TW202508560A - Processes of preparing pi3k inhibitors - Google Patents

Abstract

This disclosure provides processes of preparing compounds of Formula (I), such as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1), and salts and/or solvates thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3K[alpha]).

Description

Method for preparing PI3K inhibitor

The present disclosure provides methods for preparing compounds of formula (I) such as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1) and their salts and/or solvent complexes, which inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα).

The phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (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 driving physiological and pathophysiological functions of tumor progression, such as 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.) Inhibition of PI3K/AKT/TOR signaling (e.g., pharmacological or genetic) can lead to cancer cell death and regression of tumor growth.

Certain compounds of formula (I) are described in WO 2022/265993, which is incorporated herein by reference in its entirety. Alternative synthetic procedures for preparing compounds of formula (I) are needed. Such alternative synthetic procedures are disclosed herein.

Some embodiments provide a method for preparing a compound of formula (I): (I), or its salt and/or solvent complex; The method comprises making the compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: Reaction to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: and Contact to form , wherein R'' is a C1-C6 alkyl group; and Reaction to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein R'' is a C1-C6 alkyl group; (b) Contact with a trifluoromethylating agent to form (c) make Contact with HCl to form ; and (d) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups; and (ii) having the structure to form compound 1.

Other embodiments include those described in the implementation methods and/or patent application scope. Additional Definitions

To facilitate understanding of the present disclosure as described herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meanings as commonly understood by a person of ordinary skill in the art to which the present disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout the specification and appendices is incorporated herein by reference in its entirety.

When referring to a number or a numerical range, the term "about" means that the referenced number or numerical range is approximate, for example, within 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.

“API” means active pharmaceutical ingredient.

The term "pharmaceutically acceptable formulation" 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 of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., 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 the 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.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, the pharmaceutically acceptable salt is obtained by reacting a compound having an acidic group described herein with a base to form a salt (such as an ammonium salt, an alkali metal salt (such as a sodium or potassium salt), an alkali earth metal salt (such as a calcium or magnesium salt), an organic base (such as dicyclohexylamine, N- methyl-D-glucosamine, phenyl(hydroxymethyl)methylamine) and an amino acid (such as arginine, lysine and the like)), or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in a medicament. Examples of salts of the compounds described herein with bases include the following: salts thereof with inorganic bases (e.g., sodium, potassium, magnesium, calcium, and aluminum); salts thereof with organic bases (e.g., methylamine, ethylamine, and ethanolamine); salts thereof with basic amino acids (e.g., lysine and ornithine); and ammonium salts. The salts may be acid addition salts, which are specifically exemplified by acid addition salts formed with 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; acidic amino acids such as aspartic acid and glutamic acid.

The term "pharmaceutically acceptable solvent" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. A solvent is a crystalline solid that contains solvent molecules within its crystal lattice. In some cases, the solvent form of a compound can advantageously alter the properties of the compound, such as solubility, stability, dissolution rate, and mechanical behavior. An exemplary solvent is a hydrate, which is an aqueous solvent. When the average number of water molecules present in each repeating unit (i.e., unit cell) of the crystal lattice of the hydrate is known, the hydrate is appended with a prefix representing the average number of water molecules per 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 information, see, for example, KR Morris, Polymorphism in Pharmaceutical Solids 1999 , pp. 125-181; Jeffrey, GA Acc. Chem. Res. 1969 , 344-352; Rev. Pure Appl. Chem. , 1963 , 50-90; Encyclopedia of Pharm. Tech. , 1993 , 7, pp. 393-441, each of which is incorporated herein in its entirety.

As used herein, the term "carbonyl equivalent" refers to a reagent that, when contacted with an amine group, reacts to form, for example, a nucleophilic acyl-substituted substrate that can further react with a nucleophilic reagent such as an amine to form a urea. In some embodiments, the carbonyl equivalent is R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

As used herein, the term "isocyanate-forming reagent" refers to a reagent that reacts to form an isocyanate when in contact with an amine group. The isocyanate can further react with an amine to form a urea. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of phosgene (in toluene), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "oxo" refers to a divalent, doubly-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

The term "hydroxy" refers to an -OH group.

The term "cyano" refers to a -CN group.

The term "alkyl" refers to a saturated acyclic hydrocarbon group that may be straight or branched, containing the indicated number of carbon atoms. For example, C _1-10 indicates that there may be 1 to 10 (including 1 and 10) carbon atoms in the group. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl , t- butyl, n -hexyl. As used herein, the term "saturated" means that there are only single bonds between the constituent carbon atoms and the other available valencies are occupied by hydrogen and/or other substituents as defined herein.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with independently selected halogen groups.

The term "alkoxy" refers to an -O-alkyl group (eg, -OCH ₃ ).

The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic or polycyclic group, wherein 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 wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl and the like.

As used herein, the term "cycloalkyl" refers to a cyclic saturated alkyl group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3-10 ring carbons, or 3-6 ring carbons, wherein the cycloalkyl group may be substituted as appropriate. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups 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, bicyclo[2.2.2]octane and the like. Cycloalkyl groups also include spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. As used herein, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

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 (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, such as tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, oxazolyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ] pyridinyl ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b ][1,4]oxathiophene, isoindolyl and other groups. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl. For the purpose of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas or vinyl analogs thereof in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidone (e.g., or ), oxazolidinone (e.g., or ), pyrazinones (e.g. or ) and imidazolones (e.g., ), wherein each of the ring nitrogens adjacent to the carbonyl group is tertiary (i.e., the pendoxy group (i.e., "=O") herein is part of a heteroaryl ring).

The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic system), if it is monocyclic, it has 1-3 heteroatoms, if it is bicyclic, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-9 heteroatoms, wherein the heteroatoms are selected from O, N or S. (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted with 1-3 pendoxy groups (forming, for example, lactams) and one or more N or S atoms may be substituted with 1-2 oxo groups (forming, for example, N-oxides, S-oxides, or S,S-dioxides) when valence permits; and wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, and the like. Heterocyclic groups may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclic groups 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[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, Bicyclo[3.2.1]octane, 2-oxacyclo[1.1.0]butane, 2-oxacyclo[2.1.0]pentane, 2-oxacyclo[1.1.1]pentane, 3-oxacyclo[3.1.0]hexane, 5-oxacyclo[2.1.1]hexane, 3-oxacyclo[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, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclic groups also include spirocycles (e.g., spirobicycles in which the two rings are linked via only one atom). Non-limiting examples of spirocycloheterocyclic groups 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, 2-oxazaspiro[ [2.2]pentane, 4-oxahistrospiro[2.5]octane, 1-oxahistrospiro[3.5]nonane, 2-oxahistrospiro[3.5]nonane, 7-oxahistrospiro[3.5]nonane, 2-oxahistrospiro[4.4]nonane, 6-oxahistrospiro[2.6]nonane, 1,7-dioxahistrospiro[4.5]decane, 2,5-dioxahistrospiro[3.6]decane, 1-oxahistrospiro[5.5]undecane, 3-oxahistrospiro[5.5]undecane, 3-oxahistrospiro[5.5]undecane and similar groups.

As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, oxazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional unsaturations (as well as unsaturations due to the ring itself; for example, one or more double bonds or triple bonds between constituent ring atoms), with the proviso that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclo, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic system), it is understood that such rings and cyclic groups encompass those rings and cyclic groups having fused rings, including those rings and cyclic groups wherein the point of fusion is located on: (i) adjacent ring atoms (e.g., a [xx0] ring system where 0 represents a zero atom bridge (e.g., )); (ii) single ring atoms (spiro-fused ring systems) (e.g. , or ), or (iii) an array of adjacent ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., , or ).

In addition, the atoms making up the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

In addition, compounds disclosed generally or specifically herein are intended to include all tautomeric isomeric forms. Thus, for example, a compound containing the moiety: The compounds include those containing: Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy encompass pyridone or pyrimidone tautomeric forms.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mirror image isomers (e.g., R and S isomers); non-mirror image isomers; and mixtures of mirror image isomers (e.g., R and S isomers), including racemic mixtures; and mixtures of non-mirror image isomers; as well as individual mirror image isomers and non-mirror image isomers, which occur due to structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure that does not specify stereochemistry (e.g., a "planar" structure) and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a designated stereochemical structure (e.g., a structure with "wedges" and/or "dummy" bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomers of the compound.

The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure will be apparent from the description and drawings as well as the scope of the claims.

Cross-reference to related applications

This application claims priority to U.S. Provisional Application No. 63/532,695 filed on August 15, 2023, which is incorporated herein by reference in its entirety.

The present disclosure provides methods for preparing compounds of formula (I) such as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1) and their salts and/or solvent complexes, which inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα).

Some embodiments provide a method for preparing a compound of formula (I): (I), or its salt and/or solvent complex; The method comprises making the compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent or an isocyanate forming reagent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

Some embodiments provide a method for preparing a compound of formula (I): (I), or its salt and/or solvent complex; The method comprises making the compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

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, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy. 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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

Some embodiments provide a compound of formula (I): (I), or its salt and/or solvent complex, the compound is prepared by a method comprising: making a compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent or an isocyanate forming reagent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

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, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy. 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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

Some embodiments provide a compound of formula (I): (I), or its salt and/or solvent complex, the compound is prepared by a method comprising: making a compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

Some embodiments provide a method for preparing a compound of formula (I): (I), or its salt and/or solvent complex, the method comprises making the compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent; and (ii) a compound of formula (I-ii) (I-ii); to form a compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

In some embodiments, contacting a compound of formula (I-i) with a carbonyl equivalent and a compound of formula (I-ii) to form a compound of formula (I) comprises adding a carbonyl equivalent to a compound of formula (I-i) 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 molar ratio of the carbonyl equivalent to the compound of formula (I-i) 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 (I-i) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (I-i) is about 1.3.

In some embodiments, the molar ratio of the base to the compound of formula (I-i) 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 (I-i) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (I-i) is about 3.5.

In some embodiments, the addition of the carbonyl equivalent to the compound of formula (I-i) and the base to form mixture 1 is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 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, the addition of the carbonyl equivalent to the compound of formula (I-i) and the base to form mixture 1 is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, the addition of the carbonyl equivalent to the compound of formula (I-i) 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 (I-i) 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 (I-i) 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 (I-i) is carried out at about 0°C.

In some embodiments, after the carbonyl equivalent is added to the compound of formula (I-i) and the base, the mixture 1 is agitated 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.

In some embodiments, adding the compound of formula (I-ii) to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and adding the compound of formula (I-ii) to mixture 1. In some embodiments, adding the compound of formula (I-ii) to mixture 1 to form mixture 2 comprises adding the second base to mixture 1, followed by adding the compound of formula (I-ii) to mixture 1. In some embodiments, adding the compound of formula (I-ii) to mixture 1 to form mixture 2 comprises adding the compound of formula (I-ii) to mixture 1, followed by adding the 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)non-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the compound of formula (I-ii) to the 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 alkali to the mixture 1 and the addition of the compound of formula (I-ii) to the mixture 1 is carried out at about 0°C to about 5°C. In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the compound of formula (I-ii) to the mixture 1 is carried out at about 0°C to about 2°C. In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the compound of formula (I-ii) to the mixture 1 is carried out at about 0°C.

In some embodiments, after forming the mixture 2, the mixture 2 is heated to about 20°C to about 90°C (e.g., 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 (e.g., about 1 hour to about 3 hours or about 2 hours); then heated to about 20°C to about 90°C. (e.g., 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.) 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 a compound of formula (I).

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

In some embodiments, the method comprises recrystallizing the compound of formula (I) from a solvent. In some embodiments, the method comprises recrystallizing the compound of formula (I) from a solvent after adding an aqueous alkaline 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 from about 6:1 to about 1:10 (e.g., from about 6:1 to about 4:2, from about 1:7 to about 3:7, from about 4:6 to about 6:4, from 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, followed by water, followed by 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) comprises drying the compound of formula (I) under a pressure less than atmospheric pressure. In some embodiments, drying the compound of formula (I) comprises drying the compound of formula (I) at ambient temperature.

In some embodiments, contacting the compound of formula (I-i) with a carbonyl equivalent and a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-i) to a carbonyl equivalent and a base to form a mixture 1', followed by adding the compound of formula (I-ii) to the mixture 1' to form a mixture 2'. In some embodiments, the compound of formula (I-i) is in the form of a salt. In some embodiments, the compound of formula (I-i) is in the form of a salt, and contacting the compound of formula (I-i) with a carbonyl equivalent and a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-i) to a carbonyl equivalent and a base to form a mixture 1', followed by adding the compound of formula (I-ii) to the mixture 1' to form a mixture 2'.

In some embodiments, the salt of the compound of formula (I-i) is a hydrochloride salt.

In some embodiments, the addition of the compound of formula (I-i) to the carbonyl equivalent and the base to form the mixture 1' is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, adding the compound of formula (I-i) to the carbonyl equivalent and the base to form the mixture 1' is carried out under an inert atmosphere. In some embodiments, the contacting is carried out under nitrogen. In some embodiments, the contacting is carried out under argon.

In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (I-i) 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 (I-i) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (I-i) is about 1.3. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of formula (I-i) is about 2.0.

In some embodiments, the molar ratio of the base to the compound of formula (I-i) 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 (I-i) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (I-i) is about 3.5.

In some embodiments, the addition of the compound of formula (I-i) to the carbonyl equivalent and the base to form the mixture 1' is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, the addition of the compound of formula (I-i) to the carbonyl equivalent and the base to form a mixture 1' is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, the addition of the compound of formula (I-i) 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 (I-i) is carried out at about 5° C. or lower.

In some embodiments, adding the compound of formula (I-ii) to the mixture 1' to form the mixture 2' comprises adding a tert-alkali to the mixture 1' and adding the compound of formula (I-ii) to the mixture 1'. In some embodiments, adding the compound of formula (I-ii) to the mixture 1' to form the mixture 2' comprises adding the tert-alkali to the mixture 1', followed by adding the compound of formula (I-ii) to the mixture 1'. In some embodiments, adding the compound of formula (I-ii) to the mixture 1' to form the mixture 2' comprises adding an aqueous sodium chloride solution to the mixture 1', adding the tert-alkali to the mixture 1', and adding the compound of formula (I-ii) to the mixture 1'. In some embodiments, adding the compound of formula (I-ii) to the mixture 1' to form the mixture 2' comprises adding an aqueous sodium chloride solution to the mixture 1', adding a third base to the mixture 1', and then adding the compound of formula (I-ii) to the mixture 1'. In some embodiments, the third base is selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicycloundec-7-ene (DBU) and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

In some embodiments, the molar ratio of the compound of formula (I-ii) to the compound of formula (I-i) 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 (I-i) is about 1.15.

In some embodiments, the molar ratio of the tertiary alkali to the compound of formula (I-i) 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 tertiary alkali to the compound of formula (I-i) is about 2.0.

In some embodiments, an aqueous sodium chloride solution is added to the mixture 1', a tert-alkali is added to the mixture 1', and the addition of the compound of formula (I-ii) 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, an aqueous sodium chloride solution is added to the mixture 1', a tert-alkali is added to the mixture 1', and the addition of the compound of formula (I-ii) is carried out at about 0°C to about 5°C.

In some embodiments, after forming mixture 2', mixture 2' is agitated 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).

In some embodiments, the method includes adding water and an extraction solvent to the mixture 2' after agitating the mixture 2' to form a 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 method includes agitating and/or shaking the mixture 3'. In some embodiments, the method includes separating the organic liquid from the mixture 3'. In some embodiments, the method includes adding an alkaline aqueous solution to the organic liquid to form the mixture 4'. In some embodiments, the alkaline aqueous 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 method includes separating the organic liquid from the mixture 4'. In some embodiments, the method includes reducing the volume of the organic liquid at a pressure below atmospheric pressure. In some embodiments, the method includes adding an antisolvent to the organic liquid to form a slurry. In some embodiments, the antisolvent is hexane or heptane. In some embodiments, the antisolvent is heptane. In some embodiments, the method includes filtering the slurry to provide a solid. In some embodiments, the method includes dissolving the solid in isopropanol and adding water to the dissolved solid 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 below atmospheric pressure to provide a compound of formula (I).

In some embodiments, the compound of formula (I) is precipitated from tetrahydrofuran and heptane. In some embodiments, the compound of formula (I) is precipitated from isopropanol and water. In some embodiments, the compound of formula (I) is precipitated from tetrahydrofuran and heptane, followed by precipitation from isopropanol and water. In some embodiments, after precipitating the compound of formula (I), the compound of formula (I) is dried. In some embodiments, drying the compound of formula (I) comprises drying the compound of formula (I) at a pressure less than atmospheric pressure. In some embodiments, drying the compound of formula (I) comprises 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) comprises drying the compound of formula (I) at about 45° C. In some embodiments, drying the compound of formula (I) comprises drying the compound of formula (I) at a pressure below atmospheric pressure at about 20° C. to about 25° C.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

In some embodiments, the carbonyl equivalent is phenyl chloroformate.

In some embodiments, the carbonyl equivalent is R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy groups. In some embodiments, R' is phenyl. In some embodiments, R' is p-nitrophenyl.

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) comprises: combining R'OC(O)Cl with a base; adding the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base to form the compound of formula (Iia) .

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) comprises adding the compound of formula (Ii) to a mixture of R'OC(O)Cl and a base to form the compound of formula (Iia) .

In some embodiments, the compound of formula (I-i) is added as a solution or slurry in a solvent. In some embodiments, the compound of formula (I-i) is added as a solution in a solvent.

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

In some embodiments, the compound of formula (I-i) is in the form of a salt. In some embodiments, the salt is a hydrochloride.

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) comprises: combining R'OC(O)Cl with a base; adding the compound of formula (Ii) to the mixture of R'OC(O)Cl and the base to form the compound of formula (Iia) ; wherein the compound of formula (Ii) is in the form of a salt.

In some embodiments, combining R'OC(O)Cl with a base comprises combining a base with a solvent followed by adding R'OC(O)Cl. In some embodiments, combining a base with a solvent followed by adding R'OC(O)Cl comprises adding R'OC(O)Cl to a base and a 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) followed by adding R'OC(O)Cl.

In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 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 the base is combined with the solvent, then R'OC(O)Cl is added, (i) water is added to the base to form an aqueous alkaline solution, (ii) tetrahydrofuran is added to the aqueous alkaline solution, and then (iii) R'OC(O)Cl is added to the tetrahydrofuran and aqueous alkaline solution.

In some embodiments, the addition of the compound of formula (I-i) to the mixture of R'OC(O)Cl and the base is carried out at 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 (I-i) to the mixture of R'OC(O)Cl and the base is carried out at about -5°C to about 5°C. In some embodiments, the addition of the compound of formula (I-i) to the mixture of R'OC(O)Cl and the base is carried out at about 0°C to about 5°C. In some embodiments, the addition of the compound of formula (I-i) to the mixture of R'OC(O)Cl and the base is carried out at less than 5°C. In some embodiments, the compound of formula (I-i) is added to a mixture of R'OC(O)Cl and a base as a solution in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 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, the compound of Formula (I-i) is added to the mixture of R'OC(O)Cl and the base over a period of 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, adding the compound of formula (I-i) to a mixture of R'OC(O)Cl and a base forms mixture 3. In some embodiments, mixture 3 is agitated 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 agitated at about 0 to about 10°C (eg, about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C).

In some embodiments, stirring mixture 3 forms a two-phase mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with the aqueous phase. In some embodiments, the alkaline aqueous 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, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti-solvent is heptane.

In some embodiments, after adding the antisolvent, the mixture 4 is agitated 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 antisolvent, the mixture 4 is agitated at about 40°C to about 50°C. In some embodiments, agitation is performed 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, agitation is performed for about 30 minutes.

In some embodiments, after adding the antisolvent, the mixture 4 is allowed to stand and/or agitate 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 agitation is performed 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).

In some embodiments, after adding the antisolvent, the mixture 4 is concentrated at a pressure below atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered to provide the compound (I-i-a). In some embodiments, the compound (I-i-a) is washed with hexane or heptane (e.g., heptane). In some embodiments, after washing the compound of formula (I-i-a), the compound of formula (I-i-a) is dried. In some embodiments, drying the compound of formula (I-i-a) includes drying the compound of formula (I-i-a) at a pressure below atmospheric pressure. In some embodiments, drying the compound of formula (I-i-a) comprises drying the compound of formula (I-i-a) 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 (I-i-a) comprises drying the compound of formula (I-i-a) at about 45°C. In some embodiments, drying the compound of formula (I-i-a) comprises drying the compound of formula (I-i-a) at about 40°C to about 45°C. In some embodiments, drying the compound of formula (I-i-a) comprises drying the compound of formula (I-i-a) at about 45°C to about 50°C. In some embodiments, drying the compound of formula (I-i-a) comprises drying the compound of formula (I-i-a) under an inert atmosphere (e.g., under nitrogen).

In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (I-i) 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 (I-i) is about 1.05. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (I-i) is about 1.3. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (I-i) is about 2.0. In some embodiments, the molar ratio of R'OC(O)Cl to the compound of formula (I-i) is about 3.0.

In some embodiments, the molar ratio of the base to the compound of formula (I-i) 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 (I-i) is about 2.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (I-i) is about 2.2. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (I-i) is about 3.0. In some embodiments, the molar ratio of sodium bicarbonate to the compound of formula (I-i) is about 3.5.

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.

In some embodiments, contacting a compound of formula (I-i) with R'OC(O)Cl and a compound of formula (I-ii) to form a compound of formula (I) comprises: Contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I).

In some embodiments, contacting the compound of formula (I-i-a) with the compound of formula (I-ii) to form the compound of formula (I) 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-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-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.

In some embodiments, contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-i-a) to the compound of formula (I-ii). In some embodiments, contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-i-a) to the compound of formula (I-ii) in the absence of a base.

In some embodiments, contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-ii) to the compound of formula (I-i-a). In some embodiments, contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-ii) to the compound of formula (I-i-a); and then adding a solvent to the mixture of the compound of formula (I-ii) and the compound of formula (I-i-a). In some embodiments, the solvent is N,N-dimethylacetamide.

In some embodiments, contacting a compound of formula (I-i-a) with a compound of formula (I-ii) to form a compound of formula (I) comprises adding the compound of formula (I-ii) to the compound of formula (I-i-a) in the absence of a base.

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

In some embodiments, after adding the compound of formula (I-i-a) to the compound of formula (I-ii) or after adding the compound of formula (I-ii) to the compound of formula (I-i-a), a mixture 5 is formed. In some embodiments, the mixture 5 is agitated. In some embodiments, the mixture 5 is agitated 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, the mixture 5 is agitated for about 12 hours to about 13 hours. In some embodiments, the mixture 5 is agitated for about 3 hours. In some embodiments, the mixture 5 is agitated for about 1 hour. In some embodiments, mixture 5 is agitated at about 10°C to about 90°C (e.g., 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 50°C).

In some embodiments, after agitating the mixture 5, the method includes adding water to the mixture 5 to form a mixture 5'. In some embodiments, the method includes agitating the mixture 5'. In some embodiments, the method includes agitating the mixture 5'. In some embodiments, the method includes agitating the 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 method includes agitating the mixture 5' for about 12 hours to about 13 hours. In some embodiments, the method includes agitating the mixture 5' for about 3 hours. In some embodiments, the method comprises agitating the mixture 5' for about 1 hour.

In some embodiments, after agitating the mixture 5', a slurry is formed. In some embodiments, the slurry is filtered to provide a 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 below atmospheric pressure.

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 from about 1:3 to about 1:1 (e.g., about 1:2). In some embodiments, the ratio of isopropyl acetate to heptane is from about 6:1 to about 4:2 (e.g., about 5:2). In some embodiments, after the compound of formula (I) is recrystallized, the compound of formula (I) is rinsed with a mixture of isopropyl acetate and heptane, followed by water, followed by 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) comprises drying the compound of formula (I) at a pressure below atmospheric pressure. In some embodiments, drying the compound of formula (I) comprises drying the compound of formula (I) at ambient temperature.

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 undetectable) of the compound of formula (A) is present as an impurity together with the compound of formula (I). (A).

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 undetectable) of the compound of formula (B) is present as an impurity with the compound of formula (I). (B).

In some embodiments, the method includes (I-iii) contacting with an acid to form a compound of formula (Ii) to prepare a compound of formula (Ii); wherein R'' is a C1-C6 alkyl group; wherein R ³ is a C1-C6 halogen alkyl group.

In some embodiments, R" is isopropyl.

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 molar solution of hydrogen chloride in ethyl acetate.

In some embodiments, contacting comprises adding the compound of formula (I-iii) to an acid. In some embodiments, contacting comprises adding an acid to a compound of formula (I-iii). In some embodiments, adding is performed at 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 10°C, or about 5°C to about 15°C). In some embodiments, agitation is performed at about 0°C to about 10°C. In some embodiments, agitation is performed at about 5°C to about 15°C. In some embodiments, contacting comprises agitating the compound of formula (I-iii) and 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, contacting comprises agitating the compound of formula (I-iii) and the acid for about 3 hours to form mixture 6. In some embodiments, contacting comprises agitating the compound of formula (I-iii) and the acid for about 1 hour to form mixture 6. In some embodiments, contacting comprises agitating the compound of formula (I-iii) and the acid for at least 1 hour to form mixture 6. In some embodiments, agitation is performed at 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, agitation is performed at about 5° C. to about 15° C. In some embodiments, contacting comprises adding heptane or hexane (e.g., heptane) to mixture 6. In some embodiments, after adding heptane or hexane (e.g., heptane) to 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 agitated or allowed to stand (e.g., agitated) 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 provide a compound of formula (I-iii).

In some embodiments, the method comprises: The compound of formula (I-iii) is prepared by contacting the compound of formula (I-iv) with a trihalogen alkylating agent to form a compound of formula (I-iii); wherein R'' is a C1-C6 alkyl group. In some embodiments, contacting the compound of formula (I-iv) with a trihalogen alkylating agent comprises contacting the compound of formula (I-iv) with a trihalogen alkylating agent and a phase transfer reagent. In some embodiments, contacting the compound of formula (I-iv) with a trihalogen alkylating agent and a phase transfer reagent forms a mixture 7.

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

In some embodiments, the molar ratio of the trihalogen alkylating agent to the compound 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 trihalogen alkylating agent to the compound of formula (I-iv) is about 3.0.

In some embodiments, the molar ratio of the phase transfer agent to the compound 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 agent to the compound of formula (I-iv) is about 1.0.

In some embodiments, contacting the compound of formula (I-iv) with a trihalogen alkylating agent and a phase transfer agent comprises adding the phase transfer agent to the compound of formula (I-iv) and then adding the trihalogen alkylating agent to the mixture of the compound of formula (I-iv) and the phase transfer agent.

In some embodiments, the phase transfer reagent is added to the compound of Formula (I-iv) at about 5°C to about 40°C (e.g., 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 phase transfer reagent is added to the compound of Formula (I-iv) at about 15°C to about 20°C.

In some embodiments, after the phase transfer reagent is added 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 the phase transfer reagent is added 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.

In some embodiments, after cooling the mixture of the compound of formula (I-iv) and the phase transfer reagent, the mixture of the compound of formula (I-iv) and the phase transfer reagent 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 of the compound of formula (I-iv) and the phase transfer reagent is stirred for about 1 hour.

In some embodiments, the addition of the trihalogen alkylating agent to the mixture of the compound of formula (I-iv) and the phase transfer reagent is carried out at 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, the addition of the trihalogen alkylating agent to the mixture of the compound of formula (I-iv) and the phase transfer reagent is carried out at about -20°C to about -15°C.

In some embodiments, the trihalogen alkylating agent is added dropwise to a mixture of the compound of formula (I-iv) and the phase transfer reagent.

In some embodiments, contacting the compound of formula (I-iv) with a trihalogen alkylating agent and a phase transfer agent comprises adding the trihalogen alkylating agent to the compound of formula (I-iv) and then adding the phase transfer agent to the mixture of the compound of formula (I-iv) and the trihalogen alkylating agent.

In some embodiments, contacting the compound of formula (I-iv) with a trihalogen alkylation reagent and a phase transfer reagent is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent comprises toluene, xylene, or benzene. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent is toluene.

In some embodiments, the method comprises adding a trihalogen alkylating agent to a compound of formula (I-iv) 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 trihalogen alkylating agent is added to a compound of formula (I-iv) at about -20°C to about -10°C.

In some embodiments, the method comprises adding the trihalogen alkylating agent to the compound of formula (I-iv) over about 1 minute to about 24 hours (e.g., 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 method comprises adding the trihalogen alkylating agent to the compound of formula (I-iv) over about 1 hour.

In some embodiments, the method comprises agitating the compound of formula (I-iv), the trihalogen alkylation reagent, and the phase transfer reagent after adding the phase transfer reagent. In some embodiments, the method comprises agitating the compound of formula (I-iv), the trihalogen alkylation 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 compound of formula (I-iv) at about -20°C to about -10°C.

In some embodiments, adding a phase transfer reagent to a mixture of a compound of formula (I-iv) and a trihalogen alkylating agent comprises adding the phase transfer reagent to the mixture of a compound of formula (I-iv) and a trihalogen alkylating agent in several portions. In some embodiments, the number of portions is 7 to 13 portions. In some embodiments, the number of portions is 9 to 11 portions. In some embodiments, the number of portions is 10 portions. In some embodiments, the 10 portions are 10 portions of substantially the same weight.

In some embodiments, the method includes adding water or an aqueous acid solution to the mixture 7. In some embodiments, the method 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 (e.g., a 10 wt % aqueous ammonium chloride solution). In some embodiments, adding water or an aqueous acid solution to the mixture 7 is performed at about -10°C to about 25°C (e.g., about -5°C to about 5°C).

In some embodiments, the method 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 at a pressure below 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, concentrating the organic phase at a pressure below atmospheric pressure provides a residue. In some embodiments, the residue is purified using silica gel to provide a compound of formula (I-iv).

In some embodiments, the method includes adding water and/or an alkaline aqueous solution to the mixture 8 to form a mixture 9'. In some embodiments, the mixture 9' comprises an organic phase and an aqueous phase. In some embodiments, the method includes separating the organic phase from the mixture 9'. In some embodiments, the method includes distilling the organic phase to provide a distillate. In some embodiments, the method includes passing the distillate through carbon (e.g., activated carbon). In some embodiments, the method includes reducing the volume of the distillate at a pressure less than atmospheric pressure to form a concentrate after passing the distillate through the carbon. In some embodiments, the method includes adding water to the concentrate, followed by reducing the volume of the mixture of water and concentrate to form a mixture 9''. In some embodiments, the method includes adding an antisolvent to the mixture 9'', followed by reducing the volume of the mixture 9'' to form a mixture 9'''. In some embodiments, the antisolvent is heptane. In some embodiments, the method includes adding a portion of the compound of formula (I-iii) (e.g., a previously prepared portion) to the mixture 9''' to form a precipitate. In some embodiments, the precipitate is filtered and dried to form the compound of formula (I-iii).

In some embodiments, the trihalogen alkylating agent is selected from TMSCF ₃ , [(trifluoromethyl)thio]benzene, trimethoxy(trifluoromethyl)potassium borate, Et ₃ GeNa/C ₆ H ₅ SCF ₃ , N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)copperate (1-), (SP-4-1)-tetrakis(trifluoromethyl)goldate (1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthrenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoroalkylation reagent is a trifluoromethylation reagent. In some embodiments, the trifluoromethylation reagent is TMSCF ₃ .

In some embodiments, the phase transfer agent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributyl ammonium bromide, 1,1'-(butane-1,4-diyl)bis[4-aza-1-aziridine cation bicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decadecylammonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetrapentylammonium chloride and dimethyldipalmitylammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

In some embodiments, the method comprises: and to prepare a compound of formula (I-iv); wherein R'' is a C1-C6 alkyl group. In some embodiments, Z is O. In some embodiments, the compound of formula (Iv) is contacted with Contacting comprises contacting the compound of formula (Iv) with 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.

In some embodiments, the contacting is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

In some embodiments, the molar ratio of the condensed base to the compound of formula (I-v) is from about 0.8 to about 6.0 (e.g., from about 1.0 to about 5.0, from about 1.0 to about 4.0, from about 2.0 to about 4.0, from about 1.0 to about 5.0, from about 2.5 to about 3.5, from about 1.0 to about 2.0, from about 1.3 to about 1.7, from about 1.0 to about 1.5, from about 1.0 to about 1.4, from about 1.0 to about 1.1, from 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 (I-v) is about 1.5.

In some embodiments, the molar ratio of the condensed base to the compound of formula (I-v) is from 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 1.2, about 0.9 to about 1.1, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.95 to about 1.05, about 1.0 to about 1.04, about 0.8, about 0.9, about 0.95, about 1.0, about 1.02, 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 (I-v) is about 1.02.

In some embodiments, the compound of formula (Iv) is reacted with and the contacting of the condensation base is carried out at about 25°C to about 80°C (e.g., about 25°C to about 70°C, about 25°C to about 60°C, about 35°C to about 50°C, about 35°C to about 45°C, about 35°C, about 40°C, or about 45°C). In some embodiments, the compound of formula (Iv) is contacted with The contacting with the condensation base is carried out at about 35°C to about 45°C.

In some embodiments, the compound of formula (Iv) is reacted with and contacting the condensation base is carried out at about 25°C to about 80°C (e.g., about 25°C to about 70°C, about 25°C to about 60°C, about 35°C to about 50°C, about 35°C to about 45°C, about 35°C, about 40°C, or about 45°C).

In some embodiments, the compound of formula (Iv) is reacted with and the condensation base contacting comprises contacting the compound of formula (Iv) with and a condensed base. In some embodiments, the compound of formula (IV) is stirred with and a condensation base together comprises stirring the compound of formula (Iv) with and the condensation base 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 compound of formula (Iv) and and a condensation base together comprises stirring the compound of formula (Iv) with and condensed alkali for about 14 hours.

In some embodiments, the compound of formula (Iv) is reacted with and combined alkaline contact including to the compound of formula (Iv), and then the condensed base is added to and a mixture of compounds of formula (Iv).

In some embodiments, The addition to the compound of formula (I-iv) is carried out at about 5°C to about 40°C (e.g., about 10°C to about 35°C, about 15°C to about 25°C, about 15°C to about 20°C). The addition to the compound of formula (Iv) is carried out at about 15°C to about 20°C.

In some embodiments, a condensation base is added to and a mixture of the compound of formula (Iv) at about 5°C to about 40°C (e.g., 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 condensation base is added to and a mixture of the compound of formula (Iv) at about 15°C to about 20°C.

In some embodiments, the compound of formula (Iv) is reacted with and a condensation base to provide a mixture 10. In some embodiments, the mixture 10 is agitated 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, the mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, agitating the mixture 10 is performed 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, agitating the mixture 10 is performed at about 60° C.

In some embodiments, after agitating the mixture 10, the mixture 10 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, or about 20°C). In some embodiments, after agitating the mixture 10, the mixture 10 is cooled to about 20°C. In some embodiments, after agitating the mixture 10, the mixture 10 is cooled to about 15°C to about 25°C.

In some embodiments, cooling the mixture 10 includes forming a slurry. In some embodiments, the method includes filtering the slurry to provide a solution. In some embodiments, the method includes reducing the volume of the solution at a pressure less than atmospheric pressure. In some embodiments, the method includes (i) adding a solvent to the solution; (ii) reducing the volume of the solution at a pressure less than atmospheric pressure; optionally, (iii) adding a solvent to the solution; and optionally, (iv) reducing the volume of the solution at a pressure less 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 method 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 method includes cooling the concentrate to about 15° C. to about 25° C. In some embodiments, the method includes adding water to the concentrate after cooling the concentrate to form a mixture 10′. In some embodiments, the method comprises agitating the 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 method comprises agitating the mixture 10' for about 14 hours. In some embodiments, after agitating the mixture 10', a slurry is formed. In some embodiments, the slurry is filtered to provide a compound of Formula (I-v).

In some embodiments, the method includes concentrating the mixture 10 at a pressure below atmospheric pressure after cooling the mixture 10 to provide a compound of formula (I-iv).

In some embodiments, the method comprises in some embodiments, reacting a compound of formula (IV) with and combined alkaline contact including to the compound of formula (Iv), and then the condensed base is added to and a mixture of compounds of formula (Iv).

In some embodiments, the method comprises: The compound of formula (IV) is prepared by contacting with an acid. In some embodiments, Z is O.

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 etherate).

In some embodiments, the acid is acetic acid.

In some embodiments, contacting the compound of formula (I-vi) with an acid comprises adding the compound of formula (I-vi) to the acid. In some embodiments, contacting the compound of formula (I-vi) with an acid comprises contacting the compound of formula (I-vi) with an acid in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, adding the compound of formula (I-vi) to the acid forms mixture 11. In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is heated at 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 at about 120° C. In some embodiments, after adding the compound of formula (I-vi) to the acid, the mixture 11 is agitated 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 agitated for about 8 hours.

In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to 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 separated and washed with the aqueous phase. In some embodiments, the aqueous alkaline solution is an aqueous potassium carbonate solution (e.g., a 15 wt % aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous phase, the organic phase is agitated with water and Na ₂ S ₂ O ₄ . In some embodiments, the organic phase is agitated 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 agitated with water _{and Na2S2O4} for about 8 hours. In some embodiments, agitating the organic phase with water _{and Na2S2O4} forms a solid. 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, and 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 agitated 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 at a pressure below atmospheric pressure to provide a compound of formula (IV).

In some embodiments, the method comprises: and to prepare a compound of formula (I-vi); wherein LG is selected from chloro, bromo, iodo and trifluoromethanesulfonyl.

In some embodiments, the compound of formula (I-vii) is a compound of formula (I-vii-i) .

In some embodiments, the compound of formula (I-vii) and The contacting comprises allowing the compound of formula (I-vii) to and 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.

In some embodiments, the compound of formula (I-vii) and The contacting with the base is carried out in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

In some embodiments, the compound of formula (I-vii) and The step of contacting the compound of formula (I-vii) with an alkali , alkali and sodium iodide.

In some embodiments, the compound of formula (I-vii) and The contacting of alkali and sodium iodide is carried out at 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, the compound of formula (I-vii) and The contacting with alkali and sodium iodide is carried out at about 120°C.

In some embodiments, the compound of formula (I-vii) is added to , alkali and sodium iodide to form a mixture 13. In some embodiments, the 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, the mixture 13 is stirred for about 5 hours.

In some embodiments, the method comprises: The compound of formula (IV) is prepared by contacting with an acid; wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl. In some embodiments, Hal is chlorine. 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.

In some embodiments, the compound of formula (I-viii) The contact with the acid is carried out in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

In some embodiments, contacting the compound of formula (I-viii) with the acid is carried out at 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, contacting the compound of formula (I-viii) with the acid is carried out at about 25° C.

In some embodiments, the method comprises: and In some embodiments, Z is O. In some embodiments, R ² is C1-C6 alkyl. In some embodiments, R ² is methyl.

In some embodiments, the compound of formula (I-ix) is mixed with Contacting comprises contacting the compound of formula (I-ix) with In some embodiments, the contacting is performed in a solvent.

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

In some embodiments, the compound of formula (I-ix) is mixed with The contacting with the base is carried out at 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, the compound of formula (I-ix) is contacted with The alkaline contact was carried out at about 25°C.

In some embodiments, Z is O; m is 2; each R ¹ is fluorine; R ² is methyl; R ² is trifluoromethyl; Ring A is , wherein * represents the point of attachment to urea and ** represents the point of attachment to R ⁴ ; n is 1; and R ⁴ is -NH ₂ .

In some embodiments, the carbon substituted with R ³ has the (R) configuration.

In some embodiments, the compound of formula (I) is .

In some embodiments, the compound of formula (I) is .

In some embodiments, the compound of formula (I) is .

In some embodiments, the compound of formula (I) is not a compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, when Z is NR ^x and R ³ is methyl, Ring A is not phenyl.

In some embodiments, the compound of formula (I) is a compound of formula (X): (X) or its salts and/or solvents, wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is an independently selected halogen; m is 0, 1, 2 or 3; R ² is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with 1 or 2 fluorine groups; R ³ is a C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl or a 4-10 membered heterocyclo; each R ⁴ is independently selected from the group consisting of halogen, C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , -C(═O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(═O)(═NH)(C1-C6 alkyl), -C(═O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and 3-6 membered heterocyclic or 3-6 membered cycloalkyl each optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen, 4-6 membered heterocyclic group, C1-C6 halogenalkyl, -C(=O)(C1-C6 alkyl), _-SO2 (C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _SO2 (C1-C6 alkyl), _-SO2 ( _NH2 ; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each R ^G is independently selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^A1 R ^B1 , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO ₂ H; and wherein the compound is not selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, the compounds described herein are not compounds selected from the group of compounds that are not compounds of formula (I) described above (i.e., "excluded compounds"). In some embodiments, the excluded compounds are flat structures, as indicated above. In some embodiments, the excluded compounds are specific stereoisomers, such as specific mirror isomers or non-mirror isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more 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 excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

In some embodiments, the compound of formula (I) is formula (IA): (IA) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogen group; R ³ is a C1-C6 alkyl group, a C1-C6 halogen group, or a C3-C6 cycloalkyl group substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl group; R ⁴ is independently selected from the group consisting of a ^C1 -C6 ^alkyl group, a C1-C6 alkoxy group, a C1-C6 halogen group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), _-SO2 (C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), _-CO2 (C1-C6alkyl), a 5-6 membered heteroaryl optionally substituted with a C1-C6alkyl group, a 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; wherein ^R4 is bonded to the para position of the N atom of the urea portion in ring A1; each of ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^{R F} is independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: a hydroxyl group, a 3-6 membered cycloalkyl group, -SO ₂ (C1-C6 alkyl group) and -SO ₂ (NH ₂ ); or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^A1 R ^B1 , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl group), a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group and -CO ₂ H.

In some embodiments, Ring A1 is pyrimidinyl, pyridinyl or pyrazolyl. In some embodiments, Ring A1 is pyrimidinyl. In some embodiments, Ring A1 is pyridinyl. In some embodiments, Ring A1 is pyrazolyl.

In some embodiments, Ring A1 is 5-pyrimidinyl, 3-pyridinyl or 4-pyrazolyl. In some embodiments, Ring A1 is 5-pyrimidinyl. In some embodiments, Ring A1 is 3-pyridinyl. In some embodiments, Ring A1 is 4-pyrazolyl.

In some embodiments of Formula (IA), for , wherein: R ^4B is selected from -NR ^A R ^B and a 4-6 membered heterocyclic group comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R ^G1 ; wherein R ^G1 is selected from fluoro, hydroxy and C1-C6 alkyl.

In some embodiments of Formula (IA), ^RA and ^RB are each hydrogen.

In some embodiments, the compound of formula (I) is of formula (IB): (IB) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group, or a C3-C6 cycloalkyl group substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl groups; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group optionally substituted with -NR ^A R ^B , a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; each of ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^{R F} is independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: a hydroxyl group, a 3-6 membered cycloalkyl group, -SO ₂ (C1-C6 alkyl group) and -SO ₂ (NH ₂ ); or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^A1 R ^B1 , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl group), a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IC): (IC) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group or a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , RB, ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen or C1-C6 alkyl, ^C1 -C6 halogenalkyl substituted with hydroxyl; or ^RC and ^RD form ^a 4-6 membered heterocyclic group together with the nitrogen atom to which they are attached; each ^RG is independently selected from the group consisting of fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^{C1 RD1} and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (ID): (ID) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group or a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 membered heterocyclic group substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , RB, ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^{RE and RF are} independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently ^selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^{C1 RD1} , -CO ₂ (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is formula (IE): (IE) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group or a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 membered heterocyclic group substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^{RD, RD1 , RE} and ^RF are independently hydrogen or C1-C6 alkyl or C1-C6 halogen alkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, ^hydroxyl , C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^{C1 RD1} , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IF): (IF) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group or a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 membered heterocyclic group substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^{RD, RD1 , RE} and ^RF are independently hydrogen or C1-C6 alkyl or C1-C6 halogen alkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, ^hydroxyl , C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^{C1 RD1} , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H; wherein the compound is not .

In some embodiments, the compound of formula (I) is of formula (IG): (IG) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogenalkyl group; R ³ is a C1-C6 alkyl group, a C1-C6 halogenalkyl group or a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenalkyl group, a hydroxyl group, a cyano group, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 membered heterocyclic group substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^{RD, RD1 , RE} and ^RF are independently hydrogen or C1-C6 alkyl or C1-C6 halogen alkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, ^hydroxyl , C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^{C1 RD1} , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is formula (IH): (IH) or its salt and/or solvent complex, wherein: R ^1A is a halogen; R ^1B is a halogen, a cyano group, a cyclopropyl group or is absent (the benzene ring is monosubstituted by R ^1A ); R ² is a C1-C6 alkyl group or a C1-C6 halogen group; R ³ is a C1-C6 alkyl group or a C1-C6 halogen group; R ⁴ is independently selected from the group consisting of: a C1-C6 alkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 2 substituents independently selected from a hydroxyl group and a C3-C6 cycloalkyl group, a C1-C6 halogen group, -NR ^A R ^B , and a 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG ; each of R ^A , R ^B , R ^C1 and R ^D1 is independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 alkyl group optionally substituted with a hydroxy group or -C(=O)NR ^B2 R ^C2 , -C(=O)O(C1-C6 alkyl) or a C1-C6 halogenalkyl group; each ^RA2 , ^RB2 and ^RC2 is independently hydrogen or a C1-C6 alkyl group; each ^RG is independently selected from the group consisting of fluoro, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a C1-C6 alkoxy group, =NR ^A2 , -C(=O)NR ^C1 R ^D1 , a C1-C6 halogenalkoxy group, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

In some embodiments, the compound of formula (I) is formula (IJ): (IJ) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , which is optionally substituted with -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ₂ (C1-C6 alkyl), a 5-6 membered heteroaryl optionally substituted with a C1-C6 alkyl group, a 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; wherein R ⁴ is bonded to the para position of the N atom of the urea portion in ring A1; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , ^RD , ^RD1 , ^RE and R ^F is independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: a hydroxyl group, a 3-6 membered cycloalkyl group, -SO ₂ (C1-C6 alkyl group) and -SO ₂ (NH ₂ ); or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^A1 R ^B1 , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl group), a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group and -CO ₂ H.

In some embodiments, the compound of formula (I) is formula (IK): (IK) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, ^C1 -C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^{A R B} , -C(=O)NR ^C R ^D , —SO ₂ (NR ^E R ^F ), —SO ₂ (C1-C6 alkyl), —S(═O)(═NH)(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —CO ₂ (C1-C6 alkyl), a 5-6 membered heteroaryl optionally substituted with a C1-C6 alkyl group, a 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG groups, and a 3-6 membered cycloalkyl group optionally substituted with 1 or 2 independently selected ^RG groups; each ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , ^RD , ^RD1 , ^RE and R ^F is independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: a hydroxyl group, a 3-6 membered cycloalkyl group, -SO ₂ (C1-C6 alkyl group) and -SO ₂ (NH ₂ ); or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^A1 R ^B1 , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl group), a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IL): (IL) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclic group optionally substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen or C1-C6 alkyl, C1-C6 ^haloalkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^C1 R ^D1 and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IM): (IM) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl) ^{, 5-6 membered heteroaryl, and a 3-6 membered heterocyclic group optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1 , RE , and RF is independently hydrogen or C1} -C6 alkyl, C1-C6 halogenalkyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, ^-NRA1RB1 , -C(= ^O ) ^{NRC1R D1} , _-CO2 (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and _-CO2H .

In some embodiments, the compound of formula (I) is of formula (IN): (IN) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclic group optionally substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen or C1-C6 alkyl, C1-C6 ^haloalkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is formula (IO): (IO) or its salts and/or solvents, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogenalkyl; R ³ is C1-C6 alkyl, C1-C6 halogenalkyl or C3-C6 cycloalkyl substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, hydroxyl, cyano, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclic group optionally substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen or C1-C6 alkyl, C1-C6 ^haloalkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IP): (IP) or its salts and/or solvents, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 halogen alkyl; R ³ is C1-C6 alkyl, C1-C6 halogen alkyl or C3-C6 cycloalkyl substituted with 1 or 2 fluorine atoms; R ⁴ is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, hydroxy, cyano, -CO ₂ H, -NR ^A R ^B , -C(=O)NR ^C R ^D , -SO ₂ (NR ^E R ^F ), -SO ₂ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), _-CO2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclic group optionally substituted by 1 or 2 independently selected ^RG ; each ^RA , ^RA1 , ^RB , ^RB1 , RC, ^RC1 , ^RD , ^RD1 , ^RE and ^RF are independently hydrogen or C1-C6 alkyl, C1-C6 ^haloalkyl substituted by hydroxyl; or ^RC and ^RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each ^RG is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -NR ^{A1 RB1} , -C(=O)NR ^C1 R ^D1 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl and -CO ₂ H.

In some embodiments, the compound of formula (I) is of formula (IQ): (IQ) or its salt and/or solvent complex, wherein: R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ^1A is halogen; R ^1B is halogen, cyano, cyclopropyl or does not exist (the benzene ring is monosubstituted by R ^1A ); R ² is C1-C6 alkyl or C1-C6 haloalkyl; R ³ is C1-C6 alkyl or C1-C6 haloalkyl; R ⁴ is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NR ^A R ^B and a 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG ; each R ^A , ^RB , ^RC1 and ^RD1 are independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 alkyl group optionally substituted with a hydroxy group or -C(=O)NR ^{B2 RC2} , -C(=O)O(C1-C6 alkyl) or a C1-C6 halogenalkyl group; each ^RA2 , ^RB2 and ^RC2 are independently hydrogen or a C1-C6 alkyl group; each ^RG is independently selected from the group consisting of fluoro, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxy group, a C1-C6 alkoxy group, =NR ^A2 , -C(=O)NR ^{C1 RD1} , a C1-C6 halogenalkoxy group, -SO ₂ (C1-C6 alkyl) and -CO ₂ H.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, each R ¹ is an independently selected halogen. In some embodiments, each R ¹ is independently selected from fluorine and chlorine. In some embodiments, each R ¹ is independently selected from fluorine and bromine. In some embodiments, each R ¹ is fluorine. In some embodiments, at least one R ¹ is an independently selected halogen. In some embodiments, at least one R ¹ is independently selected from fluorine and chlorine. In some embodiments, at least one R ¹ is fluorine.

In some embodiments, at least one R ¹ is cyano. In some embodiments, at least one R ¹ is hydroxy. In some embodiments, at least one R ¹ is C1-C6 alkyl, optionally substituted with hydroxy. In some embodiments, at least one R ¹ is C1-C6 alkyl substituted with hydroxy. In some embodiments, at least one R ¹ is C1-C3 alkyl substituted with hydroxy. In some embodiments, at least one R ¹ is hydroxymethyl. In some embodiments, at least one R ¹ is unsubstituted C1-C6 alkyl. In some embodiments, at least one R ¹ is methyl. In some embodiments, at least one R ¹ is C3-C6 cycloalkyl. In some embodiments, at least one R ¹ is cyclopropyl.

In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is C1-C6 alkyl. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is methyl. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is C3-C6 cycloalkyl. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is cyclopropyl. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is cyano. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is halogen. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is fluorine.

In some embodiments, R ² is hydroxy. In some embodiments, R ² is C1-C6 alkyl, optionally substituted with hydroxy. In some embodiments, R ² is C1-C6 alkyl substituted with hydroxy. In some embodiments, R ² is C1-C3 alkyl substituted with hydroxy. In some embodiments, R ² is hydroxymethyl. In some embodiments, R ² is unsubstituted C1-C6 alkyl. In some embodiments, R ² is unsubstituted C1-C3 alkyl. In some embodiments, R ² is methyl.

In some embodiments, R ² is C1-C6 haloalkyl. In some embodiments, R ² is C1-C3 haloalkyl. In some embodiments, R ² is difluoromethyl. In some embodiments, R ² is trifluoromethyl.

In some embodiments, R ² is halogen. In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine.

In some embodiments, R ² is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 fluorine groups. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine groups. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 2 fluorine groups. In some embodiments, R ² is a C3-C4 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ² is a C3-C4 cycloalkyl group substituted with 2 fluorine groups. In some embodiments, R ² is an unsubstituted C3-C6 cycloalkyl group.

In some embodiments, R ³ is C1-C6 alkyl. In some embodiments, R ³ is C1-C3 alkyl. 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 is isopropyl.

In some embodiments, R ³ is C1-C6 haloalkyl. In some embodiments, R ³ is C1-C3 haloalkyl. In some embodiments, R ³ is difluoromethyl. In some embodiments, R ³ is trifluoromethyl.

In some embodiments, R ^{is a C3-} C6 cycloalkyl group optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl. In some embodiments, R ^{is a} C3-C6 cycloalkyl group optionally substituted with 1 or 2 fluorine groups. In some embodiments, ^R is a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine groups. In some embodiments, R ^{is a} C3-C6 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ^is a C3-C6 cycloalkyl group substituted with 1 fluorine group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, ^R is a 2,2-difluorocyclopropyl group or a 3,3-difluorocyclopropyl group. In some embodiments, R ³ is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 methyl groups. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 or 2 methyl groups. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 methyl group. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 methyl group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, R ³ is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, R ³ C3-C6 cycloalkyl group is a cyclopropyl group. In some embodiments, R ³ is a cyclopropyl group. In some embodiments, R ³ is a cyclobutyl group. In some embodiments, R ³ is a cyclopentyl group. In some embodiments, R ³ is cyclohexyl.

In some embodiments, R' is C1-C6 alkyl. In some embodiments, R' is C1-C4 alkyl. In some embodiments, R' is C1-C3 alkyl. 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.

In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl groups. In some embodiments, R' is C6-C10 aryl substituted with 1-3 independently selected C1-6 alkoxy groups.

In some embodiments, R'' is C1-C6 alkyl. In some embodiments, R'' is C1-C4 alkyl. In some embodiments, R'' is C1-C3 alkyl. 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.

In some embodiments, Hal is selected from chlorine, bromine and iodine. In some embodiments, Hal is selected from chlorine, bromine and trifluoromethyl. In some embodiments, Hal is chlorine. In some embodiments, Hal is bromine. In some embodiments, Hal is iodine. In some embodiments, Hal is trifluoromethanesulfonyl.

In some embodiments, the compound of formula (Ii) is a compound of formula (Iii): (iii).

In some embodiments, the compound of formula (I-iii) is a compound of formula (I-iii-i) .

In some embodiments, the compound of formula (I-iv) is a compound of formula (I-iv-i) .

In some embodiments, the compound of formula (IV) is a compound of formula (IVi) .

In some embodiments, the compound of formula (I-vi) is a compound of formula (I-vi-i) .

In some embodiments, the compound of formula (I-viii) is a compound of formula (I-viii-i) .

In some embodiments, the compound of formula (I) is

or a salt and/or solvent thereof, wherein R ³ , R ⁴ and Ring A are as described herein; and wherein the compound is not selected from the group consisting of: , , , , , , , and .

In some embodiments, the compound of formula (I) is or a salt and/or solvent thereof, wherein R ³ , R ⁴ and Ring A are as described herein; and wherein the compound is not selected from the group consisting of: , , , , , , , and .

In some embodiments, the compound of formula (I) is or a salt and/or solvent thereof, wherein R ³ , R ⁴ and Ring A are as described herein; and wherein the compound is not selected from the group consisting of: , , , , , , , and .

In some embodiments, the compound of formula (I) is or a salt and/or solvent complex thereof, wherein R ³ , R ⁴ and Ring A are as described herein.

In some embodiments, the compound of formula (I) is or a salt and/or solvent complex thereof, wherein R ³ , R ⁴ and Ring A are as described herein.

In some embodiments, the compound of formula (I) is or a salt and/or solvent complex thereof, wherein R ³ , R ⁴ and Ring A are as described herein.

Some embodiments provide a method for preparing compound 1: (1), or a salt and/or solvent thereof; the method comprises: With (i) a carbonyl equivalent or an isocyanate forming reagent; and (ii) having the structure to form compound 1.

Some embodiments provide Compound 1: (1), or its salt and/or solvent combination; the compound comprises With (i) a carbonyl equivalent or an isocyanate forming reagent; and (ii) having the structure The method is to contact pyrimidine-2,5-diamine.

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, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy. 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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

Some embodiments provide a method for preparing compound 1: (1), or a salt and/or solvent thereof; the method comprises: and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide Compound 1: (1), or its salt and/or solvent combination; the compound comprises and (i) a carbonyl equivalent; and (ii) having the structure The method is to contact pyrimidine-2,5-diamine.

In some embodiments, contacting with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises adding the carbonyl equivalent to and alkali to form mixture 1, and then pyrimidine-2,5-diamine is added to mixture 1 to form mixture 2.

In some embodiments, the carbonyl equivalent is The molar ratio of 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). The molar ratio of carbonyl equivalent to The molar ratio is about 1.3.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and The molar ratio is about 3.5.

In some embodiments, a carbonyl equivalent is added to and alkali to form mixture 1 is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, a carbonyl equivalent is added to and alkali to form mixture 1 is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, a carbonyl equivalent is added to and alkaline 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 carbonyl equivalent is added to In some embodiments, the carbonyl equivalent is added to In some embodiments, the carbonyl equivalent is added to The reaction is carried out at about 0°C.

In some embodiments, when adding a carbonyl equivalent to After eluting with alkali, the mixture 1 is stirred 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.

In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding the second base to mixture 1, followed by adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, adding the compound of formula (I-ii) to mixture 1 to form mixture 2 comprises adding the compound of formula (I-ii) to mixture 1, followed by adding the 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)non-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the pyrimidine-2,5-diamine to the mixture 1 is carried out at about 0 to about 10°C, such as 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 alkali to the mixture 1 and the addition of the pyrimidine-2,5-diamine to the mixture 1 is carried out at about 0°C to about 5°C. In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the pyrimidine-2,5-diamine to the mixture 1 is carried out at about 0°C to about 2°C. In some embodiments, the addition of the second alkali to the mixture 1 and the addition of the compound of formula (I-ii) to the mixture 1 is carried out at about 0°C.

In some embodiments, after forming the mixture 2, the mixture 2 is heated to about 20°C to about 90°C (e.g., 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 (e.g., about 1 hour to about 3 hours or about 2 hours); then heated to about 20°C to about 90°C. (e.g., 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.) and agitated 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.

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

In some embodiments, the method comprises recrystallizing Compound 1 from a solvent. In some embodiments, the method comprises recrystallizing Compound 1 from a solvent after adding an aqueous alkaline 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 from about 6:1 to about 1:10 (e.g., from about 6:1 to about 4:2, from about 1:7 to about 3:7, from about 4:6 to about 6:4, from 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, followed by water, followed by a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing compound 1, compound 1 is dried. In some embodiments, drying compound 1 comprises drying compound 1 at a pressure less than atmospheric pressure. In some embodiments, drying compound 1 comprises drying compound 1 at ambient temperature.

In some embodiments, with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises is added to the carbonyl equivalent and the base to form a mixture 1', and then pyrimidine-2,5-diamine is added to the mixture 1' to form a mixture 2'. In some embodiments, In some embodiments, It is in salt form and makes with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises is added to the carbonyl equivalent and the base to form mixture 1', and then pyrimidine-2,5-diamine is added to mixture 1' to form mixture 2'.

In some embodiments, The salt is hydrochloric acid.

In some embodiments, Addition to the carbonyl equivalent and the base to form a mixture 1' is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, Addition to the carbonyl equivalent and base to form mixture 1' is performed under an inert atmosphere. In some embodiments, contacting is performed under nitrogen. In some embodiments, contacting is performed under argon.

In some embodiments, the carbonyl equivalent is The molar ratio of 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). The molar ratio of carbonyl equivalent to In some embodiments, the carbonyl equivalent is about 1.3. The molar ratio is about 2.0.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and In some embodiments, sodium bicarbonate and The molar ratio is about 3.5.

In some embodiments, Addition to the carbonyl equivalent and the base to form a mixture 1' is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, The addition to the carbonyl equivalent and the base to form the mixture 1' is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, The addition 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 carbonyl equivalent is added to The temperature is about 5°C or lower.

In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 'to form mixture 2' comprises adding a tertiary alkali to mixture 1 'and adding pyrimidine-2,5-diamine to mixture 1 '. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 'to form mixture 2' comprises adding a tertiary alkali 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' comprises adding an aqueous sodium chloride solution to mixture 1 ', adding a tertiary alkali to mixture 1 ', and adding pyrimidine-2,5-diamine to mixture 1 '. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' comprises 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-diazabicycloundec-7-ene (DBU) and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

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.

In some embodiments, the molar ratio of the tertiary alkali 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 tertiary alkali to Compound 1 is about 2.0.

In some embodiments, an aqueous sodium chloride solution is added to the mixture 1', a tertial alkali is added to the mixture 1', and the addition of pyrimidine-2,5-diamine is performed 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, an aqueous sodium chloride solution is added to the mixture 1', a tertial alkali is added to the mixture 1', and the addition of pyrimidine-2,5-diamine is performed at about 0°C to about 5°C.

In some embodiments, after forming mixture 2, mixture 2 is agitated 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.

In some embodiments, the method includes adding water and an extraction solvent to the mixture 2' after agitating the mixture 2' to form a 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 method includes agitating and/or shaking the mixture 3'. In some embodiments, the method includes separating the organic liquid from the mixture 3'. In some embodiments, the method includes adding an alkaline aqueous solution to the organic liquid to form the mixture 4'. In some embodiments, the alkaline aqueous 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 method includes separating the organic liquid from the mixture 4'. In some embodiments, the method includes reducing the volume of the organic liquid at a pressure below atmospheric pressure. In some embodiments, the method includes adding an antisolvent to the organic liquid to form a slurry. In some embodiments, the antisolvent is hexane or heptane. In some embodiments, the antisolvent is heptane. In some embodiments, the method includes filtering the slurry to provide a solid. In some embodiments, the method includes dissolving the solid in isopropanol and adding water to the dissolved solid 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 below atmospheric pressure to provide Compound 1.

In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane. In some embodiments, Compound 1 is precipitated from isopropanol and water. In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane, followed by precipitation from isopropanol and water. In some embodiments, after precipitating Compound 1, Compound 1 is dried. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure less than atmospheric pressure. In some embodiments, drying Compound 1 comprises 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 comprises drying Compound 1 at about 45°C. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure below atmospheric pressure at about 20°C to about 25°C.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

In some embodiments, the carbonyl equivalent is phenyl chloroformate.

In some embodiments, the carbonyl equivalent is R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy groups. In some embodiments, R' is phenyl. In some embodiments, R' is p-nitrophenyl.

In some embodiments, The method of contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: combining R'OC(O)Cl with a base; Add to the mixture of R'OC(O)Cl and base to form .

In some embodiments, with R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprising Add to the mixture of R'OC(O)Cl and base to form .

In some embodiments, In some embodiments, Add as a solution in a solvent.

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

In some embodiments, In some embodiments, the salt is a hydrochloride.

In some embodiments, The method of contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: combining R'OC(O)Cl with a base; Add to the mixture of R'OC(O)Cl and base to form ; in It is in salt form.

In some embodiments, combining R'OC(O)Cl with a base comprises combining a base with a solvent followed by adding R'OC(O)Cl. In some embodiments, combining a base with a solvent followed by adding R'OC(O)Cl comprises adding R'OC(O)Cl to a base and a 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) followed by adding R'OC(O)Cl.

In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 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 the base is combined with the solvent, then R'OC(O)Cl is added, (i) water is added to the base to form an aqueous alkaline solution, (ii) tetrahydrofuran is added to the aqueous alkaline solution, and then (iii) R'OC(O)Cl is added to the tetrahydrofuran and aqueous alkaline solution.

In some embodiments, The addition to the mixture of R'OC(O)Cl and the base is carried out at 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 about -5°C to about 5°C. In some embodiments, The addition of R'OC(O)Cl and the base is carried out at about 0°C to about 5°C. In some embodiments, The addition to the mixture of R'OC(O)Cl and the base is carried out at a temperature below 5°C. In some embodiments, Added as a solution in a solvent to a mixture of R'OC(O)Cl and a base. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, the drug is administered over a period of 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). Add to the mixture of R'OC(O)Cl and base.

In some embodiments, Addition to the mixture of R'OC(O)Cl and base forms mixture 3. In some embodiments, mixture 3 is agitated 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 agitated 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, stirring mixture 3 forms a two-phase mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with the aqueous phase. In some embodiments, the alkaline aqueous 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, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti-solvent is heptane.

In some embodiments, after adding the antisolvent, the mixture 4 is agitated 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 antisolvent, the mixture 4 is agitated at about 40°C to about 50°C. In some embodiments, agitation is performed 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, agitation is performed for about 30 minutes.

In some embodiments, after adding the antisolvent, the mixture 4 is allowed to stand and/or agitate 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 agitation is performed 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).

In some embodiments, after adding the antisolvent, the mixture 4 is concentrated at a pressure below atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered to provide In some embodiments, the rinse is performed with hexane or heptane (e.g., heptane). In some embodiments, during rinsing Afterwards, dry In some embodiments, drying Including drying at pressures below atmospheric pressure In some embodiments, drying including drying 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 Including drying at about 45°C In some embodiments, drying including drying at about 40°C to about 45°C In some embodiments, drying including drying at about 45°C to about 50°C In some embodiments, drying This includes drying under an inert atmosphere (e.g., under nitrogen) .

In some embodiments, R'OC(O)Cl and The molar ratio of R'OC(O)Cl 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). The molar ratio of R'OC(O)Cl is about 1.05. The molar ratio of R'OC(O)Cl is about 1.3. The molar ratio of R'OC(O)Cl is about 2.0. The molar ratio is about 3.0.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and In some embodiments, sodium bicarbonate and The molar ratio of sodium bicarbonate to In some embodiments, sodium bicarbonate and The molar ratio is about 3.5.

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.

In some embodiments, Contacting with R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: It is contacted with pyrimidine-2,5-diamine to form compound 1.

In some embodiments, The contact with pyrimidine-2,5-diamine to form compound 1 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-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-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.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises reacting Add to pyrimidine-2,5-diamine.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises adding pyrimidine-2,5-diamine to In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises adding pyrimidine-2,5-diamine to Then, the solvent is added to the pyrimidine-2,5-diamine and In some embodiments, the solvent is N,N-dimethylacetamide.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises adding pyrimidine-2,5-diamine to middle.

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

In some embodiments, After adding to pyrimidine-2,5-diamine or after adding pyrimidine-2,5-diamine to After the mixture 5 is stirred, a mixture 5 is formed. In some embodiments, the mixture 5 is stirred. In some embodiments, the 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, the mixture 5 is stirred for about 12 hours to about 13 hours. In some embodiments, the mixture 5 is stirred for about 3 hours. In some embodiments, the mixture 5 is stirred for about 1 hour. In some embodiments, mixture 5 is agitated at about 10°C to about 90°C (e.g., 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).

In some embodiments, after agitating the mixture 5, the method includes adding water to the mixture 5 to form a mixture 5'. In some embodiments, the method includes agitating the mixture 5'. In some embodiments, the method includes agitating the mixture 5'. In some embodiments, the method includes agitating the 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 method includes agitating the mixture 5' for about 12 hours to about 13 hours. In some embodiments, the method includes agitating the mixture 5' for about 3 hours. In some embodiments, the method comprises agitating the mixture 5' for about 1 hour.

In some embodiments, after agitating the mixture 5', a slurry is formed. In some embodiments, the slurry is filtered to provide Compound 1. In some embodiments, Compound 1 is washed with water. In some embodiments, Compound 1 is dried at a pressure below atmospheric pressure.

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, followed by water, followed by 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 below atmospheric pressure. In some embodiments, drying compound 1 includes drying compound 1 at ambient temperature.

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, 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 undetectable) of impurity 1 is present as an impurity with Compound 1. (Impurity 1).

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 no detectable amount) of impurity 2 is present as an impurity with compound 1. (Impurity 2).

In some embodiments, the method comprises preparing crystalline hemihydrate Form 1 by a method comprising: (a) dissolving (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof in isopropanol to form a solution; (b) adding water to the solution to form a mixture; (c) lowering the temperature of the mixture and then maintaining the temperature for a first time period; (d) increasing the temperature of the mixture and then maintaining the temperature for a second time period; (e) lowering the temperature of the mixture and then maintaining the temperature for a third time period; and (f) isolating Form 1 from the mixture.

In some embodiments, Form 1 has one or more of the features described below.

In some embodiments, the XRPD pattern of Form 1 has a peak at 6.4 ± 0.2° 2θ. In some embodiments, the peak at 6.4 ± 0.2° 2θ has the highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 15.8 ± 0.2° 2θ. In some embodiments, the peak at 15.8 ± 0.2° 2θ has a second relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 18.3 ± 0.2° 2θ. In some embodiments, the peak at 18.3 ± 0.2° 2θ has the third highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 22.3 ± 0.2° 2θ. In some embodiments, the peak at 22.3 ± 0.2° 2θ has the fourth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 20.8 ± 0.2° 2θ. In some embodiments, the peak at 20.8 ± 0.2° 2θ has the fifth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 19.3 ± 0.2° 2θ. In some embodiments, the peak at 19.3 ± 0.2° 2θ has the sixth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 24.0 ± 0.2° 2θ. In some embodiments, the peak at 24.0 ± 0.2° 2θ has the seventh highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 26.9 ± 0.2° 2θ. In some embodiments, the peak at 26.9 ± 0.2° 2θ has the eighth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 14.6 ± 0.2° 2θ. In some embodiments, the peak at 14.6 ± 0.2° 2θ has the ninth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 31.3 ± 0.2° 2θ. In some embodiments, the peak at 31.3 ± 0.2° 2θ has the tenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 28.3 ± 0.2° 2θ. In some embodiments, the peak at 28.3 ± 0.2° 2θ has the eleventh highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 29.2 ± 0.2° 2θ. In some embodiments, the peak at 29.2 ± 0.2° 2θ has the twelfth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 22.8 ± 0.2° 2θ. In some embodiments, the peak at 22.8  ± 0.2° 2θ has the thirteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 28.0 ± 0.2° 2θ. In some embodiments, the peak at 28.0  ± 0.2° 2θ has the fourteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 25.3 ± 0.2° 2θ. In some embodiments, the peak at 25.3 ± 0.2° 2θ has the fifteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 21.5 ± 0.2° 2θ. In some embodiments, the peak at 21.5 ± 0.2° 2θ has the sixteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 19.9 ± 0.2° 2θ. In some embodiments, the peak at 19.9 ± 0.2° 2θ has the seventeenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 27.6 ± 0.2° 2θ. In some embodiments, the peak at 27.6 ± 0.2° 2θ has the eighteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 20.5 ± 0.2° 2θ. In some embodiments, the peak at 20.5 ± 0.2° 2θ has the nineteenth highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 21.8 ± 0.2° 2θ. In some embodiments, the peak at 21.8 ± 0.2° 2θ has the 20th highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 25.1 ± 0.2° 2θ. In some embodiments, the peak at 25.1 ± 0.2° 2θ has the 21st highest relative intensity.

In some embodiments, the XRPD pattern of Form 1 has a peak at 25.8 ± 0.2° 2θ. In some embodiments, the peak at 25.8 ± 0.2° 2θ has the 22nd highest relative intensity.

In some embodiments, Form 1 has an XRPD pattern having peaks at 6.4, 15.8, and 18.3 (± 0.2° 2θ).

In some embodiments, Form 1 has an XRPD pattern having peaks (± 0.2° 2θ) at 6.4, 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, and 31.3.

In some embodiments, Form 1 has an XRPD pattern having peaks (± 0.2° 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.

In some embodiments, Form 1 is characterized by an XRPD pattern substantially the same as that shown in FIG. 1 .

Form 1 may also have one or more of the following characteristics.

In some embodiments, Form 1 has a thermogravimetric analysis (TGA) curve characterized by about 0.5% to about 5% 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, Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5° C. In some embodiments, Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 85° C. to about 113° C.

In some embodiments, Form 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°C to about 250°C, about 162°C to about 248°C, about 230°C to about 240°C, about 240°C to about 260°C, about 240°C to about 250°C, about 242°C to about 248°C, or about 245°C). In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245°C. In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 162°C to about 248°C.

In some embodiments, Form 1 has a TGA curve substantially the same as the TGA curve shown in Figure 2. In some embodiments, the crystalline form is Form 1, whose thermogravimetric/differential scanning calorimetry (TG/DSC) thermogram is substantially the same as the thermogram shown in Figure 2.

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

In some embodiments, Form 1 has a differential scanning calorimetry (DSC) thermogram substantially the same as the thermogram shown in FIG. 3 .

In some embodiments, Form 1 has a DSC first cooling cycle thermogram characterized by a single exothermic event with an onset temperature of 151 °C and a peak temperature of 147 °C.

In some embodiments, Form 1 has a DSC first cooling cycle thermogram that is substantially the same as the cooling cycle thermogram shown in FIG. 4 .

In some embodiments, Form 1 is a hemihydrate.

In some embodiments, the image isomer 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%).

In some embodiments, Form 1 is substantially pure.

In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof comprises a free base of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof is a free base of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or its salt and/or solvent complex comprises amorphous (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or its salt and/or solvent complex is amorphous (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or its salt and/or solvent complex comprises an amorphous form of the free base of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof is an amorphous form of the free base of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof comprises Form 1*. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof is in Form 1*.

In some embodiments, the dissolution in step (a) is performed at about 40°C to 60°C (e.g., about 45°C to about 55°C or about 50°C). In some embodiments, the dissolution in step (a) is performed at about 50°C.

In some embodiments, the solution formed in step (a) has a concentration of about 0.08 g/mL to about 1.65 g/mL (e.g., 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.

In some embodiments, step (a) comprises 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) comprises cooling the solution to about 40°C. In some embodiments, the cooling is performed at 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 performed at about 1°C/min.

In some embodiments, the volume/volume ratio of water added to the solution in step (b) to the isopropyl alcohol 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 the isopropyl alcohol used for dissolution in step (a) is about 4:1.

In some embodiments, about 1/8 to about 1/32 of water is added to the solution per hour. 1/16 of water is added to the solution per hour. In some embodiments, about 1/16 of water is added to the solution per hour.

In some embodiments, the temperature of the mixture in step (c) is reduced 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) is reduced to about 5°C. In some embodiments, the first time 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 time period is about 1 hour. In some embodiments, the first time period is about 1 minute.

In some embodiments, the temperature of the mixture in step (d) is increased 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) is increased to about 40°C. In some embodiments, the second time 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 time period is about 1 hour. In some embodiments, the second time period is about 1 minute.

In some embodiments, the temperature of the mixture in step (e) is reduced 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) is reduced to about 5°C. In some embodiments, the third time 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 6 hours to about 18 hours, about 6 hours to about 24 hours, about 9 hours to about 15 hours, about 9 hours to about 14 hours, about 10 hours to about 12 hours, about 10.5 hours to about 11.5 hours, about 11 hours, about 12 hours, about 1 hour, or about 1 minute). In some embodiments, the third time period is about 11 hours. In some embodiments, the third time period is about 11 hours.

In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after rinsing to provide Form 1. In some embodiments, rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol and/or isopropanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water.

In some embodiments, step (f) comprises: filtering the mixture to provide a solid; washing the solid with methanol and water; and drying the solid to provide Form 1.

In some embodiments, drying is performed 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 comprises drying the solid at a pressure less than atmospheric pressure. In some embodiments, drying is performed at 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).

In some embodiments, the method includes preparing crystalline hemihydrate Form 1 by a method comprising: dissolving (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof in methanol to form a solution; adding water to the solution to form a first mixture; adding (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture; and separating the solid from the third mixture to provide Form 1.

In some embodiments, the method comprises preparing crystalline hemihydrate Form 1 by a method comprising: (a) dissolving (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof in methanol to form a solution; (b) adding water to the solution to form a first mixture; (c) adding (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture; (d) agitating the second mixture; (e) adding water to the second mixture to form a third mixture; (f) agitating the third mixture; and (g) Form 1 is isolated from the third mixture.

In some embodiments, the solution formed in step (a) has a concentration of about 0.03 g/mL to about 1 g/mL (e.g., 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.

In some embodiments, dissolving (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a salt and/or solvent thereof in methanol to form a solution comprises dissolving (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a first portion of methanol to form an unfiltered solution, filtering the unfiltered solution through a filter to provide a filter solution, then rinsing the filter with a second portion of methanol to provide a rinse solution, and combining the rinse solution with the filter solution to provide a solution. In some embodiments, the filtration is a polishing filtration. In some embodiments, the filter has a pore size of about 0.2 microns. In some embodiments, the weight of the first portion 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 dissolved (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the weight of the first portion of methanol is about 4 to about 8 times (e.g., about 0.5 to about 3 times, about 1 to about 3 times, or about 1.6 times (e.g., about 1.6 times)) the weight of the dissolved (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

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) comprises filtering the water through a filter and then adding the water to form a first mixture. In some embodiments, the amount of water added in step (b) is about 0.1 to about 2 times (e.g., about 0.1 to about 1.5 times, about 0.1 to about 1 times, about 0.3 to about 0.7 times, or about 0.5 times (e.g., about 0.5 times)) the weight of the (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a).

In some embodiments, the (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is about 0.1% to about 20% by weight (e.g., about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.5% to about 3%, about 0.7% to about 2.5%, about 0.7% to about 1.3%, or about 1% by weight) of the (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a). (e.g., about 1 wt %)).

In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is prepared by Method 1 described herein. In some embodiments, (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is prepared by Method 2 described herein.

In some embodiments, the agitation in step (d) is performed at 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). In some embodiments, the agitation in step (d) is performed for 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 8 hours, about 1 minute to about 6 hours, about 30 minutes to about 6 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 2.5 hours to about 3.5 hours, or about 3 hours (e.g., about 3 hours)).

In some embodiments, the water added in step (e) is purified water. In some embodiments, adding water in step (e) includes filtering 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-aminopyrimidin-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 about 1 second to about 48 hours, such as 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 (e.g., about 8 hours).

In some embodiments, the agitation in step (f) is performed at 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). In some embodiments, the agitation in step (f) is performed for about 1 minute to about 48 hours (e.g., about 1 minute to about 36 hours, about 1 minute to about 24 hours, about 4 hours to about 24 hours, about 8 hours to about 20 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours (e.g., about 16 hours)).

In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after rinsing to provide Form 1. In some embodiments, rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol and/or isopropanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water.

In some embodiments, isolating Form 1 from the third mixture comprises: (i) filtering the third mixture to provide a solid; (ii) washing the solid with methanol and water; and (iii) drying the solid to provide Form 1.

In some embodiments, the weight of methanol and water is 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-aminopyrimidin-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)).

In some embodiments, drying the solid comprises drying the solid at 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 the solid comprises drying the solid at a pressure less than atmospheric pressure. In some embodiments, drying the solid comprises drying the solid under an inert gas, e.g., nitrogen or argon (e.g., nitrogen). In some embodiments, drying the solid comprises drying the solid until the solid comprises about 1% to about 4% (e.g., about 1.5% to about 3.2%) or about 2% to about 2.6% (e.g., about 2% to about 2.6%) water by weight. In some embodiments, Form 1 obtained in step (g) comprises about 1% to about 4% (e.g., about 1.5% to about 3.2%) or about 2% to about 2.6% (e.g., about 2% to about 2.6%) water by weight.

In some embodiments, the method includes Contact with acid to form To prepare ; wherein R'' is a C1-C6 alkyl group; wherein R ³ is a C1-C6 halogen alkyl group.

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 molar solution of hydrogen chloride in ethyl acetate.

In some embodiments, contacting includes placing In some embodiments, contacting comprises adding an acid to In some embodiments, the adding is performed at 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 10°C, or about 5°C to about 15°C). In some embodiments, the agitation is performed at about 0°C to about 10°C. In some embodiments, the agitation is performed at about 5°C to about 15°C. In some embodiments, the contacting comprises and stirring 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 a mixture 6. In some embodiments, contacting comprises and stirring with an acid for about 3 hours to form a mixture 6. In some embodiments, contacting comprises and stirring with an acid for about 1 hour to form a mixture 6. In some embodiments, contacting comprises and stirring with an acid for at least 1 hour to form a mixture 6. In some embodiments, the stirring is performed at 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 10° C., or about 5° C. to about 15° C.). In some embodiments, the stirring is performed at about 5° C. to about 15° C. In some embodiments, the contacting comprises adding heptane or hexane (e.g., heptane) to the mixture 6. In some embodiments, after adding heptane or hexane (e.g., heptane) to 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 agitated or allowed to stand (e.g., agitated) 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 provide .

In some embodiments, the method includes Contact with a trifluoromethylating agent to form To prepare ; wherein R'' is a C1-C6 alkyl group.

In some embodiments, The C=N double bond in has an E geometry. In some embodiments, The C=N double bond has a Z geometry.

In some embodiments, the trifluoromethylation reagent is The molar ratio of 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 trifluoromethylation agent and The molar ratio is about 3.0.

In some embodiments, the phase shift reagent is The molar ratio of the phase transfer agent 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 phase transfer agent and The molar ratio is about 1.0.

In some embodiments, Contact with trifluoromethylating agents includes the use of In some embodiments, Contact with trifluoromethylating agents and phase transfer agents will form a mixture 7.

In some embodiments, Contacting with a trifluoromethylation reagent and a phase transfer reagent comprises adding the phase transfer reagent to Then, the trifluoromethylation reagent is added to and a mixture of a phase transfer reagent.

In some embodiments, the phase transfer reagent is added to the mixture at about 5°C to about 40°C (e.g., 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 phase transfer reagent is added to the middle.

In some embodiments, before adding a phase shift reagent to After that, and a 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, before adding the phase transfer reagent to After that, The mixture of the phase transfer reagent is cooled to about -20°C to about -15°C.

In some embodiments, during cooling and phase transfer reagent mixture, and a phase transfer reagent 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, during cooling and phase transfer reagent mixture, The mixture of the phase transfer reagent is stirred for about 1 hour.

In some embodiments, a trifluoromethylating agent is added to and a phase transfer reagent at 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, the trifluoromethylation reagent is added to and a phase transfer reagent at about -20°C to about -15°C.

In some embodiments, the trifluoromethylation reagent is added dropwise to and a mixture of a phase transfer reagent.

In some embodiments, Contacting with a trifluoromethylating agent and a phase transfer agent comprises adding the trifluoromethylating agent to Then add the phase transfer reagent to and a mixture of a trifluoromethylating agent.

In some embodiments, The contact with the trifluoromethylation reagent and the phase transfer reagent is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent comprises toluene, xylene or benzene. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent is toluene.

In some embodiments, the method comprises adding a trifluoromethylating agent to a mixture 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 trifluoromethylation reagent is added to the middle.

In some embodiments, the method comprises adding the trifluoromethylating agent to the mixture over a period of about 1 minute to about 24 hours (e.g., 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 method comprises adding a trifluoromethylation reagent to middle.

In some embodiments, the method includes agitating after adding the phase shift reagent. , a trifluoromethylation reagent, and a phase transfer reagent. In some embodiments, the method comprises agitating 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). , a trifluoromethylation reagent, and a phase transfer reagent. In some embodiments, the phase transfer reagent is added to the middle.

In some embodiments, a phase shift reagent is added to and a trifluoromethylation reagent mixture comprising adding a phase transfer reagent in several portions to and a trifluoromethylation reagent. In some embodiments, the number of parts is 7 to 13 parts. In some embodiments, the number of parts is 9 to 11 parts. In some embodiments, the number of parts is 10 parts. In some embodiments, the 10 parts are 10 parts of substantially the same weight.

In some embodiments, the method includes adding water or an aqueous acid solution to the mixture 7. In some embodiments, the method 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 (e.g., a 10 wt % aqueous ammonium chloride solution). In some embodiments, adding water or an aqueous acid solution to the mixture 7 is performed at about -10°C to about 25°C (e.g., about -5°C to about 5°C).

In some embodiments, the method 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 at a pressure below 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, concentrating the organic phase at a pressure below atmospheric pressure provides a residue. In some embodiments, the residue is purified using silica gel to provide .

In some embodiments, the method includes adding water and/or an aqueous alkaline solution to the mixture 8 to form a mixture 9'. In some embodiments, the mixture 9' comprises an organic phase and an aqueous phase. In some embodiments, the method includes separating the organic phase from the mixture 9'. In some embodiments, the method includes distilling the organic phase to provide a distillate. In some embodiments, the method includes passing the distillate through carbon (e.g., activated carbon). In some embodiments, the method includes reducing the volume of the distillate at a pressure less than atmospheric pressure to form a concentrate after passing the distillate through the carbon. In some embodiments, the method includes adding water to the concentrate, followed by reducing the volume of the mixture of water and concentrate to form a mixture 9''. In some embodiments, the method includes adding an antisolvent to the mixture 9'', and then reducing the volume of the mixture 9'' to form the mixture 9'''. In some embodiments, the antisolvent is heptane. In some embodiments, the method includes adding A portion (e.g., a portion prepared previously) is added to the mixture 9''' to form a precipitate. In some embodiments, the precipitate is filtered and dried to form .

In some embodiments, the trifluoromethylating agent is selected from TMSCF ₃ , [(trifluoromethyl)thio]benzene, trimethoxy(trifluoromethyl)potassium borate, Et ₃ GeNa/C ₆ H ₅ SCF ₃ , N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)copperate (1-), (SP-4-1)-tetrakis(trifluoromethyl)goldate (1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthrenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoromethylation reagent is TMSCF ₃ .

In some embodiments, the phase transfer agent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributyl ammonium bromide, 1,1'-(butane-1,4-diyl)bis[4-aza-1-aziridine cation bicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decadecylammonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetrapentylammonium chloride and dimethyldipalmitylammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

In some embodiments, the method includes and Contact to prepare ; wherein R'' is a C1-C6 alkyl group. In some embodiments, and Contact includes and 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.

In some embodiments, the contacting is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

In some embodiments, the condensed base and The molar ratio of 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 condensed base and The molar ratio is about 1.5.

In some embodiments, the condensed base and The molar ratio 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 1.2, about 0.9 to about 1.1, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.95 to about 1.05, about 1.0 to about 1.04, about 0.8, about 0.9, about 0.95, about 1.0, about 1.02, 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 condensed base and The molar ratio is about 1.02.

In some embodiments, and and the condensation base is contacted at about 25°C to about 80°C (e.g., about 25°C to about 70°C, about 25°C to about 60°C, about 35°C to about 50°C, about 35°C to about 45°C, about 35°C, about 40°C, or about 45°C). In some embodiments, and The contacting with the condensation base is carried out at about 35°C to about 45°C.

In some embodiments, and and contacting the condensation base is carried out at about 25°C to about 80°C (e.g., about 25°C to about 70°C, about 25°C to about 60°C, about 35°C to about 50°C, about 35°C to about 45°C, about 35°C, about 40°C, or about 45°C).

In some embodiments, and and combined alkaline contact including and and a condensed base. In some embodiments, and and condensed alkali together to stir including and and the condensation base 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). and and condensed alkali together to stir including and and condensed alkali for about 14 hours.

In some embodiments, and and combined alkaline contact including Add to Then add the condensed base to and in a mixture.

In some embodiments, Add to In some embodiments, the Add to The reaction is carried out at a temperature of about 15°C to about 20°C.

In some embodiments, a condensation base is added to and The mixture is heated at about 5°C to about 40°C (e.g., 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 condensation base is added to and The reaction is carried out at a temperature of about 15°C to about 20°C.

In some embodiments, and and a condensation base to provide a mixture 10. In some embodiments, the mixture 10 is agitated 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, the mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, agitating the mixture 10 is performed 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, agitating the mixture 10 is performed at about 60° C.

In some embodiments, after agitating the mixture 10, the mixture 10 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, or about 20°C). In some embodiments, after agitating the mixture 10, the mixture 10 is cooled to about 20°C. In some embodiments, after agitating the mixture 10, the mixture 10 is cooled to about 15°C to about 25°C.

In some embodiments, cooling the mixture 10 includes forming a slurry. In some embodiments, the method includes filtering the slurry to provide a solution. In some embodiments, the method includes reducing the volume of the solution at a pressure less than atmospheric pressure. In some embodiments, the method includes (i) adding a solvent to the solution; (ii) reducing the volume of the solution at a pressure less than atmospheric pressure; optionally, (iii) adding a solvent to the solution; and optionally, (iv) reducing the volume of the solution at a pressure less 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 method 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 method includes cooling the concentrate to about 15° C. to about 25° C. In some embodiments, the method includes adding water to the concentrate after cooling the concentrate to form a mixture 10′. In some embodiments, the method comprises agitating the 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 method comprises agitating the mixture 10' for about 14 hours. In some embodiments, after agitating the mixture 10', a slurry is formed. In some embodiments, the slurry is filtered to provide a compound of Formula (I-v).

In some embodiments, the method includes, after cooling the mixture 10, concentrating the mixture 10 at a pressure below atmospheric pressure to provide .

In some embodiments, the method includes

In some embodiments, the compound of formula (Iv) is reacted with and combined alkaline contact including is added to the compound of formula (Iv), and then the condensed base is added to and a mixture of compounds of formula (Iv).

In some embodiments, the method includes Prepared by contact with acid .

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 etherate).

In some embodiments, the acid is acetic acid.

In some embodiments, Contact with acid includes In some embodiments, Contact with acids includes use in solvents In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, Adding to the acid forms a mixture 11. In some embodiments, After addition to the acid, the mixture 11 is heated at 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). After adding to the acid, the mixture is heated at about 120°C 11. In some embodiments, After addition to the acid, the mixture 11 is agitated 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). After addition to the acid, the mixture 11 was stirred for about 8 hours.

In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to 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 separated and washed with the aqueous phase. In some embodiments, the aqueous alkaline solution is an aqueous potassium carbonate solution (e.g., a 15 wt % aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous alkaline solution, the organic phase is agitated with water and Na ₂ S ₂ O ₄ . In some embodiments, the organic phase is agitated 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 agitated with water _{and Na2S2O4} for about 8 hours. In some embodiments, agitating the organic phase with water _{and Na2S2O4} forms a solid. 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, and 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 agitated 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 at a pressure below atmospheric pressure to provide .

In some embodiments, the method includes and Contact to prepare ; wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl.

In some embodiments, and Contact includes and 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.

In some embodiments, and The contacting with the 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-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

In some embodiments, and Alkaline contact includes and , alkali and sodium iodide.

In some embodiments, and The contacting of alkali and sodium iodide is carried out at 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). and The contacting with alkali and sodium iodide is carried out at about 120°C.

In some embodiments, Add to , alkali and sodium iodide to form a mixture 13. In some embodiments, the 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, the mixture 13 is stirred for about 5 hours.

In some embodiments, the method includes The compound is contacted with an acid to prepare a compound of formula (IV); wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl. In some embodiments, Hal is chlorine. 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.

In some embodiments, The contact with the acid is carried out in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

In some embodiments, The contacting with the acid is carried out at 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). The contact with the acid is carried out at about 25°C.

In some embodiments, the method includes and In some embodiments, Z is O. In some embodiments, R ² is C1-C6 alkyl. In some embodiments, R ² is methyl.

In some embodiments, and Contact includes and In some embodiments, the contacting is performed in a solvent.

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

In some embodiments, and The contacting with the base is carried out at 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). and The alkaline contact was carried out at about 25°C.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: Reaction to form compound 1.

Some embodiments provide Compound 1 having the following structure: (1) The compound comprises The reaction was prepared in the same manner as compound 1.

In some embodiments, Reaction to form compound 1 comprises and Contact to form ; wherein R'' is a C1-C6 alkyl group.

In some embodiments, and Contact includes and 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.

In some embodiments, the contacting is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is ethyl acetate.

In some embodiments, and and combined alkaline contact including Add to Then add the condensed base to and in a mixture.

In some embodiments, Add to In some embodiments, the Add to The reaction is carried out at a temperature of about 15°C to about 20°C.

In some embodiments, a condensation base is added to and The mixture is heated at about 5°C to about 40°C (e.g., 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 condensation base is added to and The reaction is carried out at a temperature of about 15°C to about 20°C.

In some embodiments, and and a condensation base to provide a mixture 10. In some embodiments, the mixture 10 is agitated 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, the mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, agitating the mixture 10 is performed 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, agitating the mixture 10 is performed at about 60° C.

In some embodiments, after agitating the mixture 10, the mixture 10 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, or about 20°C). In some embodiments, after agitating the mixture 10, the mixture 10 is cooled to about 20°C.

After cooling the mixture 10, the mixture 10 is concentrated at a pressure below atmospheric pressure to provide .

In some embodiments, Reaction to form compound 1 comprises Contact with a trifluoromethylating agent to form ; wherein R'' is a C1-C6 alkyl group.

In some embodiments, Contact with trifluoromethylating agents includes the use of In some embodiments, Contact with trifluoromethylating agents and phase transfer agents will form a mixture 7.

In some embodiments, Contacting with a trifluoromethylation reagent and a phase transfer reagent comprises adding the phase transfer reagent to Then, a trifluoromethylation reagent is added to and a mixture of a phase transfer reagent.

In some embodiments, the phase transfer reagent is added to the mixture at about 5°C to about 40°C (e.g., 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 phase transfer reagent is added to the middle.

In some embodiments, before adding a phase shift reagent to After that, and a 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, before adding the phase transfer reagent to After that, The mixture of the phase transfer reagent is cooled to about -20°C to about -15°C.

In some embodiments, during cooling and phase transfer reagent mixture, and a phase transfer reagent 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, during cooling and phase transfer reagent mixture, The mixture of the phase transfer reagent is stirred for about 1 hour.

In some embodiments, a trifluoromethylating agent is added to and a phase transfer reagent at 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, the trifluoromethylation reagent is added to and a phase transfer reagent at about -20°C to about -15°C.

In some embodiments, the trifluoromethylation reagent is added dropwise to and a mixture of a phase transfer reagent.

In some embodiments, the method includes adding water or an aqueous acid solution to mixture 7. In some embodiments, the method includes adding an aqueous acid solution to mixture 7 to form mixture 8. In some embodiments, the aqueous acid solution is an aqueous ammonium chloride solution (e.g., a 10 wt % aqueous ammonium chloride solution).

In some embodiments, the method 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 and concentrated at a pressure below atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, concentrating the organic phase at a pressure below atmospheric pressure provides a residue. In some embodiments, the residue is purified using silica gel to provide a compound of formula (I-iv).

In some embodiments, the trifluoromethylating agent is selected from TMSCF ₃ , [(trifluoromethyl)thio]benzene, trimethoxy(trifluoromethyl)potassium borate, Et ₃ GeNa/C ₆ H ₅ SCF ₃ , N,N-dimethyl-(1-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)-tetrakis(trifluoromethyl)copperate (1-), (SP-4-1)-tetrakis(trifluoromethyl)goldate (1-), [(1,1,2,2,2-pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthrenium, 1,1,1-trifluoromethanesulfonate (1:1). In some embodiments, the trifluoroalkylation reagent is a trifluoromethylation reagent. In some embodiments, the trifluoromethylation reagent is TMSCF ₃ .

In some embodiments, the phase transfer agent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributyl ammonium bromide, 1,1'-(butane-1,4-diyl)bis[4-aza-1-aziridine cation bicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decadecylammonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetrapentylammonium chloride and dimethyldipalmitylammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

In some embodiments, Reaction to form compound 1 comprises Contact with acid to form ; wherein R'' is a C1-C6 alkyl group.

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 molar solution of hydrogen chloride in ethyl acetate.

In some embodiments, contacting includes placing In some embodiments, the adding is performed at 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 agitating is performed at about 0°C to about 10°C. In some embodiments, the contacting comprises and stirring 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, or about 1 hour) to form a mixture 6. In some embodiments, contacting comprises and stirring with an acid for about 1 hour to form a mixture 6. In some embodiments, the stirring is performed at 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 10° C., or about 5° C. to about 15° C.). In some embodiments, the stirring is performed at about 5° C. to about 15° C. In some embodiments, the contacting comprises adding heptane or hexane (e.g., heptane) to the 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., -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 agitated or allowed to stand (e.g., agitated) 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 to provide .

In some embodiments, Reaction to form compound 1 comprises and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

In some embodiments, contacting with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises adding the carbonyl equivalent to and alkali to form mixture 1, and then pyrimidine-2,5-diamine is added to mixture 1 to form mixture 2.

In some embodiments, the carbonyl equivalent is The molar ratio of 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). The molar ratio of carbonyl equivalent to The molar ratio is about 1.3.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and In some embodiments, sodium bicarbonate and The molar ratio is about 3.5.

In some embodiments, a carbonyl equivalent is added to and alkali to form mixture 1 is carried out in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, a carbonyl equivalent is added to and alkali to form mixture 1 is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, a carbonyl equivalent is added to and alkaline 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 carbonyl equivalent is added to In some embodiments, the carbonyl equivalent is added to The reaction is carried out at a temperature of about 0°C to about 2°C.

In some embodiments, when adding a carbonyl equivalent to After eluting with alkali, the mixture 1 is stirred 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.

In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and adding pyrimidine-2,5-diamine to mixture 1. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 followed by adding pyrimidine-2,5-diamine 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)non-5-ene (DBN). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

In some embodiments, adding the second base to mixture 1 and adding pyrimidine-2,5-diamine to mixture 1 is performed at about 0 to about 10°C, such as about 0°C to about 5°C, about 0°C to about 2°C, or about 0°C. In some embodiments, adding the second base to mixture 1 and adding pyrimidine-2,5-diamine to mixture 1 is performed at about 0°C to about 5°C. In some embodiments, adding the second base to mixture 1 and adding pyrimidine-2,5-diamine to mixture 1 is performed at about 0°C to about 2°C.

In some embodiments, after forming the mixture 2, the 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); then 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.) and agitated 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.

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 (e.g., about 5:2). In some embodiments, after recrystallizing Compound 1, Compound 1 is rinsed with a mixture of isopropyl acetate and heptane, followed by water, followed by 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 below atmospheric pressure. In some embodiments, drying Compound 1 includes drying Compound 1 at ambient temperature.

In some embodiments, with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises is added to the carbonyl equivalent and the base to form a mixture 1', and then pyrimidine-2,5-diamine is added to the mixture 1' to form a mixture 2'. In some embodiments, In some embodiments, It is in salt form and makes with a carbonyl equivalent and pyrimidine-2,5-diamine to form compound 1 comprises is added to the carbonyl equivalent and the base to form mixture 1', and then pyrimidine-2,5-diamine is added to mixture 1' to form mixture 2'.

In some embodiments, The salt is a hydrochloric acid salt.

In some embodiments, Addition to the carbonyl equivalent and the base to form a mixture 1' is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, Addition to the carbonyl equivalent and base to form mixture 1' is performed under an inert atmosphere. In some embodiments, contacting is performed under nitrogen. In some embodiments, contacting is performed under argon.

In some embodiments, the carbonyl equivalent is The molar ratio of 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). The molar ratio of carbonyl equivalent to In some embodiments, the carbonyl equivalent is about 1.3. The molar ratio is about 2.0.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and In some embodiments, sodium bicarbonate and The molar ratio is about 3.5.

In some embodiments, Addition to the carbonyl equivalent and the base to form a mixture 1' is performed in a solvent. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, The addition to the carbonyl equivalent and the base to form the mixture 1' is performed under an inert atmosphere. In some embodiments, the addition is performed under nitrogen. In some embodiments, the addition is performed under argon.

In some embodiments, The addition 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 carbonyl equivalent is added to The temperature is about 5°C or lower.

In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 'to form mixture 2' comprises adding a tertiary alkali to mixture 1 'and adding pyrimidine-2,5-diamine to mixture 1 '. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 'to form mixture 2' comprises adding a tertiary alkali 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' comprises adding an aqueous sodium chloride solution to mixture 1 ', adding a tertiary alkali to mixture 1 ', and adding pyrimidine-2,5-diamine to mixture 1 '. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1' to form mixture 2' comprises 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-diazabicycloundec-7-ene (DBU) and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

In some embodiments, an aqueous sodium chloride solution is added to the mixture 1', a tertial alkali is added to the mixture 1', and the addition of pyrimidine-2,5-diamine is performed 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, an aqueous sodium chloride solution is added to the mixture 1', a tertial alkali is added to the mixture 1', and the addition of pyrimidine-2,5-diamine is performed at about 0°C to about 5°C.

In some embodiments, after forming mixture 2, mixture 2 is agitated 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.

In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane. In some embodiments, Compound 1 is precipitated from isopropanol and water. In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane, followed by precipitation from isopropanol and water. In some embodiments, after precipitating Compound 1, Compound 1 is dried. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure less than atmospheric pressure. In some embodiments, drying Compound 1 comprises 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 comprises drying Compound 1 at about 45°C. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure below atmospheric pressure at about 20°C to about 25°C.

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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester.

In some embodiments, the carbonyl equivalent is phenyl chloroformate.

In some embodiments, the carbonyl equivalent is R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy groups. In some embodiments, R' is phenyl. In some embodiments, R' is p-nitrophenyl.

In some embodiments, The method of contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: combining R'OC(O)Cl with a base; Add to the mixture of R'OC(O)Cl and base to form .

In some embodiments, In some embodiments, the salt is a hydrochloride.

In some embodiments, The method of contacting R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: combining R'OC(O)Cl with a base; Add to the mixture of R'OC(O)Cl and base to form ; in It is in salt form.

In some embodiments, combining R'OC(O)Cl with a base comprises combining a base with a solvent followed by adding R'OC(O)Cl. In some embodiments, combining a base with a solvent followed by adding R'OC(O)Cl comprises adding R'OC(O)Cl to a base and a 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) followed by adding R'OC(O)Cl.

In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, The addition of R'OC(O)Cl and the base is carried out at about 0°C to about 10°C (e.g., about 0°C to about 5°C, about 0°C to about 5°C, or about 0°C). The addition of R'OC(O)Cl and the base is carried out at about 0°C to about 5°C. In some embodiments, The addition to the mixture of R'OC(O)Cl and the base is carried out at a temperature below 5°C. In some embodiments, Added as a solution in a solvent to a mixture of R'OC(O)Cl and a base. In some embodiments, the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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, the drug is administered over a period of 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). Add to the mixture of R'OC(O)Cl and base.

In some embodiments, Addition to the mixture of R'OC(O)Cl and base forms mixture 3. In some embodiments, mixture 3 is agitated 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 agitated 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, stirring mixture 3 forms a two-phase mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with the aqueous phase. In some embodiments, the alkaline aqueous 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, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti-solvent is heptane.

In some embodiments, after adding the antisolvent, the mixture 4 is concentrated at a pressure below atmospheric pressure. In some embodiments, after concentrating the mixture 4, a slurry is formed. In some embodiments, the slurry is filtered to provide In some embodiments, the rinse is performed with hexane or heptane (e.g., heptane). In some embodiments, during rinsing Afterwards, dry In some embodiments, drying Including drying at pressures below atmospheric pressure In some embodiments, drying including drying 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 Including drying at about 45°C In some embodiments, drying including drying at about 40°C to about 45°C In some embodiments, drying including drying at about 45°C to about 50°C In some embodiments, drying This includes drying under an inert atmosphere (e.g., under nitrogen) .

In some embodiments, R'OC(O)Cl and The molar ratio of R'OC(O)Cl 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, R'OC(O)Cl and The molar ratio of R'OC(O)Cl is about 1.05. The molar ratio of R'OC(O)Cl is about 1.3. The molar ratio is about 2.0.

In some embodiments, the base and The molar ratio of sodium bicarbonate to sodium bicarbonate 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, sodium bicarbonate and In some embodiments, sodium bicarbonate and The molar ratio is about 3.5.

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.

In some embodiments, Contacting with R'OC(O)Cl and pyrimidine-2,5-diamine to form compound 1 comprises: It is contacted with pyrimidine-2,5-diamine to form compound 1.

In some embodiments, The contact with pyrimidine-2,5-diamine to form compound 1 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-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-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.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises is added to pyrimidine-2,5-diamine. In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises reacting Add to pyrimidine-2,5-diamine.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises adding pyrimidine-2,5-diamine to middle.

In some embodiments, contacting with pyrimidine-2,5-diamine to form compound 1 comprises adding pyrimidine-2,5-diamine to middle.

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

In some embodiments, After adding to pyrimidine-2,5-diamine or after adding pyrimidine-2,5-diamine to After the mixture 5 is stirred, a mixture 5 is formed. In some embodiments, the 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, the mixture 5 is stirred for about 12 hours to about 13 hours. In some embodiments, the mixture 5 is stirred for about 3 hours. In some embodiments, the mixture 5 is stirred for about 1 hour.

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, 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 undetectable) of impurity 1 is present as an impurity with Compound 1. (Impurity 1).

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 no detectable amount) of impurity 2 is present as an impurity with compound 1. (Impurity 2).

In some embodiments, the method includes Prepared by contact with acid .

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 etherate).

In some embodiments, the acid is acetic acid.

In some embodiments, Contact with acid includes In some embodiments, Contact with acids includes use in solvents In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, Adding to the acid forms a mixture 11. In some embodiments, After addition to the acid, the mixture 11 is heated at 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). After adding to the acid, the mixture is heated at about 120°C 11. In some embodiments, After addition to the acid, the mixture 11 is agitated 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). After addition to the acid, the mixture 11 was stirred for about 8 hours.

In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to 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 separated and washed with the aqueous phase. In some embodiments, the aqueous alkaline solution is an aqueous potassium carbonate solution (e.g., a 15 wt % aqueous potassium carbonate solution). In some embodiments, after washing the organic phase with the aqueous alkaline solution, the organic phase is agitated with water and Na ₂ S ₂ O ₄ . In some embodiments, the organic phase is agitated 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 agitated with water _{and Na2S2O4} for about 8 hours. In some embodiments, agitating the organic phase with water _{and Na2S2O4} forms a solid. 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, and 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 agitated 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 at a pressure below atmospheric pressure to provide .

In some embodiments, the method includes and Contact to prepare ; wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl.

In some embodiments, and Contact includes and 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.

In some embodiments, and The contacting with the 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-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

In some embodiments, and Alkaline contact includes and , alkali and sodium iodide.

In some embodiments, and The contacting of alkali and sodium iodide is carried out at 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). and The contacting with alkali and sodium iodide is carried out at about 120°C.

In some embodiments, Add to , alkali and sodium iodide to form a mixture 13. In some embodiments, the 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, the mixture 13 is stirred for about 5 hours.

In some embodiments, the method includes The compound is contacted with an acid to prepare a compound of formula (IV); wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl. In some embodiments, Hal is chlorine. 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.

In some embodiments, The contact with the acid is carried out in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 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-methylpyrrolidone, dimethyl sulfoxide, water or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

In some embodiments, The contacting with the acid is carried out at 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). The contact with the acid is carried out at about 25°C.

In some embodiments, the method includes and In some embodiments, Z is O. In some embodiments, R ² is C1-C6 alkyl. In some embodiments, R ² is methyl.

In some embodiments, and Contact includes and In some embodiments, the contacting is performed in a solvent.

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

In some embodiments, and The contacting with the base is carried out at 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). and The alkaline contact was carried out at about 25°C.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: and Contact to form , wherein R'' is a C1-C6 alkyl group; and Reaction to form compound 1.

Some embodiments provide Compound 1 having the following structure: (1), or its salt and/or solvent combination; the compound comprises and Contact to form The method is to prepare the product, wherein R'' is a C1-C6 alkyl group; and Reaction to form compound 1.

In some embodiments, Reaction to form compound 1 comprises reacting Contact with a trifluoromethylating agent to form To prepare ; wherein R'' is a C1-C6 alkyl group.

In some embodiments, Reaction to form compound 1 comprises reacting Contact with acid to form To prepare .

In some embodiments, Reaction to form compound 1 comprises and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprising: (a) and Contact to form , wherein R'' is a C1-C6 alkyl group; (b) Contact with a trifluoromethylating agent to form (c) make Contact with HCl to form ; and (d) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide Compound 1 having the following structure: (1), or a salt and/or solvent thereof; the compound is prepared by a process comprising: (a) and Contact to form , wherein R'' is a C1-C6 alkyl group; (b) Contact with a trifluoromethylating agent to form (c) make Contact with HCl to form ; and (d) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprising: (a) and Contact to form , wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide Compound 1 having the following structure: (1), or a salt and/or solvent thereof; the compound is prepared by a method comprising: (a) and Contact to form , wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprising: (a) and Contact to form , wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups; and (ii) having the structure to form compound 1.

Some embodiments provide Compound 1 having the following structure: (1), or a salt and/or solvent thereof; the compound is prepared by a process comprising: (a) and Contact to form , wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups; and (ii) having the structure to form compound 1.

In some embodiments, the method includes preparing pyrimidine-2,5-diamine by contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere. In some embodiments, the palladium/carbon is palladium adsorbed on carbon. In some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere forms a mixture 14. In some embodiments, in some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere is performed at a pressure of about 15 to about 90 psi (e.g., about 25 to about 70 psi, about 55 to about 75 psi, about 60 to about 70 psi, about 35 to about 55 psi, about 40 to about 50 psi, about 60 to about 80 psi, about 65 to about 75 psi, about 40 psi, about 50 psi, about 60 psi, about 70 psi, or about 80 psi). In some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere is performed at a pressure of about 40 to about 50 psi. In some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere is performed at a pressure of about 60 to about 70 psi. In some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere is performed at a pressure of about 70 psi.

In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium/carbon under a hydrogen atmosphere comprises contacting 5-nitropyrimidine-2-amine with palladium/carbon in a solvent under a hydrogen atmosphere. In some embodiments, the solvent comprises acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, or any combination thereof. In some embodiments, the solvent is acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, or any combination thereof. In some embodiments, the solvent comprises tetrahydrofuran and methanol.

In some embodiments, the palladium/carbon comprises water. In some embodiments, the palladium/carbon comprises about 40% to about 60% water (e.g., about 45% to about 55% water or about 50% by weight water). In some embodiments, the palladium/carbon comprises water. In some embodiments, the palladium/carbon comprises about 50% by weight water.

In some embodiments, the palladium/carbon is about 5% to about 20% (e.g., about 5%, about 8% to about 12%, about 9% to about 11%, about 10%, about 13% to about 17%, about 14% to about 16%, about 15%, or about 20%) weight/weight palladium/carbon. In some embodiments, the palladium/carbon is about 10% weight/weight palladium/carbon. In some embodiments, the palladium/carbon is about 15% weight/weight palladium/carbon.

In some embodiments, the weight percentage of palladium to 5-nitropyrimidin-2-amine in palladium/carbon is about 1% to about 50% (e.g., about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 5% to about 25%, about 10% to about 50%, about 8% to about 12%, about 13% to about 17%, about 10%, about 15%, or about 20%). In some embodiments, the weight percentage of palladium to 5-nitropyrimidin-2-amine in palladium/carbon is about 10%. In some embodiments, the weight percentage of palladium to 5-nitropyrimidin-2-amine in palladium/carbon is about 20%.

In some embodiments, contacting 5-nitropyrimidin-2-amine with palladium/carbon under a hydrogen atmosphere comprises agitating 5-nitropyrimidin-2-amine and palladium/carbon under a hydrogen atmosphere. In some embodiments, agitation is performed for about 1 minute to about 48 hours (e.g., about 1 minute to about 12 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 6 hours, about 1 hour to about 4 hours, about 2.5 hours to about 3.5 hours, about 3.5 hours to about 4.5 hours, about 1 hour to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours). In some embodiments, agitation is performed for about 1 hour. In some embodiments, agitation is performed for about 2 hours. In some embodiments, agitation is performed for at least about 4 hours.

In some embodiments, agitation is performed at about 20°C to about 90°C (e.g., about 30°C to about 80°C, about 40°C to about 70°C, about 35°C to about 55°C, about 40°C to about 55°C, about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, or about 70°C).

In some embodiments, the method includes filtering the mixture 14 (e.g., through a layer of diatomaceous earth) to form a filtrate. In some embodiments, the method includes reducing the volume of the filtrate at a pressure less than atmospheric pressure to form a concentrate. In some embodiments, the method includes adding a solvent to the concentrate to form a mixture 14'. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the method includes cooling the mixture 14' to 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, a precipitate is formed in the mixture 14' after cooling. In some embodiments, the method includes filtering the mixture 14' to provide pyrimidine-2,5-diamine.

In some embodiments, the method comprises dissolving pyrimidine-2,5-diamine in a solvent to form a slurry. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, water, or any combination thereof. In some embodiments, the solvent comprises isopropanol and water. In some embodiments, the solvent is isopropanol and water. In some embodiments, the solvent comprises about 40% to about 99% isopropanol and about 1% to about 40% water (e.g., about 70% to about 97% isopropanol and about 3% to about 30% water; about 80% to about 95% isopropanol and about 5% to about 20% water; or about 90% isopropanol and about 10% water). In some embodiments, the solvent comprises about 90% isopropanol and about 10% water. In some embodiments, the slurry is heated at about 30°C to about 90°C (e.g., about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, about 60°C to about 70°C, about 50°C to about 60°C, about 70°C to about 80°C, about 60°C, about 65°C, or about 70°C). In some embodiments, the slurry is heated at about 60° C. to about 70° C. In some embodiments, the slurry is heated for about 1 minute to about 48 hours (e.g., about 1 minute to about 36 hours, about 1 minute to about 24 hours, about 1 minute to about 2 hours, about 1 hour to about 12 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 slurry is heated for about 1 hour. In some embodiments, the method includes cooling the slurry after heating the slurry. In some embodiments, cooling the slurry comprises cooling the slurry at about -20°C to about 30°C (e.g., about -10°C to about 20°C, about -5°C to about 15°C, about 0°C to about 10°C, about 0°C, about 5°C, or about 10°C). In some embodiments, cooling the slurry comprises cooling the slurry to about 0°C to about 10°C. In some embodiments, cooling the slurry comprises cooling the slurry for about 1 minute to about 72 hours (e.g., about 1 minute to about 48 hours, about 1 hour to about 36 hours, about 2 hours to about 24 hours, about 3 hours to about 18 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, about 7.5 hours to about 8.5 hours, about 8 hours, at least 1 hour, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours). In some embodiments, cooling the slurry comprises cooling the slurry for at least 8 hours. In some embodiments, the method comprises filtering the slurry after cooling the slurry to provide recrystallized pyrimidine-2,5-diamine. In some embodiments, the method comprises drying the recrystallized pyrimidine-2,5-diamine at a pressure below atmospheric pressure. In some embodiments, the method comprises heating the recrystallized pyrimidine-2,5-diamine at a temperature of about 20°C to about 70°C (e.g., about 30°C to about 60°C, about 40°C to about 50°C, about 40°C, or about 50°C). In some embodiments, the method comprises heating the recrystallized pyrimidine-2,5-diamine at a temperature of about 40°C to about 50°C.

In some embodiments of the compounds and methods described herein, Formula (I) exists as a salt. In some embodiments of the compounds and methods described herein, Formula (I) exists as a solvent complex. In some embodiments of the compounds and methods described herein, Formula (I) exists as a salt of a solvent complex. In some embodiments of the compounds and methods described herein, Compound 1 exists as a salt. In some embodiments of the compounds and methods described herein, Compound 1 exists as a solvent complex. In some embodiments of the compounds and methods described herein, Compound 1 exists as a salt of a solvent complex. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the solvent complex is a pharmaceutically acceptable solvent complex.

In some embodiments, Compound 1 exists as a solvate. In some embodiments, Compound 1 exists as a free base solvate. In some embodiments, Compound 1 exists as a hydrate. In some embodiments, Compound 1 exists as a free base hydrate. In some embodiments, Compound 1 exists as a hemihydrate. In some embodiments, Compound 1 exists as a free base hemihydrate .

Some embodiments provide compounds of formula (Ii): (Ii); wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxy, cyano, C1-C6 alkyl optionally substituted with hydroxy, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; and R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl.

In some embodiments, the compound of formula (Ii) is a compound of formula (Iii): (iii).

Some embodiments provide compounds of formula (Iia) ; wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 halogenalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine atoms; R R' is selected from C1-C6 alkyl and C6-C10 aryl which is optionally substituted with ^1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups.

In some embodiments, the compound of formula (Iia) is a compound of formula (Iiai) .

Some embodiments provide compounds of formula (I-iii) ; wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; and R '' is C1-C6 alkyl.

In some embodiments, the compound of formula (I-iii) is a compound of formula (I-iii-i) .

Some embodiments provide compounds of formula (I-iv) ; wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine atoms; and R'' is C1-C6 alkyl.

In some embodiments, the compound of formula (I-iv) is a compound of formula (I-iv-i) .

Some embodiments provide compounds of formula (IV) ; wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxy, cyano, C1-C6 alkyl optionally substituted with hydroxy, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; and R ² is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine atoms.

In some embodiments, the compound of formula (IV) is a compound of formula (IVi) .

In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for or .

Some embodiments provide compounds of formula (I-vi) ; wherein: R ² is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 halogenalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine atoms.

In some embodiments, the compound of formula (I-vi) is a compound of formula (I-vi-i) .

Some embodiments provide compounds of formula (I-viii) ; wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxy, cyano, C1-C6 alkyl optionally substituted with hydroxy, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorines; and Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl.

In some embodiments, the compound of formula (I-viii) is a compound of formula (I-viii-i) .

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, each R ¹ is an independently selected halogen. In some embodiments, each R ¹ is independently selected from fluorine and chlorine. In some embodiments, each R ¹ is independently selected from fluorine and bromine. In some embodiments, each R ¹ is fluorine. In some embodiments, at least one R ¹ is an independently selected halogen. In some embodiments, at least one R ¹ is independently selected from fluorine and chlorine. In some embodiments, at least one R ¹ is fluorine.

In some embodiments, at least one R ¹ is cyano. In some embodiments, at least one R ¹ is hydroxy. In some embodiments, at least one R ¹ is C1-C6 alkyl, optionally substituted with hydroxy. In some embodiments, at least one R ¹ is C1-C6 alkyl substituted with hydroxy. In some embodiments, at least one R ¹ is C1-C3 alkyl substituted with hydroxy. In some embodiments, at least one R ¹ is hydroxymethyl. In some embodiments, at least one R ¹ is unsubstituted C1-C6 alkyl. In some embodiments, at least one R ¹ is methyl. In some embodiments, at least one R ¹ is C3-C6 cycloalkyl. In some embodiments, at least one R ¹ is cyclopropyl.

In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is C1-C6 alkyl. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is methyl. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is C3-C6 cycloalkyl. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is cyclopropyl. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is cyano. In some embodiments, m is 2; one R ¹ is halogen; and the other R ¹ is halogen. In some embodiments, m is 2; one R ¹ is fluorine; and the other R ¹ is fluorine.

In some embodiments, R ² is hydroxy. In some embodiments, R ² is C1-C6 alkyl, optionally substituted with hydroxy. In some embodiments, R ² is C1-C6 alkyl substituted with hydroxy. In some embodiments, R ² is C1-C3 alkyl substituted with hydroxy. In some embodiments, R ² is hydroxymethyl. In some embodiments, R ² is unsubstituted C1-C6 alkyl. In some embodiments, R ² is unsubstituted C1-C3 alkyl. In some embodiments, R ² is methyl.

In some embodiments, R ² is C1-C6 haloalkyl. In some embodiments, R ² is C1-C3 haloalkyl. In some embodiments, R ² is difluoromethyl. In some embodiments, R ² is trifluoromethyl.

In some embodiments, R ² is halogen. In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine.

In some embodiments, R ² is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 fluorine groups. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine groups. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ² is a C3-C6 cycloalkyl group substituted with 2 fluorine groups. In some embodiments, R ² is a C3-C4 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ² is a C3-C4 cycloalkyl group substituted with 2 fluorine groups. In some embodiments, R ² is an unsubstituted C3-C6 cycloalkyl group.

In some embodiments, R ³ is C1-C6 alkyl. In some embodiments, R ³ is C1-C3 alkyl. 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 is isopropyl.

In some embodiments, R ³ is C1-C6 haloalkyl. In some embodiments, R ³ is C1-C3 haloalkyl. In some embodiments, R ³ is difluoromethyl. In some embodiments, R ³ is trifluoromethyl.

In some embodiments, R ^{is a C3-} C6 cycloalkyl group optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl. In some embodiments, R ^is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 fluorine groups. In some embodiments, ^R is a C3-C6 cycloalkyl group substituted with 1 or 2 fluorine groups. In some embodiments, R ^{is a} C3-C6 cycloalkyl group substituted with 1 fluorine group. In some embodiments, R ^is a C3-C6 cycloalkyl group substituted with 1 fluorine group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, ^R is a 2,2-difluorocyclopropyl group or a 3,3-difluorocyclopropyl group. In some embodiments, R ³ is a C3-C6 cycloalkyl group optionally substituted with 1 or 2 methyl groups. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 or 2 methyl groups. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 methyl group. In some embodiments, R ³ is a C3-C6 cycloalkyl group substituted with 1 methyl group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, R ³ is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, R ³ C3-C6 cycloalkyl group is a cyclopropyl group. In some embodiments, R ³ is a cyclopropyl group. In some embodiments, R ³ is a cyclobutyl group. In some embodiments, R ³ is a cyclopentyl group. In some embodiments, R ³ is cyclohexyl.

In some embodiments, R' is C1-C6 alkyl. In some embodiments, R' is C1-C4 alkyl. In some embodiments, R' is C1-C3 alkyl. 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.

In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl groups. In some embodiments, R' is a C6-C10 aryl group substituted with 1-3 independently selected C1-6 alkyl groups. In some embodiments, R' is C6-C10 aryl substituted with 1-3 independently selected C1-6 alkoxy groups.

In some embodiments, R'' is C1-C6 alkyl. In some embodiments, R'' is C1-C4 alkyl. In some embodiments, R'' is C1-C3 alkyl. 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.

In some embodiments, Hal is selected from chlorine, bromine and iodine. In some embodiments, Hal is selected from chlorine, bromine and trifluoromethyl. In some embodiments, Hal is chlorine. In some embodiments, Hal is bromine. In some embodiments, Hal is iodine. In some embodiments, Hal is trifluoromethanesulfonyl.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form ; or and Contact to form wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; and wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) when forming in step (a) When Contact with acid to form ; or when formed in step (a) When Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5-nitropyrimidine-2-amine with palladium/carbon under a hydrogen atmosphere.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5-nitropyrimidine-2-amine with palladium/carbon under a hydrogen atmosphere.

Some embodiments provide a method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups; and (ii) having the structure to form compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5-nitropyrimidine-2-amine with palladium/carbon under a hydrogen atmosphere.

Some embodiments provide a structure having Compounds.

Some embodiments provide a structure having Compounds.

Some embodiments provide a structure having Some embodiments provide compounds having the structure Some embodiments provide compounds having the structure Some embodiments provide compounds having the structure Compounds.

Some embodiments provide a structure having Some embodiments provide compounds having the structure Some embodiments provide compounds having the structure Compounds.

Some embodiments provide a structure having Some embodiments provide compounds having the structure Compounds.

Some embodiments provide a structure having Some embodiments provide compounds having the structure Some embodiments provide compounds having the structure Some embodiments provide compounds having the structure Compounds.

Some embodiments provide a structure having Compounds.

Some embodiments provide a structure having Compounds.

Some embodiments provide a structure having Preparation of Example Compounds

The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein and modifying for specific desired substituents.

Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant technical literature or from standard textbooks in the field. Although not limited to any one or more sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999 are useful and recognized reference textbooks on organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate but not limit the general procedures used to prepare the compounds of the present disclosure.

The synthetic methods disclosed herein tolerate a wide variety of functional groups; therefore, a variety of substituted starting materials can be used. These methods generally provide the desired final compound at or near the end of the entire process, although in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt and/or solvent complex. Materials and Methods

The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents may not react substantially with starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (e.g., a temperature that may range from the solidification temperature of the solvent to the boiling point of the solvent). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step may be selected by a skilled technician.

The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1st edition, Oxford University Press, 2000; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, Wiley-Interscience Publication, 2001; and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry", J. Chem. Educ., 74(11), 1297 (1997). X -ray powder diffraction (XRPD):

XRPD analysis was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the samples between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with a Mylar polymer film to support the sample. The porous plate was then placed in a diffractometer and analyzed using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1 : α2 ratio = 0.5) operating in transmission mode (step size 0.0130° 2θ, step time 18.87 s) using a 40 kV / 40 mA generator setting. XRPD analysis using a longer basis batch method was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the samples between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with a Mylar polymer film to support the sample. The porous plate was then placed in a diffractometer and analyzed using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1 : α2 ratio = 0.5) operated in transmission mode (step size 0.0130° 2θ, step time 68.595 s) using a 40 kV / 40 mA generator setting. Data were visualized and images were generated using HighScore Plus 4.7 desktop application (PANalytical, 2017). Thermogravimetric analysis/differential scanning calorimetry (TGA/DSC):

The material (3 - 10 mg) was added to a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 automatic synchronous DSC and maintained at room temperature. The sample was then heated from 30 - 400 °C at a rate of 10 °C/min, during which the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas with a flow rate of 200 cm ³ /min. Differential Scanning Calorimetry (DSC):

The material (1 - 5 mg) was weighed into an aluminum DSC pan and sealed non-hermetically with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 Differential Scanning Calorimeter equipped with an RC90 cooler. The samples and reference were heated to 210°C at a scan rate of 10°C/min and the resulting heat flow response was monitored. The samples were cooled to -80°C and then both were reheated to 210°C at 10°C/min. Nitrogen was used as the purge gas with a flow rate of 50 ^cm3 /min. Abbreviations Abbreviation Meaning ACN Acetonitrile AcOH Acetic acid Aq. Aqueous solution DCM Dichloromethane DCE 1,2-Dichloroethane DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide DMAc/DMA Dimethylacetamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol HPLC HPLC h Hours i-PrOH Isopropyl alcohol iPA Isopropyl acetate KF Karl Fischer titration MeOH Methanol min minute MTBE Methyl tert-butyl ether NaOH Sodium hydroxide Pd/C Palladium/Carbon RT or rt Room temperature RRT Relative residence time THF Tetrahydrofuran TEA Triethylamine t-BuOK Potassium tert-butoxide TBAT Tetrabutylammonium acetate (Bu ₄ OAc) TMS Trimethylsilyl UPLC UPLC XRPD X-ray powder diffraction introduction

An improved route for the synthesis of Compound 1 was developed to ensure higher standards of identity, strength, quality and purity of the active pharmaceutical ingredient (API) according to good manufacturing practices (cGMP). The route in Scheme 1 below was performed at a 300 g scale, and the cGMP route shown in Scheme 2 below was performed at an approximately 11 kg scale.

The specifications for Compound 1 (Form 1 Hemihydrate) (referred to herein as "API") were: ≥ 97.0% (area/area or "a/a"), 97.0-103.0% (weight/weight, "w/w"), unknown individual impurities ≤ 0.15% (a/a), total impurities ≤ 3.0% (a/a) by UPLC, and chiral purity ≥ 98.0% (a/a) by HPLC. The cGMP scale-up was successfully executed over 3 months to deliver 10.87 kg of API with a purity of 99.9% (a/a), 99.6% (w/w), and 0.1% of Impurity 2 was found as a single impurity by UPLC. The chiral purity was found to be 100.0% (a/a) by HPLC.

In order to successfully conduct a multi-kilogram synthesis of Compound 1 (Form 1 hemihydrate) that meets cGMP requirements and guidelines, several challenges were overcome. These challenges include: 1. Producing intermediate VI (see Scheme 1). The primary issue was the capacity of the hydrogenator required to perform the reaction in a single batch run. Alternative methods of catalytic hydrogenation were explored to reduce 5-nitropyrimidin-2-amine via hydrogen transfer from formic acid (see Example 1 ). Although hydrogen transfer conditions were found to successfully convert V to VI, removal of the salt and extraction of VI from aqueous work-up were difficult due to the high solubility of VI in water. Therefore, it was decided to use hydrogen hydrogenation to produce VI. Given the size of the hydrogenator vessel available at the cGMP manufacturing facility (20 L), this method required 6 batch runs to produce enough intermediate VI for API delivery. 2. Generation of intermediate A-2. As performed in route A, it was found that the yield dropped significantly during the free alkalization of the HCl salt intermediate. Therefore, it was decided to isolate the HCl salt (B-2) and use it in the subsequent reaction (see Scheme 2) rather than the free base form (A-2). 3. Generation of carbamate VII. Shown in brackets in route A to indicate in situ formation via reaction of the free base form A-2 with phenyl chloroformate, significant levels of impurity 1 (i.e., up to 10%) were observed when the conversion was performed in this manner. Therefore, an alternative approach was taken to generate the free base form A-2 in situ from the HCl salt B-2, which would then react rapidly with phenyl chloroformate to form intermediate VII. The carbamate was then isolated as a pure crystalline solid. Condensation between pure VII and pure VI then produced compound 1, in which no detection level of impurity 1 was observed ( see Table E7 for the structure of impurity 1 and other impurities). 4. Impurity 2 was present. It was seen in both routes and the identity of this impurity was not clearly established. Finally, impurity 2 was separated by preparative HPLC from a GLP batch of compound 1 containing 0.5% of this impurity. The chemical structure of impurity 2 was then elucidated as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5-chloro-7-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea by NMR and LC-MS ( see Table E7 ). Therefore, this impurity was identified and quantified in the final API to meet cGMP requirements. Procedure 1: Route A (GLP, 300 g scale) Overview of Route A

Compound 1 was prepared on a 300 g scale via the route shown in Scheme 1. Starting from commercially available 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (I), condensation with 1,1-dichloroethylene under alkaline conditions gave intermediate A-1, which was dehydrated/aromatized by treatment with sulfuric acid to give 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (II). The formation of (S,E)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide (III) was achieved by treating intermediate (II) with commercially available (S)-2-methylpropane-2-sulfenamide under alkaline catalysis. Image-selective addition of the trifluoromethyl group was achieved by treating intermediate III with trifluoromethyltrimethylsilane and catalytic tetrabutylammonium bromide at low temperature. Removal of the tert-butylsulfinyl group of IV was achieved by treatment with HCl followed by base to yield the free base intermediate A-2. Treatment of A-2 with phenyl chloroformate yielded the corresponding phenol carbamate (shown in parentheses to indicate in situ formation), which condensed with pyrimidine-2,5-diamine (VI) in the presence of triethylamine to yield compound 1. As described above, route A suffers from several problems: (1) significant loss of A-2 during the free base procedure, and (2) introduction of impurity 1 (i.e., up to 10%), which may be caused by hydrolysis of the intermediate phenol carbamate (shown in parentheses) back to intermediate A-2, which reacts with the phenol carbamate to produce the symmetric urea (impurity 1, Table E7 ). Procedure 2: Pathway B (cGMP, 11 kg scale) Overview of Pathway B

Compound 1 was prepared on a 10.9 kg scale using the route shown in Scheme 2 according to cGMP protocols. Route B begins with O -alkylation of commercially available 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (I) to afford intermediate B-1, which is treated with acetic acid to yield intermediate II. Aldehyde II is condensed with optically pure commercially available (S)-2-methylpropane-2-sulfenamide under base catalysis to yield intermediate III. Image-selective addition of the trifluoromethyl group is achieved by treating intermediate III with trifluoromethyltrimethylsilane in the presence of catalytic tetrabutylammonium acetate at low temperature. Removal of the tert-butylsulfenyl group of IV is achieved by treatment with HCl to afford intermediate B-2 as a stable and crystalline hydrochloride salt. The necessary intermediate VI was prepared by catalytic hydrogenation of commercially available 5-nitropyrimidin-2-amine (V). The phenol carbamate (intermediate VII) was prepared by reacting B-2 with phenyl chloroformate under modified Schotten-Baumann conditions; intermediate VII was subsequently isolated as a crystalline solid. The final step involved condensing intermediate VII with pyrimidine-2,5-diamine (VI) to generate compound 1 in crystalline form. Compound 1 (Form 1 hemihydrate) was obtained by crystallization of compound 1 from methanol-water (0.5 molar equivalent of water).

Comparison of route B to route A indicates several key differences that lead to significant process improvements. These key differences include: (1) route B uses a different method for preparing the aldehyde intermediate II, (2) route B involves the isolation of intermediate B-2 (hydrochloride salt), and (3) route B involves the isolation of the intermediate carbamate (VII).

As discussed above and described in detail herein, these differences result in increased overall yields and reduced impurity levels, particularly complete elimination of impurity 1 and a significant reduction in the amount of impurity 2. For reference, Table E7 provides an overview of putative impurities that may be present in the final API (due to side reactions or unreacted starting materials). The following examples are used to illustrate the optimization of Route B (cGMP synthesis) to produce Compound 1 (Form 1 hemihydrate). Example 1. Preparation of pyrimidine-2, 5-diamine by transfer hydrogenation

To the reaction flask were added all components in the indicated relative amounts. After the reaction was complete, the Pd/C was filtered and the volatiles were removed under vacuum. The crude mixture was redissolved in DCM and water was added to wash out the HCOOH, TEA and salts. Most of the product was found to remain in the aqueous layer. Attempts to make the aqueous layer alkaline (pH 14) using NaOH followed by extraction of the product using DCM failed to effectively extract the product (VI) from the aqueous layer. Example 2. Preparation of pyrimidine-2,5-diamine by catalytic hydrogenation in methanol

A 300 mL Parr reactor was charged with 10 g (1.0 eq) 5-nitropyrimidin-2-amine, Pd/C (1 g, 10% w/w, 50% wet in water), and MeOH (130 mL, 13 volumes, referred to herein as "V"). The resulting mixture was hydrogenated at 45 °C under 60-70 psi _H2 for 2 hours to achieve reaction completion. The catalyst was filtered through a diatomaceous earth pad and subsequently washed with MeOH (50 mL, 5 V). The MeOH was then exchanged with isopropyl acetate (50 mL, 5 V) at 60-70 °C. The slurry was slowly cooled to below 0 °C over 3 hours and then aged overnight. The solid was filtered and washed with isopropyl acetate (15 mL, 1.5 V). The wet cake was dried in a vacuum oven at 50 °C under nitrogen flow overnight to afford 6.6 g (84.2%) of the title compound as a yellow crystalline solid.

Notes: (1). The procedure of Example 2 was successfully scaled up using 85 g of 5-nitropyrimidin-2-amine in a 2 L Parr reactor to produce 57.1 g (85.5% yield) of the title compound as a yellow crystalline solid with an HPLC purity of 100.0%; and (2) It was observed that 5-nitropyrimidin-2-amine had very poor solubility in MeOH (i.e., not completely soluble in 30 V MeOH at 60 °C). Therefore, the above hydrogenation conditions were modified to add THF to the solvent mixture. At 60 °C (14 V THF) and 10 V MeOH. In addition, the catalyst loading was increased from 0.1X to 0.25X to achieve reaction completion within 2 hours, making it possible to achieve 2 runs per day when running on a larger scale. Example 3. Preparation of pyrimidine-2,5-diamine by catalytic hydrogenation in methanol-tetrahydrofuran with increasing catalyst loading Protocol: Using a 2 L Parr Hydrogenator: 1. Feed 5-nitropyrimidin-2-amine (35 g, 1.0 X). 2. Feed THF (490 mL, 14 V). 3. Feed MeOH (350 mL, 10 V). 4. Heat contents to 55-65 °C to obtain a clear solution. 5. Cool contents to 40-50 °C. 6. Feed Pd/C (8.75 g or 0.25 X, 10% w/w, 50% water). 7. Purge 3 times with nitrogen and hydrogenate at 60 °C under 70 psi _H2 pressure. 8. Monitor the reaction; typically complete after 2 hours. 9. Filter the Pd/C through a pad of celite. 10. Rinse the Parr reactor with MeOH (105 mL, 3 V) and wash the celite filter cake with the rinse. 11. Concentrate the filter liquor to about 105 mL (3 V) at 40-60 °C under reduced pressure. 12. Add isopropyl acetate (175 mL, 5 V). 13. Concentrate the batch to about 105 mL (3 V). 14. Allow the slurry to cool to room temperature and hold for 3 hours. 15. Filter the solid and wash the filter cake with isopropyl acetate (35 mL, 1 V). 16. Dry the wet filter cake in a vacuum oven at 50 °C under nitrogen purge overnight (18 h). 17. The filter cake yield was 23.8 g (86.5%) of pyrimidine-2,5-diamine as a light yellow crystalline solid. Example 4. cGMP manufacturing protocol for the preparation of pyrimidine-2,5-diamine by catalytic hydrogenation in methanol-tetrahydrofuran

The production of intermediate VI was performed in 18 L Parr reactor over 12 hydrogenation runs in 2 separate batch records (VI-B1 and VI-B2, 6 runs each) using a modified procedure as shown in Example 3. Each hydrogenation run used 0.6 kg 5-nitropyrimidin-2-amine, 0.15 kg Pd/C (10% w/w, 50% wet) in 6 L MeOH and 8.4 L THF at 70 psi _H2 and 60°C. After the reaction was complete, the catalyst was filtered through a diatomaceous earth pad. The hydrogenator was rinsed with 2.4 L MeOH and the rinse was used to wash the diatomaceous earth/catalyst filter cake. For each batch record, the combined filtrate from 6 runs was subjected to a solvent exchange from MEOH/THF to IPAc, where the product crystallized out and was isolated by filtration. The wet filter cake was dried in a vacuum oven at 45°C under nitrogen venting until all residual solvents met specifications. For VI-B1, 2.425 kg of VI was obtained in 85.2% yield with HPLC purity of 98.7% (a/a) and analysis of 99.4% (w/w). For VI-B2, 2.665 kg of VI was obtained in 91.3% yield with HPLC purity of 99.4% (a/a) and analysis of 96.9% (w/w). Equipment Reactor (R1): 18 L, stainless steel, 1-20 V, 14 L maximum working volume (15.56 V), temperature range: 15-60 °C, pressure range: 60-70 psi. Reactor 2 (R2): Glass, 1-13 V (59 L), for post-merger processing. Temperature range: -5-60 °C. Vacuum oven (D1): Temperature range: 40-50 °C Trays (T1, T2, T3): Hoechst Alloy Protocol: 1. Prepare hydrogenation reactor R1 by feeding nitrogen and evacuating. 2. Prepare reactor R2 with reflux condenser and nitrogen feed as needed. 3. Feed 0.60 kg of 5-nitropyrimidin-2-amine (target range: 0.59 - 0.61 kg) into reactor R1. 4. Feed 7.52 kg of THF (target range: 7.1 - 7.9 kg, about 14 V) into reactor R1. 5. Feed 4.75 kg of methanol (target range: 4.51 - 5.00 kg, about 10 V) into reactor R1. 6. Turn on agitation to 280 RPM and adjust the temperature of reactor R1 to 52 °C to dissolve the material. 7. Adjust the temperature of reactor R1 to 45 °C and degas the headspace with nitrogen in preparation for the Pd/C feed. 8. Feed 0.15 kg Pd/C (target range: 0.14 - 0.16 kg, 0.25X) into reactor R1. 9. Seal reactor R1 and slowly feed hydrogen to a pressure of 60 psi. Carefully adjust the temperature of reactor R1 to 50-70°C and maintain at 60-70 psi with constant agitation for 1 hour. 10. Check the mixture from reactor R1 to test the reaction conversion. The starting material disappears. 11. Carefully purge reactor R1 by feeding nitrogen and evacuating. 12. Prepare 0.15 kg of diatomaceous earth (target range: 0.14 - 0.16, 0.25X) on a filter funnel and pre-wetted filter bed with methanol. 13. Filter the contents of reactor R1 through the diatomaceous earth filter bed with the contents warmed at 41°C. 14. Feed 1.87 kg of methanol (target range: 1.8 - 2.0 kg, 3.2X) into reactor R1 to rinse the reactor and heat the rinse to 48°C. 15. Transfer the rinse from reactor R1 to the washed diatomaceous earth filter bed. Combine the filter cake wash with the mother liquor and transfer to reactor R2. Repeat steps 1-14 for 5 additional runs/batches and transfer the combined batch to R2 for use in Batch VI-B1. Combined Workup, Filtration, and Drying of Batch VI-B1 15. Determine new unit value, Y = 3.60 kg total 5-nitropyrimidin-2-amine fed to VI-B1. 16. Concentrate the contents of reactor R2 from about 50 L to about 9 L (target about 2.5 V) under vacuum while maintaining the temperature < 60 °C. 17. Stop distillation and then slowly cool the contents of reactor R2 from 45 °C to 0 °C over 3 h 1 min. 18. Hold the contents of reactor R2 at 0 °C for 17 h 18 min with constant agitation. 19. Filter the contents of reactor R2. 20. Feed 3.07 kg of isopropyl acetate (target range: 3.0 - 3.3 kg, about 1 V) into reactor R2 to rinse the reactor. 21. Transfer the rinse liquid from reactor R2 to wash the wet filter cake in the filter funnel. 22. Load the wet filter cake from the filter funnel into a Hoechst alloy tray. Net weight: 2.69 kg 23. Dry the material in a vacuum oven at 40-50°C under vacuum and nitrogen venting for 1 day 1 h 26 min. 24. Check the moisture content of each tray by KF; the result does not meet the standard. 25. Continue drying the material at 47°C for another 21 h 27 min. 26. Check the water content of each tray by KF; the result passes the standard (KF of water ≤ 0.5 % (w/w); result 0.4%) 27. Pull out 5.0 g of the reserved sample. 28. Bulk package and store for the next production step. Total net value of VI-B1: 2.425 kg

Steps 1-28 were repeated for six additional runs and these batches were combined to produce VI-B2, resulting in a total net amount of 2.665 kg of intermediate VI for batch VI-B2; the analytical test results and passing criteria for each batch are shown in Table E1 . Table E1. Analytical Results of cGMP Batches VI-B1 and VI-B2 Test/Standard Results of VI-B1 Results of VI-B2 KF of water ≤ 0.5% (w/w) 0.4% (w/w) 0.5% (w/w) HPLC purity ≥ 98.0% (a/a) 98.7% (a/a) 99.4% (a/a) HPLC analysis; report results (% w/w) 99.4% (a/a) 96.9% (a/a) Residual solvents: THF, MeOH, IPAc; Report results (ppm) MeOH: 1638 ppm THF: < 909 ppm IPAc: 1356 ppm MeOH: 1096 ppm THF: 1547 ppm IPAc: <498 ppm Pd content; reported results (ppm) 0.54 ppm ＜ 0.02 ppm Appearance; Report Results Yellow solid crystals Yellow solid crystals Example 5. Alternative cGMP manufacturing scheme for the preparation of pyrimidine-2,5-diamine by catalytic hydrogenation in methanol-tetrahydrofuran

The starting material 5-nitropyrimidin-2-amine (1 eq) was hydrogenated in a mixture of tetrahydrofuran (12 vol) and methanol (12 vol) at 40-50° C. for at least 4 hours at 40-50 psi hydrogen pressure in the presence of a palladium/carbon catalyst (15% w/w, 10% Pd loading, 50% water wet) until an in-process control by HPLC indicated <0.5% 5-nitropyrimidin-2-amine remaining relative to intermediate VI. The reaction mixture was filtered through a diatomaceous earth bed (1.5 wt eq) to remove the catalyst, followed by rinsing with methanol (3 vol). The mixture was distilled under vacuum to a concentrate (approximately 2.5 vol). Isopropyl acetate (5 vol) is added and distilled under vacuum to a concentrate (about 2.5 vol). The solution is cooled to -5 to 5°C over three hours to achieve crystallization. The batch is filtered and the filter cake is washed with isopropyl acetate (3 vol) cooled to 0-10°C. The separated solid is dried to constant weight at 40-50°C under vacuum with a nitrogen sweep. The purity of intermediate VI is controlled in-process by HPLC; if the purity does not meet the acceptance criteria for intermediate VI, optional recrystallization is performed as described below. Optional recrystallization

Intermediate VI was dissolved in a mixture of isopropanol (18 vol) and water (2 vol). The slurry was heated to 60-70°C and maintained for about 1 hour. The mixture was cooled to 0-10°C at a rate of 10°C/hour and then maintained at 0-10°C for at least 8 hours. The batch was filtered and the filter cake was washed twice with isopropanol-water solution (2 vol, 9:1) at 0-10°C. The wet filter cake was dried to constant weight at 40-50°C under vacuum with a nitrogen purge to obtain intermediate VI in approximately 56% yield. Example 6. Second alternative cGMP manufacturing scheme for the preparation of pyrimidine-2,5-diamine by catalytic hydrogenation in methanol-tetrahydrofuran

Commercially available 5-nitropyrimidin-2-amine was hydrogenated in the presence of palladium/carbon catalyst (10 wt %, 10% Pd loading, 50% water wet) in a mixture of tetrahydrofuran (12.5 wt eq) and methanol (8 wt eq) at 50-60°C for at least 1 hour at 60-70 psi hydrogen pressure until in-process control by HPLC indicated <0.5% 5-nitropyrimidin-2-amine remaining relative to intermediate VI. The reaction mixture was filtered through a diatomaceous earth bed (1.5 wt eq) to remove the catalyst, followed by rinsing with methanol (3.2 wt eq). The mixture was distilled under vacuum to a concentrate (approximately 2.5 vol). Isopropyl acetate (4.4 wt eq) was added and distilled under vacuum to a concentrate (about 2.5 vol). The solution was cooled to -5 to 5°C over three hours to achieve crystallization. The batch was filtered and the filter cake was washed with isopropyl acetate (0.9 wt eq) cooled to 0-10°C. The separated solid was dried at 40-50°C under vacuum with a nitrogen purge to constant weight. Intermediate VI was isolated in about 85% yield. Example 7. Preparation of 1-(2-(2,2-diethoxyethoxy)-3,5-difluorophenyl)ethan-1-one plan:

Using a 500 L reactor (R1) with a mechanical stirrer and temperature controller under nitrogen atmosphere: 1. DMF (256 kg) was fed into R1 at 15-20°C. 2. 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (I; 27.0 kg, 156 mol) was fed into R1 at 15-20°C. 3. 2-Bromo-1,1-diethoxyethane (32.4 kg, 163 mol) was fed into R1 at 15-20°C. 4. K ₂ CO ₃ (43.4 kg, 312 mol) was fed into R1 at 15-20°C. 5. NaI (2.35 kg, 15.6 mol) was fed into R1 at 15-20°C. 6. Heat the reaction to 120°C and stir at 120°C for 8 h. 7. Take a sample and dilute with ACN for monitoring. HPLC shows 79.0% B-1 detected. 8. Cool the reaction mixture of R1 to 20°C with circulating ethylene glycol (7°C). 9. Feed H ₂ O 1000 kg into R2 at 15-20°C. 10. Transfer the reaction mixture of R1 to R2 under stirring at 15-20°C. 11. Feed EtOAc (180 kg) into R2 and stir at 20°C for 0.5 h, then stand for 20 min and separate the organic phase. Extract the aqueous phase again with EtOAc (180 kg). 12. The organic phases were combined and washed twice with 15% aqueous NaCl solution (200 kg). 13. The organic phases were continuously concentrated by vacuum distillation at 50°C to produce B-1 (43.6 kg, purity = 83.2%) as a brown oil. Example 8. Preparation of 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde plan:

Using a 1000 L reactor (R1) with a mechanical stirrer and temperature control under _N2 protection: 1. Feed AcOH (430 kg) into R1 at 15-20°C. 2. Feed 1-(2-(2,2-diethoxyethoxy)-3,5-difluorophenyl)ethan-1-one (B-1; 43.0 kg, 149 mol) into R1 at 15-20°C. 3. Feed DMF (10.9 kg, 149 mol) into R1 at 15-20°C. 4. Heat the reactants to 120°C and stir at 120°C for 8 h. 5. Take a sample and dilute with ACN for monitoring. HPLC indicated that 73.1% of 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (II) was detected. 6. Cool the reaction mixture of R1 to 20°C with circulating ethylene glycol (7°C). 7. Pour 1000 kg of H ₂ O into R2 at 15-20°C. 8. Pour the reaction mixture of R1 into R2 under stirring at 15-20°C. 9. Pour EtOAc (180 kg) into R2 and stir at 20°C for 0.5 h, then stand for 20 min and separate the organic phase. Extract the aqueous phase again with EtOAc (180 kg). 10. Combine the organic phases and wash twice with 15% K ₂ CO ₃ aqueous solution (100 kg). 11. Feed the organic phase (400 kg) into R1 at 15-20°C. 12. Feed H ₂ O (300 kg) into R1 at 15-20°C. 13. Feed Na ₂ S ₂ O ₄ (75 kg) into R1 at 15-20°C with stirring and stir for 8 h. (A pale yellow solid precipitates). 15. Filter the solid and wash the filter cake with EtOAc (50 kg). 15. Separate the filtrate and wash the aqueous phase twice with EtOAc (50 kg). 16. Feed the aqueous phase and filter cake into R1 at 15-20°C. 17. EtOAc (180 kg) was fed into R1 at 15-20°C with stirring. 18. The pH of the solution in R1 was adjusted to 9-10 with K ₂ CO ₃ (solid) and stirred at 15-20°C for 5 h. 19. The solution of R1 was separated and the organic phase was collected. 20. The aqueous phase was extracted with EtOAc (90 kg). 21. The organic phases were combined and washed twice with 15% aqueous NaCl solution (100 kg). 22. The organic phase was continuously concentrated by vacuum distillation at 50°C to produce 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (19.2 kg, purity = 99.2%) as a light yellow solid and confirmed by HPLC. Example 9. Preparation of (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide plan:

Under N ₂ protection, use a 1000 mL reactor (R1) with a mechanical stirrer and temperature control: 1. EtOAc (170 kg) was fed into R1 at 15-20°C. 2. 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (II; 19.0 kg, 96.8 mol) was fed into R1 at 15-20°C. 3. (S)-2-methylpropane-2-sulfenamide (11.9 kg, 98.7 mol) was fed into R1 at 15-20°C. 4. K ₂ CO ₃ (20.0 kg, 145 mol) was fed into R1 at 15-20°C. 5. The reactants were heated to 60°C and stirred at 60°C for 5 h. 6. Take a sample and dilute with ACN for monitoring. HPLC indicated 97.7% of (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide was detected. 7. Cool the reaction mixture of R1 to 20°C with circulating ethylene glycol (7°C). 8. Filter the solution of the reaction mixture with a diatomaceous earth pad (20 kg) to remove (K ₂ CO ₃ ) and wash the filter cake with EtOAc (30 kg). 9. Combine the organic phases and wash twice with 15% NaCl aqueous solution (100 kg). 10. The organic phase was continuously concentrated by vacuum distillation at 50°C to produce (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide (25.1 kg, purity = 99.2%), which was confirmed by HPLC as a light brown solid. Example 10. cGMP Preparation of (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide

Intermediate II (1 eq) was reacted with (S)-2-methylpropane-2-sulfenamide (1.02 eq) in the presence of potassium carbonate (1.5 eq) in THF (10 vol) at 35-45°C for at least 14 hours until in-process control by HPLC indicated <3% of intermediate II remained relative to intermediate III. The reaction mixture was cooled to 15-25°C and then filtered. The mixture was distilled under vacuum to a concentrate (about 3 vol), after which ethanol (10 vol) was added and the batch was distilled under vacuum to a concentrate (about 3 vol). Ethanol (10 vol) was added and the batch was distilled under vacuum to a final concentrate (about 5 vol). The solution was cooled to 15-25°C, water (5 vol) was added, and the slurry was stirred for at least 14 hours. The batch was filtered and the filter cake was washed twice with ethanol-water (2 vol, 1:1). The separated solid was dried at 40-50°C under vacuum with a nitrogen sweep to constant weight. Intermediate III was isolated in approximately 88% yield. Example 11. Preparation of (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide plan:

Using a 1000 L reactor (R1) with a mechanical stirrer and temperature control under _N2 protection: 1. THF (224 kg) was fed into R1 at 15-20°C. 2. (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide (III; 25.0 kg, 83.6 mol) was fed into R1 at 15-20°C. 3. Tetrabutylammonium acetate (25.1 kg 83.6 mol) was fed into R1 at 15-20°C. 4. The reaction was cooled to -20°C to about -15°C and stirred at -20°C to about -15°C for 1 h. 5. TMSCF ₃ (35.6 kg, 250 mol) was added dropwise at -20°C to about -15°C. (Keep the temperature below -15°C) 6. Take a sample and dilute with ACN for monitoring. HPLC showed that 71.1% of (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide was detected. 7. The reaction mixture was added to 10% NH ₄ Cl aqueous solution (1000 kg) in R2 under stirring at 0~5°C. 8. The solution was extracted with EtOAc (180 kg×2) and the organic phase was washed twice with 15% NaCl aqueous solution 200 kg. 9. The organic phase was continuously concentrated by vacuum distillation at 50°C to give crude (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (52 kg) as a light brown oil. 10. The crude was purified by column chromatography to give (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (13.1 kg, 97.67%, 42.5% yield) as a yellow solid.

Single non-mirror isomer: HPLC purity (220 nM): 97.67% (a/a); chiral purity by SFC: ee% = 100% LC/MS: exact mass 369.08; m/z = 369.9 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CHLOROFORM-d6) δ = 6.99 (dd, J = 2.4, 7.6 Hz, 1H), 6.91 - 6.84 (m, 1H), 5.04 (quintet, J = 7.2 Hz, 1H), 4.29 (br d, J = 8.0 Hz, 1H), 2.28 (s, 3H), 1.299 (m, 9H). ¹⁹ F NMR δ = -74.288 ppm. Example 12. Preparation of (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide

Intermediate III (1 eq) was dissolved in toluene (10 vol) and cooled to -20 to -10°C. Trimethyl(trifluoromethyl)silane (3 eq) was added over at least 1 hour, followed by tetrabutylammonium acetate (1 eq) as a solid in ten equal portions, maintaining the internal reaction temperature below -10°C. The reaction was stirred at -20 to -10°C for at least 3 hours until in-process control by HPLC indicated <0.5% intermediate III remained relative to intermediate IV. The reaction mixture was quenched into 10 wt% aqueous ammonium hydrochloride solution (20 vol) at -5 to 5°C. The lower aqueous layer was removed and the organic layer was washed twice with water (5 vol), 5 wt% aqueous sodium bicarbonate solution (10 vol), and twice with water (5 vol). The organic layer was co-distilled twice with toluene (10 vol) and then filtered through a cartridge containing activated carbon. The mixture was distilled under vacuum to a concentrate (about 5 vol). Water (3 vol) was added and the mixture was distilled under vacuum to a concentrate (about 3 vol). n-Heptane (5 vol) was added and the batch was distilled under vacuum to a concentrate (about 3 vol). n-Heptane (3 vol) was added and the IPC of the residual toluene showed <1% by GC. The mixture was inoculated with intermediate IV (0.003 wt eq) and stirred at 20°C for at least 24 hours. The batch was filtered and the filter cake was washed with 1:1 n-heptane-water (2 vol). The separated solid was dried to constant weight at 25-35°C under vacuum with a nitrogen purge. Intermediate IV was isolated in about 50% yield. Example 13. Preparation of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine hydrochloride plan:

Using a dry 2.0 L reactor (R1) with mechanical stirrer and temperature control under _N2 protection: 1. Charge EtOAc (570 mL, 2.1 eq, 5.7 V) containing 1M HCl. 2. Cool the contents to 0-10°C. 3. Charge (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (IV; 100.0 g, 1.0 eq). 4. Adjust the batch temperature to 5-15°C. 5. After 1 hour, HPLC analysis showed 99.2% conversion. 6. Add heptane (1.5 L, 15.0 V) slowly over 3 hours at 5-15°C. 7. Slowly cool to -10 °C over 6 hours. 8. Stir at -10 °C for 18 hours. 9. Filter the solid and wash the filter cake with heptane (400 mL, 4.0 V). 10. Dry the wet filter cake in a vacuum oven at 50 °C under nitrogen venting for 18 hours. 11. The dry filter cake weighed 75.1 g (95% yield). Example 14. cGMP Preparation of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride

Intermediate IV (1 eq) was treated with a solution of hydrogen chloride in ethyl acetate (about 1 M, 2.5 eq, about 6 vol) at 5-15°C for at least 3 hours until the in-process control indicated <1% of intermediate IV remained relative to intermediate B-2. n-Heptane (15 vol) was added and the mixture was cooled to -15 to -5°C over 6 hours and then kept at -15 to -5°C for at least 24 hours to complete crystallization. The batch was filtered and the filter cake was washed twice with n-heptane (1 vol). The filter cake was dried at 40-50°C under vacuum with a nitrogen purge for at least 16 hours until constant weight. Intermediate B-2 was isolated in about 70% yield. Example 15. Alternative cGMP Preparation of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine Hydrochloride

Intermediate IV was treated with a solution of hydrogen chloride in ethyl acetate (approximately 1 mole, 5 wt eq) at 5-15°C for at least 1 hour until the in-process control indicated <1 volume % of intermediate IV remained relative to intermediate B-2. n-Heptane (10 wt eq) was added, and the mixture was cooled to -15 to -5°C and held for at least 24 hours to complete crystallization. The batch was filtered and the filter cake was washed with n-heptane (2 x 1.4 wt eq). The filter cake was dried at 40-50°C under vacuum with a nitrogen purge for at least 16 hours until constant weight. Intermediate B-2 was isolated in approximately 80% yield. Example 16. Preparation of Compound 1 from (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine via one-pot cascade carbamate formation/condensation with pyrimidine-2,5-diamine

To a slurry of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (A-2; 10 g, 1.0 eq) and NaHCO ₃ (8.36 g, 3.0 eq) in 120 mL THF at 0° C. under nitrogen was slowly added phenyl chloroformate (6.5 mL, 1.05 eq) while maintaining the batch temperature below 2° C. The resulting mixture was stirred at 0° C. overnight to achieve 99.2% conversion. TEA (9.2 mL, 2.0 eq) was slowly added while maintaining the batch temperature below 2° C. After 15 minutes, pyrimidine-2,5-diamine was added over 20 minutes. The reaction was then warmed to 30 °C over 2 hours and maintained at 30 °C overnight to achieve completion. Work-up was performed by first quenching with 5% _NaHCO3 (50 mL, 5 V) and extracting the product using isopropyl acetate (100 mL, 10 V). The product was crystallized from isopropyl acetate (40 mL, 4 V) and heptane (140 mL, 14 V). The product was filtered and washed sequentially with 20% IPAc/heptane (50 mL, 5 V), water (50 mL, 5 V) and then 20% isopropyl acetate/heptane (50 mL, 5 V). After drying under vacuum overnight at ambient temperature, 11.5 g (76%) of crude compound 1 was obtained as an off-white solid with an HPLC purity of 98.6% (peak area), and 1.3% (peak area) of 1,3-bis((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Impurity 1). Example 17. Preparation of compound 1 from (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine hydrochloride via one-pot cascade carbamate formation/condensation with pyrimidine-2,5-diamine

To a mixture of phenyl chloroformate (2.75 mL, 1.3 eq) and NaHCO ₃ (4.9 g, 3.5 eq) in 50 mL (10 V) THF and 10 mL (2 V) water was added a solution of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (B-2; 5.0 g, 1.0 eq) in 10 mL (2 V) THF and 5 mL (1 V) water slowly over 1 hour at 0° C. under nitrogen while maintaining the batch temperature below 5° C. The reaction was found to be clean and the addition was controlled, meaning that the reaction was complete after the addition of B-2 was complete. Brine (10% NaCl in water, 20 mL, 4 V) was added and the batch was allowed to settle for layer separation. HPLC analysis of the aqueous layer showed no loss of the intermediate carbamate (VII). DIPEA (5.8 mL, 2.0 eq) was added over 1 hour at 0-10 °C, followed by a solution of pyrimidine-2,5-diamine (VI; 2.1 g, 1.15 eq). The resulting mixture was stirred at 0-10 °C under nitrogen overnight to achieve approximately 80% conversion. The reaction was aged for an additional day to achieve completion. Workup was performed by first adding 20 mL of water (4 V), settling, and separating the layers. THF was partially removed from the organic layer to approximately 25 mL (5 V) under a rotary evaporator. The product in the aqueous layer was back-extracted with isopropyl acetate (50 mL, 10 V). The combined organic layers (5 V THF + 10 V isopropyl acetate) were washed with 5% NaHCO ₃ (25 mL, 5 V) to remove residual phenol, and then washed with 10% brine (25 mL, 5 V). The final organic layer was concentrated to 10 mL (2 V) to obtain a slurry, and heptane (50 mL, 10 V) was slowly added as an anti-solvent. After stirring at ambient temperature for several hours, the product was filtered and washed sequentially with heptane (10 mL, 2 V). The wet cake was redissolved in isopropanol (30 mL, 6 V) and then concentrated to approximately 15 mL (3 V) at 45°C. Water (50 mL, 10 V) was added slowly to give a white slurry. The slurry was cooled to 0-10 °C and stirred at 0-10 °C for several hours. The solid was filtered and washed with water (10 mL, 2 V). The wet cake was dried in a vacuum oven at 45 °C under nitrogen venting overnight to give 5.3 g (78%) of compound 1 with an HPLC purity of 99.45% (peak area) and 0.05% (peak area) impurity 1. An additional impurity was also observed at 0.50% (peak area); impurity 2, identified as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5-chloro-7-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea ( see Table E7 ), was likely formed from an exchange reaction of the chloride with a fluorine on the benzofuran ring under conditions of elevated chloride ion concentrations. In repeated runs of this procedure, high levels of impurity 1 (>1.0% peak area) were consistently obtained. Therefore, it was concluded that in order to control the level of impurities, the intermediate carbamate (VII) was best isolated and then condensed with VI in a separate reaction to produce compound 1. Example 18. Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate

To a mixture of 15.2 g NaHCO ₃ (3.0 eq) in 30 mL water and 120 mL THF at 0-5° C. was added 10 mL phenyl chloroformate (1.3 eq), followed by the slow addition of a solution of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (B-2; 20 g, 1.0 eq) in 20 mL water and 40 mL THF over 1 hour. HPLC analysis showed the reaction was complete after 21 hours (i.e., 0.1% B-2 remained). Water (50 mL) was added to completely dissolve the NaHCO ₃ and the batch was allowed to settle to cut the aqueous layer into waste. The organic layer was then washed with 100 mL of 5% aqueous NaHCO ₃ solution and then THF was replaced with heptane (100 mL), where (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII) crystallized out as a white solid. The crude product was filtered and washed with 30 mL of heptane. The wet cake was dried in a vacuum oven at 45-50° C. under nitrogen purging overnight to give 18.1 g (71%) of (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate as a white crystalline solid. The yield was later optimized to 80-90%, and the optimization procedure is shown in Example 13 . Example 19. Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate; Optimization procedure plan:

Using a 2 L jacketed flask with temperature control and nitrogen protection: 1. Add NaHCO ₃ (42.0 g, 3.0 eq). 2. Add H ₂ O (100 mL, 2.0 V). 3. Add THF (400 mL, 8.0 V). 4. Cool the contents to 0-5°C. 5. Add phenyl chloroformate (42 mL, 2.0 eq) at 0-5°C. 6. Slowly add a solution of 50.0 g (1.0 eq) (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (B-2) in water (50 mL, 1.0 V) and THF (100 mL, 2.0 V) at 0-5°C over 3 hours. 7. HPLC analysis shows 0.15% B-2 after 2 hours. 8. Settle and separate the layers. 9. Concentrate the organic layer to 150 mL (3 V) under reduced pressure at below 40°C. 10. Add heptane (300 mL, 6.0 V). 11. Concentrate to approximately 150 mL (3 V) under reduced pressure at below 40°C. 12. Cool the slurry to -10 °C and keep at -10 °C overnight (18 hours). 13. Filter and wash the filter cake with heptane (100 mL, 2 V). 14. Dry the wet filter cake in a vacuum oven at 40-45 °C under nitrogen purging for 18 hours. 15. The dry filter cake weighed 54.0 g (84.5% yield) of (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate as an off-white crystalline solid. Example 20. cGMP Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate

A solution of intermediate B-2 (1 eq) in tetrahydrofuran (2 vol) and water (1 vol) was added to a mixture of tetrahydrofuran (8 vol) and water (2 vol) containing sodium bicarbonate (2 eq) and phenyl chloroformate (3 eq) at -5 to 5°C. The reaction mixture was stirred for about 3 hours, after which the in-process control indicated <0.5% intermediate B-2 remained relative to intermediate VII. The lower aqueous layer was removed, and the organic layer was distilled under vacuum at less than 50°C to about 3 volumes. n-Heptane (6 vol) was added, and the mixture was stirred at 40-50°C for at least 30 minutes, after which the lower aqueous layer was removed. The organic layer was distilled at 35-50°C under vacuum to about 3 volumes and polish filtered. The solution was heated to 40-50°C, after which n-heptane (6 vol) was added, and the solution was distilled at 35-50°C under vacuum to about 5 volumes, after which IPC showed that residual tetrahydrofuran was ≤ 0.2% by GC. The mixture was cooled to -10 to 0°C over at least 2 hours, then stirred at -10 to 0°C for at least 18 hours. The batch was filtered, the filter cake was washed with n-heptane (4 vol) at -10 to 0°C, and dried to constant weight at 40-50°C under vacuum with a nitrogen purge. Intermediate VII was isolated in about 95% yield. Example 21. Alternative cGMP Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate

A solution of intermediate B-2 (1 eq) in tetrahydrofuran (1.8 wt eq) and water (1 wt eq) was added to a mixture of tetrahydrofuran (6.2 wt eq) and water (2 wt eq) containing sodium bicarbonate (2.2 mol eq) and phenyl chloroformate (2.0 mol eq) at 0-10°C. The reaction mixture was stirred for about 1 hour, after which the in-process control indicated <0.5 volume % of intermediate B-2 remained. The lower aqueous layer was removed, and the organic layer was distilled under vacuum at less than 50°C to about 3 volumes. n-Heptane (3.4 wt eq) was added, and the mixture was stirred at 40-50°C for at least 30 minutes, after which the lower aqueous layer was removed. The organic layer was distilled at 35-50°C under vacuum to about 3 volumes, after which n-heptane (3.4 wt eq) was added and the solution was distilled at 35-50°C under vacuum to about 3 volumes. n-heptane (1.4 wt eq) was added, and the solution was cooled to 35-40°C, after which intermediate VII seeds (0.5 mol eq) were added. The mixture was distilled to about 4 volumes, then cooled to -10 to 0°C over at least 3 hours. The batch was filtered and dried to constant weight at 40-50°C under vacuum with a nitrogen purge. Intermediate VII was isolated in about 80% yield. Example 22. Preparation of 1,3-bis((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Impurity 1)

A solution of (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII) in THF was treated with 5% _aqueous NaHCO3 to neutral pH and then kept in the refrigerator to give 31% 1,3-bis((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Impure 1) over the weekend and then 65% Impure 1 after another 3 days at room temperature. Since impurity 1 is insoluble in THF/heptane, while carbamate VII is soluble, impurity 1 was separated from a THF solution containing VII/impurity 1 (35%/65%) by crystallization in THF/heptane to obtain 1,3-bis((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (impurity 1) as a white crystalline solid. Example 23. Base screening for the preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1) from pyrimidine-2,5-diamine (VI) and carbamate VII

Pyrimidine-2,5-diamine (VI) is highly soluble in water, whereas (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII) has limited stability in aqueous media. Therefore, it is expected that the choice of base may have an impact on the efficiency of the desired urea formation relative to side reactions that produce impurity 1 or other possible impurities. Base screening was performed in a THF/water solvent system according to the following protocol: To a mixture of 80 mg (1.1 eq) pyrimidine-2,5-diamine (VI) and base (3.0 eq) in THF (2 mL) and water (2 mL) was added dropwise 250 mg (1.0 eq) (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII, in THF (2 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature and samples were taken at 1 hour, 4 hours and 20 hours for HPLC analysis. The results are summarized in Table E2 . Table E2. Effect of base on the relative percentage (peak area %) of compounds in the reaction mixture Alkali A-2% Compound 1% Impurities 2% VII% Impurities 1% NaHCO ₃ 4.88% (1 hour) 68.73% (1 hour) 0.21% (1 h) 20.97% (1 hour) 5.21% (1 hour) 7.79% (4 hours) 82.05% (4 hours) 0.26% (4 hours) 0.00% (4 h 9.17% (4 hours) 2.91% (20 hours) 84.77% (20 hours) 0.25% (20 h 0.00% (20 hours) 11.22% (20 hours) K ₂ CO ₃ 8.07% (1 hour) 87.21% (1 hour) 0.25% (1 h) 3.29% (1 hour) 1.18% (1 hour) 7.47% (4 hours) 88.53% (4 hours) 0.23% (4 h) 0.00% (4 hours) 2.17% (4 hours) 7.59% (20 hours) 85.57% (20 h) 0.17% (20 h) 0.00% (20 h 2.19% (20 hours) _{K3PO4 ​} 29.57% (1 hour) 69.94% (1 hour) 0.16% (1 h) 0.00% (1 hour) 0.34% (1 h) 27.23% (4 hours) 61.07% (4 hours) 0.21% (4 hours) 0.00% (4 hours) 0.42% (4 h 26.86% (20 hours) 58.37% (20 hours) 0.27% (20 h) 0.00% (20 hours) 0.51% (20 h) DIPEA 8.34% (1 h 79.28% (1 hour) 0.23% (1 h) 8.11% (1 h) 4.05% (1 h) 4.62% (4 hours) 87.11% (4 hours) 0.25% (4 h) 0.29% (4 h) 6.97% (4 hours) 2.61% (20 hours) 87.63% (20 h) 0.22% (20 h) 0.00% (20 hours) 7.90% (20 hours) TEA 15.19% (1 hour) 73.19% (1 hour) 0.22% (1 h) 0.64% (1 h) 10.24% (1 hour) 8.05% (4 hours) 76.95% (4 hours) 0.24% (4 h) 0.00% (4 hours) 13.84% (4 hours) 7.29% (20 hours) 76.65% (20 h) 0.19% (20 h) 0.00% (20 hours) 15.00% (20 hours)

As shown in Table E2 , for inorganic bases, the following trends were identified: the weaker the base (NaHCO ₃ ), the more impurity 1 (11.22% at 20 h), and the stronger the base (K ₃ PO ₄ ), the less impurity 1 (2.19% at 20 h). However, due to hydrolysis, the stronger the base, the more A-2 was obtained, for example 29.57% at 1 h. For organic bases, under the same conditions, DIPEA was superior to TEA. Example 24. Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1) from pyrimidine-2,5-diamine (VI) and carbamate VII in DMA

Pyrimidine-2,5-diamine was found to be highly soluble in N,N' -dimethylacetamide (DMA), and it was expected that the formation of impurity 1 would be reduced if the urea formation was run under anhydrous conditions. In practice, condensation of carbamate VII with pyrimidine-2,5-diamine (VI) in anhydrous DMA in the presence of DIPEA yields the desired compound 1 neat according to the following procedure: A mixture of (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII; 0.5 g, 1.0 eq), pyrimidine-2,5-diamine (VI; 0.15 g, 1.1 eq) and DIPEA (0.5 mL, 2.2 eq) in 5 mL (10 V) of anhydrous DMA was stirred under nitrogen at ambient temperature. HPLC analysis after 1 hour revealed 99.7% (peak area) pure compound 1, with 0.3% (peak area) impurity 2, and no detectable levels of impurity 1. The above reaction conditions were tested in the absence of DIPEA, and the reaction was found to be clean, but slower than observed in the presence of DIPEA. In detail, for the 5 g scale reaction, there was 72% conversion after 3 hours and 100% conversion after 18 hours at ambient temperature. Therefore, it was concluded that DIPEA catalysis was better. Example 25. Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1, Form 1 Hemihydrate) from Pyrimidine-2,5-diamine (VI) and Carbamate VII by Crystallization in DMA Protocol: 1. Feed pyrimidine-2,5-diamine (VI; 6.3 g, 1.1 eq) at room temperature under nitrogen. 2. Feed (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII; 20.0 g, 1.0 eq). 3. Feed anhydrous DMA (60 mL, 3 V). 4. Stir at 45-50 °C. 5. HPLC analysis shows completion after 3 hours. 6. Cool to room temperature. 7. Slowly add 200 mL (10 V) of water over 2 hours. 8. Stir the slurry for another 3 hours at room temperature. 9. Filter and wash the filter cake with 80 mL (4 V) of water. 10. Dry in a vacuum oven at 40 °C under nitrogen purging overnight (22 h). 11. The dried filter cake weighed 20.1 g (98.6% yield) of crude compound 1 as a white solid. 12. HPLC analysis revealed 99.11% (peak area) compound 1, with 0.39% (peak area) impurity 2, and 0.04% (peak area) impurity 1, plus two unknown impurities RRT 1.16 = 0.14% (peak area) and RRT 1.32 = 0.11% peak area). 13. Redissolve the crude API in isopropanol (80 mL, 5 V) at 50-60 °C. 14. Concentrate to 50 mL (2.5 V) at 40-60°C. 15. Cool to 20-30°C. 16. Slowly add 150 mL of water (7.5 V) over 2 hours. 17. Stir at 20-30°C for 3 hours. 18. Filter and wash the filter cake with water (80 mL, 4 V). 19. Dry in a vacuum oven at 40°C under nitrogen vent for 20 h to give 19.5 g (97% yield) of compound 1.

HPLC (peak area %) = 99.06% Compound 1, 0.38% Impurity 2, 0.05% Impurity 1, and 100.0% chiral purity; KF = 2.5% (w/w) water; and XRPD = Form 1. Figure 1 depicts an XRPD diffraction pattern of Compound 1 (Form 1 hemihydrate). Figure 2 depicts a TG/DSC thermogram of Form 1. Figure 3 depicts a DSC thermogram of Form 1 (first thermal cycle). Figure 4 depicts a DSC thermogram of Form 1 (first cooling cycle). Example 26. Synthesis of cGMP from 5-pyrimidine-2,5-diamine (VI) and (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (IV) to produce (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1, Form 1 Hemihydrate) Note: Stoichiometric and operating parameters are approximate. All solvent charges are by weight and +/- 10% Overview of Synthetic Procedures Procedure 1. Preparation of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine hydrochloride

(S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (IV) was treated with a solution of hydrogen chloride in ethyl acetate (approximately 1 mol, 5 wt eq) at 5-15°C for at least 1 hour until IPC indicated <1 volume % IV remained relative to the title compound. n -Heptane (10 wt eq) was added and the mixture was cooled to -15 to -5°C and held for at least 24 hours to complete crystallization. The batch was filtered and the filter cake was washed with n -heptane (2 x 1.4 wt eq). The filter cake was dried at 40-50°C under vacuum with a nitrogen purge for at least 16 hours until constant weight. (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl-1-amine hydrochloride (B-2) was isolated in about 80% yield. Step 2. Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamic acid phenyl ester

A solution of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (B-2; 1 eq) in THF (1.8 wt eq) and water (1 wt eq) was added to a mixture of THF (6.2 wt eq) and water (2 wt eq) containing sodium bicarbonate (2.2 mol eq) and phenyl chloroformate (2.0 mol eq) at 0-10°C. The reaction mixture was stirred for about 1 hour until HPLC monitoring indicated <0.5 volume % starting material remained. The lower aqueous layer was removed, and the organic layer was distilled under vacuum at less than 50°C to about 3 volumes. n -Heptane (3.4 wt eq) was added and the mixture was stirred at 40-50°C for at least 30 minutes before removing the lower aqueous layer. The organic layer was distilled at 35-50°C under vacuum to approximately 3 volumes before adding n -heptane (3.4 wt eq) and distilling the solution at 35-50°C under vacuum to approximately 3 volumes. n -Heptane (1.4 wt eq) was added and the solution was cooled to 35-40°C before adding seeds of Intermediate VII (0.5 mol eq). The mixture was distilled to approximately 4 volumes before cooling to -10 to 0°C over at least 3 hours. The batch was filtered and dried to constant weight at 40-50°C under vacuum with a nitrogen purge. The title compound was isolated in approximately 80% yield. Step 3. Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

A mixture of (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII; 1 eq) and pyrimidine-2,5-diamine (VI; 1.1 eq) in DMAc (2.8 wt eq) was heated at 35-45°C for approximately 6 hours until HPLC monitoring indicated VII <0.5 area %. The batch was cooled to 15-25°C and purified water (12 wt eq) was added slowly. The batch was stirred for approximately 6 hours before being filtered and washed twice with water (2 wt eq and 5 wt eq). The product was dried under vacuum at 35-45°C to constant weight. Step 4. Preparation of Compound 1 Alkali Hemihydrate Form 1

The intermediate product of step 3 was dissolved in methanol (6.3 wt eq) at 20-30°C and then filtered through a 0.2 micron filter followed by a reactor rinse (1.6 wt eq). The batch was cooled to 15-25°C and then purified water (0.5 wt eq) was added through a 0.2 micron filter followed by the addition of Compound 1 (free base hemihydrate Form 1) seeds (0.01 wt eq). The mixture was stirred at 15-25°C for about 3 hours and then purified water (4.5 wt eq) was added through a 0.2 micron filter over a period of about 8 hours. The batch was then stirred at 15-25°C for about 16 hours to achieve complete crystallization. The batch was filtered and washed with a premixed solution of methanol (1.1 wt eq) and purified water (0.7 wt eq) through a 0.2 micron filter. The product was dried at 35-45°C under vacuum with a nitrogen sweep for at least 24 hours until constant weight and KF indicated a water content of 2.0-2.6 wt %. Compound 1 (basic hemihydrate Form 1) was discharged into a double bag LDPE liner bag in a HDPE drum. The expected yield is approximately 90%. cGMP Protocol Step 1. Preparation of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine hydrochloride

(S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (IV, from Example 8 ; 16.00 kg, 1.0 eq) was converted to (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (B-2) using 1 M HCl in EtOAc. First, the deprotection reaction was carried out overnight (i.e., 11 hours) at 5-10° C. using 2.1 eq HCl (1 M in EtOAc, 97.18 kg) to reach completion, at which stage the desired salt crystallized from the solution. Heptane (164.06 kg) was added slowly over 3 hours as a counter solvent to maximize the yield. The resulting slurry was stirred at 5-10° C. over the weekend. The product was filtered using a filter dryer and the filter cake was washed with heptane (44.66 kg). The dried wet filter cake was placed under vacuum with nitrogen purging and intermittent agitation at 50 °C jacket temperature for 24 hours to give 11.51 kg (83.2%) of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride with UPLC purity of 99.7% (peak area), analytical of 94.5% (w/w) and HPLC chiral purity of 99.4% (peak area). Equipment Reactor 1 (R1): 400 L, glass, 23 V, temperature range: -15 - 15 °C, pressure range: full vacuum to atmosphere Receiver (V1): glass lined or Hoechst alloy; filter dryer (D1): maximum temperature: 50 °C, pressure range: full vacuum to atmosphere Protocol: 1. Prepare R1 by feeding nitrogen and evacuating and repeating as needed to maintain under nitrogen during the process. 2. Feed 97.18 kg of 1.0 M HCl solution in EtOAc (feed range: 94.31 - 100.04 kg) into R1. 3. Turn on agitation and cool the contents of R1 to 8 °C. 4. 12.86 kg was fed to R1 (feed range 12.77 - 13.03 kg). 5. 3.10 kg (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (IV) was fed (feed range 3.07 - 3.13 kg). 6. The contents of R1 were kept at 5-10°C overnight for about 11 h. 7. The mixture was sampled from R1 to test for reaction conversion. The results passed the criteria (no SM detected). 8. 164.06 kg of heptane was fed slowly to R1 over 3 h 11 min while maintaining the temperature of R1 at 5-7°C. 9. Slowly cool the contents of R1 from 7°C to -11°C over 6 hours. 10. Keep the contents of R1 at -11 to -10°C for 2 days 7 h 28 min. 11. Filter the contents of R1 through filter D1 and send the filtrate to V1. Set the jacket of the filter dryer to 0°C. 12. Drain the filtrate from V1 and weigh 184.20 kg. 13. Feed 22.26 kg of heptane into R1 to rinse the reactor walls and impeller blades, and then transfer the contents to wash the wet filter cake in the filter dryer, and send the filtrate to the receiver. 14. Feed 22.40 kg of heptane into R1 to rinse the reactor walls and impeller blades, and then transfer the contents to wash the wet filter cake in the filter-dryer and send the filtrate to the receiver. 15. Drain the contents of V1 into a closed top HDPE drum. Net weight: 49.60 kg. 16. Keep the material in the filter-dryer overnight for 17 h 10 min with a jacket temperature of 50 °C and an internal temperature of about 27 °C. 17. Continue drying with agitation turned on in the filter, and intermittent drying for another 23 h 50 min. 18. Sample the material from the filter-dryer. The results passed the criteria ( see Table E3 ). 19. Bulk packaging material for the next production step. Net weight of packaging: 11.26 kg. Table E3. Analytical results of cGMP batch of intermediate B-2 Test/Standard B-2 cGMP Batch Results HPLC purity ≥ 99.0% (a/a) 99.7% (a/a) HPLC analysis: 90.0- 100.0% (w/w) 94.5% (w/w) Residual solvents detected by GC: Heptane ≤ 5000 ppm Ethyl acetate ≤ 5000 ppm Heptane: 4236 ppm Ethyl acetate: < LOQ (100 ppm) Residual impurities found by GC5: Reported results (ppm) 7022 ppm Visual appearance: white to yellow solid White solid Chiral purity measured by HPLC ≥ 99.0% (a/a) 99.4% (a/a) Step 3. Preparation of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate

(R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan- _1- amine hydrochloride (B-2; 11.24 kg, 1.0 eq) was converted into (R)-phenyl(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII) using phenylchloroformate (17.72 kg) in the presence of THF (90.24 kg) and water (33.80 kg) containing NaHCO 3 (8.62 kg). After the reaction was completed, the reaction mixture was allowed to settle and the layers were separated. THF was exchanged for heptane by vacuum distillation at less than 50°C. The resulting slurry in heptane (45 L, 4 V) was cooled to 0°C and stirred at 0°C for about 10 hours. The product was filtered in a filter dryer and the filter cake was washed with the cold mother liquor. The wet filter cake was dried under vacuum with nitrogen purge and intermittent stirring at 50°C jacket temperature until KF ≤ 0.5% (w/w). The dry filter cake was 13.10 kg (80.6%) VII with a UPLC purity of 98.2% (peak area) and an assay of 83.5% (w/w). Equipment Reactor 1 (R1): Hoechst alloy, 16 V, temperature range: -10 - 50 °C, pressure range: full vacuum to atmosphere Reactor 2 (R2): Glass, 3 V, temperature range: 20 - 30 °C, pressure range: full vacuum to atmosphere Receiver (V1): Hoechst alloy; as required Receiver (V2): Glass lined; as required Filter Dryer (D1): Maximum temperature: 50 °C, pressure range: full vacuum to atmosphere Protocol: 1. Prepare R1 and R2, as well as V1 and V2 and D1 by feeding nitrogen and evacuating and repeating as required to maintain under nitrogen during the process. 2. Add 11.24 kg of (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine hydrochloride (B-2) to R2, followed by 11.30 kg of purified water and then 20.04 kg of THF. 3. Add 8.62 kg of sodium bicarbonate (target range: 8.35 - 8.87 kg) to R1. 4. Add 22.50 kg of purified water (target range: 21.39 - 23.65 kg) to R1. 5. Add 70.2 kg of THF (target range: 66.55 - 73.53 kg) to R1 and start stirring. 6. Cool the contents of R1 from 20°C to 3°C. 7. Slowly feed 11.72 kg of phenyl chloroformate over 19 min while maintaining the temperature at 1-3°C. 8. Slowly transfer the solution of B-2 from R2 to R1 over 3 h 5 min while maintaining the temperature of R1 at 1-2°C. 9. Feed 10.0 kg of THF into R2 to rinse the reactants. Slowly transfer the rinse from R2 to R1 while maintaining the temperature at 1-2°C. 10. Stir the contents of R1 for 1 hour and 25 min. 11. Sample the mixture from R1 to test the reaction conversion. The result does not meet the standard: 47.4% (peak area). 12. Carefully feed 3.00 kg of phenyl chloroformate into R1 while maintaining the temperature at 3-6°C and keeping the contents of R1 at 4-6°C for 1 hour with constant agitation. 13. Sample the mixture from R1 to test the reaction conversion. The result does not meet the criteria: 5.89% (peak area). 14. Carefully feed 3.00 kg of phenyl chloroformate into R1 while maintaining the temperature at 4°C and keeping the contents of R1 at 4°C for 12 h 10 min with constant agitation. 15. Sample the mixture from R1 to test the reaction conversion. The result passes the criteria: 0.05% (peak area). 16. Stop agitation in R1 for 30 min and allow the phases to separate. Transfer the bottom aqueous layer to V1 and drain the contents of V1 into a drum. Net weight of the aqueous layer: 39.0 kg. 17. Concentrate the contents of R1 while maintaining the temperature < 50°C, with a target final volume of approximately 34 L. Collect a total of 68.6 kg of distillate. 18. Feed 38.6 kg of heptane into R1 and adjust the temperature to 48°C. 19. Stir the contents of R1 for 15 min, then stop stirring and hold for 30 min to allow the phases to separate. 20. Transfer the bottom aqueous layer to V1 and drain the contents of V1 into a drum. Net weight of the aqueous layer: 3.8 kg. 21. Concentrate the contents of R1 while maintaining the temperature < 50°C, targeting a final volume of approximately 34 L. Collect a total of 34.4 kg of distillate. 22. Feed 38.6 kg of heptane to R1. 23. Concentrate the contents of R1 while maintaining the temperature < 50°C, targeting a final volume of approximately 56 L. Collect a total of 19.6 kg of distillate. 24. Adjust the temperature of R1 from 46°C to 40°C. 25. Sample the mixture from R1 to test for residual THF. The results pass the criteria. 26. The certified solution in R1 was clear, then 56.5 g of VII seeds were fed to R1. After the seed feed, the seeds were observed to continue to be present in the solution. 27. Agitate the contents of R1 at 38°C for 2 hours. 28. Concentrate the contents of R1 while maintaining the temperature at 25-40°C, targeting a final volume of approximately 45 L. Collect a total of 8.0 kg of distillate. 29. Adjust the temperature of R1 from 28°C to 37°C. 30. Adjust the temperature of R1 to 25°C. 31. Slowly feed 19.28 kg of heptane into R1 over 2 hours at ambient temperature. 32. Slowly cool the contents of R1 from 20°C to 0°C over 9 hours 41 min with constant agitation. 33. Filter the contents of R1 through D1 and send the filtrate to V1. Set the jacket of the filter-dryer to -10-0°C. 34. Use the filtrate to rinse R1 and V2, transfer it to wash the wet filter cake in D1. 35. Collect all the filtrate in a HDPE drum. Net weight: 28. kg 36. Keep the material in the filter-dryer with a jacket temperature of 50°C for 3 days 16 h 18 min. 37. Sample the material from the filter-dryer to test the moisture content. The result does not meet the standard: 0.6% w/w 38. Keep the product in D1 for about another 17 h. Sample the material from the filter-dryer to test the moisture content. Results passed criteria: 0.5% w/w. 39. Material was sampled from the filter dryer for purity and analysis. Results did not meet criteria ( see Table E4 ). Approved to proceed. 40. 13.05 kg of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate (VII) was packaged. Total yield: 13.10 kg before sampling. Table E4. Analytical results for cGMP batches of intermediate VII Test/Standard VII cGMP Batch Results Water content measured by KF ≤ 0.5% (w/w) 0.5% (w/w), by Appearance: Report Results Off-white solid Purity measured by UPLC ≥ 99.0% (a/a) 98.2% (a/a), unqualified UPLC ≥ 90.0% (w/w) 83.5% (w/w), unqualified Step 4-5. Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1), Hemihydrate Form 1

Compound 1 (hemihydrate Form 1) was prepared from phenyl (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (VII; 13.02 kg) and pyrimidine-2,5-diamine (VI; 4.06 kg, from the combined VI-B1 and VI-B1 batches of Example 4 ) at 40°C in DMA. First, a mixture of VII (13.02 kg) and VI (4.06 kg) in DMA (36.46 kg) was stirred at 40°C overnight (i.e., 12 hours and 36 minutes) to completion. The reaction mixture was cooled to 20°C, and then water (156.6 kg) was slowly added to crystallize the product from solution. The solid was filtered in a filter dryer with an agitator and the filter cake was washed with water. The wet filter cake was dried under vacuum under nitrogen purging and stirred intermittently at a jacket temperature of up to 65° C. for 18 hours to obtain 13.16 kg of crude compound 1 containing 13.5% (w/w) water. Next, crude compound 1 was dissolved in MeOH (74.2 kg) and then polish filtered using an in-line cartridge filter, using another 18.6 kg of MeOH as a rinse. To this MeOH solution was added 4.41 kg of water and then 115.9 g of compound 1 (hemihydrate form 1) seeds. The resulting mixture was stirred at 20° C. for 3 hours and water (53.32 kg) was added slowly over 8 hours to maximize the yield. After stirring at 20° C. overnight (17 hours), the solid was filtered in a filter dryer and the filter cake was washed with 20.4 kg of premixed MeOH:water (2:1). The wet filter cake was dried under vacuum under nitrogen purging and stirred intermittently at 40° C. jacket temperature for 45 hours to give 10.87 kg of compound 1 with a UPLC purity of 99.9% (peak area), an analytical of 100.4% (w/w) and an HPLC chiral purity of 100.0 (peak area or ee). Equipment Reactor 1 (R1): Hoechst alloy, 14 V, Temperature range: 15 - 45 °C, Pressure range: full vacuum to atmospheric pressure Reactor 1 (R2): Glass lining; as needed Receiver (V1): Hoechst alloy; as needed Filter dryer (D1): Maximum temperature: 50 °C, Pressure range: full vacuum to atmospheric pressure Protocol: 1. Feed 13.02 kg of (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate (VII) to R1. 2. Feed 4.06 kg of pyrimidine-2,5-diamine (VI) to R1. 3. Feed 36.46 kg of N,N-dimethylacetamide to R1. 4. Turn on agitation and adjust the temperature of R1 to 40°C. 5. Keep the contents of R1 at about 40°C overnight for 12 h 36 min under constant agitation. 6. Take a sample of the mixture from R1 to test the reaction conversion. The result passes the standard. 7. Cool the contents of R1 from 40°C to 19°C. 8. Slowly feed 156.6 kg of water into R1 over 3 hours, then keep at 19-20°C for 6 hours 5 min under constant agitation. 9. Transfer the contents of R1 to D1 to filter the contents, and send the filtrate to V1. 10. Rinse R1 with 26.4 kg water and transfer the rinse to wash the wet filter cake in D1. 11. Clean R1 with methanol (14.0 kg) as needed and transfer to waste. 12. Feed 67.2 kg water directly into D1 and slurry in D1 for 1 hour with agitation. Then filter the contents and send the filtrate to V1. 13. Keep the product in the filter dryer under vacuum with the jacket temperature set to 40-60°C with intermittent agitation for 11 hours 22 minutes 14. Feed 68.4 kg water directly into D1 and slurry the filter cake for 1 hour. The contents of D1 were then filtered and the filtrate sent to V1. 15. 62.4 kg of water were fed directly into D1 and the filter cake was slurried for 1 hour. The contents of D1 were then filtered and the filtrate sent to V1. 16. The product was kept in a filter-dryer under vacuum with the jacket temperature set to 40-65°C with intermittent agitation for 17 hours and 52 minutes. 17. The material was sampled from the filter-dryer to test the moisture content. The result did not meet the standard. Result: 15.3% w/w. 18. The product was kept in a filter-dryer under vacuum for 50 minutes with the jacket temperature set to approximately 65°C with intermittent agitation. 19. Sample the material from the filter dryer to test for moisture content. The result is not within the specification. Result: 13.5% w/w. 20. Transfer the filter cake of D1 to a clean tared container. Net weight: 13.16 kg. 21. Based on the analytical correction amount of Compound 1, establish a new unit value of Y = 11.67 kg. 22. Feed the encapsulated 13.11 kg of Compound 1 into R1. 23. Feed 74.2 kg of methanol into R1. 24. Turn on agitation and adjust the temperature to 22°C. Keep the contents at 22-24°C for approximately 1 h. 25. Visually confirm that the contents of R1 are completely dissolved and then proceed. 26. Polish filter by transferring the contents of R1 to R2 under vacuum through an in-line cartridge filter. 27. Rinse R1 with 18.6 kg of methanol and transfer the rinse to R1 through an in-line cartridge filter. 28. Clean R1 with methanol as needed. 29. Methanol-water premix in R1: Feed 12.4 kg of methanol into R1 through an in-line cartridge filter. Then feed 8.0 kg of water into R1 through an in-line cartridge filter. 30. Agitate the contents of R1 for 23 min at 21-24°C. 31. Turn on agitation in R2. 32. Feed 4.41 kg of water into R2 through an in-line cartridge filter. 33. Feed 115.9 g of Compound 1 (hemihydrate Form 1) seed into R2. 34. Agitate R2 at 20-21°C for 3 hours. 35. Slowly feed 53.32 kg of water through a cartridge filter over 8 hours. 36. Keep the contents of R2 at 17-21°C for about 17 hours with constant agitation. 37. Transfer the contents of R2 to D1 to filter the contents. 38. Transfer the contents of R1 (MeOH:water 2:1 solution) to rinse R2 and transfer the rinse to the slurry-washed filter cake in D1. 39. Keep the product in a filter dryer with a jacket temperature of 40°C for 1 day and 20 h 36 min with intermittent agitation. 40. Take samples of the material from the filter dryer to test for moisture content and residual solvents. The results pass the standards. 41. Take samples of the material from the filter dryer to test for purity and analysis. The results pass the standards ( see Table E5 ). 42. Pack the bulk material from the filter dryer in a tared clean container (HDPE drum lined with double bag PE continuous liner). Pull samples from the bulk packaged material as needed for release testing. Net weight of packaged product: 10.58 kg. New weight before sampling: 10.87 kg. Table E5. Analytical results of cGMP batches of Compound 1 (Form 1) Test/Standard cGMP Batch Results Water content in hemihydrate form 1, 2.0% ≤ KF ≤ 2.6% (w/w) 2.2% (w/w) Residual solvents found by GC: MeOH ≤ 3000 ppm, DMA ≤ 1090 ppm MeOH: 1633 ppm DMA: < LOQ (100 ppm) Purity of hemihydrate form 1 ≥ 98.0% (a/a), UPLC 99.9% (a/a) Analysis report results of hemihydrate form 1, UPLC 100.4% (w/w) Example 27. Alternative Procedure for the Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1, Form 1 Hemihydrate)

The intermediate product (2.5 g) was dissolved in 20 mL (8 vol.) 2-propanol at 50°C in a 100 mL temperature controlled reactor. Once dissolved, the mixture was cooled to 40°C at 1°C/min. At 40°C, 80 mL (32 vol.) of water was added to the mixture at 5 mL/h (2 vol./hour). After the antisolvent addition was complete, the mixture was cooled to 5°C at 0.2°C/min. The mixture was temperature cycled between 5°C and 40°C with the temperature ramped at 0.1°C/min and held for 1 hour between steps for 1 cycle before returning to 5°C. After approximately 11 h at 5°C, the separation was performed by Buchner filtration and analyzed by XRPD. The isolated solid was dried under vacuum at 40 °C for about 18 h, followed by drying under vacuum at ambient temperature for an additional 65 h. Example 28. Alternative cGMP Procedure for the Preparation of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1, Form 1 Hemihydrate)

A solution of intermediate VII (1 eq) in dimethylacetamide (3 vol) was added to a slurry of 5-aminopyrimidin-2-amine (1.1 eq) in dimethylacetamide (2 vol) at 15-30°C over approximately 1 hour. The reaction mixture was stirred for at least 4 hours, after which the in-process control indicated that ≤ 0.5% intermediate VII remained relative to compound 1 (hemihydrate form 1). Then, water (24 vol) was fed to the batch over 2 hours. The slurry was stirred at 15-30°C for at least 6 hours and filtered. The filter cake was washed with water (6 vol) and dried at 40-50°C under vacuum with a nitrogen purge for at least 24 hours until constant weight. The batch was dissolved in methanol (8 vol) at 15-30°C and polish filtered through a cartridge containing activated carbon. The resulting solution was fed with water (0.6 vol) and seeded with compound 1 (free base hemihydrate form 1) (0.005 wt eq). Water (5 vol) was added over 12 hours, and the resulting slurry was stirred for at least 16 hours, followed by filtration. The filter cake was washed with water (6 vol) and dried at 40-50°C under vacuum with a nitrogen purge for at least 24 hours until constant weight to afford STX-478 free base hemihydrate form 1 in 85% yield. Example 29. General Properties of (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1, Form 1 Hemihydrate)

Figure 1 depicts an XRPD diffraction pattern of Compound 1 (Form 1 hemihydrate). Figure 2 depicts a TG/DSC thermogram of Form 1. Figure 3 depicts a DSC thermogram of Form 1 (first thermal cycle). Figure 4 depicts a DSC thermogram of Form 1 (first cooling cycle).

Other properties of Compound 1 (free base hemihydrate form 1) are presented in Table E6 . Table E6. General properties of Compound 1 (free base hemihydrate form 1) characteristic describe Physical condition Crystalline solid Optical activity Single mirror image isomer, ( R )-configuration Melting range Onset at 178.6℃; peak at 180.5℃ (endothermic at 123℃ and 166℃ (dehydration and possible form change) Hygroscopicity Non-hygroscopic Organic solubility (mg/mL) 4:1 Acetonitrile-Water >1 Methanol 200 Ethanol 90 Isopropanol 70 Acetone 130 MTBE 9 Heptane <10 Dichloromethane <10 Dimethylacetamide >500 Water solubility (μg/mL) 0.1N HCl (pH 2) 29 25 mM NaOAc (pH 4) 7 PBS/Blank FaSSIF (pH 6.5) 5 Water 8 pKa 2.6 Log P 3.5 Log D _7.4 3.6 Permeability, Papp (AB), Caco-2 13 (10 ^-6 cm/s) Table E7. Identified and Potential Impurities in Compound 1 (Form 1 Hemihydrate) Impurities Structure Path A* Path B* Impurities 1 1.38% Not detected Impurities 2 0.58% 0.11% Impurities 3 Not detected Not detected Intermediate VI - ＜LOQ** Impurities 4 - Not detected Intermediate V - Not detected Intermediate IV Not detected Not detected A-2 Not detected Not detected Intermediate VII Not detected Not detected Impurities 5 - N/A Impurities 6 - ＜LOQ *Peak area%; **LOQ=Level of quantification

Figure 1 depicts an XRPD diffraction pattern of Compound 1 (Form 1 hemihydrate). Figure 2 depicts a TG/DSC thermogram of Form 1. Figure 3 depicts a DSC thermogram of Form 1 (first thermal cycle). Figure 4 depicts a DSC thermogram of Form 1 (first cooling cycle).

Claims (26)

A method for preparing a compound of formula (I): (I), or its salt and/or solvent complex; The method comprises making the compound of formula (Ii): (Ii) contacting (i) a carbonyl equivalent; and (ii) a compound of formula (I-ii) (I-ii); to form the compound of formula (I), wherein: Z is O or NR ^x ; R ^x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R ¹ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R ² is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluorine groups; R ³ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, a C3-C8 cycloalkyl group, a 5-10 membered heteroaryl group or a 4-10 membered heterocyclo group; each R ⁴ is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or -NR ^A R ^B , (iii) C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl groups and C3-C6 cycloalkyl groups, (iv) C1-C6 halogen alkyl group, (v) hydroxyl group, (vi) cyano group, (vii) -CO ₂ H, (viii) -NR ^A R ^B , (ix) =NR ^A2 , (x) -C(=O)NR ^C R ^D , (xi) -SO ₂ (NR ^E R ^F ), (xii) _-SO2 (C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) _-CO2 (C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclic group optionally substituted with 1 or 2 independently selected ^RG , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected ^RG ; n is 0, 1 or 2; each of ^RA , ^RA1 , ^RB , ^RB1 , ^RC , ^RC1 , RD, ^{RD1 , RE and RF} is independently (i) hydrogen, (ii) hydroxy, (iii) (iv) C1-C6 halogen alkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) _-SO2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of hydroxy, -C(=O)NR ^B2 R ^C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, _-SO2 (C1-C6 alkyl), _-CO2H and _-SO2 ( _NH2 ); or R ^C and R ^D together with the nitrogen atom to which it is attached forms a 4-10 membered heterocyclic group which is optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, halogen, -C(=O)NR ^B1 R ^C1 , -SO ₂ (C1-C6 alkyl), -CO ₂ H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 halogen alkoxy; each R ^A2 , R ^B2 and R ^C2 is independently hydrogen or C1-C6 alkyl; and each ^RG is 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 , -CO ₂ (C1-C6 alkyl), C1-C6 halogenalkyl, C3-C6 cycloalkyl, C1-C6 halogenalkoxy, -SO ₂ (C1-C6 alkyl) and -CO ₂ H. A method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1. The method of claim 2, wherein the method comprises: Contact with acid to form To prepare . The method of claim 3, wherein the method comprises: Contact with a trifluoromethylating agent to form To prepare ; wherein R'' is a C1-C6 alkyl group. The method of claim 3 or 4, wherein the method comprises: and Contact to prepare . The method of claim 5, wherein the method comprises: Prepared by contact with acid . The method of claim 6, wherein the method comprises: and Contact to prepare ; wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl. The method of claim 5, wherein the method comprises: Prepared by contact wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl. The method of claim 8, wherein the method comprises: and Contact to prepare . A method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: Reaction to form compound 1. The method of claim 10, wherein Reaction to form compound 1 comprises and Contact to form ; wherein R'' is a C1-C6 alkyl group. The method of claim 11, wherein Reaction to form compound 1 comprises Contact with a trifluoromethylating agent to form ; wherein R'' is a C1-C6 alkyl group. The method of claim 12, wherein Reaction to form compound 1 comprises Contact with acid to form . The method of claim 10, wherein Reaction to form compound 1 comprises and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1. A method for preparing compound 1 having the following structure: (1), or a salt and/or solvent thereof; the method comprises: and Contact to form , wherein R'' is a C1-C6 alkyl group; and Reaction to form compound 1. The method of claim 15, wherein Reaction to form compound 1 comprises reacting Contact with a trifluoromethylating agent to form To prepare ; wherein R'' is a C1-C6 alkyl group. A method as claimed in any one of claims 15 to 16, wherein Reaction to form compound 1 comprises reacting Contact with acid to form To prepare . A method as claimed in any one of claims 15 to 17, wherein Reaction to form compound 1 comprises and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1. A method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein R'' is a C1-C6 alkyl group; (b) Contact with a trifluoromethylating agent to form (c) make Contact with HCl to form ; and (d) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1. A method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein LG is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) a carbonyl equivalent; and (ii) having the structure to form compound 1. A method for preparing compound 1 having the following structure: (1), or its salt and/or solvent combination; The method comprises: (a) and Contact to form , wherein Hal is selected from chlorine, bromine, iodine and trifluoromethanesulfonyl; (b) Contact with acid to form (c) make and Contact to form , wherein R'' is a C1-C6 alkyl group; (d) Contact with a trifluoromethylating agent to form (e) make Contact with HCl to form ; and (f) cause and (i) R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl or C1-6 alkoxy groups; and (ii) having the structure to form compound 1. A method as claimed in any one of claims 1 to 21, wherein the carbonyl equivalent is R'OC(O)Cl, wherein R' is selected from C1-C6 alkyl and C6-C10 aryl substituted with 1-3 independently selected C1-6 alkyl, nitro or C1-6 alkoxy groups. The method of 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-dioxopyrrolidin-1-yl) carbonate, 1,1'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, chlorocarbonic acid, and 1-methylvinyl ester. The method of any one of claims 1 to 23, wherein the carbonyl equivalent is phenyl chloroformate. The method of any one of claims 3 to 24, wherein the acid is HCl. The method of any one of claims 4 to 25, wherein the trifluoromethylation reagent is TMSCF ₃ .