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WO2025038699A1 - Procédés de préparation d'inhibiteurs de pi3k - Google Patents

Procédés de préparation d'inhibiteurs de pi3k Download PDF

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WO2025038699A1
WO2025038699A1 PCT/US2024/042223 US2024042223W WO2025038699A1 WO 2025038699 A1 WO2025038699 A1 WO 2025038699A1 US 2024042223 W US2024042223 W US 2024042223W WO 2025038699 A1 WO2025038699 A1 WO 2025038699A1
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compound
alkyl
mixture
formula
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WO2025038699A9 (fr
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David ST. JEAN, Jr.
Andrew David Jones
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Scorpion Therapeutics Inc
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Scorpion Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This disclosure provides processes of preparing compounds of Formula (I), such as (R)-l- (2-aminopyrimidin-5-yl)-3-(l-(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 (PI3Ka).
  • PI3K phosphatidylinositol 4, 5 -bisphosphate 3-kinase
  • PI3K/AKT signaling Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka)
  • Some embodiments provide a process of preparing a compound of Formula (I): salt and/or solvate thereof; comprising contacting a compound of Formula (I-i): with
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with
  • Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R 4 is independently selected from the group consisting of:
  • (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C( O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), -CChH, and -SO 2 (NH 2 ); or
  • Some embodiments provide a process of preparing Compound 1, having the structure:
  • Some embodiments provide a process of preparing Compound 1, having the structure:
  • Some embodiments provide a process of preparing Compound 1, having the structure: comprising contacting form wherein R” is C1-C6 alkyl; and reacting
  • Some embodiments provide a process of preparing Compound 1, having the structure: salt and/or solvate thereof; comprising:
  • Some embodiments provide a process of preparing Compound 1, having the structure:
  • LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl
  • R is C1-C6 alkyl; carbonyl equivalent; and (ii) pyrimidine-2,5- diamine having the structure ; to form Compound 1.
  • Some embodiments provide a process of preparing Compound 1, having the structure: wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; (b) contacting
  • R is C1-C6 alkyl
  • API refers to an active pharmaceutical ingredient.
  • pharmaceutically acceptable excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, 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.
  • 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.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having 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 a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: 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.
  • 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, tart
  • solvate refers to a solvate 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 solvate is a crystalline solid that contains molecules of solvent inside its crystal lattice. Solvate forms of a compound can, in some instances, favorably alter the properties of the compound, such as solubility, stability, dissolution rate, and mechanical behavior.
  • An exemplary solvate is a hydrate, which is a water solvate.
  • each repeating unit i.e., unit cell
  • the hydrate is affixed with a prefix denoting the average number of water molecules in each unit cell.
  • a monohydrate contains an average of one water molecule per unit cell
  • a dihydrate contains an average of two water molecules per unit cell
  • a hemihydrate contains an average of half of a water molecule per unit cell.
  • carbonyl equivalent refers to a reagent that, when contacted with an amino group, reacts to form, e.g., a substrate of nucleophilic acyl substitution that can further react with a nucleophile such as an amine to form a urea.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkyl, nitro, or Cl-6 alkoxy.
  • 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-l-yl) carbonate, l,l'-carbonyl diimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methylethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • isocyanate-forming reagent refers to a reagent that, when contacted with an amino group, reacts to form an isocyanate.
  • the isocyanate can further react with an amine to form a urea.
  • the isocyanate-forming reagent is selected from the group consisting of: phosgene (toluene solution), tri chloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2- trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methylethenyl ester.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • cyano refers to a -CN radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, Zc/7-butyl, w-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 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 by a substituent.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated hydrocarbon groups having, e.g., 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 optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l. l.l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.E l]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 also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls 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.
  • saturated as used in this context means only single bonds present between constituent carbon atoms.
  • heteroaryl means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 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 does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazoliny
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms 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 by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxid
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[ 1.1.1 ]pentane, 3 -azabicyclo[3.
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms
  • 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
  • FIG. 1 depicts a XRPD diffractogram of Compound 1, Form 1 hemi hydrate.
  • FIG. 2 depicts a TG/DSC thermogram of Form 1.
  • FIG. 3 depicts a DSC thermogram (first heat cycle) of Form 1.
  • FIG. 4 depicts a DSC thermogram (first cool cycle) of Form 1.
  • This disclosure provides processes of preparing compounds of Formula (I), such as (R)-l- (2-aminopyrimidin-5-yl)-3-(l-(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 (PI3Ka).
  • PI3K phosphatidylinositol 4, 5 -bisphosphate 3-kinase
  • Some embodiments provide a process of preparing a compound of Formula (I): salt and/or solvate thereof; comprising contacting a compound of Formula (I-i): (i) a carbonyl equivalent or an isocyanate-forming reagent; and
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro 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 heterocyclyl; each R 4 is independently selected from the group consisting of:
  • (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C( O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO 2 (NH2); or
  • Some embodiments provide a process of preparing a compound of Formula (I): salt and/or solvate thereof; comprising contacting a compound of Formula (I-i): with
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with
  • Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R 4 is independently selected from the group consisting of:
  • (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C( O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), -CChH, and -SO 2 (NH 2 ); or
  • the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl, nitro, or Cl -6 alkoxy.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent.
  • the isocyanate-forming reagent is selected from the group consisting of: phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroform ate, phenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2- tri fluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methyl ethenyl ester.
  • Some embodiments provide a compound of Formula (I): salt and/or solvate thereof prepared by a process comprising: contacting a compound of Formula (I-i): with
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro 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 heterocyclyl; each R 4 is independently selected from the group consisting of:
  • the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl, nitro, or Cl -6 alkoxy.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carb onochlori die acid, and 1 -methylethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2- trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methylethenyl ester.
  • Some embodiments provide a compound of Formula (I): salt and/or solvate thereof prepared by a process comprising: contacting a compound of Formula (I-i):
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro 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 heterocyclyl; each R 4 is independently selected from the group consisting of:
  • cycloalkyl optionally substituted with 1 or 2 independently selected R G ; n is 0, 1, or 2; each R A , R A1 , R B , R B1 , R c , R C1 , R D , R D1 , R E , and R F is independently
  • (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C( O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or
  • Some embodiments provide a process of preparing a compound of Formula (I): salt and/or solvate thereof comprising contacting a compound of Formula (I-i): with
  • 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, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with
  • Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R 4 is independently selected from the group consisting of:
  • (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C( O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), -CChH, and -SO 2 (NH 2 ); or
  • contacting the compound of Formula (I-i) with the carbonyl equivalent and the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the carbonyl equivalent to the compound of Formula (I-i) and a base to form mixture 1, then adding the compound of Formula (I-ii) to mixture 1 to form mixture 2.
  • 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.
  • 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 the sodium bicarbonate to the compound of Formula (I-i) is about 3.0. In some embodiments, the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 3.5.
  • adding the carbonyl equivalent to the compound of Formula (I-i) and a base to form mixture 1 is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding 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 adding is performed under nitrogen. In some embodiments, the adding is performed under argon.
  • adding the carbonyl equivalent to the compound of Formula (I-i) and the base is performed 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, adding the carbonyl equivalent to the compound of Formula (I-i) is performed at about 0 °C to about 5 °C. In some embodiments, adding the carbonyl equivalent to the compound of Formula (I-i) is performed at about 0 °C to about 2 °C. In some embodiments, adding the carbonyl equivalent to the compound of Formula (I-i) is performed at about 0 °C.
  • 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.
  • 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.
  • adding the compound of Formula (I-ii) to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and 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 a second base to mixture 1 then 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 then the second base to mixture 1.
  • the second base is selected from N,N-diisopropylethylamine, triethylamine, l,8-diazabicycloundec-7-ene (DBU), and l,5-diazabicyclo(4.3.0)non-5-ene (DBN).
  • the second base is triethylamine.
  • the second base is N,N- diisopropylethylamine.
  • adding a second base to mixture 1 and the compound of Formula (I-ii) to mixture 1 is performed 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, adding a second base to mixture 1 and the compound of Formula (I-ii) to mixture 1 is performed at about 0 °C to about 5 °C. In some embodiments, adding a second base to mixture 1 and the compound of Formula (I-ii) to mixture 1 is performed at about 0 °C to about 2 °C.
  • adding a second base to mixture 1 and the compound of Formula (I-ii) to mixture 1 is performed at about 0 °C.
  • mixture 2 is warmed 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 agitated at 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
  • warming then agitating mixture 2 to form the compound of Formula (I) comprises adding an aqueous base and a workup solvent after the warming and agitating.
  • the aqueous base is aqueous sodium bicarbonate.
  • the aqueous base is 5% w/w aqueous sodium bicarbonate.
  • the workup solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.
  • method comprises recrystallizing the compound of Formula (I) from a solvent.
  • the process comprises recrystallizing the compound of Formula (I) from a solvent after adding the aqueous base and the workup solvent.
  • the solvent is a mixture of isopropyl acetate and heptane.
  • the ratio of isopropyl acetate to heptane is about 6: 1 to about 1 : 10 (e.g., about 6: 1 to about 4:2, about 1 :7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3: 1, about 2:7, about 1 : 1, or about 5:2).
  • the compound of Formula (I) after recrystallizing the compound of Formula (I), the compound of Formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane.
  • the compound of Formula (I) after rinsing the compound of Formula (I), is dried.
  • drying the compound of Formula (I) comprises drying the compound of Formula (I) at a pressure lesser than atmospheric pressure.
  • drying the compound of Formula (I) comprises drying the compound of Formula (I) at ambient temperature.
  • contacting the compound of Formula (I-i) with the carbonyl equivalent and the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’, then adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’.
  • the compound of Formula (I-i) is in the form of a salt.
  • the compound of Formula (I-i) is in the form of a salt
  • contacting the compound of Formula (I-i) with the carbonyl equivalent and the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’, then adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’.
  • the compound of Formula (I-i) salt is a hydrochloride salt.
  • adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’ is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere.
  • the contacting is performed under nitrogen.
  • the contacting is performed under argon.
  • 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).
  • the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.05.
  • the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.3.
  • the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 2.0.
  • 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 the sodium bicarbonate to the compound of Formula (I-i) is about 3.0. In some embodiments, the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 3.5.
  • adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1 ’ is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere. In some embodiments, the adding is performed under nitrogen. In some embodiments, the adding is performed under argon.
  • adding the compound of Formula (I-i) to the carbonyl equivalent and a base 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, adding the carbonyl equivalent to the compound of Formula (I-i) is performed at about 5 °C or lower.
  • adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’ comprises adding a third base to mixture 1’ and the compound of Formula (I-ii) to mixture 1’.
  • adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’ comprises adding a third base to mixture 1’ then the compound of Formula (I-ii) to mixture 1’.
  • adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, and the compound of Formula (I-ii) to mixture 1’.
  • adding the compound of Formula (I-ii) to mixture 1’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, then the compound of Formula (I-ii) to mixture 1’ .
  • the third base is selected from N,N-diisopropylethylamine, triethylamine, 1,8- diazabicycloundec-7-ene (DBU), and l,5-diazabicyclo(4.3.0)non-5-ene (DBN).
  • the third base is triethylamine.
  • the third base is N,N- diisopropylethylamine.
  • 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.
  • the molar ratio of the third base 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 third base to the compound of Formula (I-i) is about 2.0.
  • adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and the compound of Formula (I-ii) 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, adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and the compound of Formula (I-ii) is performed at about 0 °C to about 5 °C.
  • 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 day, 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).
  • about 10 °C e g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C
  • 1 hour to about 7 days e.g., about 1 hour to about 4 days, about 5 hours to about 4 day, about 12 hours to about
  • the process comprises adding water and an extraction solvent to mixture 2’ after agitating mixture 2’ to form mixture 3’.
  • the extraction solvent is ethyl acetate or isopropyl acetate.
  • the extraction solvent is isopropyl acetate.
  • the process comprises agitating and/or shaking mixture 3’.
  • the process comprises separating an organic liquid from mixture 3’.
  • the process comprises adding an aqueous base to the organic liquid to form mixture 4’.
  • the aqueous base is aqueous sodium bicarbonate.
  • the aqueous sodium bicarbonate is 5% w/w aqueous sodium bicarbonate.
  • the process comprises separating the organic liquid from mixture 4’. In some embodiments, the process comprises reducing the volume of the organic liquid at a pressure lesser than atmospheric pressure. In some embodiments, the process comprises adding an anti-solvent to the organic liquid to form a slurry. In some embodiments, the anti-solvent is hexanes or heptane. In some embodiments, the anti-solvent is heptane. In some embodiments, the process comprises filtering the slurry to provide a solid. In some embodiments, the process comprises 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 lesser than atmospheric pressure to provide the compound of Formula (I).
  • 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, then precipitated 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 lesser than atmospheric pressure.
  • 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 lesser than atmospheric pressure at about 20 °C to about 25 °C.
  • the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bi s(trichlorom ethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroform ate, bis(2,5- dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carb onochlori die acid, and 1- methylethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl, nitro, or Cl-6 alkoxy.
  • R’ is phenyl.
  • R’ is paranitrophenyl.
  • contacting the compound of Formula (I-i) with R’OC(O)C1 and the compound of Formula (I-ii) to form the compound of Formula (I) comprises: combining R’OC(O)C1 with a base; adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base to form a compound of Formula
  • contacting the compound of Formula (I-i) with R’OC(O)C1 and the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the compound of Formula (I-i) to a mixture of R’OC(O)C1 and a base to form a compound of Formula (I-i-a)
  • 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.
  • the mixture of R’OC(O)C1 and the base is a solution or slurry in a solvent. In some embodiments, the mixture of R’OC(O)C1 and the base is a solution in a solvent.
  • the compound of Formula (I-i) is in the form of a salt.
  • the salt is a hydrochloride salt.
  • contacting the compound of Formula (I-i) with R’OC(O)C1 and the compound of Formula (I-ii) to form the compound of Formula (I) comprises: combining R’OC(O)C1 with a base; adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base to form a compound of Formula wherein the compound of Formula (I-i) is in the form of a salt.
  • combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1.
  • combining the base with a solvent, then adding the R’OC(O)C1 comprises adding the R’OC(O)C1 to the base and solvent at about 0 to about 10 °C (e g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C), then adding the R’OC(O)C1.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • the base when the base is combined with the solvent then R’OC(O)C1 added, (i) water is added to the base to form an aqueous base, (ii) tetrahydrofuran is added to the aqueous base, then (iii) R’OC(O)C1 is added to the tetrahydrofuran and aqueous base.
  • adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base is performed 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).
  • adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base is performed at about -5 °C to about 5 °C.
  • adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base is performed at about 0 °C to about 5 °C. In some embodiments, adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base is performed at lesser than 5 °C. In some embodiments, the compound of Formula (I-i) is added to the mixture of R’OC(O)C1 and the base as a solution in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • the compound of Formula (I-i) is added to the mixture of R’OC(O)C1 and the base over a time 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).
  • 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
  • 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).
  • agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase.
  • the organic phase is separated from the aqueous phase.
  • the organic phase is washed with an aqueous base.
  • the aqueous base is aqueous sodium bicarbonate.
  • the organic phase is concentrated at a pressure lesser than atmospheric pressure.
  • an anti-solvent is added to the concentrated organic phase to form mixture 4.
  • the anti-solvent is hexane or heptane.
  • the anti -solvent is heptane.
  • 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, mixture 4 is agitated at about 40 °C to about 50 °C.
  • the agitating 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, the agitating is performed for about 30 minutes.
  • mixture 4 after adding the anti-solvent, mixture 4 is stood and/or agitated 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 agitating 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 anti-solvent, mixture 4 is concentrated at a pressure lesser than atmospheric pressure.
  • a slurry is formed.
  • the slurry is fdtered to provide the compound of (I-i-a).
  • the compound of (I-i-a) is rinsed with hexane or heptane (e.g., heptane).
  • the compound of Formula (I-i-a) is dried.
  • drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at a pressure lesser than atmospheric pressure.
  • 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.
  • 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).
  • the molar ratio of the R’OC(O)C1 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).
  • the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 1.05.
  • the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 1.3.
  • the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 2.0. In some embodiments, the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 3.0.
  • 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.
  • the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 2.0.
  • the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 2.2.
  • the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 3.0.
  • the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 3.5.
  • 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.
  • contacting the compound of Formula (I-i) with R’OC(O)C1 and the compound of Formula (I-ii) to form the compound of Formula (I) comprises: contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the compound of Formula (I).
  • contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the compound of Formula (I) is performed in the presence of a third base.
  • the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), l,8-diazabicycloundec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate.
  • the third base is triethylamine.
  • the third base is N,N- di i sopropy 1 ethyl ami ne .
  • contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the compound of Formula (I-i-a) to the compound of Formula (I-ii). 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) comprises adding the compound of Formula (I-i-a) to the compound of Formula (I-ii) in the absence of a base.
  • contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the compound of Formula (I) comprises adding the compound of Formula (I-ii) to the compound of Formula (I-i-a). 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) comprises adding the compound of Formula (I-ii) to the compound of Formula (I-i-a); 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.
  • contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the 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.
  • contacting the compound of Formula (I-i-a) with the compound of Formula (I-ii) to form the compound of Formula (I) is performed 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 performed 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 performed 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 performed under argon.
  • the N-N-dimethylacetamide comprises less than 2% water by volume (e.g., less than 1.5% water by volume, less than 1% water by volume, less than 0.5% water by volume, less than 0.3% water by volume, less than 0.2% water by volume, less than 0.1% water by volume, less than 0.05% water by volume, or less than 0.02% water by volume). In some embodiments, the N-N-dimethylacetamide comprises less than 0.3% water by volume.
  • mixture 5 is formed 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).
  • mixture 5 is agitated.
  • 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).
  • mixture 5 is agitated for about 12 hours to about 13 hours.
  • mixture 5 is agitated for about 3 hours. In some embodiments, 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 °C).
  • 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
  • the process comprises adding water to mixture 5 to form mixture 5’. In some embodiments, the process comprises agitating mixture 5’. In some embodiments, the process comprises agitating 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
  • the process comprises agitating mixture 5’ for about 12 hours to about 13 hours. In some embodiments, the process comprises agitating mixture 5’ for about 3 hours. In some embodiments, the process comprises agitating mixture 5’ for about 1 hour.
  • a slurry is formed.
  • the slurry is filtered to provide the compound of Formula (I).
  • the compound of Formula (I) is washed with water.
  • the compound of Formula (I) is dried at a pressure lesser than atmospheric pressure.
  • the compound of Formula (I) is recrystallized from a solvent.
  • the solvent is a mixture of isopropyl alcohol and water.
  • the solvent is a mixture of isopropyl acetate and heptane.
  • the ratio of isopropyl alcohol to water is about 1:3 to about 1 : 1 (e.g., about 1 :2).
  • the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2).
  • the compound of Formula (I) after recrystallizing the compound of Formula (I), the compound of Formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane.
  • the compound of Formula (I) after rinsing the compound of Formula (I), is dried.
  • drying the compound of Formula (I) comprises drying the compound of Formula (I) at a pressure lesser than atmospheric pressure.
  • drying the compound of Formula (I) comprises drying the compound of Formula (I) at ambient temperature.
  • 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 no detectable amount) of a compound of Formula (A) is present as an impurity with the compound of Formula (I).
  • 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
  • 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
  • a compound of Formula (B) is present as an impurity with the compound of Formula (I).
  • the process comprises preparing the compound of Formula (I-i) by contacting -iii) with an acid to form the compound of Formula (I-i); wherein R” is C1-C6 alkyl; wherein R 3 is C1 -C6 haloalkyl.
  • R” is isopropyl
  • the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-di oxane. 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.
  • the contacting comprises adding the compound of Formula (I-iii) to the acid. In some embodiments, the contacting comprises adding the acid to the compound of Formula (I-iii). 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
  • the agitating is performed at about 0 °C to about 10 °C. In some embodiments, the agitating is performed at about 5 °C to about 15 °C. In some embodiments, the contacting comprises agitating the compound of Formula (I-iii) with the acid for about 5 minutes to about 24 hours (e.g., about 5 minutes to about 10 hours, about 5 minutes to about 5 hours, about 5 minutes to about 3 hours, about 30 minutes to about 1.5 hours, about 3 hours or about 1 hour) to form mixture 6. In some embodiments, the contacting comprises agitating the compound of Formula (I-iii) with the acid for about 3 hours to form mixture 6.
  • the contacting comprises agitating the compound of Formula (I-iii) with the acid for about 1 hour to form mixture 6. In some embodiments, the contacting comprises agitating the compound of Formula (I-iii) with the acid for at least 1 hour to form mixture 6. In some embodiments, the agitating 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 agitating is performed at about 5 °C to about 15 °C.
  • the contacting comprises adding heptane or hexanes (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)) then agitated or permitted 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
  • the process comprises preparing the compound of Formula (I-iii) by contacting a compound of Formula (I-iv) trihaloalkylating reagent to form the compound of Formula (I-iii); wherein R” is C1-C6 alkyl.
  • contacting the compound of Formula (I-iv) with the trihaloalkylating reagent comprises contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and a phase transfer reagent.
  • contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent forms mixture 7.
  • the molar ratio of the phase transfer reagent 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 reagent to the compound of Formula (I-iv) is about 1.0.
  • contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent comprises adding the phase transfer reagent to the compound of Formula (I-iv), then adding the trihaloalkylating reagent to the mixture of the compound of Formula (I-iv) and the phase transfer reagent.
  • 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.
  • 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).
  • the mixture of the compound of Formula (I-iv) and the phase transfer reagent is cooled to about -20 °C to about -15 °C.
  • the mixture of the compound of Formula (I-iv) and the phase transfer reagent is agitated 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 (T-iv) and the phase transfer reagent, the mixture of the compound of Formula (I-iv) and the phase transfer reagent is agitated for about 1 hour.
  • adding the trihaloalkylating reagent to the mixture of the compound of Formula (I-iv) and the phase transfer reagent is performed 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, adding the trihaloalkylating reagent to the mixture of the compound of Formula (I-iv) and the phase transfer reagent is performed at about -20 °C to about -15 °C.
  • the trihaloalkylating reagent is added to the mixture of the compound of Formula (I-iv) and the phase transfer reagent dropwise.
  • contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent comprises adding the trihaloalkylating reagent to the compound of Formula (I-iv), then adding the phase transfer reagent to the mixture of the compound of Formula (I-iv) and the trihaloalkylating reagent.
  • contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent comprises toluene, xylene, or benzene.
  • the solvent comprises toluene.
  • the solvent is toluene.
  • the process comprises adding the trihaloalkylating reagent to the 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).
  • the trihaloalkylating reagent is added to the compound of Formula (I-iv) at about -20 °C to about -10 °C.
  • the process comprises adding the trihaloalkylating reagent 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.
  • the process comprises adding the trihaloalkylating reagent to the compound of Formula (I-iv) over about 1 hour.
  • the process comprises agitating the compound of Formula (I-iv), the trihaloalkylating reagent, and the phase transfer reagent after adding the phase transfer reagent.
  • the process comprises agitating the compound of Formula (I-iv), the trihaloalkylating reagent, and the phase transfer reagent at about -78 °C to about 25 °C (e.g., about -78 °C to about 0 °C, about -78 °C to about -5 °C, about -50 °C to about 10 °C, about -40 °C to about 0 °C, about -30 °C to about 0 °C, about -20 °C to about -10 °C, about -20 °C, or about -10 °C).
  • the phase transfer reagent is added to the compound of Formula (I-iv) at about -20 °C to about -10 °C.
  • adding the phase transfer reagent to the mixture of the compound of Formula (I-iv) and the trihaloalkylating reagent comprises adding the phase transfer reagent to the mixture of the compound of Formula (I-iv) and the trihaloalkylating reagent in several portions.
  • the several portions are 7 to 13 portions.
  • the several portions are 9 to 11 portions.
  • the several portions are 10 portions.
  • the 10 portions are 10 portions that are substantially the same in weight.
  • the process comprises adding water or an aqueous acid to mixture 7. In some embodiments, the process comprises adding an aqueous acid to mixture 7 to form mixture 8. In some embodiments, the aqueous acid is aqueous ammonium chloride (e.g., 10% aqueous ammonium chloride by weight). In some embodiments, adding the water or aqueous acid to mixture 7 is performed at about -10 °C to about 25 °C (e.g., about -5 °C to about 5 °C).
  • the process comprises adding a solvent to mixture 8 to form mixture 9.
  • mixture 9 is biphasic.
  • mixture 9 comprises an organic phase and an aqueous phase.
  • the organic phase is separated from mixture 9 and concentrated under at a pressure lesser than atmospheric pressure.
  • the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether.
  • the solvent is ethyl acetate.
  • concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue.
  • the residue is purified using silica gel to provide the compound of Formula (I-iv).
  • the process comprises adding water and/or aqueous base to mixture 8 to form mixture 9’.
  • mixture 9’ comprises an organic phase and an aqueous phase.
  • the process comprises separating the organic phase from mixture 9’.
  • the process comprises distilling the organic phase to provide a distillate.
  • the process comprises passing the distillate through carbon (e.g., activated carbon).
  • the process comprises reducing the volume of the distillate under a pressure lesser than atmospheric pressure to form a concentrate after passing the distillate through carbon.
  • the process comprises adding water to the concentrate, then reducing the volume of the mixture of water and concentrate to form mixture 9’ ’ .
  • the process comprises adding an anti-solvent to mixture 9”, then reducing the volume of mixture 9’ ’ to form mixture 9” ’.
  • the anti-solvent is heptane.
  • the process comprises adding a portion (e.g., a previously prepared portion) of the compound of Formula (I-iii) to mixture 9”’ to form a precipitate.
  • the precipitate is fdtered and dried to form the compound of Formula (I-iii).
  • the trihaloalkylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,
  • EtsGeNa/CeHsSCFs N,N-dimethyl-(l-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S- (trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)- tetraki s(trifluoromethyl)cuprate( 1 -), (SP-4- 1 )-tetrakis(trifluoromethy l)argentate( 1 -), [( 1 , 1 ,2,2,2- pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthrenium, 1,1,1- trifluoromethanesulfonate (1 : 1).
  • the trifluoroalkylating reagent is a trifluoromethylating reagent.
  • the trifluoromethylating reagent is TMSCF3.
  • the phase transfer reagent is selected from tetrabutyl ammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, l, l'-(butane-l,4-diyl)bis[4-aza-l-azoniabicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, t
  • the process comprises preparing the compound of Formula (I-iv)
  • contacting the compound of Formula (I-v) with comprises contacting the compound of Formula (I-v) with
  • the condensing 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 condensing base is potassium carbonate.
  • the contacting is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is ethyl acetate.
  • the solvent is tetrahydrofuran.
  • the molar ratio of the condensing base to the compound of Formula (I-v) is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.3 to about 1.7, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the condensing base to the compound of Formula (I-v) is about 1.5.
  • contacting the compound of Formula (I-v) with and the condensing base is performed 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, contacting the compound of Formula (I-v) with O and the condensing base is performed at about 35 °C to about 45 °C.
  • contacting the compound of Formula (I-v) with and the condensing base is performed 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).
  • contacting the compound of Formula (I-v) with and the O condensing base comprises agitating the compound of Formula (I-v) with and the condensing base. In some embodiments, agitating the compound of Formula (I-v) with
  • O and the condensing base comprises agitating the compound of Formula (I-v) with an j condensing 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).
  • 0 rsj" agitating the compound of Formula (I-v) with H 2 N R" and the condensing base comprises
  • contacting the compound of Formula (I-v) with H 2 N R" and a condensing base comprises adding the to the compound of Formula (I-v), then adding
  • adding the to the compound of Formula (I-v) is performed at about 5 °C to about 40 °C (e.g., about 10 °C to about 35 °C, about 15 °C to about 25
  • adding the to the compound of Formula (I-v) is performed at about 15 °C to about 20 °C.
  • adding the condensing base to the mixture of and the compound of Formula (I-v) is performed 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 adding the
  • O condensing base to the mixture of and the compound of Formula (I-v) is performed at about 15 °C to about 20 °C.
  • contacting the compound of Formula (I-v) with and a condensing base provides mixture 10.
  • 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).
  • mixture 10 is agitated for about 15 minutes to about 5 hours.
  • agitating 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 mixture 10 is performed at about 60 °C.
  • 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 mixture 10, mixture 10 is cooled to about 20 °C. In some embodiments, after agitating mixture 10, mixture 10 is cooled to about 15 °C to about 25 °C.
  • cooling mixture 10 comprises forming a slurry.
  • the process comprises filtering the slurry to provide a solution.
  • the process comprises reducing the volume of the solution under a pressure lesser than atmospheric pressure.
  • the process comprises (i) adding a solvent to the solution; (ii) reducing the volume of the solution under a pressure lesser than atmospheric pressure; optionally (iii) adding a solvent to the solution; and optionally (iv) reducing the volume of the solution under a pressure lesser than atmospheric pressure to form a concentrate.
  • the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol.
  • steps (iii) and (iv) are required.
  • the process comprises 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).
  • the process comprises cooling the concentrate to about 15 °C to about 25 °C.
  • the process comprises adding water to the concentrate after cooling the concentrate to form mixture 10’.
  • the process comprises agitating 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).
  • the process comprises agitating mixture 10’ for about 14 hours.
  • a slurry is formed.
  • the slurry is fdtered to provide the compound of Formula (I-v).
  • the process comprises concentrating mixture 10 at a pressure lesser than atmospheric pressure to provide the compound of Formula (I-iv) after cooling mixture 10.
  • the process comprises
  • O condensing base comprises adding the to the compound of Formula (I-v), then adding the condensing base to the mixture of and the compound of Formula (I-v).
  • the process comprises preparing the compound of Formula (I-v) by contacting a compound of Formula (I-vi) acid.
  • Z is O.
  • the acid is a protic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron (III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).
  • the acid is acetic acid.
  • 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 the acid in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • adding the compound of Formula (I-vi) to the acid forms mixture 11.
  • 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).
  • mixture 11 is heated at about 120 °C.
  • 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, mixture 11 is agitated for about 8 hours.
  • mixture 12 is biphasic.
  • mixture 12 comprises an organic phase and an aqueous phase.
  • the organic phase is isolated and washed with an aqueous base.
  • the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight).
  • the organic phase is agitated with water and Na2S2O4.
  • 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 Na2S2C forms a solid. In some embodiments, the solid is separated from the solvent and water.
  • 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 biphasic mixture.
  • the biphasic mixture comprises an organic phase and an aqueous phase.
  • the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide the compound of Formula (I-v).
  • the process comprises preparing the compound of Formula (I-vi) by contacting a compound of Formula (I-vii) wherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.
  • the compound of Formula (I-vii) is a compound of Formula (I-vii- diments, contacting the compound of Formula (I-vii) mprises contacting the compound of Formula (I-vii)
  • the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-di isopropyl ethyl amine, triethylamine, and citric acid. In some embodiments, the base is potassium carbonate.
  • contacting the compound of Formula (I-vii) with an d a base is performed in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • OEt with LG ⁇ An ° C Et and a base comprises contacting the compound of Formula (I-vii) with a base, and sodium iodide.
  • OEt with a base, and sodium iodide is performed 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).
  • Formula (I-vii) base, and sodium iodide is performed at about 120 °C.
  • mixture 13 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 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 13 is agitated for about 5 hours.
  • the process comprises preparing the compound of Formula (I-v) by
  • Hal ( Rl)r "-LJLJ > / contacting a compound of Formula (I-viii) H O with an acid; wherein Hal is selected from chloro, bromo, iodo, and trifluorom ethanesulfonyl. In some embodiments, Hal is chloro.
  • the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.
  • contacting the compound of Formula (I-viii) w i h the acid is performed in a solvent.
  • 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-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.
  • contacting the compound of Formula (I-viii) with the acid is performed 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 performed at about 25 °C.
  • the process comprises preparing the compound of Formula (I-viii) by contacting a compound of Formula (I-ix) some embodiments, Z is O. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl.
  • contacting the compound of Formula (I-ix) with ⁇ Hal comprises
  • the base is potassium tert-butoxide.
  • the contacting is performed in a solvent.
  • 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-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.
  • contacting the compound of Formula (I-ix) with an d a base is performed 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).
  • 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.
  • contacting the compound of Formula (I-ix) with and a base is performed at about 25 °C.
  • Z is O; m is 2; each R 1 is fluoro; R 2 is methyl; R 2 is trifluoromethyl;
  • Ring A is , wherein * denotes the point of attachment to the urea and ** denotes the point of attachment to R 4 ; n is 1; and R 4 is -NH2.
  • the carbon substituted with R 3 has the (R) configuration.
  • the compound of Formula (I) In some embodiments, the compound of Formula (I) is not a compound selected from the
  • Ring A is not phenyl.
  • the compound of Formula (I) is a compound of Formula (X): or a salt and/or solvate thereof, 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 halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;
  • the compounds described herein are not compounds that are selected from the group of compounds that are not a compound of Formula (I) described above (i.e., the “excluded compounds”).
  • the excluded compounds are flat structures, as indicated above.
  • the excluded compounds are specific stereoisomers, e.g. specific enantiomers or diastereomers.
  • the excluded compounds are R isomers.
  • the excluded compounds are S isomers.
  • one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers.
  • the excluded compounds are R isomers.
  • one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.
  • the compound of Formula (I) is Formula (I-A): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with
  • Ring Al is a 6 membered heteroaryl
  • Ring Al is pyrimidinyl, pyridyl, or pyrazolyl.
  • Ring Al is pyrimidinyl.
  • Ring Al is pyridyl.
  • Ring Al is pyrazolyl.
  • Ring Al is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, Ring Al is 5-pyrimidinyl. In some embodiments, Ring Al is 3-pyridyl. In some embodiments, Ring Al is 4-pyrazolyl.
  • R 4B is selected from -NR A R B and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1 ; wherein R G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.
  • R A and R B are each hydrogen.
  • the compound of Formula (I) is Formula (I-B): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;
  • the compound of Formula (I) is Formula (I-C): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-D): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-E): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1 -C6 haloalkyl;
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-F): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-G): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-H): or a salt and/or solvate thereof, wherein:
  • R 1A is halogen
  • R 1B is halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • the compound of Formula (I) is Formula (I-J): or a salt and/or solvate thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;
  • Ring Al is a 6 membered heteroaryl
  • the compound of Formula (I) is Formula (I-K): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;
  • R 1A is halogen;
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;
  • the compound of Formula (I) is Formula (I-L): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a Cl -C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-M): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a Cl -C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-N): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-O): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl
  • R 1A is halogen
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-P): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;
  • R 1A is halogen;
  • R 1B is halogen or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;
  • the compound of Formula (I) is Formula (I-Q): or a salt and/or solvate thereof, wherein:
  • R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl
  • R 1A is halogen
  • R 1B is halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R 1A );
  • R 2 is a C1-C6 alkyl or C1-C6 haloalkyl
  • R 3 is a C1-C6 alkyl or a C1-C6 haloalkyl
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • each R 1 is an independently selected halogen. In some embodiments, each R 1 is independently selected from fluoro and chloro. In some embodiments, each R 1 is independently selected from fluoro and bromo. In some embodiments, each R 1 is fluoro. In some embodiments, at least one R 1 is an independently selected halogen. In some embodiments, at least one R 1 is independently selected from fluoro and chloro. In some embodiments, at least one R 1 is fluoro.
  • At least one R 1 is cyano. In some embodiments, at least one R 1 is hydroxyl. In some embodiments, at least one R 1 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R 1 is C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R 1 is C1-C3 alkyl substituted with hydroxyl. 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.
  • m is 2; one R 1 is halogen; and the other R 1 is C 1-C6 alkyl. In some embodiments, m is 2; one R 1 is fluoro; 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 fluoro; 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.
  • m is 2; one R 1 is fluoro; and the other R 1 is fluoro.
  • R 2 is hydroxyl.
  • R 2 is C1-C6 alkyl optionally substituted with hydroxyl.
  • R 2 is C1-C6 alkyl substituted with hydroxyl.
  • R 2 is C1-C3 alkyl substituted with hydroxyl.
  • R 2 is hydroxymethyl.
  • R 2 is an unsubstituted C1-C6 alkyl.
  • R 2 is unsubstituted C1-C3 alkyl.
  • R 2 is methyl.
  • R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C3 haloalkyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.
  • R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro.
  • R 2 is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R 2 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R 2 is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R 2 is C3-C6 cycloalkyl substituted with 2 fluoro. In some embodiments, R 2 is C3-C4 cycloalkyl substituted with 1 fluoro. In some embodiments, R 2 is C3-C4 cycloalkyl substituted with 2 fluoro. In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.
  • R 3 is a C1-C6 alkyl. In some embodiments, R 3 is a 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.
  • R 3 is a C1-C6 haloalkyl. In some embodiments, R 3 is a C1-C3 haloalkyl. In some embodiments, R 3 is difluoromethyl. In some embodiments, R 3 is trifluoromethyl.
  • R 3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R 3 is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 fluoro at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I).
  • R 3 is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R 3 is C3- C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 methyl. In some embodiments, R 3 is C3-C6 cycloalkyl substituted with 1 methyl at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I).
  • R 3 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, the R 3 C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.
  • 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.
  • R’ is C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkyl or Cl-6 alkoxy. In some embodiments, R’ is C6-C10 aryl substituted with 1- 3 independently selected Cl-6 alkyl or Cl-6 alkoxy. In some embodiments, R’ is C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkyl. In some embodiments, R’ is C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkoxy. In some embodiments, R’ is C6-C10 aryl substituted with 1-3 independently selected Cl-6 alkyl. In some embodiments, R’ is C6-C10 aryl substituted with 1-3 independently selected Cl-6 alkoxy.
  • 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.
  • Hal is selected from chloro, bromo, and iodo. In some embodiments, Hal is selected from chloro, bromo, and trifluoromethyl. In some embodiments, Hal is chloro. In some embodiments, Hal is bromo. In some embodiments, Hal is iodo. In some embodiments, Hal is trifluoromethanesulfonyl.
  • the compound of Formula (I-i) is a compound of Formula (I-i-i):
  • the compound of Formula (I-iii) is a compound of Formula (I-iii-i) the compound of Formula (I-iv) is a compound of Formula (I-iv-i)
  • the compound of Formula (I-v) is a compound of Formula (I-v-i)
  • the compound of Formula (I-viii) is a compound of Formula (I-viii-
  • the compound of Formula (I) is or a salt and/or solvate thereof, wherein R 3 , R 4 , and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of: or a salt and/or solvate thereof, wherein R 3 , R 4 , and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:
  • the compound of Formula (I) is or a salt and/or solvate thereof, wherein R 3 , R 4 , and Ring A are as described herein.
  • the compound of Formula (I) is or a salt and/or solvate thereof, wherein R 3 , R 4 , and Ring A are as described herein.
  • the compound of Formula (I) is or a salt and/or solvate thereof, wherein R 3 , R 4 , and Ring A are as described herein.
  • Some embodiments provide a process of preparing Compound 1 :
  • Some embodiments provide Compound 1 : salt and/or solvate thereof; prepared by a process comprising contacting
  • the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl, nitro, or Cl -6 alkoxy.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methyl ethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent.
  • the isocyanate-forming reagent is selected from the group consisting of: phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bi s(tri chloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2- trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methyl ethenyl ester.
  • Some embodiments provide a process of preparing Compound 1 :
  • Compound 1 prepared by a process comprising contacting
  • contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form Compound 1 comprises adding the carbonyl equivalent to base to form mixture 1, then adding pyrimidine-2,5-diamine to mixture
  • the molar ratio of the carbonyl equivalent 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 the base 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.
  • the molar ratio of the sodium bicarbonate to to form mixture 1 is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent to form mixture 1 is performed under an inert atmosphere. In some embodiments, the adding is performed under nitrogen. In some embodiments, the adding is performed under argon.
  • adding the carbonyl equivalent is performed 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, adding the carbonyl equivalent performed at about 0 °C to about 5 °C. In some embodiments, adding the carbonyl equivalent to the base, 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.
  • 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
  • adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and 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 then 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 then the second base to mixture 1.
  • the second base is selected from N,N-diisopropylethylamine, triethylamine, l,8-diazabicycloundec-7-ene (DBU), and l,5-diazabicyclo(4.3.0)non-5-ene (DBN).
  • the second base is triethylamine.
  • the second base is N,N-diisopropylethylamine.
  • adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed 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, adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed at about 0 °C to about 5 °C. In some embodiments, adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed at about 0 °C to about 2 °C. In some embodiments, adding a second base to mixture 1 and the compound of Formula (I-ii) to mixture 1 is performed at about 0 °C.
  • mixture 2 is warmed 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 agitated at 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
  • warming then agitating mixture 2 to form Compound 1 comprises adding an aqueous base and a workup solvent after the warming and agitating.
  • the aqueous base is aqueous sodium bicarbonate.
  • the aqueous base is 5% w/w aqueous sodium bicarbonate.
  • the workup solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.
  • the process comprises recrystallizing Compound 1 from a solvent.
  • the process comprises Compound 1 from a solvent after adding the aqueous base and the workup solvent.
  • the solvent is a mixture of isopropyl acetate and heptane.
  • the ratio of isopropyl acetate to heptane is about 6: 1 to about 1 : 10 (e.g., about 6:1 to about 4:2, about 1 :7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3: 1, about 2:7, about 1: 1, or about 5:2).
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere.
  • the contacting is performed under nitrogen.
  • the contacting is performed under argon.
  • the molar ratio of the carbonyl equivalent 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
  • the molar ratio of the carbonyl equivalent 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.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere. In some embodiments, the adding is performed under nitrogen. In some embodiments, the adding is performed under argon.
  • adding the carbonyl equivalent and a base 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, adding the carbonyl equivalent performed at about 5 °C or lower. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 ’ to form mixture 2’ comprises adding a third base to mixture 1’ and pyrimidine-2,5-diamine to mixture 1’.
  • adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’ comprises adding a third base to mixture 1’ then pyrimidine-2,5-diamine to mixture 1’.
  • adding pyrimidine-2,5-diamine to mixture 1 ’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, and pyrimidine-2,5-diamine to mixture 1’.
  • adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, then pyrimidine-2,5- diamine to mixture 1’.
  • the third base is selected from N,N- diisopropylethylamine, triethylamine, l,8-diazabicycloundec-7-ene (DBU), and 1,5- diazabicyclo(4.3.0)non-5-ene (DBN).
  • DBU l,8-diazabicycloundec-7-ene
  • DBN 1,5- diazabicyclo(4.3.0)non-5-ene
  • the third base is triethylamine.
  • the third base is N,N-diisopropylethylamine.
  • 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.
  • the molar ratio of the third base to Compound 1 is about 1.0 to about 4.0 (e g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the third base to Compound 1 is about 2.0.
  • adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and 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, adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and pyrimidine-2,5-diamine is performed at about 0 °C to about 5 °C.
  • 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 day, 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.
  • 1 hour to about 4 days e.g., about 5 hours to about 4 day, 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,
  • the process comprises adding water and an extraction solvent to mixture 2’ after agitating mixture 2’ to form mixture 3’.
  • the extraction solvent is ethyl acetate or isopropyl acetate.
  • the extraction solvent is isopropyl acetate.
  • the process comprises agitating and/or shaking mixture 3’.
  • the process comprises separating an organic liquid from mixture 3’.
  • the process comprises adding an aqueous base to the organic liquid to form mixture 4’.
  • the aqueous base is aqueous sodium bicarbonate.
  • the aqueous sodium bicarbonate is 5% w/w aqueous sodium bicarbonate.
  • the process comprises separating the organic liquid from mixture 4’. In some embodiments, the process comprises reducing the volume of the organic liquid at a pressure lesser than atmospheric pressure. In some embodiments, the process comprises adding an anti-solvent to the organic liquid to form a slurry. In some embodiments, the anti-solvent is hexanes or heptane. In some embodiments, the anti-solvent is heptane. In some embodiments, the process comprises filtering the slurry to provide a solid. In some embodiments, the process comprises 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 lesser than atmospheric pressure to provide Compound 1.
  • 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, then precipitated 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 lesser than atmospheric pressure.
  • 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 lesser than atmospheric pressure at about 20 °C to about 25 °C.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carb onochlori die acid, and 1- methylethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkyl, nitro, or Cl-6 alkoxy.
  • R’ is phenyl.
  • R’ is paranitrophenyl.
  • 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base;
  • the mixture of R’OC(O)C1 and the base is a solution or slurry in a solvent. In some embodiments, the mixture of R’OC(O)C1 and the base is a solution in a solvent.
  • the form of a salt in some embodiments, is a hydrochloride salt.
  • 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base;
  • combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1.
  • combining the base with a solvent, then adding the R’OC(O)C1 comprises adding the R’OC(O)C1 to the base and solvent at about 0 to about 10 °C (e g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C), then adding the R’OC(O)C1.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxi de, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • the base when the base is combined with the solvent then R’OC(O)C1 added, (i) water is added to the base to form an aqueous base, (ii) tetrahydrofuran is added to the aqueous base, then (iii) R’OC(O)C1 is added to the tetrahydrofuran and aqueous base.
  • adding the mixture of R’OC(O)C1 and the base is performed 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 5 °C, or about 0 °C).
  • adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base is performed at about -5 °C to about 5 °C.
  • adding the mixture of R’OC(O)C1 and the base is performed at about 0 °C to about 5 °C. In some
  • the solvent comprises acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.
  • added to the mixture of R’OC(O)C1 and the base over a time 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).
  • adding the mixture of R’OC(O)C1 and the base forms mixture 3.
  • 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).
  • 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).
  • agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase.
  • the organic phase is separated from the aqueous phase.
  • the organic phase was washed with an aqueous base.
  • the aqueous base is aqueous sodium bicarbonate.
  • the organic phase is concentrated at a pressure lesser than atmospheric pressure.
  • an anti-solvent is added to the concentrated organic phase to form mixture 4.
  • the anti-solvent is hexane or heptane.
  • the anti-solvent is heptane.
  • 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, mixture 4 is agitated at about 40 °C to about 50 °C.
  • the agitating 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, the agitating is performed for about 30 minutes.
  • mixture 4 after adding the anti-solvent, mixture 4 is stood and/or agitated 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 agitating 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 anti-solvent, mixture 4 is concentrated at a pressure lesser than atmospheric pressure. In some embodiments, after concentrating mixture 4, a slurry is pressure lesser than atmospheric pressure. In some embodiments, drying
  • 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
  • the molar ratio of the base 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.
  • the molar ratio of in some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, tri ethyl amine, trimethylamine, and citric acid.
  • the base is sodium bicarbonate.
  • 2,5-diamine to form Compound 1 comprises: contacting In some embodiments, contacting pyrimidine-2,5-diamine to form Compound 1 is performed in the presence of a third base.
  • the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8- diazabicycloundec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate.
  • the third base is triethylamine.
  • the third base is N,N-diisopropylethylamine.
  • contacting pyrimidine-2,5-diamine to form Compound 1 comprises adding pyrimidine-2,5-diamine. In some embodiments, contacting pyrimidine-2,5-diamine to form
  • Compound 1 comprises adding pyrimidine-2,5-diamine in the absence of a base.
  • contacting to form Compound 1 comprises adding pyrimidine-2,5-diamine
  • the solvent is N,N-dimethylacetamide. absence of a base.
  • contacting pyrimidine-2,5-diamine to form Compound 1 is performed in N,N-dimethylacetamide. In some embodiments, contacting pyrimidine-2,5-diamine to form Compound 1 is performed under an inert atmosphere. In some embodiments, contacting pyrimidine-
  • the N-N-dimethylacetamide comprises less than 2% water by volume (e.g., less than 1.5% water by volume, less than 1% water by volume, less than 0.5% water by volume, less than 0.3% water by volume, less than 0.2% water by volume, less than 0.1% water by volume, less than 0.05% water by volume, or less than 0.02% water by volume). In some embodiments, the N-N-dimethylacetamide comprises less than 0.3% water by volume.
  • mixture 5 is formed.
  • mixture 5 is agitated.
  • 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).
  • mixture 5 is agitated for about 12 hours to about 13 hours.
  • mixture 5 is agitated for about 3 hours.
  • mixture 5 is agitated for about 1 hour.
  • 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
  • the process comprises adding water to mixture 5 to form mixture 5’.
  • the process comprises agitating mixture 5’.
  • the process comprises agitating 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).
  • the process comprises agitating mixture 5’ for about 12 hours to about 13 hours.
  • the process comprises agitating mixture 5’ for about 3 hours.
  • the process comprises agitating mixture 5’ for about 1 hour.
  • a slurry is formed.
  • the slurry is filtered to provide Compound 1.
  • Compound 1 is washed with water.
  • Compound 1 is dried at a pressure lesser than atmospheric pressure.
  • Compound 1 is recrystallized from a solvent.
  • the solvent is a mixture of isopropyl alcohol and water.
  • the solvent is a mixture of isopropyl acetate and heptane.
  • the ratio of isopropyl alcohol to water is about 1 :3 to about 1 : 1 (e.g., about 1:2).
  • the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2).
  • 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 no detectable amount) of Impurity 1 is present as an impurity with Compound 1. (Impurity 1).
  • Impurity 1 is present as an impurity with Compound 1. (Impurity 1).
  • 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
  • Impurity 2 is present as an impurity with Compound 1.
  • the process comprises preparing a crystalline hemihydrate Form 1 by a method comprising:
  • Form 1 has one or more characteristics described below.
  • the XRPD pattern of Form 1 has a peak at 6.4 ⁇ 0.2 degrees 20. In some embodiments, the peak at 6.4 ⁇ 0.2 degrees 20 has the highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 15.8 ⁇ 0.2 degrees 20. In some embodiments, the peak at 15.8 ⁇ 0.2 degrees 20 has the second relative intensity.
  • the XRPD pattern of Form 1 has a peak at 18.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 18.3 ⁇ 0.2 degrees 20 has the third highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 22.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 22.3 ⁇ 0.2 degrees 20 has the fourth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 20.8 ⁇ 0.2 degrees 20. In some embodiments, the peak at 20.8 ⁇ 0.2 degrees 20 has the fifth highest relative intensity. In some embodiments, the XRPD pattern of Form 1 has a peak at 19.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 19.3 ⁇ 0.2 degrees 20 has the sixth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 24.0 ⁇ 0.2 degrees 20. In some embodiments, the peak at 24.0 ⁇ 0.2 degrees 20 has the seventh highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 26.9 ⁇ 0.2 degrees 20. In some embodiments, the peak at 26.9 ⁇ 0.2 degrees 20 has the eighth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 14.6 ⁇ 0.2 degrees 20. In some embodiments, the peak at 14.6 ⁇ 0.2 degrees 20 has the ninth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 31.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 31.3 ⁇ 0.2 degrees 20 has the tenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 28.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 28.3 ⁇ 0.2 degrees 20 has the eleventh highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 29.2 ⁇ 0.2 degrees 20. In some embodiments, the peak at 29.2 ⁇ 0.2 degrees 20 has the twelfth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 22.8 ⁇ 0.2 degrees 20. In some embodiments, the peak at 22.8 ⁇ 0.2 degrees 20 has the thirteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 28.0 ⁇ 0.2 degrees 20. In some embodiments, the peak at 28.0 ⁇ 0.2 degrees 20 has the fourteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 25.3 ⁇ 0.2 degrees 20. In some embodiments, the peak at 25.3 ⁇ 0.2 degrees 20 has the fifteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 21.5 ⁇ 0.2 degrees 20. In some embodiments, the peak at 21.5 ⁇ 0.2 degrees 20 has the sixteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 19.9 ⁇ 0.2 degrees 20. In some embodiments, the peak at 19.9 ⁇ 0.2 degrees 20 has the seventeenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 27.6 ⁇ 0.2 degrees 20. In some embodiments, the peak at 27.6 ⁇ 0.2 degrees 20 has the eighteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 20.5 ⁇ 0.2 degrees 20. In some embodiments, the peak at 20.5 ⁇ 0.2 degrees 20 has the nineteenth highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 21.8 ⁇ 0.2 degrees 20. In some embodiments, the peak at 21.8 ⁇ 0.2 degrees 20 has the twentieth highest relative intensity. In some embodiments, the XRPD pattern of Form 1 has a peak at 25.1 ⁇ 0.2 degrees 20. In some embodiments, the peak at 25.1 ⁇ 0.2 degrees 29 has the twenty -first highest relative intensity.
  • the XRPD pattern of Form 1 has a peak at 25.8 ⁇ 0.2 degrees 20. In some embodiments, the peak at 25.8 ⁇ 0.2 degrees 20 has the twenty-second highest relative intensity.
  • the XRPD pattern of Form 1 has peaks ( ⁇ 0.2 degrees 20) at 6.4,
  • the XRPD pattern of Form 1 has peaks ( ⁇ 0.2 degrees 29) at 6.4,
  • the XRPD pattern of Form 1 has peaks ( ⁇ 0.2 degrees 20) at 6.4,
  • Form 1 is characterized by an XRPD pattern substantially the same as that shown in FIG. 1.
  • Form 1 can also have one or more of the following characteristics.
  • Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.3%) at about 70 °C to about 140 °C (e.g., about 90 °C to about 130 °C, about 90 °C to about 120 °C, about 90 °C to about 115 °C, about 100 °C to about 140 °C, about 110 °C to about 140 °C, about 100 °C to about 120 °C, about 105 °C to about 120 °C, about 109 °C to about 115 °C, about 75 °C to about 125 °C, about 85 °C to about 113 °C, about 85 °C to about 105 °C, or about 112 °C.
  • TGA thermogravimetric analysis
  • the 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.
  • TGA thermogravimetric analysis
  • 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).
  • 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
  • Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245 °C. In some embodiments, the Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 162 °C to about 248 °C.
  • the Form 1 has a TGA curve that is substantially the same as that shown in FIG. 2.
  • the crystalline form is Form 1 having a Thermal Gravimetric/Differential Scanning Calorimetry (TG/DSC) thermogram that is substantially the same as that shown in FIG. 2.
  • TG/DSC Thermal Gravimetric/Differential Scanning Calorimetry
  • the Form 1 has a differential scanning calorimetry (DSC) first heat cycle thermogram having an endothermic event having an onset temperature of about 105 °C and a peak of about 129 °C, an endothermic event having an onset temperature of about 158 °C and a peak of about 162 °C and an endothermic event having an onset temperature of about 174 °C and a peak of about 177 °C.
  • DSC differential scanning calorimetry
  • the Form 1 has a Differential Scanning Calorimetry (DSC) thermogram that is substantially the same as that shown in FIG. 3.
  • DSC Differential Scanning Calorimetry
  • the Form 1 has a DSC first cooling cycle thermogram characterized by a single exothermic event at with an onset temperature of 151 °C and a peak temperature of 147 °C.
  • the Form 1 has a DSC first cooling cycle thermogram substantially the same as that shown in FIG. 4.
  • the Form 1 is a hemihydrate.
  • the enantiomeric 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%.
  • the Form 1 is substantially pure.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof comprises the free base of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof is the free base of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof comprises amorphous (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof is amorphous (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof comprises the free base amorphous form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.
  • the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof is the free base amorphous form of (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a salt and/or solvate thereof comprises Form 1*.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a salt and/or solvate thereof is Form 1 *.
  • the dissolving 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 dissolving in step (a) is performed at about 50 °C.
  • 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.
  • 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 per minute to about 5 °C per minute (e.g., about 0.5 °C per minute to about 2 °C per minute, or about 1 °C per minute). In some embodiments, the cooling is performed at about 1 °C per minute.
  • the volume/volume ratio of water added to the solution in step (b) to the isopropanol used in the dissolving 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 isopropanol used in the dissolving in step (a) is about 4: 1.
  • about l/8 th to about l/32 nd of the water is added to the solution per hour. 1 /16 th of the water is added to the solution per hour. In some embodiments, about 1/16 th of the water is added to the solution per hour.
  • 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.
  • the first period of time 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).
  • the first period of time is about 1 hour. In some embodiments, the first period of time is about 1 minute.
  • 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.
  • the second period of time 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).
  • the second period of time is about 1 hour. In some embodiments, the second period of time is about 1 minute.
  • 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.
  • the third period of time 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).
  • the third period of time is about 11 hours. In some embodiments, the third period of time is about 11 hours.
  • step (f) comprises filtering the mixture to provide Form 1.
  • step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1.
  • rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1.
  • the rinsing the solid comprises rinsing the solid with a solvent.
  • the solvent comprises an alcohol.
  • the alcohol is methanol, ethanol, and/or isopropanol.
  • the solvent comprises water.
  • the solvent comprises an alcohol and water.
  • the solvent comprises methanol and water.
  • the solvent is methanol and water.
  • step (f) comprises: filtering the mixture to provide a solid; rinsing the solid with methanol and water; and drying the solid to provide Form 1.
  • drying the 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.
  • drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure.
  • the drying is performed at a temperature of about 25 °C to about 100 °C (e.g., about 25 °C to about 80 °C, about 35 °C to about 80 °C, about 45 °C to about 70 °C, about 45 °C to about 60 °C).
  • the process comprises preparing a crystalline hemihydrate Form 1 by a method comprising: dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof in methanol to form a solution; adding water to the solution to form a first mixture; adding (R)- 1 -(2-aminopyrimidin-5 -y 1) - 3 -( 1 -(5 , 7-difluoro-3 -methylbenzofuran-2-y 1)-
  • the process comprises preparing a crystalline hemihydrate Form 1 by a method comprising:
  • 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.
  • dissolving the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a salt and/or solvate thereof in methanol to form a solution comprises dissolving the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(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 filtrate, then rinsing the filter with a second portion of methanol to provide a rinse that is combined with the filtrate to provide the solution.
  • the filtering is a polish filtering. 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 the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved.
  • 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 the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofur
  • 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 (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved.
  • 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 the water in step (b).
  • the water added in step (b) is purified water.
  • adding the water in step (b) comprises filtering the water through a filter, then adding the water to form the first mixture.
  • the 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)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- tri fluoroethyl )urea that is dissolved in step (a).
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(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% by weight, about 0.1% to about 10% by weight, about 0.1% to about 5% by weight, about 0.1% to about 3% by weight, about 0.5% to about 3% by weight, about 0.7% to about 2.5% by weight, about 0.7% to about 1.3% by weight, or about 1% by weight (e.g., about 1% by weight)) of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved in step (a).
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(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.
  • the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(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.
  • the agitating 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)).
  • °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)).
  • the agitating 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)).
  • 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)).
  • the water added in step (e) is purified water. In some embodiments, adding the water in step (e) comprises filtering the water through a filter, then adding the water to form the 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 the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea that is dissolved in step (a).
  • adding the water in step (e) comprises filtering the water through a filter, then adding the water to form the third mixture.
  • the water added in step (e) is about 0.1 to about 20 times (e.g.,
  • the water added in step (e) is added over a period of about 1 second to about 48 hours (e g., 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)).
  • the agitating 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 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 5 °C to about 35 °C (e.g., about 10 °C to about 30 °C, about 15 °C to about 25 °C
  • the agitating 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 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 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 1 minute to about
  • step (f) comprises filtering the mixture to provide Form 1.
  • step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1.
  • rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1.
  • the rinsing the solid comprises rinsing the solid with a solvent.
  • the solvent comprises an alcohol.
  • the alcohol is methanol, ethanol, and/or isopropanol.
  • the solvent comprises water.
  • the solvent comprises an alcohol and water.
  • the solvent comprises methanol and water.
  • the solvent is methanol and water.
  • isolating Form 1 from the third mixture comprises:
  • the weight of the 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 the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved in step (a).
  • 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)).
  • 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)).
  • drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure.
  • drying the solid comprises drying the solid under an inert gas (e.g., nitrogen or argon (e.g., nitrogen)).
  • drying the solid comprises drying the solid until the solid includes 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%) by weight of water.
  • the Form 1 obtained in step (g) includes 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%) by weight of water.
  • the process comprises preparing contacting wherein R 3 is C1-C6 haloalkyl.
  • the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-di oxane. 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.
  • the contacting comprises adding
  • the contacting comprises adding the acid t 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).
  • the agitating is performed at about 0 °C to about 10 °C. In some embodiments, the agitating is performed at about 5 °C to about 15 °C.
  • the contacting comprises agitating 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, the contacting comprises agitating the acid for about 3 hours to form mixture 6. In some embodiments, the contacting comprises agitating contacting comprises agitating the acid for at least 1 hour to form mixture 6.
  • the agitating 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
  • the agitating is performed at about 5 °C to about 15 °C.
  • the contacting comprises adding heptane or hexanes (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)) then agitated or permitted 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.
  • the solid is filtered to provide
  • the molar ratio of the trifluoromethylating reagent to 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).
  • the molar ratio of the trifluoromethylating reagent out 3.0.
  • the molar ratio of the phase transfer reagent t is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the phase transfer reagent t
  • trifluoromethylating reagent comprises contacting the trifluoromethylating reagent and a phase transfer reagent. In some embodiments, contacting trifluoromethylating reagent and the phase transfer reagent forms mixture 7.
  • trifluoromethylating reagent and the phase transfer reagent comprises adding the phase transfer reagent to then adding the trifluoromethylating reagent to the mixture of the phase transfer reagent. In some embodiments, the phase transfer reagent is added t
  • phase transfer reagent is added t about 15 °C to about 20 °C.
  • phase transfer reagent after adding the phase transfer reagent the phase transfer reagent is cooled to about -40 °C to about 0
  • phase transfer reagent after adding the phase transfer reagent the phase transfer reagent is cooled to about -20 °C to about -15 °C. In some embodiments, after cooling the mixture transfer reagent, the mixture about 5 minutes to about 3 hours (e g., about 5 minutes to about 2 hours, about 30 minutes to about
  • the phase transfer reagent is agitated for about 1 hour.
  • adding the trifluoromethylating reagent to the mixture of the phase transfer reagent is performed at about -40 °C to about 0 °C (e.g.,
  • adding the trifluoromethylating reagent to the mixture transfer reagent is performed at about -20 °C to about -15 °C. In some embodiments, the trifluoromethylating reagent is added to the mixture of the phase transfer reagent dropwise.
  • contacting with the trifluoromethylating reagent and the phase transfer reagent comprises adding the trifluoromethylating reagent to , then adding the phase transfer reagent to the mixture and the trifluoromethylating reagent.
  • contacting with the trifluoromethylating reagent and the phase transfer reagent is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent comprises toluene, xylene, or benzene.
  • the solvent comprises toluene.
  • the solvent is toluene.
  • the process comprises adding the trifluoromethylating reagent to 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).
  • the trifluoromethylating reagent is added t t about -20 °C to about -10 °C.
  • the process comprises adding the trifluoromethylating reagent to 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.
  • the process comprises adding the trifluoromethylating reagent over about 1 hour.
  • the process comprises agitating , the trifluoromethylating reagent, and the phase transfer reagent after adding the phase transfer reagent.
  • the process comprises agitatin the trifluoromethylating 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).
  • the phase transfer reagent is added t 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
  • adding the phase transfer reagent to the mixture of lating reagent comprises adding the phase transfer r eagent to the mixture the trifluoromethylating reagent in several portions.
  • the several portions are 7 to 13 portions.
  • the several portions are 9 to 11 portions.
  • the several portions are 10 portions.
  • the 10 portions are 10 portions that are substantially the same in weight.
  • the process comprises adding water or an aqueous acid to mixture 7. In some embodiments, the process comprises adding an aqueous acid to mixture 7 to form mixture 8. In some embodiments, the aqueous acid is aqueous ammonium chloride (e.g., 10% aqueous ammonium chloride by weight). In some embodiments, adding the water or aqueous acid to mixture 7 is performed at about -10 °C to about 25 °C (e.g., about -5 °C to about 5 °C).
  • the process comprises adding a solvent to mixture 8 to form mixture 9.
  • mixture 9 is biphasic.
  • mixture 9 comprises an organic phase and an aqueous phase.
  • the organic phase is separated from mixture 9 and concentrated under at a pressure lesser than atmospheric pressure.
  • the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether.
  • the solvent is ethyl acetate.
  • concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue.
  • the process comprises adding water and/or aqueous base to mixture 8 to form mixture 9’.
  • mixture 9’ comprises an organic phase and an aqueous phase.
  • the process comprises separating the organic phase from mixture 9’.
  • the process comprises distilling the organic phase to provide a distillate.
  • the process comprises passing the distillate through carbon (e g., activated carbon).
  • the process comprises reducing the volume of the distillate under a pressure lesser than atmospheric pressure to form a concentrate after passing the distillate through carbon.
  • the process comprises adding water to the concentrate, then reducing the volume of the mixture of water and concentrate to form mixture 9’ ’ .
  • the process comprises adding an anti-solvent to mixture 9”, then reducing the volume of mixture 9’ ’ to form mixture 9” ’.
  • the anti-solvent is heptane.
  • the process comprises adding a portion (e.g., a previously prepared portion) mixture 9”’ to form a precipitate.
  • the precipitate is filtered and dried to form
  • the trifluoromethylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,
  • EtsGeNa/CsHsSCFs N,N-dimethyl-(l-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S-
  • the trifluoromethylating reagent is TMSCF3.
  • the phase transfer reagent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, l,l'-(butane-l,4-diyl)bis[4-aza-l-azoniabicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, te
  • the phase transfer reagent is tetrabutylammonium acetate. o and a condensing base.
  • the condensing base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid.
  • the condensing base is potassium carbonate.
  • the contacting is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- di methyl acetamide, N-methylnyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is ethyl acetate.
  • the solvent is tetrahydrofuran.
  • the molar ratio of the condensing base about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.3 to about 1.7, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 0.8, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the condensing base t about 1.5.
  • the molar ratio of the condensing base to ' is about 0.8 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.3 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
  • the molar ratio of the condensing base about 1.02. In some embodiments, contacting and the condensing base is performed 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
  • contacting and the condensing base is performed at about 35 °C to about 45 °C.
  • contacting and the condensing base is performed at about 25 °C to about 80 °C (e.g., about 25 °C to about 70 °C, 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 condensing base for about 14 hours.
  • 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
  • adding the condensing base to the mixture of and performed 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 adding the condensing base to the mixture performed at about 15
  • contacting condensing base provides mixture 10.
  • 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).
  • mixture 10 is agitated for about 15 minutes to about 5 hours.
  • agitating 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 mixture 10 is performed at about 60 °C.
  • 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 mixture 10, mixture 10 is cooled to about 20 °C. In some embodiments, after agitating mixture 10, mixture 10 is cooled to about 15 °C to about 25 °C.
  • cooling mixture 10 comprises forming a slurry.
  • the process comprises filtering the slurry to provide a solution.
  • the process comprises reducing the volume of the solution under a pressure lesser than atmospheric pressure.
  • the process comprises (i) adding a solvent to the solution; (ii) reducing the volume of the solution under a pressure lesser than atmospheric pressure; optionally (iii) adding a solvent to the solution; and optionally (iv) reducing the volume of the solution under a pressure lesser than atmospheric pressure to form a concentrate.
  • the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol.
  • steps (iii) and (iv) are required.
  • the process comprises 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).
  • the process comprises cooling the concentrate to about 15 °C to about 25 °C.
  • the process comprises adding water to the concentrate after cooling the concentrate to form mixture 10’.
  • the process comprises agitating 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).
  • the process comprises agitating mixture 10’ for about 14 hours.
  • a slurry is formed.
  • the slurry is filtered to provide the compound of Formula (I-v).
  • the process comprises concentrating mixture 10 at a pressure lesser than atmospheric pressure to provide after cooling mixture 10.
  • the process comprises
  • contacting the compound of Formula (I-v) with H 2 N R" and a O condensing base comprises adding the to the compound of Formula (I-v), then adding O the condensing base to the mixture of and the compound of Formula (I-v).
  • the process comprises preparing contacting acid.
  • the acid is a protic acid. In some embodiments, the acid is a Lewis acids. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron (III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).
  • the acid is acetic acid.
  • contacting acid comprises adding , an acid comprises contacting the acid in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • adding the acid forms mixture 11.
  • mixture 11 is heated at about 80 °C to about 160 °C (e.g., about
  • mixture 11 is heated at about 120 °C.
  • 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 acid, mixture 11 is agitated for about 8 hours.
  • mixture 12 is biphasic.
  • mixture 12 comprises an organic phase and an aqueous phase.
  • the organic phase is isolated and washed with an aqueous base.
  • the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight).
  • the organic phase is agitated with water and Na2S2O4.
  • 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 NazS2O4 forms a solid. In some embodiments, the solid is separated from the solvent and water.
  • 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 biphasic mixture.
  • the biphasic mixture comprises an organic phase and an aqueous phase.
  • the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide
  • the process comprises preparing
  • LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.
  • contacting comprises contacting base.
  • the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, tri ethylamine, and citric acid.
  • the base is potassium carbonate.
  • contacting and a base is performed in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • contacting base comprises contacting base, and sodium iodide.
  • iodide is performed 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).
  • contacting base, and sodium iodide is performed at about 120 °C.
  • adding base, and sodium iodide forms mixture 13.
  • mixture 13 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 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours).
  • mixture 13 is agitated for about 5 hours.
  • the process comprises preparing the compound of Formula (I-v) by contacting a compound acid; wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl. In some embodiments, Hal is chloro.
  • the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.
  • contacting the acid is performed in a solvent.
  • 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-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.
  • contacting the acid is performed at about
  • the process comprises preparing the compound of Formula (I-viii) some embodiments, Z is O. In some embodiments,
  • R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl.
  • contacting comprises contacting base.
  • the base is potassium tert- butoxide.
  • the contacting is performed in a solvent.
  • 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-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-di methyl acetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.
  • contacting performed 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).
  • contacting base is performed at about 25 °C.
  • contacting R" comprises contacting condensing base.
  • the condensing base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid.
  • the condensing base is potassium carbonate.
  • the contacting is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is ethyl acetate. 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
  • adding the condensing base to the mixture of H 2 N R " and performed 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 adding the condensing base to the mixture performed at about 15
  • contacting condensing base provides mixture 10.
  • 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).
  • mixture 10 is agitated for about 15 minutes to about 5 hours.
  • agitating 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
  • agitating mixture 10 is performed at about 60 °C.
  • 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 mixture 10, mixture 10 is cooled to about 20 °C.
  • reacting form Compound 1 comprises contacting
  • R” is C1-C6 alkyl.
  • contacting the trifluoromethylating reagent comprises contacting phase transfer reagent. In some embodiments, contacting trifluoromethylating reagent and the phase transfer reagent forms mixture 7.
  • tri fluoromethyl ating reagent and the phase transfer reagent comprises adding the phase transfer reagent to then adding the trifluoromethylating reagent to the mixture of the phase transfer reagent.
  • the phase transfer reagent is added about
  • the phase transfer reagent is added about 15 °C to about 20 °C.
  • phase transfer reagent after adding the phase transfer reagent the phase transfer reagent is cooled to about -40 °C to about 0 °C (e.g., -30 °C to about -5 °C, -25 °C to about -10 °C, -20 °C to about -15 °C). In some embodiments, after adding the phase transfer reagent the phase transfer reagent is cooled to about -20 °C to about -15 °C.
  • the mixture transfer reagent after cooling the mixture transfer reagent, the mixture about 5 minutes to about 3 hours (e.g., about 5 minutes to about 2 hours, about 30 minutes to about
  • the phase transfer reagent is agitated for about 1 hour.
  • adding the trifluorom ethylating reagent to the mixture of the phase transfer reagent is performed at about -40 °C to about 0 °C (e.g.,
  • adding the trifluoromethylating reagent to the mixture the phase transfer reagent is performed at about -20 °C to about -15 °C.
  • the trifluoromethylating reagent is added to the mixture of the phase transfer reagent dropwise.
  • the process comprises adding water or an aqueous acid to mixture 7. In some embodiments, the process comprises adding an aqueous acid to mixture 7 to form mixture 8. In some embodiments, the aqueous acid is aqueous ammonium chloride (e.g., 10% aqueous ammonium chloride by weight).
  • the process comprises adding a solvent to mixture 8 to form mixture 9.
  • mixture 9 is biphasic.
  • mixture 9 comprises an organic phase and an aqueous phase.
  • the organic phase is isolated and concentrated under at a pressure lesser than atmospheric pressure.
  • the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether.
  • the solvent is ethyl acetate.
  • concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue.
  • the residue is purified using silica gel to provide the compound of Formula (I-iv).
  • the trifluoromethylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,
  • EhGeNa/CeHsSCFs N,N-dimethyl-(l-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S- (trifluoromethyl)dibenzothiophenium tetrafluoroborate, (SP-4-1)- tetrakis(trifluoromethyl)cuprate(l -), (SP-4- l)-tetrakis(trifluoromethyl)argentate(l -), [(1,1 ,2,2,2- pentafluoroethyl)sulfonyl]benzene, 5-(trifluoromethyl)-thianthrenium, 1,1,1- trifluoromethanesulfonate (1 : 1).
  • the trifluoroalkylating reagent is a trifluoromethylating reagent.
  • the trifluoromethylating reagent is TMSCF3.
  • the phase transfer reagent is selected from tetrabutyl ammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, 1, l'-(butane-l,4-diyl)bis[4-aza-l-azoniabicyclo[
  • reacting form Compound 1 comprises alkyl
  • the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-di oxane. 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.
  • the contacting comprises adding the acid.
  • 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).
  • the agitating is performed at about 0 °C to about 10 °C.
  • the contacting comprises agitating 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 mixture 6.
  • the contacting comprises agitating the acid for about 1 hour to form mixture 6.
  • the agitating 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).
  • the agitating is performed at about 5 °C to about 15 °C.
  • the contacting comprises adding heptane or hexanes (e.g., heptane) to 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) then agitated or permitted 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.
  • a carbonyl equivalent e.g., a carbonyl equivalent
  • contacting the carbonyl equivalent and pyrimidine-2,5-diamine to form Compound 1 comprises adding the carbonyl equivalent to base to form mixture 1, then adding pyrimidine-2,5-diamine to mixture
  • the molar ratio of the carbonyl equivalent t 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 t 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 t 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
  • the molar ratio of the base 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.
  • the molar ratio of the sodium bicarbonate to to form mixture 1 is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent the base to form mixture 1 is performed under an inert atmosphere. In some embodiments, the adding is performed under nitrogen. In some embodiments, the adding is performed under argon.
  • adding the carbonyl equivalent the base is performed 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, adding the carbonyl equivalent performed at about 0 °C to about 5 °C. In some embodiments, adding the carbonyl equivalent to performed at about 0 °C to about 2 °C.
  • 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.
  • 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.
  • adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1.
  • adding pyrimidine-2,5-diamine to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 then pyrimidine-2,5-diamine to mixture 1.
  • the second base is selected from N,N-diisopropylethylamine, triethylamine, l,8-diazabicycloundec-7- ene (DBU), and l,5-diazabicyclo(4.3.0)non-5-ene (DBN).
  • the second base is triethylamine.
  • the second base is N,N-diisopropylethylamine.
  • adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed 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, adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed at about 0 °C to about 5 °C. In some embodiments, adding a second base to mixture 1 and pyrimidine-2,5-diamine to mixture 1 is performed at about 0 °C to about 2 °C.
  • mixture 2 is warmed 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 agitated at about 20 °C to about 60 °C (e.g., about 20 °C to about 50 °C, about 20 °C to about 40 °C, about 25 °C to about 35 °C, or about 30 °C) for about 1 hour to about 7 days (e.g., about 1 hour to about 2 days, about 5 hours to about 1 day, about 10 hours to about 18 hours, about 10 hours to about 14 hours, about 14 hours to about 18 hours, about 12 hours to about 16 hours, about 14 hours to about 16 hours, or about 16 hours) to form Compound 1.
  • Compound 1 is recrystallized from a solvent.
  • the solvent is a mixture of isopropyl acetate and heptane.
  • the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2).
  • Compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane.
  • After rinsing Compound 1, Compound 1 is dried.
  • drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure.
  • drying Compound 1 comprises drying Compound 1 at ambient temperature. carbonyl equivalent and a base to form mixture 1’, then adding pyrimidine-2,5-diamine to mixture Compound 1 comprises adding the carbonyl equivalent and a base to form mixture 1’, then adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’. to form mixture 1 ’ is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere.
  • the contacting is performed under nitrogen.
  • the contacting is performed under argon.
  • the molar ratio of the carbonyl equivalent t 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
  • the molar ratio of the sodium bicarbonate to to form mixture 1 ’ is performed in a solvent.
  • the solvent comprises acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere.
  • the adding is performed under nitrogen.
  • the adding is performed under argon.
  • adding the carbonyl equivalent and a base 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, adding the carbonyl equivalent performed at about 5 °C or lower.
  • adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’ comprises adding a third base to mixture 1’ and 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 third base to mixture 1’ then pyrimidine-2,5-diamine to mixture 1’. In some embodiments, adding pyrimidine-2,5-diamine to mixture 1 ’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, and pyrimidine-2,5-diamine to mixture 1’.
  • adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’ comprises adding aqueous sodium chloride to mixture 1’, a third base to mixture 1’, then pyrimidine-2,5- diamine to mixture 1’.
  • the third base is selected from N,N- di isopropyl ethyl amine, triethylamine, l,8-diazabicycloundec-7-ene (DBU), and 1,5- diazabicyclo(4.3.0)non-5-ene (DBN).
  • the third base is tri ethyl amine.
  • the third base is N,N-diisopropylethylamine.
  • adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and 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, adding aqueous sodium chloride to mixture 1’, the third base to mixture 1’, and pyrimidine-2,5-diamine is performed at about 0 °C to about 5 °C.
  • 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 day, 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.
  • 1 hour to about 4 days e.g., about 5 hours to about 4 day, 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,
  • 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, then precipitated 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 lesser than atmospheric pressure.
  • 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 lesser than atmospheric pressure at about 20 °C to about 25 °C.
  • 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-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carb onochlori die acid, and 1- methylethenyl ester.
  • the carbonyl equivalent is phenyl chloroformate.
  • the carbonyl equivalent is R’OC(O)C1, wherein R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl-6 alkyl, nitro, or Cl-6 alkoxy.
  • R’ is phenyl.
  • R’ is paranitrophenyl.
  • contacting pyrimidine- 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base; the salt is a hydrochloride salt.
  • contacting pyrimidine- 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base; wherein
  • combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1.
  • combining the base with a solvent, then adding the R’OC(O)C1 comprises adding the R’OC(O)C1 to the base and solvent at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C), then adding the R’OC(O)C1.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is tetrahydrofuran.
  • the solvent is a combination of tetrahydrofuran and water.
  • adding the mixture of R’OC(O)C1 and the base is performed at about 0 °C to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about
  • R’OC(O)C1 and the base is performed at about 0 °C to about 5 °C. In some embodiments, adding the mixture of R’OC(O)C1 and the base is performed at lesser than 5 °C.
  • the solvent comprises acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxi de, water, or any combination thereof.
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.
  • added to the mixture of R’OC(O)C1 and the base over a time 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).
  • adding the mixture of R’OC(O)C1 and the base forms mixture 3.
  • 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).
  • 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).
  • agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase.
  • the organic phase is separated from the aqueous phase.
  • the organic phase was washed with an aqueous base.
  • the aqueous base is aqueous sodium bicarbonate.
  • the organic phase is concentrated at a pressure lesser than atmospheric pressure.
  • an anti-solvent is added to the concentrated organic phase to form mixture 4.
  • the anti-solvent is hexane or heptane.
  • the anti-solvent is heptane.
  • mixture 4 is concentrated at a pressure lesser than atmospheric pressure.
  • a slurry is pressure lesser than atmospheric pressure.
  • drying mixture 3 is concentrated at a pressure lesser than atmospheric pressure.
  • drying comprises drying
  • 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
  • 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.
  • 2,5-diamine to form Compound 1 comprises: contacting in some embodiments, contacting pyrimidine-2,5-diamine to form Compound 1 is performed in the presence of a third base.
  • the third base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8- diazabicycloundec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), sodium bicarbonate, potassium carbonate, and potassium phosphate.
  • the third base is triethylamine.
  • the third base is N,N-diisopropylethylamine.
  • contacting pyrimidine-2,5-diamine to form Compound 1 is performed in N,N-dimethylacetamide. In some embodiments, contacting pyrimidine-2,5-diamine to form Compound 1 is performed under an inert atmosphere. In some embodiments, contacting
  • the N-N- dimethylacetamide comprises less than 2% water by volume (e.g., less than 1.5% water by volume, less than 1% water by volume, less than 0.5% water by volume, less than 0.3% water by volume, less than 0.2% water by volume, less than 0.1% water by volume, less than 0.05% water by volume, or less than 0.02% water by volume). In some embodiments, the N-N-dimethylacetamide comprises less than 0.3% water by volume.
  • mixture 5 is formed after adding after adding pyrimidine-2,5-diamine. In some embodiments, 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
  • mixture 5 is agitated for about 12 hours to about 13 hours. In some embodiments, mixture 5 is agitated for about 3 hours. In some embodiments, mixture 5 is agitated for about 1 hour. In some embodiments, Compound 1 has a purity of at least 90% (e.g., at least 92%, at least
  • 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
  • Impurity 1 1%, about 1.3%, about 0.05%, or no detectable amount of Impurity 1 is present as an impurity with Compound 1.
  • 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
  • Impurity 2 is present as an impurity with Compound 1.
  • the acid is a protic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron (III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).
  • the acid is acetic acid.
  • contacting acid comprises adding
  • contacting an acid comprises contacting the acid in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- di methyl acetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • mixture 11 is heated at about 120 °C. In some embodiments, after adding the acid, 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 acid, mixture 11 is agitated for about 8 hours.
  • mixture 12 is biphasic.
  • mixture 12 comprises an organic phase and an aqueous phase.
  • the organic phase is isolated and washed with an aqueous base.
  • the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight).
  • the organic phase is agitated with water and Na2S2O4.
  • 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 Na2S2Ch forms a solid. In some embodiments, the solid is separated from the solvent and water.
  • 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 biphasic mixture.
  • the biphasic mixture comprises an organic phase and an aqueous phase.
  • the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide
  • the process comprises preparing
  • LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.
  • contacting comprises contacting base.
  • the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid.
  • the base is potassium carbonate.
  • contacting and a base is performed in a solvent.
  • the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is N,N-dimethylformamide.
  • contacting base comprises contacting base, and sodium iodide.
  • contacting base, and sodium iodide is performed 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).
  • contacting base, and sodium iodide is performed at about 120 °C.
  • adding base, and sodium iodide forms mixture 13.
  • mixture 13 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 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 13 is agitated for about 5 hours.
  • the process comprises preparing the compound of Formula (I-v) by contacting a compound acid; wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl. In some embodiments, Hal is chloro.
  • the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.
  • contacting the acid is performed in a solvent.
  • 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-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N -dim ethyl acetami de, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.
  • contacting the acid is performed 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 acid is performed at about 25 °C.
  • the process comprises preparing the compound of Formula (I-viii) some embodiments, Z is O. In some embodiments,
  • R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, contacting comprises contacting base. In some embodiments, the base is potassium tert- butoxide. In some embodiments, the contacting is performed in a solvent.
  • 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-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, di chloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof.
  • the solvent is methyl tert-butyl ether.

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Abstract

La présente divulgation concerne des procédés de préparation de composés de formule (I), tels que (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-méthylbenzofuran-2-yl)-2,2,2-trifluoroéthyl)urée (composé 1), et des sels et/ou solvates de ceux-ci, qui inhibent l'isoforme alpha (PI3Kα) de phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K).
PCT/US2024/042223 2023-08-15 2024-08-14 Procédés de préparation d'inhibiteurs de pi3k Pending WO2025038699A1 (fr)

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Citations (2)

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WO2010125350A1 (fr) * 2009-05-01 2010-11-04 University Court Of The University Of Dundee Traitement ou prophylaxie d'états prolifératifs
WO2022265993A1 (fr) 2021-06-14 2022-12-22 Scorpion Therapeutics, Inc. Dérivés d'urée pouvant être utilisés pour traiter le cancer

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