about 0.03 g / mL to about 1 g / mL (for example, about 0.03 g / mL to about 0.5 g / mL, about 0.05 g / mL to about 0.3 g / mL, about 0.1 g / mL to about 0.2 g / mL, about 0.13 g / mL to about 0.18 g / mL, or about 0.16 g / mL). In some embodiments, the solution formed in step (a) has a concentration of about 0.16 g / mL.

[0347] In some embodiments, dissolving (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its salt and / or solvate, in methanol to form a solution includes dissolving (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a first part of methanol to form an unfiltered solution, filtering the unfiltered solution through a filter to obtain a filtrate, then rinsing the filter with a second part of methanol to obtain a rinse, and combining this with the filtrate to obtain a solution. In some embodiments, filtration is abrasive filtration. In some embodiments, the filter has a pore size of about 0.2 microns. In some embodiments, the weight of the first part of methanol is about 4 to about 8 times (e.g., about 5 to about 8 times, about 6 to about 7 times, or about 6.3 times (e.g., about 6.3 times)) the weight of the (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea to be dissolved.

[0348] In some embodiments, the solution is cooled to about 5°C to about 35°C (e.g., about 10°C to about 30°C, about 15°C to about 25°C, about 15°C to about 20°C, about 20°C to about 25°C, about 17°C to about 23°C, about 15°C, about 20°C, or about 25°C (e.g., about 15°C to about 25°C)) before adding water in step (b). In some embodiments, the water added in step (b) is purified water. In some embodiments, adding water in step (b) involves filtering the water through a filter and then adding the water to form the first mixture. In some embodiments, the amount of water added in step (b) is about 0.1 to about 2 times the weight of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a) (e.g., about 0.1 to about 1.5 times, about 0.1 to about 1 time, about 0.3 to about 0.7 times, or about 0.5 times (e.g., about 0.5 times)).

[0349] In some embodiments, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is dissolved in step (a) The concentration of urea is approximately 0.1% to 20% by weight (for example, approximately 0.1% to 15% by weight, approximately 0.1% to 10% by weight, approximately 0.1% to 5% by weight, approximately 0.1% to 3% by weight, approximately 0.5% to 3% by weight, approximately 0.7% to 2.5% by weight, approximately 0.7% to 1.3% by weight, or approximately 1% by weight (for example, approximately 1%)).

[0350] In some embodiments, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is prepared by Method 1 as specified herein. In some embodiments, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is prepared by Method 2 as specified herein.

[0351] In some embodiments, the stirring in step (d) is carried out at a temperature of approximately 5°C to approximately 35°C (e.g., approximately 10°C to approximately 30°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C, approximately 20°C to approximately 25°C, approximately 17°C to approximately 23°C, approximately 15°C, approximately 20°C, or approximately 25°C (e.g., approximately 15°C to approximately 25°C)). In some embodiments, the stirring in step (d) is carried out at a temperature of approximately 1 minute to approximately 24 hours (e.g., approximately 1 minute to approximately 18 hours, approximately 1 minute to approximately 12 hours, approximately 1 minute to approximately 8 hours, approximately 1 minute to approximately 6 hours, approximately 30 minutes to approximately 6 hours, approximately 1 hour to approximately 5 hours, approximately 2 hours to approximately 4 hours, approximately 2.5 hours to approximately 3.5 hours, or approximately 3 hours (e.g., approximately 3 hours)).

[0352] In some embodiments, the water added in step (e) is purified water. In some embodiments, the addition of water in step (e) involves filtering the water through a filter and then adding water to form a third mixture. In some embodiments, the water added in step (e) is about 0.1 to about 20 times (e.g., about 0.1 to about 15 times, about 0.1 to about 10 times, about 1 to about 9 times, about 3 to about 7 times, about 4 to about 5 times, or about 4.5 times (e.g., about 4.5 times)) the weight of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a). In some embodiments, the water added in step (e) is added over a period of time ranging from about 1 second to about 48 hours (for example, about 1 minute to about 24 hours, about 1 minute to about 18 hours, about 1 hour to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, or about 8 hours (for example, about 8 hours)).

[0353] In some embodiments, the stirring in step (f) is carried out at a temperature of approximately 5°C to approximately 35°C (e.g., approximately 10°C to approximately 30°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C, approximately 20°C to approximately 25°C, approximately 17°C to approximately 23°C, approximately 15°C, approximately 20°C, or approximately 25°C (e.g., approximately 15°C to approximately 25°C)). In some embodiments, the stirring in step (f) is carried out at a temperature of approximately 1 minute to approximately 48 hours (e.g., approximately 1 minute to approximately 36 hours, approximately 1 minute to approximately 24 hours, approximately 4 hours to approximately 24 hours, approximately 8 hours to approximately 20 hours, approximately 12 hours to approximately 20 hours, approximately 14 hours to approximately 18 hours, approximately 15 hours to approximately 17 hours, or approximately 16 hours (e.g., approximately 16 hours)).

[0354] In some embodiments, step (f) includes filtering the mixture to obtain form 1. In some embodiments, step (f) includes filtering the mixture to obtain a solid and rinsing the solid to obtain form 1. In some embodiments, rinsing the solid to provide form 1 includes drying the solid after rinsing to obtain form 1. In some embodiments, rinsing the solid includes rinsing the solid with a solvent. In some embodiments, the solvent includes an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent includes water. In some embodiments, the solvent includes alcohol and water. In some embodiments, the solvent includes methanol and water. In some embodiments, the solvent is methanol and water.

[0355] In some embodiments, isolating Form 1 from the third mixture is (i) Filter the third mixture to obtain a solid, (ii) Rinsing the solid with methanol and water, (iii) The process includes drying the solid to obtain form 1.

[0356] In some embodiments, the weights of methanol and water are about 0.5 to about 5 times (e.g., about 0.5 to about 4 times, about 0.5 to about 3 times, about 1 to about 3 times, about 1.5 to about 2.1 times, or about 1.8 times (e.g., about 1.8 times)) the weight of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a). In some embodiments, the ratio of methanol to water is about 1:100 to about 100:1 (e.g., about 20:80 to about 90:10, about 30:70 to about 90:10, about 50:50 to about 80:20, about 55:45 to about 65:35, or about 61:39 (e.g., about 61:39)).

[0357] In some embodiments, drying a solid includes drying the solid at a temperature of about 30°C to about 60°C (e.g., about 30°C to about 50°C, about 35°C to about 45°C, about 35°C to about 40°C, about 40°C to about 45°C, about 35°C, about 40°C, or about 45°C (e.g., about 35°C to about 45°C)). In some embodiments, drying a solid includes drying the solid at a pressure lower than atmospheric pressure. In some embodiments, drying a solid includes drying the solid under an inert gas (e.g., nitrogen or argon (e.g., nitrogen)). In some embodiments, drying a solid includes drying the solid until it contains about 1% to about 4% by weight of water (e.g., about 1.5% to about 3.2% by weight or about 2% to about 2.6% by weight (e.g., about 2% to about 2.6%)). In some embodiments, form 1 obtained in step (g) contains about 1% to about 4% by weight of water (e.g., about 1.5% to about 3.2% by weight or about 2% to about 2.6% by weight (e.g., about 2% to about 2.6%)).

[0358] In some embodiments, this process is [ka] Bring it into contact with the acid [ka] By forming, [ka] This includes preparing a formula in which R'' is a C1-C6 alkyl, where R 3 These are C1-C6 haloalkyl groups.

[0359] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-dioxane. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate. In some embodiments, the acid is a 1 mole solution of hydrogen chloride in ethyl acetate.

[0360] In some embodiments, contact is made [ka] This includes adding to the acid. In some embodiments, contact is made with the acid [ka] This includes adding to [a certain substance]. In some embodiments, the adding is done at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, stirring is done at a temperature of about 0°C to about 10°C. In some embodiments, stirring is done at a temperature of about 5°C to about 15°C. In some embodiments, contact is [a certain substance]. [ka] This involves stirring with the acid for about 5 minutes to about 24 hours (for example, about 5 minutes to about 10 hours, about 5 minutes to about 5 hours, about 5 minutes to about 3 hours, about 30 minutes to about 1.5 hours, about 3 hours, or about 1 hour) to form mixture 6. In some embodiments, contact is performed. [ka] This involves stirring with an acid for about 3 hours to form mixture 6. In some embodiments, contact is performed. [ka] This involves stirring with the acid for about 1 hour to form mixture 6. In some embodiments, contact is performed. [ka] The process includes stirring with an acid for at least one hour to form mixture 6. In some embodiments, the stirring is carried out at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, the stirring is carried out at a temperature of about 5°C to about 15°C. In some embodiments, contact includes adding heptane or hexane (e.g., heptane) to mixture 6. In some embodiments, heptane or hexane (e.g., heptane) is added to the mixture 6, and the mixture is cooled to about -20°C to about 0°C (e.g., about -15°C to about -5°C, or about -10°C (e.g., about -15°C to about -5°C)) over about 5 minutes to about 48 hours (e.g., about 5 minutes to about 24 hours, about 3 hours to about 9 hours, about 24 hours, or about 6 hours (e.g., about 6 hours)), and then stirred or allowed to stand (e.g., stirred) for about 10 hours to about 2 days (e.g., about 12 hours to about 24 hours, about 14 hours to about 22 hours, about 18 hours to about 30 hours, about 22 hours to about 26 hours, about 24 hours, or about 18 hours (e.g., about 24 hours)) to form a solid. In some embodiments, the solid is filtered [ka] To obtain.

[0361] In some embodiments, this process is [ka] Contact with the trifluoromethylation reagent [ka] By forming [ka] The process involves preparing a compound, where R'' is a C1-C6 alkyl group.

[0362] In some embodiments, [ka] In some embodiments, the C=N double bond has an E shape. [ka] The C=N double bond in this structure has a Z shape.

[0363] In some embodiments, [ka] The molar ratio of the trifluoromethylating agent to the is about 1.0 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of the trifluoromethylating agent to the given substance is approximately 3.0.

[0364] In some embodiments, [ka] The molar ratio of the phase transfer reagent to is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of the phase-transfer reagent to the given amount is approximately 1.0.

[0365] In some embodiments, [ka] Contacting it with a trifluoromethylation reagent is [ka] This includes contacting with a trifluoromethylation reagent and a phase transfer reagent. In some embodiments, [ka] By contacting it with a trifluoromethylation reagent and a phase transfer reagent, mixture 7 is formed.

[0366] In some embodiments, [ka] Contacting the trifluoromethylation reagent and the phase transfer reagent with the phase transfer reagent [ka] Add to, then the trifluoromethylation reagent [ka] This includes adding it to a mixture of the phase transfer reagent.

[0367] In some embodiments, the phase transfer reagent is used at approximately 5°C to approximately 40°C (e.g., approximately 10°C to approximately 35°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C). [ka] It is added to the mixture. In some embodiments, the phase transfer reagent is used at approximately 15°C to approximately 20°C. [ka] It is added to it.

[0368] In some embodiments, the phase transfer reagent is [ka] After adding it, [ka] The mixture of the phase transfer reagent is cooled to approximately -40°C to approximately 0°C (e.g., -30°C to approximately -5°C, -25°C to approximately -10°C, -20°C to approximately -15°C). In some embodiments, the phase transfer reagent is [ka] After adding it, [ka] The mixture of the phase transfer reagent is cooled to approximately -20°C to approximately -15°C.

[0369] In some embodiments, [ka] After cooling the mixture with the phase transfer reagent, [ka] The mixture of the phase transfer reagent is stirred for about 5 minutes to about 3 hours (for example, about 5 minutes to about 2 hours, about 30 minutes to about 1.5 hours, or about 1 hour). In some embodiments, [ka] After cooling the mixture with the phase transfer reagent, [ka] The mixture of the phase transfer reagent is stirred for approximately 1 hour.

[0370] In some embodiments, the trifluoromethylation reagent is used [ka] The addition of the mixture with the phase transfer reagent is carried out at approximately -40°C to approximately 0°C (e.g., -30°C to approximately -5°C, -25°C to approximately -10°C, -20°C to approximately -15°C). In some embodiments, the trifluoromethylation reagent is [ka] The addition of the reagent to the mixture with the phase transfer reagent is performed at approximately -20°C to approximately -15°C.

[0371] In some embodiments, the trifluoromethylating reagent is, [ka] It is added dropwise to a mixture of the phase transfer reagent.

[0372] In some embodiments, [ka] Contacting the trifluoromethylation reagent and the phase transfer reagent with the trifluoromethylation reagent [ka] Add to the, then the phase transfer reagent [ka] This includes adding it to a mixture of a trifluoromethylating agent.

[0373] In some embodiments, [ka] Contact with the trifluoromethylation reagent and the phase transfer reagent is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent includes toluene, xylene, or benzene. In some embodiments, the solvent includes toluene. In some embodiments, the solvent is toluene.

[0374] In some embodiments, this process involves using a trifluoromethylating reagent. [ka] This includes adding the reagent at a temperature of approximately -78°C to approximately 25°C (for example, approximately -78°C to approximately 0°C, approximately -78°C to approximately -5°C, approximately -50°C to approximately 10°C, approximately -40°C to approximately 0°C, approximately -30°C to approximately 0°C, approximately -20°C to approximately -10°C, approximately -20°C, or approximately -10°C). In some embodiments, the trifluoromethylation reagent is [ka] It is added at approximately -20°C to approximately -10°C.

[0375] In some embodiments, this process involves using a trifluoromethylating reagent. [ka] The process involves adding the trifluoromethylating reagent over a period of approximately 1 minute to 24 hours (for example, approximately 1 minute to 12 hours, approximately 12 hours to 24 hours, approximately 6 hours to 12 hours, approximately 1 minute to 12 hours, approximately 1 minute to 9 hours, approximately 1 minute to 6 hours, approximately 1 minute to 4 hours, approximately 1 minute to 3 hours, approximately 1 minute to 2 hours, approximately 30 minutes to 1.5 hours, approximately 45 minutes to 1.25 hours, or approximately 1 hour). In some embodiments, the process involves adding the trifluoromethylating reagent over a period of approximately 1 minute to 24 hours (for example, approximately 1 minute to 12 hours, approximately 12 hours to 12 hours, approximately 1 minute to 9 hours, approximately 1 minute to 6 hours, approximately 1 minute to 4 hours, approximately 1 minute to 3 hours, approximately 1 minute to 2 hours, approximately 30 minutes to 1.5 hours, approximately 45 minutes to 1.25 hours, or approximately 1 hour). [ka] This includes adding it over a period of about one hour.

[0376] In some embodiments, this process involves adding a phase transfer reagent, [ka] The process includes stirring the trifluoromethylation reagent and the phase transfer reagent. In some embodiments, this process is [ka] The process involves stirring the trifluoromethylation reagent and the phase transfer reagent at approximately -78°C to approximately 25°C (for example, approximately -78°C to approximately 0°C, approximately -78°C to approximately -5°C, approximately -50°C to approximately 10°C, approximately -40°C to approximately 0°C, approximately -30°C to approximately 0°C, approximately -20°C to approximately -10°C, approximately -20°C, or approximately -10°C). In some embodiments, the phase transfer reagent is [ka] It is added at approximately -20°C to approximately -10°C.

[0377] In some embodiments, the phase transfer reagent is [ka] Adding it to a mixture of the trifluoromethylating reagent will transfer the phase transfer reagent. [ka] This involves adding the mixture of the trifluoromethylating agent in several portions. In some embodiments, the number of portions is 7 to 13. In some embodiments, the number of portions is 9 to 11. In some embodiments, the number of portions is 10. In some embodiments, the number of portions is 10 portions in which the weight is substantially the same.

[0378] In some embodiments, the process includes adding water or an aqueous acid solution to the mixture 7. In some embodiments, the process includes adding the aqueous acid solution to the mixture 7 to form a mixture 8. In some embodiments, the aqueous acid solution is an aqueous ammonium chloride solution (e.g., a 10% by weight aqueous ammonium chloride solution). In some embodiments, the addition of water or an aqueous acid solution to the mixture 7 is carried out at a temperature of about -10°C to about 25°C (e.g., about -5°C to about 5°C).

[0379] In some embodiments, the process includes adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from mixture 9 and concentrated under a pressure lower than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, a residue is obtained by concentrating the organic phase at a pressure lower than atmospheric pressure. In some embodiments, the residue is purified using silica gel. [ka] You can obtain this.

[0380] In some embodiments, the process includes adding water and / or an aqueous base solution to mixture 8 to form mixture 9'. In some embodiments, mixture 9' includes an organic phase and an aqueous phase. In some embodiments, the process includes separating the organic phase from mixture 9'. In some embodiments, the process includes distilling the organic phase to obtain a distillate. In some embodiments, the process includes passing the distillate through carbon (e.g., activated carbon). In some embodiments, after passing the distillate through carbon, the process includes reducing the volume of the distillate under a pressure lower than atmospheric pressure to form a concentrate. In some embodiments, the process includes adding water to the concentrate and then reducing the volume of the mixture of water and concentrate to form mixture 9''. In some embodiments, the process includes adding a poor solvent to mixture 9'' and then reducing the volume of mixture 9'' to form mixture 9''''. In some embodiments, the poor solvent is heptane. In some embodiments, the process is [ka] This includes adding a portion of (for example, a previously prepared portion) to the mixture 9''' to form a precipitate. In some embodiments, the precipitate is filtered and dried. [ka] It forms.

[0381] In some embodiments, the trifluoromethylating reagent is selected from TMSCF3, [(trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate, Et3GeNa / C6H5SCF3, N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)cuplate (1-), (SP-4-1)-tetrakis(trifluoromethyl)argentate (1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoromethylating reagent is TMSCF3.

[0382] In some embodiments, the phase transfer reagent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, 1,1'-(buta-1,4-diyl)bis[4-aza-1-azoniabicyclo[2.2.2]octane]dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmytilammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

[0383] In some embodiments, this process is [ka] By bringing it into contact with [ka] This includes preparing a formula in which R'' is a C1-C6 alkyl group. In some embodiments, [ka] To bring it into contact with, [ka] and includes contact with a condensation base. In some embodiments, the condensation base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the condensation base is potassium carbonate.

[0384] In some embodiments, contact is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0385] In some embodiments, [ka] The molar ratio of the condensed base to the base is approximately 0.8 to approximately 6.0 (e.g., approximately 1.0 to approximately 5.0, approximately 1.0 to approximately 4.0, approximately 2.0 to approximately 4.0, approximately 1.0 to approximately 5.0, approximately 2.5 to approximately 3.5, approximately 1.0 to approximately 2.0, approximately 1.3 to approximately 1.7, approximately 1.0 to approximately 1.5, approximately 1.0 to approximately 1.4, approximately 1.0 to approximately 1.1, approximately 1.2 to approximately 1.4, approximately 0.8, approximately 0.9, approximately 0.95, approximately 1.0, approximately 1.05, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 2.0, approximately 2.5, approximately 3.0, or approximately 3.5). In some embodiments, [ka] The molar ratio of the condensed base to the given base is approximately 1.5.

[0386] In some embodiments, [ka] The molar ratio of the condensed base to the base is approximately 0.8 to 6.0 (for example, approximately 1.0 to 5.0, approximately 1.0 to 4.0, approximately 2.0 to 4.0, approximately 1.0 to 5.0, approximately 2.5 to 3.5, approximately 1.0 to 2.0, approximately 1.3 to 1.7, approximately 1.0 to 1.5, approximately 1.0 to 1.4, approximately 0.8 to 1.2, approximately 0.9 to 1). (0.1, approximately 1.0 to approximately 1.1, approximately 1.2 to approximately 1.4, approximately 0.95 to approximately 1.05, approximately 1.0 to approximately 1.04, approximately 0.8, approximately 0.9, approximately 0.95, approximately 1.0, approximately 1.02, approximately 1.05, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 2.0, approximately 2.5, approximately 3.0, or approximately 3.5). In some embodiments, [ka] The molar ratio of the condensed base to the given base is approximately 1.02.

[0387] In some embodiments, [ka] And contact with the condensed base is carried out at approximately 25°C to approximately 80°C (for example, approximately 25°C to approximately 70°C, approximately 25°C to approximately 60°C, approximately 35°C to approximately 50°C, approximately 35°C to approximately 45°C, approximately 35°C, approximately 40°C, or approximately 45°C). In some embodiments, [ka] The contact with the condensed base is carried out at approximately 35°C to 45°C.

[0388] In some embodiments, [ka] Contact with the condensed base is carried out at approximately 25°C to 80°C (for example, approximately 25°C to 70°C, approximately 25°C to 60°C, approximately 35°C to 50°C, approximately 35°C to 45°C, approximately 35°C, approximately 40°C, or approximately 45°C).

[0389] In some embodiments, [ka] And contact with a condensed base, [ka] and includes stirring with a condensed base. In some embodiments, [ka] And stirring with the condensed base is [ka] and stirring with the condensed base for about 1 to 48 hours (for example, about 2 to 36 hours, about 2 to 24 hours, about 2 to 12 hours, about 6 to 24 hours, about 9 to 19 hours, about 11 to 17 hours, about 13 to 15 hours, about 13.5 to 14.5 hours, or about 14 hours). In some embodiments, [ka] And stirring with the condensed base is [ka] This also includes stirring with the condensed base for about 14 hours.

[0390] In some embodiments, [ka] And contact with a condensed base, [ka] Add to, then add the condensed base [ka] This includes adding it to a mixture of the following.

[0391] In some embodiments, [ka] The addition is carried out at temperatures of approximately 5°C to 40°C (for example, approximately 10°C to 35°C, approximately 15°C to 25°C, and approximately 15°C to 20°C). In some embodiments, [ka] The addition is done at a temperature of approximately 15°C to 20°C.

[0392] In some embodiments, the condensed base is [ka] Adding to the mixture is done at a temperature of about 5°C to about 40°C (for example, about 10°C to about 35°C, about 15°C to about 25°C, about 15°C to about 20°C). In some embodiments, the condensed base is [ka] Adding it to the mixture is done at a temperature of approximately 15°C to 20°C.

[0393] In some embodiments, [ka] And by contact with a condensation base, mixture 10 is obtained. In some embodiments, mixture 10 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is stirred for about 15 minutes to about 5 hours. In some embodiments, stirring of mixture 10 is carried out at about 25°C to about 110°C (e.g., 40°C to about 80°C, 50°C to about 70°C, 55°C to about 65°C, or about 60°C). In some embodiments, stirring of mixture 10 is carried out at about 60°C.

[0394] In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 5°C to about 35°C (for example, about 10°C to about 30°C, about 15°C to about 25°C, or about 20°C). In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 20°C. In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 15°C to about 25°C.

[0395] In some embodiments, cooling the mixture 10 includes forming a slurry. In some embodiments, the process includes filtering the slurry to provide a solution. In some embodiments, the process includes reducing the volume of the solution under a pressure lower than atmospheric pressure. In some embodiments, the process includes (i) adding a solvent to the solution, (ii) reducing the volume of the solution under a pressure lower than atmospheric pressure, optionally (iii) adding a solvent to the solution, and optionally (iv) reducing the volume of the solution under a pressure lower than atmospheric pressure to form a concentrate. In some embodiments, the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol. In some embodiments, steps (iii) and (iv) are required. In some embodiments, the process includes cooling the concentrate to about 5°C to about 35°C (e.g., about 10°C to about 30°C, about 15°C to about 25°C, or about 20°C). In some embodiments, the process includes cooling the concentrate to about 15°C to about 25°C. In some embodiments, the process includes cooling the concentrate and then adding water to the concentrate to form mixture 10'. In some embodiments, the process includes stirring mixture 10' for about 1 hour to about 48 hours (e.g., about 2 hours to about 36 hours, about 2 hours to about 24 hours, about 2 hours to about 12 hours, about 6 hours to about 24 hours, about 9 hours to about 19 hours, about 11 hours to about 17 hours, about 13 hours to about 15 hours, about 13.5 hours to about 14.5 hours, or about 14 hours). In some embodiments, the process includes stirring mixture 10' for about 14 hours. In some embodiments, after stirring mixture 10', a slurry is formed. In some embodiments, the slurry is filtered to obtain the compound of formula (Iv).

[0396] In some embodiments, the process involves cooling the mixture 10 and then concentrating the mixture 10 at a pressure lower than atmospheric pressure. [ka] This includes obtaining.

[0397] In some embodiments, this process In some embodiments, the compound of formula (Iv) is used [ka] And contact with a condensed base, [ka] Add to the compound of formula (Iv), then add the condensed base [ka] This includes adding it to a mixture of the compound of formula (Iv).

[0398] In some embodiments, this process is [ka] By bringing it into contact with an acid [ka] This includes preparing [the product / service].

[0399] In some embodiments, the acid is a protonic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron(III) bromide, and boron trifluoride (e.g., boron trifluoride ether).

[0400] In some embodiments, the acid is acetic acid.

[0401] In some embodiments, [ka] Contacting it with an acid is [ka] This includes adding to the acid. In some embodiments, [ka] Contacting it with an acid is [ka] This involves contacting the acid with a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, [ka] By adding to the acid, mixture 11 is formed. In some embodiments, [ka] After adding to the acid, the mixture 11 is heated to about 80°C to about 160°C (for example, about 90°C to about 150°C, about 100°C to about 140°C, about 110°C to about 130°C, about 115°C to about 125°C, or about 120°C). In some embodiments, [ka] After adding to the acid, the mixture 11 is heated to approximately 120°C. In some embodiments, [ka] After adding to the acid, the mixture 11 is stirred for about 15 minutes to about 2 days (for example, about 30 minutes to about 24 hours, about 2 hours to about 16 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, or about 8 hours). In some embodiments, [ka] After adding to the acid, the mixture 11 is stirred for about 8 hours.

[0402] In some embodiments, after stirring the mixture 11, water is added to the mixture 11. In some embodiments, after adding water to the mixture 11, a solvent is added to the mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base solution. In some embodiments, the aqueous base solution is an aqueous potassium carbonate solution (e.g., a 15% by weight aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous base solution, the organic phase is stirred with water and Na2S2O4. In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 8 hours. In some embodiments, a solid is formed by stirring the organic phase with water and Na2S2O4. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, the pH of the solution is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10), and then stirred for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a two-phase mixture. In some embodiments, the two-phase mixture includes an organic phase and an aqueous phase. In some embodiments, the organic phase is concentrated under a pressure lower than atmospheric pressure. [ka] To obtain.

[0403] In some embodiments, this process is [ka] By bringing it into contact with [ka] The preparation of a formula in which LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl.

[0404] In some embodiments, [ka] To bring it into contact with, [ka] and contact with a base. In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the base is potassium carbonate.

[0405] In some embodiments, [ka] Contact with a base is carried out in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

[0406] In some embodiments, [ka] And contact with a base, [ka] This includes contact with a base and sodium iodide.

[0407] In some embodiments,

[0408] [ka] Contact with the base and sodium iodide is carried out at a temperature of approximately 80°C to 160°C (for example, approximately 90°C to 150°C, approximately 100°C to 140°C, approximately 110°C to 130°C, approximately 115°C to 125°C, or approximately 120°C). In some embodiments, [ka] Contact with the base and sodium iodide is carried out at approximately 120°C.

[0409] In some embodiments, [ka] Mixture 13 is formed by adding a base and sodium iodide. In some embodiments, mixture 13 is stirred for about 15 minutes to about 2 days (e.g., about 30 minutes to about 24 hours, about 2 hours to about 16 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 13 is stirred for about 5 hours.

[0410] In some embodiments, this process is [ka] The process involves preparing a compound of formula (Iv) by contacting the compound with an acid, where Hal is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. In some embodiments, Hal is chloro. In some embodiments, the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.

[0411] In some embodiments, [ka] Contact with the acid is carried out in a solvent. In some embodiments, the solvent includes methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

[0412] In some embodiments, [ka] Contact with the acid is carried out at a temperature of approximately 10°C to approximately 60°C (for example, approximately 15°C to approximately 55°C, approximately 15°C to approximately 35°C, approximately 20°C to approximately 30°C, approximately 23°C to approximately 27°C, or approximately 25°C). In some embodiments, [ka] The contact with the acid is carried out at approximately 25°C.

[0413] In some embodiments, this process is [ka] The process involves preparing compounds of formula (I-viii) by contacting them with . In some embodiments, Z is O. In some embodiments, R 2is a C1-C6 alkyl group. In some embodiments, R 2 It is methyl.

[0414] In some embodiments, [ka] To bring it into contact with, [ka] and contact with a base. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the contact is carried out in a solvent.

[0415] In some embodiments, the solvent includes methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

[0416] In some embodiments, [ka] And contact with the base is carried out at a temperature of about 10°C to about 60°C (for example, about 15°C to about 55°C, about 15°C to about 35°C, about 20°C to about 30°C, about 23°C to about 27°C, or about 25°C). In some embodiments, [ka] The contact with the base is carried out at approximately 25°C.

[0417] Some embodiments have the following structure: [ka] A process for preparing compound 1 having, or a salt and / or solvate thereof, [ka] The present invention provides a process that includes reacting to form compound 1.

[0418] Compound 1 in some embodiments has the following structure: [ka] Includes, [ka] Compound 1 is prepared by a process that includes reacting to form compound 1.

[0419] In some embodiments, [ka] Reacting them to form compound 1 is [ka] Make contact with [ka] This includes forming a compound, where R'' is a C1-C6 alkyl group.

[0420] In some embodiments, [ka] To bring it into contact with, [ka] and includes contact with a condensation base. In some embodiments, the condensation base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the condensation base is potassium carbonate.

[0421] In some embodiments, contact is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is ethyl acetate.

[0422] In some embodiments, [ka] And contact with a condensed base, [ka] Add to, then add the condensed base [ka] This includes adding it to a mixture of the following.

[0423] In some embodiments, [ka] The addition is carried out at temperatures of approximately 5°C to 40°C (for example, approximately 10°C to 35°C, approximately 15°C to 25°C, and approximately 15°C to 20°C). In some embodiments, [ka] The addition is done at a temperature of approximately 15°C to 20°C.

[0424] In some embodiments, the condensed base is [ka] Adding to the mixture is done at a temperature of about 5°C to about 40°C (for example, about 10°C to about 35°C, about 15°C to about 25°C, about 15°C to about 20°C). In some embodiments, the condensed base is [ka] Adding it to the mixture is done at a temperature of approximately 15°C to 20°C.

[0425] In some embodiments, [ka] And by contact with a condensation base, mixture 10 is obtained. In some embodiments, mixture 10 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is stirred for about 15 minutes to about 5 hours. In some embodiments, stirring of mixture 10 is carried out at about 25°C to about 110°C (e.g., 40°C to about 80°C, 50°C to about 70°C, 55°C to about 65°C, or about 60°C). In some embodiments, stirring of mixture 10 is carried out at about 60°C.

[0426] In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 5°C to about 35°C (for example, about 10°C to about 30°C, about 15°C to about 25°C, or about 20°C). In some embodiments, after stirring the mixture 10, the mixture 10 is cooled to about 20°C.

[0427] After cooling the mixture 10, the mixture 10 is concentrated at a pressure lower than atmospheric pressure. [ka] To obtain.

[0428] In some embodiments, [ka] Reacting them to form compound 1 is [ka] Contact with the trifluoromethylation reagent [ka] This includes forming a compound, where R'' is a C1-C6 alkyl group.

[0429] In some embodiments, [ka] Contacting it with a trifluoromethylation reagent is [ka] This includes contacting with a trifluoromethylation reagent and a phase transfer reagent. In some embodiments, [ka] By contacting it with a trifluoromethylation reagent and a phase transfer reagent, mixture 7 is formed.

[0430] In some embodiments, [ka] Contacting the trifluoromethylation reagent and the phase transfer reagent with the phase transfer reagent [ka] Add to, then the trifluoromethylation reagent [ka] This includes adding it to a mixture of the phase transfer reagent.

[0431] In some embodiments, the phase transfer reagent is [ka] It is added at approximately 5°C to approximately 40°C (for example, approximately 10°C to approximately 35°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C). In some embodiments, the phase transfer reagent is [ka] It is added at approximately 15°C to 20°C.

[0432] In some embodiments, the phase transfer reagent is [ka] After adding it, [ka] The mixture of the phase transfer reagent is cooled to approximately -40°C to approximately 0°C (e.g., -30°C to approximately -5°C, -25°C to approximately -10°C, -20°C to approximately -15°C). In some embodiments, the phase transfer reagent is [ka] After adding it, [ka] The mixture of the phase transfer reagent is cooled to approximately -20°C to approximately -15°C.

[0433] In some embodiments, [ka] After cooling the mixture with the phase transfer reagent, [ka] The mixture of the phase transfer reagent is stirred for about 5 minutes to about 3 hours (for example, about 5 minutes to about 2 hours, about 30 minutes to about 1.5 hours, or about 1 hour). In some embodiments, [ka] After cooling the mixture with the phase transfer reagent, [ka] The mixture of the phase transfer reagent is stirred for approximately 1 hour.

[0434] In some embodiments, the trifluoromethylation reagent is used [ka] The addition of the mixture with the phase transfer reagent is carried out at approximately -40°C to approximately 0°C (e.g., -30°C to approximately -5°C, -25°C to approximately -10°C, -20°C to approximately -15°C). In some embodiments, the trifluoromethylation reagent is [ka] The addition of the reagent to the mixture with the phase transfer reagent is performed at approximately -20°C to approximately -15°C.

[0435] In some embodiments, the trifluoromethylating reagent is, [ka] It is added dropwise to a mixture of the phase transfer reagent.

[0436] In some embodiments, the process includes adding water or an aqueous acid solution to the mixture 7. In some embodiments, the process includes adding an aqueous acid solution to the mixture 7 to form a mixture 8. In some embodiments, the aqueous acid solution is an aqueous ammonium chloride solution (for example, a 10% by weight aqueous ammonium chloride solution).

[0437] In some embodiments, the process involves adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and concentrated under a pressure lower than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, a residue is obtained by concentrating the organic phase at a pressure lower than atmospheric pressure. In some embodiments, the residue is purified using silica gel to obtain compounds of formula (I-iv).

[0438] In some embodiments, the trifluoromethylating reagent is selected from TMSCF3, [(trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate, Et3GeNa / C6H5SCF3, N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)cuplate(1-), (SP-4-1)-tetrakis(trifluoromethyl)argentate(1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoroalkylating reagent is the trifluoromethylating reagent. In some embodiments, the trifluoromethylating reagent is TMSCF3.

[0439] In some embodiments, the phase transfer reagent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, 1,1'-(buta-1,4-diyl)bis[4-aza-1-azoniabicyclo[2.2.2]octane]dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmytilammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

[0440] In some embodiments, [ka] Reacting them to form compound 1 is [ka] Bring it into contact with the acid [ka] This includes forming a compound, where R'' is a C1-C6 alkyl group.

[0441] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-dioxane. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate. In some embodiments, the acid is a 1 mole solution of hydrogen chloride in ethyl acetate.

[0442] In some embodiments, contact is made [ka] This includes adding to the acid. In some embodiments, the addition is carried out at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, stirring is carried out at a temperature of about 0°C to about 10°C. In some embodiments, contact is [ka] This involves stirring with the acid for about 5 minutes to about 24 hours (for example, about 5 minutes to about 10 hours, about 5 minutes to about 5 hours, about 5 minutes to about 3 hours, about 30 minutes to about 1.5 hours, or about 1 hour) to form mixture 6. In some embodiments, contact is performed. [ka] The process includes stirring with an acid for about 1 hour to form mixture 6. In some embodiments, the stirring is carried out at a temperature of about 0°C to about 30°C (e.g., about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 10°C, or about 5°C to about 15°C). In some embodiments, the stirring is carried out at a temperature of about 5°C to about 15°C. In some embodiments, contact includes adding heptane or hexane (e.g., heptane) to mixture 6. In some embodiments, heptane or hexane (e.g., heptane) is added to the mixture 6, the mixture is cooled to about -20°C to about 0°C (e.g., -15°C to about -5°C or about -10°C) over about 5 minutes to about 24 hours (e.g., about 3 hours to about 9 hours, or about 6 hours), and then stirred or allowed to stand (e.g., stirred) for about 10 hours to about 2 days (e.g., about 12 hours to about 24 hours, about 14 hours to about 22 hours, about 18 hours to about 30 hours, about 22 hours to about 26 hours, about 24 hours, or about 18 hours) to form a solid. In some embodiments, the solid is filtered [ka] To obtain.

[0443] In some embodiments, [ka] Reacting them to form compound 1 is [ka] of, (i) Carbonyl equivalents, and (ii) Structure [ka] By contacting it with pyrimidine-2,5-diamine having, The present invention provides a process that includes forming compound 1.

[0444] In some embodiments, [ka] Contacting the carbonyl equivalent with the pyrimidine-2,5-diamine to form compound 1 means that the carbonyl equivalent [ka] The method includes adding the mixture to a base to form mixture 1, and then adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2.

[0445] In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is about 1.0 to about 4.0 (e.g., about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3). In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.05. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.3.

[0446] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5.

[0447] In some embodiments, the carbonyl equivalent is used [ka] The addition of the base to form mixture 1 is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0448] In some embodiments, the carbonyl equivalent is used [ka] The addition to the base to form mixture 1 is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0449] In some embodiments, the carbonyl equivalent is used [ka] The addition to the base is carried out at approximately 0 to approximately 10°C (for example, approximately 0°C to approximately 5°C, approximately 0°C to approximately 2°C, or approximately 0°C). In some embodiments, the carbonyl equivalent is [ka] The addition is carried out at approximately 0°C to approximately 5°C. In some embodiments, the carbonyl equivalent is added. [ka] The addition is done at a temperature of approximately 0°C to 2°C.

[0450] In some embodiments, the carbonyl equivalent is used [ka] After adding the base, mixture 1 is stirred for about 1 hour to about 7 days (for example, about 1 hour to about 2 days, about 5 hours to about 1 day, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours).

[0451] In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 includes adding a second base to mixture 1 and then adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 includes adding a second base to mixture 1 and then adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, the second base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

[0452] In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C). In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0°C to about 5°C. In some embodiments, the addition of the second base to mixture 1 and the addition of pyrimidine-2,5-diamine to mixture 1 is carried out at about 0°C to about 2°C.

[0453] In some embodiments, after forming mixture 2, mixture 2 is heated to about 20°C to about 60°C (e.g., about 20°C to about 50°C, about 20°C to about 40°C, about 25°C to about 35°C, or about 30°C) over about 15 minutes to about 5 hours (e.g., about 1 hour to about 3 hours, or about 2 hours), and then stirred at about 20°C to about 60°C (e.g., about 20°C to about 50°C, about 20°C to about 40°C, about 25°C to about 35°C, or about 30°C) for about 1 hour to about 7 days (e.g., about 1 hour to about 2 days, about 5 hours to about 1 day, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours) to form compound 1.

[0454] In some embodiments, compound 1 is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6:1 to about 4:2 (for example, about 5:2). In some embodiments, after recrystallizing compound 1, compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then with water, and then with a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing compound 1, compound 1 is dried. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure. In some embodiments, the step of drying compound 1 includes drying compound 1 at ambient temperature.

[0455] In some embodiments, [ka] Contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 is [ka] This includes adding a carbonyl equivalent and a base to form mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2'. In some embodiments, [ka] This is a form of salt. In some embodiments, [ka] It is a form of salt, [ka] Contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 is [ka] The process involves adding a carbonyl equivalent and a base to form mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2'.

[0456] In some embodiments, [ka] Salt is a hydrochloride salt.

[0457] In some embodiments, [ka] The addition of the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0458] In some embodiments, [ka] The addition of to the carbonyl equivalent and base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the contact is carried out under nitrogen. In some embodiments, the contact is carried out under argon.

[0459] In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0). In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.05. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 1.3. In some embodiments, [ka] The molar ratio of the carbonyl equivalent to is approximately 2.0.

[0460] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5.

[0461] In some embodiments, [ka] The addition of the carbonyl equivalent and the base to form mixture 1' is carried out in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0462] In some embodiments, [ka] The addition of to the carbonyl equivalent and base to form mixture 1' is carried out under an inert atmosphere. In some embodiments, the addition is carried out under nitrogen. In some embodiments, the addition is carried out under argon.

[0463] In some embodiments, [ka] The addition of the carbonyl equivalent and the base is carried out at approximately 0 to approximately 10°C (e.g., approximately 0°C to approximately 5°C, approximately 0°C to approximately 5°C, or approximately 0°C). In some embodiments, the carbonyl equivalent is [ka] The addition should be done at a temperature of approximately 5°C or below.

[0464] In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' includes adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1' and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' involves adding an aqueous sodium chloride solution to mixture 1', adding a third base to mixture 1', and then adding pyrimidine-2,5-diamine to mixture 1'. In some embodiments, the third base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundeca-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0465] In some embodiments, the addition of an aqueous sodium chloride solution to mixture 1', the addition of a third base to mixture 1', and the addition of pyrimidine-2,5-diamine are carried out at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

[0466] In some embodiments, after forming mixture 2, mixture 2' is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 days, about 12 hours to about 3 days, about 1 day to about 3 days, about 24 hours to about 36 hours, about 30 hours to about 40 hours, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours) to form compound 1.

[0467] In some embodiments, compound 1 precipitates from tetrahydrofuran and heptane. In some embodiments, compound 1 precipitates from isopropanol and water. In some embodiments, compound 1 precipitates from tetrahydrofuran and heptane, and then precipitates from isopropanol and water. In some embodiments, after precipitation of compound 1, compound 1 is dried. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure. In some embodiments, drying compound 1 includes drying compound 1 at about 25°C to about 70°C (e.g., about 20°C to about 25°C, about 30°C to about 60°C, about 40°C to about 50°C, or about 45°C). In some embodiments, drying compound 1 includes drying compound 1 at about 45°C. In some embodiments, drying compound 1 includes drying compound 1 at a pressure lower than atmospheric pressure and at about 20°C to about 25°C.

[0468] In some embodiments, the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl esters.

[0469] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0470] In some embodiments, the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyls and C6-C10 aryls optionally substituted with 1-3 independently selected C1-C6 alkyls, nitros, or C1-C6 alkoxys. In some embodiments, R' is phenyl. In some embodiments, R' is para-nitrophenyl.

[0471] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is Combine R'OC(O)Cl with a base. [ka] Add to a mixture of R'OC(O)Cl and a base. [ka] This includes forming.

[0472] In some embodiments, [ka] This is in the form of a salt. In some embodiments, the salt is a hydrochloride salt.

[0473] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is Combine R'OC(O)Cl with a base. [ka] Add to a mixture of R'OC(O)Cl and a base. [ka] Including forming, [ka] It is a form of salt.

[0474] In some embodiments, combining R'OC(O)Cl with a base involves combining the base with a solvent and then adding R'OC(O)Cl. In some embodiments, combining the base with a solvent and then adding R'OC(O)Cl involves adding R'OC(O)Cl to the base and solvent at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C) and then adding R'OC(O)Cl.

[0475] In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0476] In some embodiments, [ka] The addition of to the mixture of R'OC(O)Cl and the base is carried out at approximately 0°C to approximately 10°C (e.g., approximately 0°C to approximately 5°C, approximately 0°C to approximately 5°C, or approximately 0°C). In some embodiments, [ka] The addition of R'OC(O)Cl to the mixture of the base is carried out at approximately 0°C to approximately 5°C. In some embodiments, [ka] The addition of R'OC(O)Cl to the mixture of base is carried out at temperatures below 5°C. In some embodiments, [ka] It is added to a mixture of R'OC(O)Cl and a base as a solution in a solvent. In some embodiments, the solvent includes acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0477] In some embodiments, [ka] It is added to the mixture of R'OC(O)Cl and the base over a period of approximately 15 minutes to approximately 48 hours (for example, approximately 15 minutes to approximately 2 hours, approximately 18 hours to approximately 30 hours, approximately 18 hours to approximately 24 hours, approximately 15 minutes to approximately 24 hours, approximately 1 hour to approximately 7 hours, approximately 1 hour to approximately 5 hours, approximately 2 hours to approximately 4 hours, approximately 3 hours to approximately 7 hours, approximately 24 hours, approximately 21 hours, approximately 18 hours, approximately 16 hours, approximately 12 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, or approximately 1 hour).

[0478] In some embodiments, [ka] Mixture 3 is formed by adding to a mixture of R'OC(O)Cl and a base. In some embodiments, Mixture 3 is stirred for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, Mixture 3 is stirred at about 0 to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

[0479] In some embodiments, a two-phase mixture containing an organic phase and an aqueous phase is formed by stirring mixture 3. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with a basic aqueous solution. In some embodiments, the basic aqueous solution is an aqueous solution of sodium bicarbonate. In some embodiments, the organic phase is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the organic phase, a poor solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the poor solvent is hexane or heptane. In some embodiments, the poor solvent is heptane.

[0480] In some embodiments, after adding a poor solvent, the mixture 4 is concentrated at a pressure lower than atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered. [ka] In some embodiments, [ka] It is rinsed with hexane or heptane (e.g., heptane). In some embodiments, [ka] After rinsing, [ka] To dry. In some embodiments, [ka] Drying is done at a pressure lower than atmospheric pressure. [ka] This includes drying. In some embodiments, [ka] Drying can be done at a temperature of approximately 25°C to 70°C (for example, approximately 30°C to 60°C, approximately 40°C to 50°C, approximately 40°C to 45°C, approximately 45°C to 50°C, or approximately 45°C).

[0481] [ka] This includes drying. In some embodiments, [ka] Drying it at approximately 45°C [ka] This includes drying. In some embodiments, [ka] Drying it can be done at approximately 40°C to 45°C. [ka] This includes drying. In some embodiments, [ka] Drying it can be done at approximately 45°C to 50°C. [ka] This includes drying. In some embodiments, [ka] Drying can be done under an inert atmosphere (e.g., under nitrogen). [ka] This includes drying.

[0482] In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.0 to approximately 4.0 (e.g., approximately 1.0 to approximately 3.0, approximately 1.0 to approximately 2.0, approximately 1.0 to approximately 1.5, approximately 1.0 to approximately 1.4, approximately 1.0 to approximately 1.1, approximately 1.2 to approximately 1.4, approximately 1.05, approximately 1.1, approximately 1.2, approximately 1.3, approximately 2.0). In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.05. In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 1.3. In some embodiments, [ka] The molar ratio of R'OC(O)Cl to is approximately 2.0.

[0483] In some embodiments, [ka] The molar ratio of base to is about 1.0 to about 5.0 (e.g., about 1.0 to about 3.0, about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 2.2, about 3.0, or about 3.5). In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.0. In some embodiments, [ka] The molar ratio of sodium bicarbonate to is approximately 3.5.

[0484] In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, trimethylamine, and citric acid. In some embodiments, the base is sodium bicarbonate.

[0485] In some embodiments, [ka] Contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 is [ka] This includes contacting with pyrimidine-2,5-diamine to form compound 1.

[0486] In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out in the presence of a third base. In some embodiments, the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0487] In some embodiments, [ka] Contacting with pyrimidine-2,5-diamine to form compound 1 is [ka] This includes adding to pyrimidine-2,5-diamine. In some embodiments, [ka] Forming compound 1 by contacting it with pyrimidine-2,5-diamine is possible in the absence of a base. [ka] This includes adding to pyrimidine-2,5-diamine.

[0488] In some embodiments, [ka] Contacting pyrimidine-2,5-diamine to form compound 1 means that pyrimidine-2,5-diamine [ka] This includes adding it to.

[0489] In some embodiments, [ka] Contacting pyrimidine-2,5-diamine to form compound 1 is performed in the absence of a base, and pyrimidine-2,5-diamine is formed [ka] This includes adding it to.

[0490] In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out in N,N-dimethylacetamide. In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out under an inert atmosphere. In some embodiments, [ka] The formation of compound 1 by contacting with pyrimidine-2,5-diamine is carried out under nitrogen. In some embodiments, NN-dimethylacetamide contains less than 2% by volume of water (e.g., less than 1.5% by volume, less than 1% by volume, less than 0.5% by volume, less than 0.3% by volume, less than 0.2% by volume, less than 0.1% by volume, less than 0.05% by volume, or less than 0.02% by volume). In some embodiments, N,N-dimethylacetamide contains less than 0.3% by volume of water.

[0491] In some embodiments, [ka] After adding to pyrimidine-2,5-diamine, or after adding pyrimidine-2,5-diamine [ka] After being added, mixture 5 is formed. In some embodiments, mixture 5 is stirred for about 1 minute to about 48 hours (e.g., 1 minute to about 24 hours, 1 minute to about 12 hours, 1 minute to about 6 hours, 1 minute to about 3 hours, about 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is stirred for about 12 hours to about 13 hours. In some embodiments, mixture 5 is stirred for about 3 hours. In some embodiments, mixture 5 is stirred for about 1 hour.

[0492] In some embodiments, compound 1 has a purity of at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, about 98%, about 98.5%, about 99%, about 99.5%). In some embodiments, impurities 1 are present as impurities together with compound 1 in amounts of less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount). [ka]

[0493] In some embodiments, impurities 2 are present as impurities together with compound 1 in amounts of less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or an undetectable amount). [ka]

[0494] In some embodiments, this process is [ka] By bringing it into contact with an acid [ka] This includes preparing [the product / service].

[0495] In some embodiments, the acid is a protonic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron(III) bromide, and boron trifluoride (e.g., boron trifluoride ether).

[0496] In some embodiments, the acid is acetic acid.

[0497] In some embodiments, [ka] Contacting it with an acid is [ka] This includes adding to the acid. In some embodiments, [ka] Contacting it with an acid is [ka] This involves contacting the acid with a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, [ka] By adding to the acid, mixture 11 is formed. In some embodiments, [ka] After adding to the acid, the mixture 11 is heated to about 80°C to about 160°C (for example, about 90°C to about 150°C, about 100°C to about 140°C, about 110°C to about 130°C, about 115°C to about 125°C, or about 120°C). In some embodiments, [ka] After adding to the acid, the mixture 11 is heated to approximately 120°C. In some embodiments, [ka] After adding to the acid, the mixture 11 is stirred for about 15 minutes to about 2 days (for example, about 30 minutes to about 24 hours, about 2 hours to about 16 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, or about 8 hours). In some embodiments, [ka] After adding to the acid, the mixture 11 is stirred for about 8 hours.

[0498] In some embodiments, after stirring the mixture 11, water is added to the mixture 11. In some embodiments, after adding water to the mixture 11, a solvent is added to the mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base solution. In some embodiments, the aqueous base solution is an aqueous potassium carbonate solution (e.g., a 15% by weight aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous base solution, the organic phase is stirred with water and Na2S2O4. In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is stirred with water and Na2S2O4 for about 8 hours. In some embodiments, a solid is formed by stirring the organic phase with water and Na2S2O4. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, the pH of the solution is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10), and then stirred for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a two-phase mixture. In some embodiments, the two-phase mixture includes an organic phase and an aqueous phase. In some embodiments, the organic phase is concentrated under a pressure lower than atmospheric pressure. [ka] To obtain.

[0499] In some embodiments, this process is [ka] By bringing it into contact with [ka] The preparation of a formula in which LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl.

[0500] In some embodiments, [ka] To bring it into contact with, [ka] and contact with a base. In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the base is potassium carbonate.

[0501] In some embodiments, [ka] Contact with a base is carried out in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acet...

Claims

1. Equation (I): 【Chemistry 1】 A process for preparing a compound, or a salt and / or solvate thereof, Equation (I - i): 【Chemistry 2】 The compound, (i) Carbonyl equivalents, and (ii) Formula (I-ii) 【Transformation 3】 By bringing it into contact with the compound, This includes forming a compound of formula (I), wherein, Z is O or NR ｘ And, R ｘ These are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, Each R １ However, they are independently selected from halogens, hydroxyls, cyanos, C1-C6 alkyls optionally substituted with hydroxyls, and C3-C6 cycloalkyls. m is 0, 1, 2, or 3, R ２ However, these are halogens, hydroxyls, C1-C6 alkyls optionally substituted with hydroxyls, C1-C6 haloalkyls, and C3-C6 cycloalkyls optionally substituted with one or two fluoros. R ３ However, it is a C3-C6 cycloalkyl group substituted with a C1-C6 alkyl group, a C1-C6 haloalkyl group, or one or two substituents optionally selected independently from fluoro and C1-C6 alkyl groups. Ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl. Each R ４ However, they became independent, (i) Halogen, (ii) Optionally one or two hydroxyl or -NR Ａ R Ｂ C1-C6 alkyl groups that are substituted with (iii) C1-C6 alkoxy molecules substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. (iv) C1-C6 haloalkyl, (v) Hydroxyl, (vi) Cyano, (vii)-CO ２ H、 ())) Ａ ( Ｂ 、 (ix)=NR Ａ２ 、 (x)-C(=O)NR Ｃ R Ｄ 、 (xi)-SO ２ (NR Ｅ - Ｆ ) (xi)-SO ２ (C1-C6 alkyl), (xiiii)-S(=O)(=NH)(C1-C6 alkyl), (xiv)-C(=O)(C1-C6 alkyl), (xv)-CO ２ (C1-C6 alkyl), (xvi) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, (xvii) One or two independently selected R Ｇ A 3- to 9-membered heterocycline that is substituted by, and (xviiii) One or two independently selected R Ｇ Selected from the group consisting of 3- to 6-membered cycloalkyl groups that are substituted with, n is 0, 1, or 2. Each R Ａ , R Ａ１ , R Ｂ , R Ｂ１ , R Ｃ , R Ｃ１ , R Ｄ , R Ｄ１ , R Ｅ , and R Ｆ However, they became independent, (i) Hydrogen, (ii) Hydroxyl, (iii) 4-6 member heterocycline, (iv) C1-C6 haloalkyl, (v)-C(=O)(C1-C6 alkyl), (vi)-C(=O)O(C1-C6 alkyl), (vii) - SO ２ (C1-C6 alkyl), (viiii) A 3- to 6-membered cycloalkyl group optionally substituted with a hydroxyl group, or (ix) Optionally hydroxyl, -C(=O)NR Ｂ２ R Ｃ２ , 5-6 member heteroaryl, 3-6 member cycloalkyl, -SO ２ (C1-C6 alkyl), -CO ２ H, and -SO ２ (NH ２ ) is a C1-C6 alkyl group substituted with one or two substituents independently selected from ) or R Ｃ and R Ｄ However, together with the nitrogen atom to which they are bonded, they can selectively form hydroxyl, halogen, and -C(=O)NR Ｂ１ R Ｃ１ , -SO ２ (C1-C6 alkyl), -CO ２ H forms a 4-10 membered heterocycline substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy groups, which are optionally substituted with hydroxyl. Each R Ａ２ , R Ｂ２ , and R Ｃ２ These are independently hydrogen or C1-C6 alkyl groups. Each R Ｇ However, independently, fluoro, cyano, hydroxyl, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, -NR Ａ１ R Ｂ１ , = NR Ａ２ , -C(=O)NR Ｃ１ R Ｄ１ , -CO ２ (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO ２ (C1-C6 alkyl), and -CO ２ A process selected from the group consisting of H.

2. structure: 【Chemistry 4】 A process for preparing compound 1 having, or a salt and / or solvate thereof, 【Transformation 5】 of, (i) Carbonyl equivalents, and (ii) Structure 【Transformation 6】 By contacting it with pyrimidine-2,5-diamine having, A process comprising forming compound 1. 【Request Item 3】 【Chemistry 7】 When brought into contact with acid, 【Transformation 8】 By forming, 【Chemistry 9】 The process according to claim 2, comprising preparing the following. 【Request Item 4】 【Chemistry 10】 Contact it with a trifluoromethylation reagent, 【Chemistry 11】 By forming, 【Chemistry 12】 The process according to claim 3, comprising preparing a formula in which R'' is a C1-C6 alkyl group. 【Request Item 5】 【Chemistry 13】 By bringing it into contact with, 【Chemistry 14】 The process according to claim 3 or 4, comprising preparing the following. 【Request Item 6】 【Chemistry 15】 By bringing it into contact with an acid, 【Chemistry 16】 The process according to claim 5, comprising preparing the following. 【Request Item 7】 【Chemistry 17】 By bringing it into contact with, [Chemistry 18] The process according to claim 6, comprising preparing a formula wherein LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. 【Request Item 8】 【Chemistry 19】 By bringing it into contact with an acid, 【Chemistry 20】 The process according to claim 5, comprising preparing a formula in which Hal is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. 【Request Item 9】 【Chemistry 21】 By bringing it into contact with, 【Chemistry 22】 The process according to claim 8, comprising preparing the following.

10. structure: 【Chemistry 23】 A process for preparing compound 1 having, or a salt and / or solvate thereof, 【Chemistry 24】 A process comprising reacting to form compound 1. 【Request Item 11】 【Chemistry 25】 By reacting them, compound 1 can be formed. 【Chemistry 26】 Make contact with it, 【Chemistry 27】 The process according to claim 10, comprising forming a formula in which R'' is a C1-C6 alkyl group. 【Request Item 12】 【Chemistry 28】 By reacting them, compound 1 can be formed. 【Chemistry 29】 Contact it with a trifluoromethylation reagent, 【Transformation 30】 The process according to claim 11, comprising forming a formula in which R'' is a C1-C6 alkyl group. 【Request Item 13】 【Chemistry 31】 By reacting them, compound 1 can be formed. 【Chemistry 32】 When brought into contact with acid, 【Transformation 33】 The process according to claim 12, comprising forming a 【Request Item 14】 【Chemistry 34】 By reacting them, compound 1 can be formed. 【Chemistry 35】 of, (i) Carbonyl equivalents, and (ii) Structure 【Transformation 36】 By contacting it with pyrimidine-2,5-diamine having, The process according to claim 10, comprising forming compound 1.

15. structure: 【Chemistry 37】 A process for preparing compound 1 having, or a salt and / or solvate thereof, 【Chemistry 38】 Make contact with it, 【Chemistry 39】 The formation of a formula in which R'' is C1 to C6 alkyl, and 【Chemistry 40】 A process comprising reacting to form compound 1. 【Request Item 16】 【Chemistry 41】 By reacting them, compound 1 can be formed. 【Chemistry 42】 Contact it with a trifluoromethylation reagent, 【Chemistry 43】 By forming, 【Chemistry 44】 The process according to claim 15, comprising preparing a formula in which R'' is a C1-C6 alkyl group. 【Request Item 17】 【Chemistry 45】 By reacting them, compound 1 can be formed. 【Chemistry 46】 When brought into contact with acid, 【Chemistry 47】 By forming, 【Chemistry 48】 The process according to any one of claims 15 to 16, comprising preparing the following. 【Request Item 18】 【Chemistry 49】 By reacting them, compound 1 can be formed. [Transformation 50] of, (i) Carbonyl equivalents, and (ii) Structure 【Chemistry 51】 By contacting it with pyrimidine-2,5-diamine having, The process according to any one of claims 15 to 17, comprising forming compound 1.

19. structure: 【Chemistry 52】 A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) 【Chemistry 53】 Make contact with it, 【Chemistry 54】 The process involves forming a compound in which R'' is a C1-C6 alkyl compound. (b) 【Transformation 55】 Contact it with a trifluoromethylation reagent, 【Transformation 56】 To form, (c) 【Chemistry 57】 Bring it into contact with HCl, [Chem. 58] To form, and (d) 【Chemistry 59】 (i) carbonyl equivalent, and (ii) structure 【Transformation 60】 By contacting it with pyrimidine-2,5-diamine having, A process comprising forming compound 1.

20. structure: 【Chemistry 61】 A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) 【Transformation 62】 Make contact with it, 【Transformation 63】 The formation of a formula in which LG is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. (b) 【Chemistry 64】 When brought into contact with acid, 【Transformation 65】 To form, (c) [Chem. 66] Make contact with it, 【Transformation 67】 The process involves forming a compound in which R'' is a C1-C6 alkyl compound. (d) 【Transformation 68】 Contact it with a trifluoromethylation reagent, 【Transformation 69】 To form, (e) 【Transformation 70】 Bring it into contact with HCl, 【Chemistry 71】 To form, and (f) 【Chemistry 72】 (i) carbonyl equivalent, and (ii) structure 【Transformation 73】 By contacting it with pyrimidine-2,5-diamine having, A process comprising forming compound 1.

21. structure: 【Chemistry 74】 A process for preparing compound 1 having, or a salt and / or solvate thereof, (a) 【Chemistry 75】 Make contact with it, 【Transformation 76】 The formation of a formula in which Hal is selected from chloro, bromo, iodine, and trifluoromethanesulfonyl. (b) [Chem 77] When brought into contact with acid, 【Transformation 78】 To form, (c) 【Chemistry 79】 Make contact with it, 【Chemistry 80】 The process involves forming a compound in which R'' is a C1-C6 alkyl compound. (d) 【Chemistry 81】 Contact it with a trifluoromethylation reagent, 【Chemistry 82】 To form, (e) 【Chemistry 83】 Bring it into contact with HCl, 【Chemical 84】 To form, (f) 【Chemical 85】 (i) R'OC(O)Cl (wherein R' is selected from C1-C6 alkyls and C6-C10 aryls substituted with 1-3 independently selected C1-C6 alkyls or C1-C6 alkoxys), and (ii) structure [Chemical 86] By contacting it with pyrimidine-2,5-diamine having, A process for forming compound 1.

22. The process according to any one of claims 1 to 21, wherein the carbonyl equivalent is R'OC(O)Cl, where R' is selected from C1-C6 alkyl and C6-C10 aryls substituted with 1 to 3 independently selected C1-C6 alkyl, nitro, or C1-C6 alkoxys.

23. The process according to any one of claims 1 to 22, wherein the carbonyl equivalent is selected from the group consisting of phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidine-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1-methylethenyl ester.

24. The process according to any one of claims 1 to 23, wherein the carbonyl equivalent is phenyl chloroformate.

25. The process according to any one of claims 3 to 24, wherein the acid is HCl.

26. The trifluoromethylation reagent is TMSCF ３ The process according to any one of claims 4 to 25.

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