Processes of preparing pi3k inhibitors

Abstract

This disclosure provides processes of preparing compounds of Formula (I), such as (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (Compound 1), and salts and / or solvates thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα).

Description

[0001] Processes of Preparing PT3K Inhibitors

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 532,695, filed on August 15, 2023, which is incorporated by reference herein in its entirety.

[0004] TECHNICAL FIELD

[0005] 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).

[0006] BACKGROUND

[0007] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), encoded by the PIK3CA gene is a part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several investigators have demonstrated the role of PI3K / AKT signaling in physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis and metastasis. (See, Fruman, D A. The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol.2018, 15, 273-291.) Suppression (e.g., pharmacological or genetic) of PI3K / AKT / TOR signaling may cause cancer cell death and regression of tumor growth.

[0008] Certain compounds of Formula (I) are described in WO 2022 / 265993, which is incorporated by reference herein in its entirety. There exists a need for alternative synthetic procedures for the preparation of compounds of Formula (I). Such alternative synthetic procedures are disclosed herein.

[0009] SUMMARY

[0010] 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

[0011] (i) a carbonyl equivalent; and

[0012] (ii) a compound of Formula (I-ii)

[0013] H2N-( A 4- (R4)n

[0014] (i-ii); to form the compound of Formula (I), wherein:

[0015] Z is O or NRx;

[0016] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0017] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0018] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with

[0019] 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;

[0020] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0021] (i) halogen,

[0022] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0023] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0024] (iv) C1-C6 haloalkyl, (v) hydroxyl,

[0025] (vi) cyano,

[0026] (vii) -CChH,

[0027] (viii) -NRARB,

[0028] (ix) =NRA2,

[0029] (x) -C(=O)NRcRD,

[0030] (xi) -SO2(NRERF),

[0031] (xii) -SCh(Cl-C6 alkyl),

[0032] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0033] (xiv) -C(=O)(C1-C6 alkyl),

[0034] (xv) -CCh(Cl-C6 alkyl),

[0035] (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0036] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0037] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently

[0038] (i) hydrogen,

[0039] (ii) hydroxyl,

[0040] (iii) 4-6 membered heterocyclyl,

[0041] (iv) C1-C6 haloalkyl,

[0042] (v) -C(=O)(C1-C6 alkyl),

[0043] (vi) -C(=O)O(C1-C6 alkyl),

[0044] (vii) -SO2(C1-C6 alkyl),

[0045] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0046] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CChH, and -SO2(NH2); or

[0047] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0048] Some embodiments provide a process of preparing Compound 1, having the structure:

[0049] (i) a carbonyl equivalent; and

[0050] (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0051] Some embodiments provide a process of preparing Compound 1, having the structure:

[0052] Some embodiments provide a process of preparing Compound 1, having the structure: comprising contacting form wherein R” is C1-C6 alkyl; and reacting

[0053] Some embodiments provide a process of preparing Compound 1, having the structure: salt and / or solvate thereof; comprising:

[0054] (a) contacting , wherein R” is C1-C6 alkyl; (d) contacting carbonyl equivalent; and (ii) pyrimidine-2,5- diamine having the structure ; to form Compound 1.

[0055] Some embodiments provide a process of preparing Compound 1, having the structure:

[0056] LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl;

[0057] (b) contacting

[0058] (c) contacting wherein

[0059] R” is C1-C6 alkyl; carbonyl equivalent; and (ii) pyrimidine-2,5- diamine having the structure ; to form Compound 1.

[0060] Some embodiments provide a process of preparing Compound 1, having the structure: wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; (b) contacting

[0061] (c) contacting wherein

[0062] R” is C1-C6 alkyl;

[0063] (e) contacting

[0064] (f) contacting wherein R’ is selected from Cl-

[0065] C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl-

[0066] 6 alkoxy; and (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0067] Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions

[0068] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0069] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0070] “API” refers to an active pharmaceutical ingredient.

[0071] The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense 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. ; Rowe etal., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0072] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with 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. In some instances, 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. The pharmacologically acceptable salt is not specifically limited as far as it can be used in medicaments. 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.

[0073] The term “pharmaceutically acceptable 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. When the average number of water molecules present in each repeating unit (i.e., unit cell) of the crystal lattice of a hydrate is known, the hydrate is affixed with a prefix denoting the average number of water molecules in each unit cell. For example, a monohydrate contains an average of one water molecule per unit cell, a dihydrate contains an average of two water molecules per unit cell, and a hemihydrate contains an average of half of a water molecule per unit cell. For more information, see, e.g., K.R. Morris, Polymorphism in Pharmaceutical Solids 1999, pages 125-181; Jeffrey, G.A. Acc. Chem. Res. 1969, 344-352; Rev. Pure Appl. Chem., 1963, 50-90; Encyclopedia of Pharm. Tech. 1993, 7, pages 393-441, each of which is incorporated herein in its entirety. As used herein, the term “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. In some embodiments, 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. In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidin-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. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0074] As used herein, the term “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. In some embodiments, 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.

[0075] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0076] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0077] The term "hydroxyl" refers to an -OH radical.

[0078] The term "cyano" refers to a -CN radical.

[0079] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, 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. The term “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. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0080] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0081] The term "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. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0082] The term "cycloalkyl" as used herein 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. Examples of 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). Non-limiting examples of 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. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0083] The term “heteroaryl”, as used herein, 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. Examples of heteroaryl 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, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-£>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[d][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[ / >][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0084] The term "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-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of 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. Non-limiting examples of 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. 1 .0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7 azabi cy cl o [2.2.1 ] heptane, 6-azabicyclo[3.1.1 ]heptane, 7-azabicyclo[4.2.0]octane, 2 azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2 oxabicyclo[2.1.0]pentane, 2-oxabicyclo[ 1.1.1 ]pentane, 3-oxabicyclo[3.1.0]hexane, 5 oxabicyclo[2. 1. l]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2. l]heptane, 6-oxabicyclo[3.1.1 ]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. 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- oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5- dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.

[0085] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0086] As used herein, 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. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

[0087] (e.g., [x.x.O] ring systems, in which 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.,

[0088] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0089] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0090] 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. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when 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.

[0091] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0092] DESCRIPTION OF DRAWINGS

[0093] FIG. 1 depicts a XRPD diffractogram of Compound 1, Form 1 hemi hydrate.

[0094] FIG. 2 depicts a TG / DSC thermogram of Form 1.

[0095] FIG. 3 depicts a DSC thermogram (first heat cycle) of Form 1.

[0096] FIG. 4 depicts a DSC thermogram (first cool cycle) of Form 1.

[0097] DETAILED DESCRIPTION

[0098] 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).

[0099] 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

[0100] (ii) a compound of Formula (I-ii) to form the compound of Formula (I), wherein:

[0101] Z is O or NRX;

[0102] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0103] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0104] R3is 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;

[0105] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0106] (i) halogen,

[0107] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0108] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0109] (iv) C1-C6 haloalkyl,

[0110] (v) hydroxyl,

[0111] (vi) cyano,

[0112] (vii) -CO2H,

[0113] (viii) -NRARB,

[0114] (ix) =NRA2,

[0115] (x) -C(=O)NRCRD,

[0116] (xi) -SO2(NRERF),

[0117] (xii) -SO2(C1-C6 alkyl),

[0118] (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl),

[0119] (xv) -CO2(C1-C6 alkyl),

[0120] (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0121] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0122] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently

[0123] (i) hydrogen,

[0124] (ii) hydroxyl,

[0125] (iii) 4-6 membered heterocyclyl,

[0126] (iv) C1-C6 haloalkyl,

[0127] (v) -C(=O)(C1-C6 alkyl),

[0128] (vi) -C(=O)O(C1-C6 alkyl),

[0129] (vii) -SO2(C1-C6 alkyl),

[0130] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0131] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0132] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SC>2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0133] 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

[0134] (i) a carbonyl equivalent; and

[0135] (ii) a compound of Formula (I-ii)

[0136] H2N-( A £ (R4)n

[0137] (i-ii); to form the compound of Formula (I), wherein:

[0138] Z is O or NRx;

[0139] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0140] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0141] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with

[0142] 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;

[0143] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0144] (i) halogen,

[0145] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0146] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0147] (iv) C1-C6 haloalkyl, (v) hydroxyl,

[0148] (vi) cyano,

[0149] (vii) -CChH,

[0150] (viii) -NRARB,

[0151] (ix) =NRA2,

[0152] (x) -C(=O)NRcRD,

[0153] (xi) -SO2(NRERF),

[0154] (xii) -SCh(Cl-C6 alkyl),

[0155] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0156] (xiv) -C(=O)(C1-C6 alkyl),

[0157] (xv) -CCh(Cl-C6 alkyl),

[0158] (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0159] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0160] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently

[0161] (i) hydrogen,

[0162] (ii) hydroxyl,

[0163] (iii) 4-6 membered heterocyclyl,

[0164] (iv) C1-C6 haloalkyl,

[0165] (v) -C(=O)(C1-C6 alkyl),

[0166] (vi) -C(=O)O(C1-C6 alkyl),

[0167] (vii) -SO2(C1-C6 alkyl),

[0168] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0169] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CChH, and -SO2(NH2); or

[0170] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SC>2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0171] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, 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. In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and

[0172] 1 -methyl ethenyl ester. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0173] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of: phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl 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.

[0174] 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

[0175] (i) a carbonyl equivalent or an isocyanate-forming reagent; and

[0176] (ii) a compound of Formula (I-ii) to form the compound of Formula (I), wherein:

[0177] Z is O or NRX;

[0178] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0179] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0180] R3is 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;

[0181] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0182] (i) halogen,

[0183] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0184] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0185] (iv) C1-C6 haloalkyl,

[0186] (v) hydroxyl,

[0187] (vi) cyano,

[0188] (vii) -CO2H,

[0189] (viii) -NRARB,

[0190] (ix) =NRA2, (x) -C(=O)NRCRD,

[0191] (xi) -SO2(NRERF),

[0192] (xii) -SO2(C1-C6 alkyl),

[0193] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0194] (xiv) -C(=O)(C1-C6 alkyl),

[0195] (xv) -CO2(C1-C6 alkyl),

[0196] (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0197] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0198] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently

[0199] (i) hydrogen,

[0200] (ii) hydroxyl,

[0201] (iii) 4-6 membered heterocyclyl,

[0202] (iv) C1-C6 haloalkyl,

[0203] (v) -C(=O)(C1-C6 alkyl),

[0204] (vi) -C(=O)O(C1-C6 alkyl),

[0205] (vii) -SO2(C1-C6 alkyl),

[0206] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0207] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0208] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -

[0209] SO2(C1-C6 alkyl), and -CO2H.

[0210] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, 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. In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidin-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. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0211] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent. In some embodiments, the isocyanate-forming reagent is selected from the group consisting of: phosgene (toluene solution), trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), 4-nitrophenyl chloroformate, phenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyldiimidazole, 2,2,2- trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carbonochloridic acid, and 1 -methylethenyl ester.

[0212] 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):

[0213] NH2

[0214] (Rl)m 1 L / W

[0215] R3

[0216] R2(I-i) with

[0217] (i) a carbonyl equivalent; and

[0218] (ii) a compound of Formula (I-ii) -ii); to form the compound of Formula (I), wherein:

[0219] Z is O or NRX;

[0220] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0221] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0222] R3is 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;

[0223] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0224] (i) halogen,

[0225] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0226] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0227] (iv) C1-C6 haloalkyl,

[0228] (v) hydroxyl,

[0229] (vi) cyano,

[0230] (vii) -CO2H,

[0231] (viii) -NRARB,

[0232] (ix) =NRA2,

[0233] (x) -C(=O)NRcRD,

[0234] (xi) -SO2(NRERF),

[0235] (xii) -SO2(C1-C6 alkyl),

[0236] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0237] (xiv) -C(=O)(C1-C6 alkyl),

[0238] (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0239] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0240] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, Rc, RC1, RD, RD1, RE, and RFis independently

[0241] (i) hydrogen,

[0242] (ii) hydroxyl,

[0243] (iii) 4-6 membered heterocyclyl,

[0244] (iv) C1-C6 haloalkyl,

[0245] (v) -C(=O)(C1-C6 alkyl),

[0246] (vi) -C(=O)O(C1-C6 alkyl),

[0247] (vii) -SO2(C1-C6 alkyl),

[0248] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0249] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0250] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SC>2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0251] 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

[0252] (i) a carbonyl equivalent; and

[0253] (ii) a compound of Formula (I-ii)

[0254] H2N-( A £ (R4)n

[0255] (i-ii); to form the compound of Formula (I), wherein:

[0256] Z is O or NRx;

[0257] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0258] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0259] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with

[0260] 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;

[0261] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of:

[0262] (i) halogen,

[0263] (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,

[0264] (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0265] (iv) C1-C6 haloalkyl, (v) hydroxyl,

[0266] (vi) cyano,

[0267] (vii) -CChH,

[0268] (viii) -NRARB,

[0269] (ix) =NRA2,

[0270] (x) -C(=O)NRcRD,

[0271] (xi) -SO2(NRERF),

[0272] (xii) -SCh(Cl-C6 alkyl),

[0273] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0274] (xiv) -C(=O)(C1-C6 alkyl),

[0275] (xv) -CCh(Cl-C6 alkyl),

[0276] (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,

[0277] (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and

[0278] (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently

[0279] (i) hydrogen,

[0280] (ii) hydroxyl,

[0281] (iii) 4-6 membered heterocyclyl,

[0282] (iv) C1-C6 haloalkyl,

[0283] (v) -C(=O)(C1-C6 alkyl),

[0284] (vi) -C(=O)O(C1-C6 alkyl),

[0285] (vii) -SO2(C1-C6 alkyl),

[0286] (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or

[0287] (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CChH, and -SO2(NH2); or

[0288] Rcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SC>2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0289] In some embodiments, 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.

[0290] In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.0 to about 4.0 (e.g., about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3). In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.3.

[0291] In some embodiments, the molar ratio of the base to the compound of Formula (I-i) is about 1.0 to about 5.0 (e g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of 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.

[0292] In some embodiments, adding the carbonyl equivalent to the compound of Formula (I-i) and a base to form mixture 1 is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0293] In some embodiments, 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.

[0294] In some embodiments, 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.

[0295] In some embodiments, after adding the carbonyl equivalent to the compound of Formula (I-i) and 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.

[0296] In some embodiments, adding the compound of Formula (I-ii) to mixture 1 to form mixture 2 comprises adding a second base to mixture 1 and 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. In some embodiments, 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). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N- diisopropylethylamine.

[0297] 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 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. 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. In some embodiments, after forming mixture 2, 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 14 hours to about 16 hours, or about 16 hours) to form the compound of Formula (I).

[0298] In some embodiments, 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. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the aqueous base is 5% w / w aqueous sodium bicarbonate. In some embodiments, the workup solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.

[0299] In some embodiments, method comprises recrystallizing the compound of Formula (I) from a solvent. In some embodiments, the process comprises recrystallizing the compound of Formula (I) from a solvent after adding the aqueous base and the workup solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6: 1 to about 1 : 10 (e.g., about 6: 1 to about 4:2, about 1 :7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3: 1, about 2:7, about 1 : 1, or about 5:2). In some embodiments, after recrystallizing the compound of Formula (I), the compound of Formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing the compound of Formula (I), the compound of Formula (I) is dried. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at a pressure lesser than atmospheric pressure. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at ambient temperature.

[0300] In some embodiments, 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’. In some embodiments, the compound of Formula (I-i) is in the form of a salt. In some embodiments, the compound of Formula (I-i) is in the form of a salt, and contacting the compound of Formula (I-i) with 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’.

[0301] In some embodiments, the compound of Formula (I-i) salt is a hydrochloride salt.

[0302] In some embodiments, adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1’ is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0303] In some embodiments, 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 contacting is performed under nitrogen. In some embodiments, the contacting is performed under argon.

[0304] In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0). In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.05. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 1.3. In some embodiments, the molar ratio of the carbonyl equivalent to the compound of Formula (I-i) is about 2.0.

[0305] In some embodiments, the molar ratio of the base to the compound of Formula (I-i) is about 1.0 to about 5.0 (e.g., about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 3.0, or about 3.5. In some embodiments, the molar ratio of 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.

[0306] In some embodiments, adding the compound of Formula (I-i) to the carbonyl equivalent and a base to form mixture 1 ’ is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0307] In some embodiments, 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.

[0308] In some embodiments, 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.

[0309] In some embodiments, 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’. In some embodiments, 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’. In some embodiments, 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’. In some embodiments, 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’ . In some embodiments, 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). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N- diisopropylethylamine.

[0310] In some embodiments, the molar ratio of the compound of Formula (I-ii) to the compound of Formula (I-i) is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the compound of Formula (I-ii) to the compound of Formula (I-i) is about 1.15. In some embodiments, the molar ratio of the 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.

[0311] 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 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.

[0312] In some embodiments, after forming mixture 2’, mixture 2’ is agitated at about 0 to about 10 °C (e g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 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).

[0313] In some embodiments, the process comprises adding water and an extraction solvent to mixture 2’ after agitating mixture 2’ to form mixture 3’. In some embodiments, the extraction solvent is ethyl acetate or isopropyl acetate. In some embodiments, the extraction solvent is isopropyl acetate. In some embodiments, the process comprises agitating and / or shaking mixture 3’. In some embodiments, the process comprises separating an organic liquid from mixture 3’. In some embodiments, the process comprises adding an aqueous base to the organic liquid to form mixture 4’. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the aqueous sodium bicarbonate is 5% w / w aqueous sodium bicarbonate. In some embodiments, 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).

[0314] In some embodiments, the compound of Formula (I) is precipitated from tetrahydrofuran and heptane. In some embodiments, the compound of Formula (I) is precipitated from isopropanol and water. In some embodiments, the compound of Formula (I) is precipitated from tetrahydrofuran and heptane, 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. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at about 25 °C to about 70 °C (e g., about 20 °C to about 25 °C, about 30 °C to about 60 °C, about 40 °C to about 50 °C, or about 45 °C). In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at about 45 °C. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at a pressure lesser than atmospheric pressure at about 20 °C to about 25 °C.

[0315] In some embodiments, 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.

[0316] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0317] In some embodiments, 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. In some embodiments, R’ is phenyl. In some embodiments, R’ is paranitrophenyl.

[0318] In some embodiments, 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

[0319] In some embodiments, 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)

[0320] In some embodiments, the compound of Formula (I-i) is added as a solution or slurry in a solvent. In some embodiments, the compound of Formula (I-i) is added as a solution in a solvent.

[0321] In some embodiments, 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.

[0322] In some embodiments, the compound of Formula (I-i) is in the form of a salt. In some embodiments, the salt is a hydrochloride salt.

[0323] In some embodiments, 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.

[0324] In some embodiments, combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1. In some embodiments, 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. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water. In some embodiments, when the base is combined with the solvent then R’OC(O)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.

[0325] In some embodiments, 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0326] In some embodiments, 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).

[0327] In some embodiments, adding the compound of Formula (I-i) to the mixture of R’OC(O)C1 and the base forms mixture 3. In some embodiments, mixture 3 is agitated for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, mixture 3 is agitated at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C).

[0328] In some embodiments, agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase is washed with an aqueous base. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the organic phase is concentrated at a pressure lesser than atmospheric pressure. In some embodiments, after concentrating the organic phase, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti -solvent is heptane.

[0329] In some embodiments, after adding the anti-solvent, 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. In some embodiments, 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.

[0330] In some embodiments, 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 formed. In some embodiments, the slurry is fdtered to provide the compound of (I-i-a). In some embodiments, the compound of (I-i-a) is rinsed with hexane or heptane (e.g., heptane). In some embodiments, after rinsing the compound of Formula (I-i-a), the compound of Formula (I-i-a) is dried. In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at a pressure lesser than atmospheric pressure. In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at about 25 °C to about 70 °C (e.g., about 30 °C to about 60 °C, about 40 °C to about 50 °C, about 40 °C to about 45 °C, about 45 °C to about 50 °C, or about 45 °C). In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at about 45 °C. In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at about 40 °C to about 45 °C. In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) at about 45 °C to about 50 °C. In some embodiments, drying the compound of Formula (I-i-a) comprises drying the compound of Formula (I-i-a) under an inert atmosphere (e.g., under nitrogen).

[0331] In some embodiments, 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). In some embodiments, the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 1.05. In some embodiments, the molar ratio of the R’OC(O)C1 to the compound of Formula (I-i) is about 1.3. In some embodiments, 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.

[0332] In some embodiments, the molar ratio of the base to the compound of Formula (I-i) is about 1.0 to about 5.0 (e.g., about 1.0 to about 3.0, about 2.0 to about 5.0, about 2.0 to about 4.0, about 2.5 to about 3.5, about 2.0, about 2.2, about 3.0, or about 3.5. In some embodiments, the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 2.0. In some embodiments, the molar ratio of the sodium bicarbonate to the compound of Formula (I-i) is about 2.2. 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.

[0333] In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, trimethylamine, and citric acid. In some embodiments, the base is sodium bicarbonate.

[0334] In some embodiments, 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).

[0335] 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 in the presence of a third base. In some embodiments, 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. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N- di i sopropy 1 ethyl ami ne .

[0336] 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 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.

[0337] 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). 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. 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) in the absence of a base.

[0338] 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 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. In some embodiments, 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.

[0339] In some embodiments, after adding the compound of Formula (I-i-a) to the compound of Formula (I-ii) or after adding the compound of Formula (I-ii) to the compound of Formula (I-i-a), mixture 5 is formed. In some embodiments, mixture 5 is agitated. 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 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is 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, 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).

[0340] In some embodiments, after agitating mixture 5, 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

[0341] 2 hours to about 4 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about

[0342] 3 hours, or about 1 hour). In some embodiments, 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.

[0343] In some embodiments, after agitating mixture 5’, a slurry is formed. In some embodiments, the slurry is filtered to provide the compound of Formula (I). In some embodiments, the compound of Formula (I) is washed with water. In some embodiments, the compound of Formula (I) is dried at a pressure lesser than atmospheric pressure.

[0344] In some embodiments, the compound of Formula (I) is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl alcohol and water. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl alcohol to water is about 1:3 to about 1 : 1 (e.g., about 1 :2). In some embodiments, the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2). In some embodiments, after recrystallizing the compound of Formula (I), the compound of Formula (I) is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing the compound of Formula (I), the compound of Formula (I) is dried. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at a pressure lesser than atmospheric pressure. In some embodiments, drying the compound of Formula (I) comprises drying the compound of Formula (I) at ambient temperature.

[0345] In some embodiments, the compound of Formula (I) has a purity of at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, about 98%, about 98.5%, about 99%, about 99.5%). In some embodiments, less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or no detectable amount) of a compound of Formula (A) is present as an impurity with the compound of Formula (I).

[0346] 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 (B) is present as an impurity with the compound of Formula (I).

[0347] In some embodiments, 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 R3is C1 -C6 haloalkyl.

[0348] In some embodiments, R” is isopropyl.

[0349] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-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.

[0350] In some embodiments, 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

[0351] 15 °C). In some embodiments, 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. In some embodiments, 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. In some embodiments, the contacting comprises adding heptane or hexanes (e.g., heptane) to mixture 6. In some embodiments, after adding the 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. In some embodiments, the solid is filtered to provide the compound of Formula (I-iii).

[0352] In some embodiments, 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. In some embodiments, 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. In some embodiments, contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent forms mixture 7.

[0353] In some embodiments, the C=N double bond in the compound of Formula (I-iv) has E geometry. In some embodiments, the C=N double bond in the compound of Formula (I-iv) has Z geometry. In some embodiments, the molar ratio of the tri haloalkylating reagent to the compound of Formula (I-iv) is about 1.0 to about 6.0 (e.g., about 1.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to about 4.0, about 1.0 to about 5.0, about 2.5 to about 3.5, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the trihaloalkylating reagent to the compound of Formula (I-iv) is about 3.0.

[0354] In some embodiments, 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.

[0355] In some embodiments, 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.

[0356] In some embodiments, the phase transfer reagent is added to the compound of Formula (I- iv) at about 5 °C to about 40 °C (e.g., about 10 °C to about 35 °C, about 15 °C to about 25 °C, about 15 °C to about 20 °C). In some embodiments, the phase transfer reagent is added to the compound of Formula (I-iv) at about 15 °C to about 20 °C.

[0357] In some embodiments, after adding the phase transfer reagent to the compound of Formula (I-iv), the mixture of the compound of Formula (I-iv) and the phase transfer reagent is cooled to about -40 °C to about 0 °C (e.g., -30 °C to about -5 °C, -25 °C to about -10 °C, -20 °C to about -15 °C). In some embodiments, after adding the phase transfer reagent to the compound of Formula (I-iv), the mixture of the compound of Formula (I-iv) and the phase transfer reagent is cooled to about -20 °C to about -15 °C.

[0358] In some embodiments, after cooling the mixture of the compound of Formula (I-iv) and the phase transfer reagent, the mixture of the compound of Formula (I-iv) and the phase transfer reagent is 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.

[0359] 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 -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.

[0360] In some embodiments, the trihaloalkylating reagent is added to the mixture of the compound of Formula (I-iv) and the phase transfer reagent dropwise.

[0361] In some embodiments, 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.

[0362] In some embodiments, contacting the compound of Formula (I-iv) with the trihaloalkylating reagent and the phase transfer reagent is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent comprises toluene, xylene, or benzene. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent is toluene.

[0363] In some embodiments, 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). In some embodiments, the trihaloalkylating reagent is added to the compound of Formula (I-iv) at about -20 °C to about -10 °C.

[0364] In some embodiments, 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. In some embodiments, the process comprises adding the trihaloalkylating reagent to the compound of Formula (I-iv) over about 1 hour.

[0365] In some embodiments, the process comprises agitating the compound of Formula (I-iv), the trihaloalkylating reagent, and the phase transfer reagent after adding the phase transfer reagent. In some embodiments, 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). In some embodiments, the phase transfer reagent is added to the compound of Formula (I-iv) at about -20 °C to about -10 °C.

[0366] In some embodiments, 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. In some embodiments, the several portions are 7 to 13 portions. In some embodiments, the several portions are 9 to 11 portions. In some embodiments, the several portions are 10 portions. In some embodiments, the 10 portions are 10 portions that are substantially the same in weight.

[0367] In some embodiments, 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).

[0368] In some embodiments, the process comprises adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from mixture 9 and concentrated under at a pressure lesser than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue. In some embodiments, the residue is purified using silica gel to provide the compound of Formula (I-iv). In some embodiments, the process comprises adding water and / or aqueous base to mixture 8 to form mixture 9’. In some embodiments, mixture 9’ comprises an organic phase and an aqueous phase. In some embodiments, the process comprises separating the organic phase from mixture 9’. In some embodiments, the process comprises distilling the organic phase to provide a distillate. In some embodiments, the process comprises passing the distillate through carbon (e.g., activated carbon). In some embodiments, 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. In some embodiments, the process comprises adding water to the concentrate, then reducing the volume of the mixture of water and concentrate to form mixture 9’ ’ . In some embodiments, the process comprises adding an anti-solvent to mixture 9”, then reducing the volume of mixture 9’ ’ to form mixture 9” ’. In some embodiments, the anti-solvent is heptane. In some embodiments, 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. In some embodiments, the precipitate is fdtered and dried to form the compound of Formula (I-iii).

[0369] In some embodiments, the trihaloalkylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,

[0370] 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). In some embodiments, the trifluoroalkylating reagent is a trifluoromethylating reagent. In some embodiments, the trifluoromethylating reagent is TMSCF3.

[0371] In some embodiments, 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, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmitylammonium bromide. Tn some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

[0372] In some embodiments, the process comprises preparing the compound of Formula (I-iv)

[0373] (Rl)m4 JL^CHOft by contacting a compound of Formula (I-v)r2with ^2^R" ; wherein R” is C1-C6 alkyl. In some embodiments, Z is O. In some embodiments, contacting the compound of Formula (I-v) with comprises contacting the compound of Formula (I-v) with

[0374] O n and a condensing base. In some embodiments, 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.

[0375] In some embodiments, the contacting is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0376] In some embodiments, 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.

[0377] In some embodiments, 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 0.8 to about 1.2, about 0.9 to about 1.1, about 1 .0 to about 1.1 , about 1 .2 to about 1 .4, about 0.95 to about 1 .05, about 1 .0 to about 1 .04, about 0.8, about 0.9, about 0.95, about 1.0, about 1.02, about 1.05, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 2.0, about 2.5, about 3.0, or about 3.5). In some embodiments, the molar ratio of the condensing base to the compound of Formula (I-v) is about 1.02.

[0378] O

[0379] In some embodiments, 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.

[0380] O

[0381] In some embodiments, 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).

[0382] O

[0383] In some embodiments, 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

[0384] O and the condensing base comprises agitating the compound of Formula (I-v) with anj 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). In some embodiments, 0 rsj" agitating the compound of Formula (I-v) withH2NR" and the condensing base comprises

[0385] O agitating the compound of Formula (I-v) with and the condensing base for about 14 hours.

[0386] O tsi"

[0387] In some embodiments, contacting the compound of Formula (I-v) withH2NR" and a condensing base comprises adding the to the compound of Formula (I-v), then adding

[0388] O the condensing base to the mixture of and the compound of Formula (I-v).

[0389] O

[0390] In some embodiments, 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

[0391] O

[0392] °C, about 15 °C to about 20 °C). In some embodiments adding the to the compound of Formula (I-v) is performed at about 15 °C to about 20 °C.

[0393] O

[0394] In some embodiments, 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

[0395] O condensing base to the mixture of and the compound of Formula (I-v) is performed at about 15 °C to about 20 °C.

[0396] O

[0397] In some embodiments, contacting the compound of Formula (I-v) with and a condensing base provides mixture 10. In some embodiments, mixture 10 is agitated for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, 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.

[0398] In some embodiments, after agitating mixture 10, 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.

[0399] In some embodiments, cooling mixture 10 comprises forming a slurry. In some embodiments, the process comprises filtering the slurry to provide a solution. In some embodiments, the process comprises reducing the volume of the solution under a pressure lesser than atmospheric pressure. In some embodiments, 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. In some embodiments, the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol. In some embodiments, steps (iii) and (iv) are required. In some embodiments, the process 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). In some embodiments, the process comprises cooling the concentrate to about 15 °C to about 25 °C. In some embodiments, the process comprises adding water to the concentrate after cooling the concentrate to form mixture 10’. In some embodiments, 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). In some embodiments, the process comprises agitating mixture 10’ for about 14 hours. In some embodiments, after agitating mixture 10’, a slurry is formed. In some embodiments, the slurry is fdtered to provide the compound of Formula (I-v). In some embodiments, 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.

[0400] In some embodiments, the process comprises

[0401] IS)"

[0402] In some embodiments, contacting the compound of Formula (I-v) withH2N R" and a

[0403] 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).

[0404] In some embodiments, the process comprises preparing the compound of Formula (I-v) by contacting a compound of Formula (I-vi) acid. In some embodiments, Z is O.

[0405] In some embodiments, the acid is a protic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron (III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).

[0406] In some embodiments, the acid is acetic acid.

[0407] In some embodiments, contacting the compound of Formula (I-vi) with an acid comprises adding the compound of Formula (I-vi) to the acid. In some embodiments, contacting the compound of Formula (I-vi) with an acid comprises contacting the compound of Formula (I-vi) with the acid in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, adding the compound of Formula (I-vi) to the acid forms mixture 11. In some embodiments, after adding the compound of Formula (I-vi) to the acid, mixture 11 is heated at about 80 °C to about 160 °C (e.g., about 90 °C to about 150 °C, about 100 °C to about 140 °C, about 110 °C to about 130 °C, about 115 °C to about 125 °C, or about 120 °C). In some embodiments, after adding the compound of Formula (I-vi) to the acid, mixture 11 is heated at about 120 °C. In some embodiments, after adding the compound of Formula (I-vi) to 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 compound of Formula (I-vi) to the acid, mixture 11 is agitated for about 8 hours.

[0408] In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base. In some embodiments, the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight). In some embodiments, after washing the organic phase with the aqueous base, the organic phase is agitated with water and Na2S2O4. In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 8 hours. In some embodiments, agitating the organic phase with water and Na2S2C forms a solid. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, and the pH of the solution is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10) and then agitated for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a biphasic mixture. In some embodiments, the biphasic mixture comprises an organic phase and an aqueous phase. In some embodiments, the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide the compound of Formula (I-v).

[0409] In some embodiments, 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. In some embodiments, 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)

[0410] OEt with and a base. In some embodiments, 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.

[0411] In some embodiments, contacting the compound of Formula (I-vii) with and a base is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is N,N-dimethylformamide.

[0412] In some embodiments, contacting the compound of Formula (I-vii)

[0413] OEt withLG\An °CEtand a base comprises contacting the compound of Formula (I-vii) with a base, and sodium iodide.

[0414] In some embodiments, contacting the compound of Formula (I-vii)

[0415] 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). In some embodiments, contacting the compound of

[0416] Formula (I-vii) base, and sodium iodide is performed at about 120 °C.

[0417] OEt

[0418] LG^ Jx

[0419] In some embodiments, adding the compound of Formula (I-vii) to OEt, a base, and sodium iodide forms mixture 13. In some embodiments, 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.

[0420] In some embodiments, the process comprises preparing the compound of Formula (I-v) by

[0421] Hal (Rl)r"-LJLJ>= / contacting a compound of Formula (I-viii)HO with an acid; wherein Hal is selected from chloro, bromo, iodo, and trifluorom ethanesulfonyl. In some embodiments, Hal is chloro. In some embodiments, the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.

[0422] In some embodiments, contacting the compound of Formula (I-viii) wi h the acid is performed in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether.

[0423] In some embodiments, 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.

[0424] In some embodiments, 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, R2is C1-C6 alkyl. In some embodiments, R2is methyl.

[0425] Hal

[0426] In some embodiments, contacting the compound of Formula (I-ix) with ^^Hal comprises

[0427] Hal contacting the compound of Formula (I-ix) with "^^Hal and a base. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the contacting is performed in a solvent.

[0428] In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, 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. In some embodiments, the solvent is methyl tert-butyl ether.

[0429] Hal

[0430] In some embodiments, contacting the compound of Formula (I-ix) with and 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). In some

[0431] Hal embodiments, contacting the compound of Formula (I-ix) with and a base is performed at about 25 °C.

[0432] In some embodiments, Z is O; m is 2; each R1is fluoro; R2is methyl; R2is trifluoromethyl;

[0433] Ring A is , wherein * denotes the point of attachment to the urea and ** denotes the point of attachment to R4; n is 1; and R4is -NH2.

[0434] In some embodiments, the carbon substituted with R3has the (R) configuration.

[0435] In some embodiments, the compound of Formula (I) In some embodiments, the compound of Formula (I) is not a compound selected from the

[0436] o

[0437] In some embodiments, when Z is NRXand R3is methyl, Ring A is not phenyl.

[0438] In some embodiments, the compound of Formula (I) is a compound of Formula (X): or a salt and / or solvate thereof, wherein:

[0439] Z is O or NRx;

[0440] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is an independently selected halogen; m is 0, 1, 2, or 3;

[0441] R2is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0442] R3is 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;

[0443] Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: halogen, C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and a 3-6 membered heterocyclyl or 3-6 membered cycloalkyl each optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SC>2(C1-C6 alkyl), -SO2(NH2; or

[0444] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and wherein the compound is not a compound selected from the group consisting of:

[0445]

[0446] In some embodiments, 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”). In some embodiments, the excluded compounds are flat structures, as indicated above. In some embodiments, the excluded compounds are specific stereoisomers, e.g. specific enantiomers or diastereomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

[0447] In some embodiments, the compound of Formula (I) is Formula (I-A): or a salt and / or solvate thereof, wherein:

[0448] R1Ais halogen;

[0449] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0450] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0451] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with

[0452] 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl;

[0453] Ring Al is a 6 membered heteroaryl;

[0454] R4is independently selected from the group consisting of C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring Al that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SCh(Cl-C6 alkyl), and -SO2(NH2); or

[0455] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H. In some embodiments, Ring Al is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, Ring Al is pyrimidinyl. In some embodiments, Ring Al is pyridyl. In some embodiments, Ring Al is pyrazolyl.

[0456] In some embodiments, 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.

[0457] In some embodiments of Formula (I-A), wherein: R4Bis selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0458] In some embodiments of Formula (I-A), RAand RBare each hydrogen.

[0459] In some embodiments, the compound of Formula (I) is Formula (I-B): or a salt and / or solvate thereof, wherein:

[0460] R1Ais halogen;

[0461] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0462] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0463] R3is 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;

[0464] R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SC>2(NH2); or

[0465] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0466] In some embodiments, the compound of Formula (I) is Formula (I-C): or a salt and / or solvate thereof, wherein:

[0467] R1Ais halogen;

[0468] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0469] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0470] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0471] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0472] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-D): or a salt and / or solvate thereof, wherein:

[0473] R1Ais halogen;

[0474] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0475] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0476] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0477] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or

[0478] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1„ -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0479] In some embodiments, the compound of Formula (I) is Formula (I-E): or a salt and / or solvate thereof, wherein:

[0480] R1Ais halogen;

[0481] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1 -C6 haloalkyl;

[0482] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0483] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0484] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0485] In some embodiments, the compound of Formula (I) is Formula (I-F): or a salt and / or solvate thereof, wherein:

[0486] R1Ais halogen;

[0487] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0488] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0489] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0490] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0491] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and wherein the compound is not

[0492] In some embodiments, the compound of Formula (I) is Formula (I-G): or a salt and / or solvate thereof, wherein:

[0493] R1Ais halogen;

[0494] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0495] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0496] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0497] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0498] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CC>2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0499] In some embodiments, the compound of Formula (I) is Formula (I-H): or a salt and / or solvate thereof, wherein:

[0500] R1Ais halogen;

[0501] R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A);

[0502] R2is a C1-C6 alkyl or C1-C6 haloalkyl;

[0503] R3is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0504] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRclRD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0505] In some embodiments, the compound of Formula (I) is Formula (I-J): or a salt and / or solvate thereof, wherein: Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0506] R1Ais halogen;

[0507] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0508] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0509] R3is 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;

[0510] Ring Al is a 6 membered heteroaryl;

[0511] R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring Al that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and REis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0512] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0513] In some embodiments, the compound of Formula (I) is Formula (I-K): or a salt and / or solvate thereof, wherein:

[0514] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen;

[0515] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0516] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0517] R3is 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;

[0518] R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0519] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0520] In some embodiments, the compound of Formula (I) is Formula (I-L): or a salt and / or solvate thereof, wherein:

[0521] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0522] R1Ais halogen;

[0523] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0524] R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a Cl -C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0525] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0526] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, and -CO2H.

[0527] In some embodiments, the compound of Formula (I) is Formula (I-M): or a salt and / or solvate thereof, wherein:

[0528] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0529] R1Ais halogen;

[0530] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0531] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0532] R3is a C1-C6 alkyl, a Cl -C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0533] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or

[0534] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1„ -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0535] In some embodiments, the compound of Formula (I) is Formula (I-N): or a salt and / or solvate thereof, wherein:

[0536] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0537] R1Ais halogen;

[0538] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0539] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0540] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0541] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl - C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0542] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-O): or a salt and / or solvate thereof, wherein:

[0543] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0544] R1Ais halogen;

[0545] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0546] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0547] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0548] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0549] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0550] In some embodiments, the compound of Formula (I) is Formula (I-P): or a salt and / or solvate thereof, wherein:

[0551] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen;

[0552] R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A);

[0553] R2is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0554] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0555] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRcRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or

[0556] Rcand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRc1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0557] In some embodiments, the compound of Formula (I) is Formula (I-Q): or a salt and / or solvate thereof, wherein:

[0558] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0559] R1Ais halogen;

[0560] R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A);

[0561] R2is a C1-C6 alkyl or C1-C6 haloalkyl;

[0562] R3is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0563] R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRclRD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0564] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0565] In some embodiments, each R1is an independently selected halogen. In some embodiments, each R1is independently selected from fluoro and chloro. In some embodiments, each R1is independently selected from fluoro and bromo. In some embodiments, each R1is fluoro. In some embodiments, at least one R1is an independently selected halogen. In some embodiments, at least one R1is independently selected from fluoro and chloro. In some embodiments, at least one R1is fluoro.

[0566] In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R1is C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R1is hydroxymethyl. In some embodiments, at least one R1is unsubstituted C1-C6 alkyl. In some embodiments, at least one R1is methyl. In some embodiments, at least one R1is C3-C6 cycloalkyl. In some embodiments, at least one R1is cyclopropyl.

[0567] In some embodiments, m is 2; one R1is halogen; and the other R1is C 1-C6 alkyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is methyl In some embodiments, m is 2; one R1is halogen; and the other R1is C3-C6 cycloalkyl. In some embodiments, m is 2; one R1is halogen; and the other R1is cyclopropyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is cyano. In some embodiments, m is 2; one R1is halogen; and the other R1is halogen. In some embodiments, m is 2; one R1is fluoro; and the other R1is fluoro. In some embodiments, R2is hydroxyl. In some embodiments, R2is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R2is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R2is C1-C3 alkyl substituted with hydroxyl. In some embodiments, R2is hydroxymethyl. In some embodiments, R2is an unsubstituted C1-C6 alkyl. In some embodiments, R2is unsubstituted C1-C3 alkyl. In some embodiments, R2is methyl.

[0568] In some embodiments, R2is a C1-C6 haloalkyl. In some embodiments, R2is a C1-C3 haloalkyl. In some embodiments, R2is difluoromethyl. In some embodiments, R2is trifluoromethyl.

[0569] In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0570] In some embodiments, R2is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is an unsubstituted C3-C6 cycloalkyl.

[0571] In some embodiments, R3is a C1-C6 alkyl. In some embodiments, R3is a C1-C3 alkyl. In some embodiments, R3is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0572] In some embodiments, R3is a C1-C6 haloalkyl. In some embodiments, R3is a C1-C3 haloalkyl. In some embodiments, R3is difluoromethyl. In some embodiments, R3is trifluoromethyl.

[0573] In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R3is C3- C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is an unsubstituted C3-C6 cycloalkyl. In some embodiments, the R3C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0574] In some embodiments, R’ is C1-C6 alkyl. In some embodiments, R’ is C1-C4 alkyl. In some embodiments, R’ is C1-C3 alkyl. In some embodiments, R’ is isopropyl. In some embodiments, R’ is methyl. In some embodiments, R’ is ethyl. In some embodiments, R’ is n- propyl.

[0575] In some embodiments, 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.

[0576] In some embodiments, R” is C1-C6 alkyl. In some embodiments, R” is C1-C4 alkyl. In some embodiments, R” is C1-C3 alkyl. In some embodiments, R” is isopropyl. In some embodiments, R” is methyl. In some embodiments, R” is ethyl. In some embodiments, R” is n- propyl.

[0577] In some embodiments, 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.

[0578] In some embodiments, the compound of Formula (I-i) is a compound of Formula (I-i-i):

[0579] In some embodiments, 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)

[0580] In some embodiments, the compound of Formula (I-v) is a compound of Formula (I-v-i)

[0581] In some embodiments, the compound of Formula (I-viii) is a compound of Formula (I-viii- In some embodiments, the compound of Formula (I) is or a salt and / or solvate thereof, wherein R3, R4, 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 R3, R4, and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0582] or a salt and / or solvate thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0583] In some embodiments, the compound of Formula (I) is or a salt and / or solvate thereof, wherein R3, R4, and Ring A are as described herein.

[0584] In some embodiments, the compound of Formula (I) is or a salt and / or solvate thereof, wherein R3, R4, and Ring A are as described herein.

[0585] In some embodiments, the compound of Formula (I) is or a salt and / or solvate thereof, wherein R3, R4, and Ring A are as described herein.

[0586] Some embodiments provide a process of preparing Compound 1 :

[0587] (i) a carbonyl equivalent or an isocyanate-forming reagent; and

[0588] (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0589] Some embodiments provide Compound 1 : salt and / or solvate thereof; prepared by a process comprising contacting

[0590] (i) a carbonyl equivalent or an isocyanate-forming reagent; and

[0591] (ii) pyrimidine-2,5-diamine having the structure

[0592] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is a carbonyl equivalent. In some embodiments, 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. In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidin-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. In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0593] In some embodiments, the carbonyl equivalent or isocyanate-forming reagent is an or isocyanate-forming reagent. In some embodiments, 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.

[0594] Some embodiments provide a process of preparing Compound 1 :

[0595] (i) a carbonyl equivalent; and

[0596] (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0597] Some embodiments provide Compound 1 : prepared by a process comprising contacting

[0598] (i) a carbonyl equivalent; and

[0599] (ii) pyrimidine-2,5-diamine having the structure

[0600] In some embodiments, 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

[0601] 1 to form mixture 2.

[0602] In some embodiments, 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). In some In some embodiments, 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). In some embodiments, the molar ratio of the sodium bicarbonate to to form mixture 1 is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0603] In some embodiments, 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.

[0604] In some embodiments, 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.

[0605] In some embodiments, 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. In some embodiments, 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). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

[0606] In some embodiments, 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.

[0607] In some embodiments, after forming mixture 2, 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 14 hours to about 16 hours, or about 16 hours) to form Compound 1.

[0608] In some embodiments, warming then agitating mixture 2 to form Compound 1 comprises adding an aqueous base and a workup solvent after the warming and agitating. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the aqueous base is 5% w / w aqueous sodium bicarbonate. In some embodiments, the workup solvent is isopropyl acetate or isopropyl alcohol. In some embodiments, the solvent is isopropyl acetate.

[0609] In some embodiments, the process comprises recrystallizing Compound 1 from a solvent. In some embodiments, the process comprises Compound 1 from a solvent after adding the aqueous base and the workup solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6: 1 to about 1 : 10 (e.g., about 6:1 to about 4:2, about 1 :7 to about 3:7, about 4:6 to about 6:4, about 4:2 to about 3: 1, about 2:7, about 1: 1, or about 5:2). In some embodiments, after recrystallizing Compound 1, Compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing Compound 1, Compound 1 is dried. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure. In some embodiments, drying Compound 1 comprises drying Compound 1 at ambient temperature.

[0610] carbonyl equivalent and a base to form mixture 1’, then adding pyrimidine-2,5-diamine to mixture mixture 1’, then adding pyrimidine-2,5-diamine to mixture 1’ to form mixture 2’. to form mixture 1 ’ is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0611] In some embodiments, adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere. In some embodiments, the contacting is performed under nitrogen. In some embodiments, the contacting is performed under argon.

[0612] In some embodiments, 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

[0613] 1.2, about 1.3, about 2.0). In some embodiments, 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. In some embodiments, the molar ratio of the sodium bicarbonate to

[0614] to form mixture 1 ’ is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0615] In some embodiments, 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.

[0616] In some embodiments, 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’. 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’. 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’, then pyrimidine-2,5- diamine to mixture 1’. In some embodiments, 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). In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0617] In some embodiments, the molar ratio of pyrimidine-2,5-diamine to Compound 1 is about 1.0 to about 4.0 (e.g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of pyrimidine- 2,5-diamine to Compound 1 is about 1.15.

[0618] In some embodiments, the molar ratio of the third base to Compound 1 is about 1.0 to about 4.0 (e g., about 1.0 to about 3.0, about 1.0 to about 2.0, about 1.0 to about 1.5, about 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.15, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the third base to Compound 1 is about 2.0.

[0619] 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 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.

[0620] In some embodiments, after forming mixture 2, mixture 2 is agitated at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 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.

[0621] In some embodiments, the process comprises adding water and an extraction solvent to mixture 2’ after agitating mixture 2’ to form mixture 3’. In some embodiments, the extraction solvent is ethyl acetate or isopropyl acetate. In some embodiments, the extraction solvent is isopropyl acetate. In some embodiments, the process comprises agitating and / or shaking mixture 3’. In some embodiments, the process comprises separating an organic liquid from mixture 3’. In some embodiments, the process comprises adding an aqueous base to the organic liquid to form mixture 4’. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the aqueous sodium bicarbonate is 5% w / w aqueous sodium bicarbonate. In some embodiments, 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.

[0622] In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane. In some embodiments, Compound 1 is precipitated from isopropanol and water. In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane, 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. In some embodiments, drying Compound 1 comprises drying Compound 1 at about 25 °C to about 70 °C (e.g., about 20 °C to about 25 °C, about 30 °C to about 60 °C, about 40 °C to about 50 °C, or about 45 °C). In some embodiments, drying Compound 1 comprises drying Compound 1 at about 45 °C. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure at about 20 °C to about 25 °C.

[0623] In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5- dioxopyrrolidin-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.

[0624] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0625] In some embodiments, 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. In some embodiments, R’ is phenyl. In some embodiments, R’ is paranitrophenyl.

[0626] In some embodiments, contacting pyrimidine-

[0627] 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base;

[0628] in some embodiments, 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.

[0629] In some embodiments, the form of a salt. In some embodiments, the salt is a hydrochloride salt.

[0630] In some embodiments, contacting pyrimidine¬

[0631] 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base;

[0632] In some embodiments, combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1. In some embodiments, 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.

[0633] In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water. In some embodiments, when the base is combined with the solvent then R’OC(O)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.

[0634] In some embodiments, 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). In some embodiments, 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. In some embodiments, adding the mixture of R’OC(O)C1 and the base is performed at about 0 °C to about 5 °C. In some

[0635] R’OC(O)C1 and the base as a solution in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0636] In some embodiments, 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).

[0637] In some embodiments, adding the mixture of R’OC(O)C1 and the base forms mixture 3. In some embodiments, mixture 3 is agitated for about 15 minutes to about 48 hours (e g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, mixture 3 is agitated at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C).

[0638] In some embodiments, agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase was washed with an aqueous base. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the organic phase is concentrated at a pressure lesser than atmospheric pressure. In some embodiments, after concentrating the organic phase, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti-solvent is heptane.

[0639] In some embodiments, after adding the anti-solvent, 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. In some embodiments, 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.

[0640] In some embodiments, 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

[0641] (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

[0642] °C to about 50 °C, or about 45 °C). In some embodiments,

[0643] (e.g., under nitrogen).

[0644] In some embodiments, the molar ratio of the

[0645] 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

[0646] 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0, or about 3.0). In some embodiments, the molar ratio of the R’OC(O)C1 to about 1.05. In some embodiments, the molar ratio of the R’OC(O)C1 to about 1.3. In some embodiments, the molar ratio of the R’OC(O)C1 to about 2.0. In some embodiments, the molar ratio of the R’OC(O)C1 to about 3.0. In some embodiments, 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. In some embodiments, 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. In some embodiments, the base is sodium bicarbonate.

[0647] In some embodiments, contacting pyrimidine¬

[0648] 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. In some embodiments, 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. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0649] In some embodiments, 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

[0650] Compound 1 comprises adding pyrimidine-2,5-diamine in the absence of a base.

[0651] In some embodiments, contacting to form Compound 1 comprises adding pyrimidine-2,5-diamine

[0652] embodiments, the solvent is N,N-dimethylacetamide. absence of a base.

[0653] In some embodiments, 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-

[0654] 2,5-diamine to form Compound 1 is performed under nitrogen. In some embodiments, contacting pyrimidine-2,5-diamine to form Compound 1 is performed under argon. In some embodiments, 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.

[0655] In some embodiments, after adding \ to pyrimidine-2,5-diamine or after adding pyrimidine-2,5-diamine mixture 5 is formed. In some embodiments, mixture 5 is agitated. 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 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is 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, 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

[0656] °C, about 35 °C to about 60 °C, about 40 °C to about 55 °C, about 45 °C to about 50 °C, about 45 °C, about 50 °C, or about 55°C).

[0657] In some embodiments, after agitating mixture 5, 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 2 hours to about 4 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, the process 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.

[0658] In some embodiments, after agitating mixture 5’, a slurry is formed. In some embodiments, the slurry is filtered to provide Compound 1. In some embodiments, Compound 1 is washed with water. In some embodiments, Compound 1 is dried at a pressure lesser than atmospheric pressure.

[0659] In some embodiments, Compound 1 is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl alcohol and water. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl alcohol to water is about 1 :3 to about 1 : 1 (e.g., about 1:2). In some embodiments, the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2). In some embodiments, after recrystallizing Compound 1, Compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing Compound 1, Compound 1 is dried. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure. In some embodiments, drying Compound 1 comprises drying Compound 1 at ambient temperature.

[0660] In some embodiments, Compound 1 has a purity of at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, about 98%, about 98.5%, about 99%, about 99.5%). In some embodiments, less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or no detectable amount) of Impurity 1 is present as an impurity with Compound 1. (Impurity 1).

[0661] In some embodiments, less than 10% (e.g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or no detectable amount) of Impurity 2 is present as an impurity with Compound 1.

[0662] (Impurity 2).

[0663] In some embodiments, the process comprises preparing a crystalline hemihydrate Form 1 by a method comprising:

[0664] (a) 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 isopropanol to form a solution;

[0665] (b) adding water to the solution to form a mixture;

[0666] (c) reducing the temperature of the mixture then maintaining the temperature for a first period of time;

[0667] (d) increasing the temperature of the mixture then maintaining the temperature for a second period of time;

[0668] (e) reducing the temperature of the mixture then maintaining the temperature for a third period of time; and

[0669] (f) isolating Form 1 from the mixture.

[0670] In some embodiments, Form 1 has one or more characteristics described below.

[0671] In some embodiments, 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.

[0672] In some embodiments, 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.

[0673] In some embodiments, 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.

[0674] In some embodiments, 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.

[0675] In some embodiments, 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.

[0676] In some embodiments, 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.

[0677] In some embodiments, 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.

[0678] In some embodiments, 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.

[0679] In some embodiments, 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.

[0680] In some embodiments, 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.

[0681] In some embodiments, 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.

[0682] In some embodiments, 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.

[0683] In some embodiments, 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.

[0684] In some embodiments, 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.

[0685] In some embodiments, 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.

[0686] In some embodiments, 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.

[0687] In some embodiments, 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.

[0688] In some embodiments, 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.

[0689] In some embodiments, 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.

[0690] In some embodiments, 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.

[0691] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 20) at 6.4,

[0692] 15.8, and 18.3.

[0693] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 29) at 6.4,

[0694] 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, and 31.3.

[0695] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 20) at 6.4,

[0696] 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, 31.3. 28.3, 29.2, 22.8, 28.0, 25.3, 21.5, 19.9, 27.6, 20.5, 21.8, 25.1, and 25.8.

[0697] In some embodiments, Form 1 is characterized by an XRPD pattern substantially the same as that shown in FIG. 1.

[0698] Form 1 can also have one or more of the following characteristics.

[0699] In some embodiments, 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. In some embodiments, 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.

[0700] In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 5% to about 30% (e.g., about 5% to about 27%, about 5% to about 25%, about 5% to about 22%, about 10% to about 25%, about 20% to about 22%, about 14% to about 20%, or about 17.6%) at about 150 °C to about 250 °C (e.g., about 230 to about 260 °C about 230 °C to about 250 °C, about 162 °C to about 248 °C, about 230 °C to about 240 °C, about 240 °C to about 260 °C, about 240 °C to about 250 °C, about 242 °C to about 248 °C, or about 245 °C). In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245 °C. In some embodiments, the Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 162 °C to about 248 °C.

[0701] In some embodiments, the Form 1 has a TGA curve that is substantially the same as that shown in FIG. 2. In some embodiments, 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.

[0702] In some embodiments, 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.

[0703] In some embodiments, the Form 1 has a Differential Scanning Calorimetry (DSC) thermogram that is substantially the same as that shown in FIG. 3.

[0704] In some embodiments, 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.

[0705] In some embodiments, the Form 1 has a DSC first cooling cycle thermogram substantially the same as that shown in FIG. 4.

[0706] In some embodiments, the Form 1 is a hemihydrate.

[0707] In some embodiments, 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%.

[0708] In some embodiments, the Form 1 is substantially pure.

[0709] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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*. In some embodiments, 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 *.

[0710] In some embodiments, 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.

[0711] In some embodiments, the solution formed in step (a) has a concentration of about 0.08 g / mL to about 1.65 g / mL (e.g., about 0.09 g / mL to about 1.55 g / mL, about 0.1 g / mL to about 0.145 g / mL, about 0.1 g / mL to about 0.135 g / mL, about 0.12 g / mL to about 0.13 g / mL, or about 0.125 g / mL). In some embodiments, the solution formed in step (a) has a concentration of about 0.125 g / mL.

[0712] In some embodiments, step (a) comprises cooling the solution to about 30 °C to 50 °C (e.g., about 35 °C to about 45 °C, or about 40 °C). In some embodiments, step (a) comprises cooling the solution to about 40 °C. In some embodiments, the cooling is performed at about 0.1 °C 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. 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 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.

[0713] In some embodiments, about l / 8thto about l / 32ndof the water is added to the solution per hour. 1 / 16thof the water is added to the solution per hour. In some embodiments, about 1 / 16thof the water is added to the solution per hour.

[0714] In some embodiments, the temperature of the mixture in step (c) is reduced to about 1 °C to about 15 °C (e.g., about 1 °C to about 10 °C, about 2 °C to about 8 °C, about 3 °C to about 7 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (c) is reduced to about 5 °C. In some embodiments, the first 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). In some embodiments, the first period of time is about 1 hour. In some embodiments, the first period of time is about 1 minute.

[0715] In some embodiments, the temperature of the mixture in step (d) is increased to about 25 °C to about 60 °C (e.g., about 25 °C to about 50 °C, about 30 °C to about 60 °C, about 30 °C to about 50 °C, about 35 °C to about 45 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (c) is increased to about 40 °C. In some embodiments, the second 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). In some embodiments, the second period of time is about 1 hour. In some embodiments, the second period of time is about 1 minute.

[0716] In some embodiments, the temperature of the mixture in step (e) is reduced to about 1 °C to about 15 °C (e.g., about 1 °C to about 10 °C, about 2 °C to about 8 °C, about 3 °C to about 7 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (e) is reduced to about 5 °C. In some embodiments, the third 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). In some embodiments, the third period of time is about 11 hours. In some embodiments, the third period of time is about 11 hours.

[0717] In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1. In some embodiments, the rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water.

[0718] In some embodiments, 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.

[0719] In some embodiments, 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. In some embodiments, drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure. In some embodiments, 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).

[0720] In some embodiments, 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)-

[0721] 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture; and isolating a solid from the third mixture to provide Form 1.

[0722] In some embodiments, the process comprises preparing a crystalline hemihydrate Form 1 by a method comprising:

[0723] (a) 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;

[0724] (b) adding water to the solution to form a first mixture;

[0725] (c) adding (R)- 1 -(2-aminopyrimidin-5 -y 1) - 3 -( 1 -(5 , 7-difluoro-3 -methylbenzofuran-2-y 1)- 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture;

[0726] (d) agitating the second mixture;

[0727] (e) adding water to the second mixture to form a third mixture;

[0728] (f) agitating the third mixture; and

[0729] (g) isolating Form 1 from the third mixture.

[0730] In some embodiments, the solution formed in step (a) has a concentration of about 0.03 g / mL to about 1 g / mL (e.g., about 0.03 g / mL to about 0.5 g / mL, about 0.05 g / mL to about 0.3 g / mL, about 0.1 g / mL to about 0.2 g / mL, about 0.13 g / mL to about 0.18 g / mL, or about 0.16 g / mL). In some embodiments, the solution formed in step (a) has a concentration of about 0.16 g / mL.

[0731] In some embodiments, 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. In some embodiments, 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. In some embodiments, the weight of the first portion of methanol is about 4 to about 8 times (e.g., about 0.5 to about 3 times, about 1 to about 3 times, or about 1.6 times (e.g., about 1.6 times)) the weight of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved.

[0732] In some embodiments, the solution is cooled to about 5 °C to about 35 °C (e.g., about 10 °C to about 30 °C, about 15 °C to about 25 °C, about 15 °C to about 20 °C, about 20 °C to about 25 °C, about 17 °C to about 23 °C, about 15 °C, about 20 °C, or about 25 °C (e.g., about 15 °C to about 25 °C)) before adding the water in step (b). In some embodiments, the water added in step (b) is purified water. In some embodiments, adding the water in step (b) comprises filtering the water through a filter, then adding the water to form the first mixture. In some embodiments, 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).

[0733] In some embodiments, 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).

[0734] In some embodiments, 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. In some embodiments, 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.

[0735] In some embodiments, 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)). In some embodiments, 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)).

[0736] In some embodiments, 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). In some embodiments, 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)).

[0737] In some embodiments, 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

[0738] 15 °C to about 25 °C)). In some embodiments, 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

[0739] 16 hours)).

[0740] In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1. In some embodiments, the rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water. In some embodiments, isolating Form 1 from the third mixture comprises:

[0741] (i) filtering the third mixture to provide a solid;

[0742] (ii) rinsing the solid with methanol and water; and

[0743] (iii) drying the solid to provide Form 1.

[0744] In some embodiments, 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). In some embodiments, the ratio of methanol to water is about 1 : 100 to about 100: 1 (e.g., about 20:80 to about 90: 10, about 30:70 to about 90: 10, about 50:50 to about 80:20, about 55:45 to about 65:35, or about 61 :39 (e.g., about 61 :39)).

[0745] In some embodiments, drying the solid comprises drying the solid at about 30 °C to about 60 °C (e.g., about 30 °C to about 50 °C, about 35 °C to about 45 °C, about 35 °C to about 40 °C, about 40 °C to about 45 °C, about 35 °C, about 40 °C, or about 45 °C (e.g., about 35 °C to about 45 °C)). In some embodiments, drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure. In some embodiments, drying the solid comprises drying the solid under an inert gas (e.g., nitrogen or argon (e.g., nitrogen)). In some embodiments, drying the solid comprises drying the solid until the solid 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. In some embodiments, 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.

[0746] In some embodiments, the process comprises preparing contacting wherein R3is C1-C6 haloalkyl.

[0747] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-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.

[0748] In some embodiments, the contacting comprises adding

[0749] In some embodiments, 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). In some embodiments, 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 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. 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

[0750] 15 °C). In some embodiments, the agitating is performed at about 5 °C to about 15 °C. In some embodiments, the contacting comprises adding heptane or hexanes (e.g., heptane) to mixture 6. In some embodiments, after adding the 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. In some embodiments, the solid is filtered to provide

[0751] In some embodiments, the process comprises preparing In some embodiments, the C=N double bond has E geometry. In some embodiments, the C=N double bond i has Z geometry.

[0752] In some embodiments, 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). In some embodiments, the molar ratio of the trifluoromethylating reagent out 3.0.

[0753] In some embodiments, 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

[0754] 1.0. 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

[0755] 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 t about 15 °C to about 20 °C.

[0756] In some embodiments, after adding the phase transfer reagent the phase transfer reagent is cooled to about -40 °C to about 0

[0757] °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. 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

[0758] 1.5 hours, or about 1 hour). In some embodiments, after cooling the mixture and the phase transfer reagent, the mixture the phase transfer reagent is agitated for about 1 hour.

[0759] In some embodiments, adding the trifluoromethylating reagent to the mixture of the phase transfer reagent is performed at about -40 °C to about 0 °C (e.g.,

[0760] -30 °C to about -5 °C, -25 °C to about -10 °C, -20 °C to about -15 °C). In some embodiments, 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.

[0761] In some embodiments, 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.

[0762] In some embodiments, contacting with the trifluoromethylating reagent and the phase transfer reagent is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent comprises toluene, xylene, or benzene. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent is toluene.

[0763] In some embodiments, 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). In some embodiments, the trifluoromethylating reagent is added t t about -20 °C to about -10 °C.

[0764] In some embodiments, 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. In some embodiments, the process comprises adding the trifluoromethylating reagent over about 1 hour.

[0765] In some embodiments, the process comprises agitating , the trifluoromethylating reagent, and the phase transfer reagent after adding the phase transfer reagent.

[0766] In some embodiments, 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). In some embodiments, the phase transfer reagent is added t about -

[0767] 20 °C to about -10 °C.

[0768] In some embodiments, 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. In some embodiments, the several portions are 7 to 13 portions. In some embodiments, the several portions are 9 to 11 portions. In some embodiments, the several portions are 10 portions. In some embodiments, the 10 portions are 10 portions that are substantially the same in weight.

[0769] In some embodiments, 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).

[0770] In some embodiments, the process comprises adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from mixture 9 and concentrated under at a pressure lesser than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue. In some embodiments, the

[0771] In some embodiments, the process comprises adding water and / or aqueous base to mixture 8 to form mixture 9’. In some embodiments, mixture 9’ comprises an organic phase and an aqueous phase. In some embodiments, the process comprises separating the organic phase from mixture 9’. In some embodiments, the process comprises distilling the organic phase to provide a distillate. In some embodiments, the process comprises passing the distillate through carbon (e g., activated carbon). In some embodiments, 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. In some embodiments, the process comprises adding water to the concentrate, then reducing the volume of the mixture of water and concentrate to form mixture 9’ ’ . In some embodiments, the process comprises adding an anti-solvent to mixture 9”, then reducing the volume of mixture 9’ ’ to form mixture 9” ’. In some embodiments, the anti-solvent is heptane. In some embodiments, the process comprises adding a portion (e.g., a previously prepared portion) mixture 9”’ to form a precipitate. In some embodiments, the precipitate is filtered and dried to form

[0772] In some embodiments, the trifluoromethylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,

[0773] EtsGeNa / CsHsSCFs, N,N-dimethyl-(l-phenyl-2,2,2-trifluoroethoxytrimethylsilyl)-amine, S-

[0774] (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). In some embodiments, the trifluoromethylating reagent is TMSCF3.

[0775] In some embodiments, the phase transfer reagent is selected from tetrabutylammonium acetate, tetrabutylphosphonium bromide, triethylbenzylammonium chloride, decyltrimethylammonium bromide, tetraethylammonium trifluoromethanesulfonate, benzyldodecyldimethylammonium chloride, benzyldimethyltetradecylammonium chloride, benzoylcholine bromide, benzyldimethylphenylammonium chloride, benzyltributylammonium bromide, l,l'-(butane-l,4-diyl)bis[4-aza-l-azoniabicyclo[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, tetrapropyl ammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmitylammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate. o and a condensing base. In some embodiments, 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.

[0776] In some embodiments, the contacting is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is tetrahydrofuran.

[0777] In some embodiments, 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.

[0778] F

[0779] JL JLCH0

[0780] In some embodiments, 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

[0781] 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 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

[0782] 40 °C, or about 45 °C). In some embodiments, contacting and the condensing base is performed at about 35 °C to about 45 °C.

[0783] 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

[0784] 25 °C to about 60 °C, about 35 °C to about 50 °C, about 35 °C to about 45 C, about 35 °C, about

[0785] 40 °C, or about 45 °C).

[0786] 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

[0787] °C to about 20 °C). In some embodiments adding the performed at about 15 °C to about 20 °C. o

[0788] In some embodiments, 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

[0789] °C to about 20 °C.

[0790] In some embodiments, contacting condensing base provides mixture 10. In some embodiments, mixture 10 is agitated for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, 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.

[0791] In some embodiments, after agitating mixture 10, 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.

[0792] In some embodiments, cooling mixture 10 comprises forming a slurry. In some embodiments, the process comprises filtering the slurry to provide a solution. In some embodiments, the process comprises reducing the volume of the solution under a pressure lesser than atmospheric pressure. In some embodiments, 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. In some embodiments, the solvent is methanol, ethanol, or isopropanol. In some embodiments, the solvent is ethanol. In some embodiments, steps (iii) and (iv) are required. In some embodiments, the process 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). In some embodiments, the process comprises cooling the concentrate to about 15 °C to about 25 °C. In some embodiments, the process comprises adding water to the concentrate after cooling the concentrate to form mixture 10’. In some embodiments, 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). In some embodiments, the process comprises agitating mixture 10’ for about 14 hours. In some embodiments, after agitating mixture 10’, a slurry is formed. In some embodiments, the slurry is filtered to provide the compound of Formula (I-v).

[0793] In some embodiments, the process comprises concentrating mixture 10 at a pressure lesser than atmospheric pressure to provide after cooling mixture 10.

[0794] In some embodiments, the process comprises

[0795] O fsj’!

[0796] In some embodiments, contacting the compound of Formula (I-v) withH2NR" 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). In some embodiments, the process comprises preparing contacting acid.

[0797] In some embodiments, 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).

[0798] In some embodiments, the acid is acetic acid.

[0799] In some embodiments, contacting acid comprises adding , an acid comprises contacting the acid in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, adding the acid forms mixture 11. In some embodiments, after adding the acid, mixture 11 is heated at about 80 °C to about 160 °C (e.g., about

[0800] 90 °C to about 150 °C, about 100 °C to about 140 °C, about 110 °C to about 130 °C, about 115 °C to about 125 °C, or about 120 °C). In some embodiments, after adding the acid, mixture 11 is heated at about 120 °C. In some embodiments, after adding to 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.

[0801] In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base. In some embodiments, the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight). In some embodiments, after washing the organic phase with the aqueous base, the organic phase is agitated with water and Na2S2O4. In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 8 hours. In some embodiments, agitating the organic phase with water and NazS2O4 forms a solid. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, and the pH of the solution is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10) and then agitated for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a biphasic mixture. In some embodiments, the biphasic mixture comprises an organic phase and an aqueous phase. In some embodiments, the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide

[0802] In some embodiments, the process comprises preparing

[0803] OEt contacting witl ; wherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.

[0804] In some embodiments, contacting comprises contacting base. In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, tri ethylamine, and citric acid. In some embodiments, the base is potassium carbonate. In some embodiments, contacting and a base is performed in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide.

[0805] In some embodiments, 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).

[0806] In some embodiments, contacting base, and sodium iodide is performed at about 120 °C.

[0807] In some embodiments, adding base, and sodium iodide forms mixture 13. In some embodiments, 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).

[0808] In some embodiments, mixture 13 is agitated for about 5 hours.

[0809] In some embodiments, 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. In some embodiments, the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.

[0810] In some embodiments, contacting the acid is performed in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, 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. In some embodiments, the solvent is methyl tert-butyl ether.

[0811] In some embodiments, contacting the acid is performed at about

[0812] 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 In some embodiments, the process comprises preparing the compound of Formula (I-viii) some embodiments, Z is O. In some embodiments,

[0813] R2is C1-C6 alkyl. In some embodiments, R2is methyl.

[0814] 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.

[0815] In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, 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. In some embodiments, the solvent is methyl tert-butyl ether.

[0816] In some embodiments, 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). In some embodiments, contacting base is performed at about 25 °C. Some embodiments provide a process of preparing Compound 1, having the structure:

[0817] Some embodiments Compound 1, having the structure:

[0818] C6 alkyl.

[0819] In some embodiments, contacting R" comprises contacting condensing base. In some embodiments, 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.

[0820] In some embodiments, the contacting is performed in a solvent. In some embodiments, 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. In some embodiments, 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

[0821] °C to about 20 °C). In some embodiments adding the performed at about 15 °C to about 20 °C. O ts?"

[0822] In some embodiments, adding the condensing base to the mixture ofH2N 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

[0823] °C to about 20 °C.

[0824] In some embodiments, contacting condensing base provides mixture 10. In some embodiments, mixture 10 is agitated for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 24 hours, about 15 minutes to about 16 hours, about 15 minutes to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours). In some embodiments, mixture 10 is agitated for about 15 minutes to about 5 hours. In some embodiments, 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

[0825] °C, or about 60 °C). In some embodiments, agitating mixture 10 is performed at about 60 °C.

[0826] In some embodiments, after agitating mixture 10, 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.

[0827] After cooling mixture 10, mixture 10 is concentrated at a pressure lesser than atmospheric pressure t In some embodiments, reacting form Compound 1 comprises contacting

[0828] R” is C1-C6 alkyl.

[0829] In some embodiments, 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.

[0830] In some embodiments, the phase transfer reagent is added about

[0831] 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 about 15 °C to about 20 °C.

[0832] In some embodiments, 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.

[0833] 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

[0834] 1.5 hours, or about 1 hour). In some embodiments, after cooling the mixture and the phase transfer reagent, the mixture the phase transfer reagent is agitated for about 1 hour.

[0835] In some embodiments, 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.,

[0836] -30 °C to about -5 °C, -25 °C to about -10 °C, -20 °C to about -15 °C). In some embodiments, adding the trifluoromethylating reagent to the mixture the phase transfer reagent is performed at about -20 °C to about -15 °C.

[0837] In some embodiments, the trifluoromethylating reagent is added to the mixture of the phase transfer reagent dropwise.

[0838] In some embodiments, 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).

[0839] In some embodiments, the process comprises adding a solvent to mixture 8 to form mixture 9. In some embodiments, mixture 9 is biphasic. In some embodiments, mixture 9 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and concentrated under at a pressure lesser than atmospheric pressure. In some embodiments, the solvent is dichloromethane, chloroform, ethyl acetate, or diethyl ether. In some embodiments, the solvent is ethyl acetate. In some embodiments, concentrating the organic phase at a pressure lesser than atmospheric pressure provides a residue. In some embodiments, the residue is purified using silica gel to provide the compound of Formula (I-iv).

[0840] In some embodiments, the trifluoromethylating reagent is selected from TMSCF3, [(Trifluoromethyl)thio]benzene, potassium trimethoxy(trifluoromethyl)borate,

[0841] 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). In some embodiments, the trifluoroalkylating reagent is a trifluoromethylating reagent. In some embodiments, the trifluoromethylating reagent is TMSCF3. In some embodiments, 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[2.2.2]octane] dibromide, ethylhexadecyldimethylammonium bromide, decamethonium bromide, tetrapropylammonium iodide, tetrahexylammonium iodide, tetra(decyl)ammonium bromide, tetraamylammonium chloride, and dimethyldipalmitylammonium bromide. In some embodiments, the phase transfer reagent is tetrabutylammonium acetate.

[0842] In some embodiments, reacting form Compound 1 comprises alkyl.

[0843] In some embodiments, the acid is hydrogen chloride. In some embodiments, the acid is a solution of hydrogen chloride in ethyl acetate, diethyl ether, or 1,4-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.

[0844] In some embodiments, the contacting comprises adding the acid.

[0845] In some embodiments, the adding is performed at about 0 °C to about 30 °C (e.g., about 0 °C to about 25 °C, about 0 °C to about 20 °C, about 0 °C to 10 °C, or about 5 °C to about 15 °C). In some embodiments, the agitating is performed at about 0 °C to about 10 °C. In some embodiments, 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. In some embodiments, the contacting comprises agitating the acid for about 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. In some embodiments, the contacting comprises adding heptane or hexanes (e.g., heptane) to mixture 6. In some embodiments, after adding the 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. In some (i) a carbonyl equivalent; and

[0846] (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0847] In some embodiments, 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

[0848] 1 to form mixture 2.

[0849] 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

[0850] 1.3.

[0851] In some embodiments, 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. In some embodiments, the molar ratio of the sodium bicarbonate to to form mixture 1 is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0852] In some embodiments, 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.

[0853] In some embodiments, 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.

[0854] F

[0855] In some embodiments, after adding the carbonyl equivalent to 'c and 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.

[0856] In some embodiments, 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, 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). In some embodiments, the second base is triethylamine. In some embodiments, the second base is N,N-diisopropylethylamine.

[0857] In some embodiments, 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.

[0858] In some embodiments, after forming mixture 2, 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.

[0859] In some embodiments, Compound 1 is recrystallized from a solvent. In some embodiments, the solvent is a mixture of isopropyl acetate and heptane. In some embodiments, the ratio of isopropyl acetate to heptane is about 6: 1 to about 4:2 (e.g., about 5:2). In some embodiments, after recrystallizing Compound 1, Compound 1 is rinsed with a mixture of isopropyl acetate and heptane, then water, then a mixture of isopropyl acetate and heptane. In some embodiments, after rinsing Compound 1, Compound 1 is dried. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure. In some embodiments, 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. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0860] In some embodiments, adding the carbonyl equivalent and a base to form mixture 1’ is performed under an inert atmosphere. In some embodiments, the contacting is performed under nitrogen. In some embodiments, the contacting is performed under argon.

[0861] 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 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

[0862] 1.2, about 1.3, about 2.0). In some embodiments, the molar ratio of the carbonyl equivalent to

[0863] 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 to form mixture 1 ’ is performed in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water. In some embodiments, 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.

[0864] In some embodiments, 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.

[0865] 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’. 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’. 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’, then pyrimidine-2,5- diamine to mixture 1’. In some embodiments, 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). In some embodiments, the third base is tri ethyl amine. In some embodiments, the third base is N,N-diisopropylethylamine.

[0866] 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 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. In some embodiments, after forming mixture 2, mixture 2 is agitated at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C) for about 1 hour to about 7 days (e.g., about 1 hour to about 4 days, about 5 hours to about 4 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.

[0867] In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane. In some embodiments, Compound 1 is precipitated from isopropanol and water. In some embodiments, Compound 1 is precipitated from tetrahydrofuran and heptane, 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. In some embodiments, drying Compound 1 comprises drying Compound 1 at about 25 °C to about 70 °C (e.g., about 20 °C to about 25 °C, about 30 °C to about 60 °C, about 40 °C to about 50 °C, or about 45 °C). In some embodiments, drying Compound 1 comprises drying Compound 1 at about 45 °C. In some embodiments, drying Compound 1 comprises drying Compound 1 at a pressure lesser than atmospheric pressure at about 20 °C to about 25 °C.

[0868] In some embodiments, the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5- dioxopyrrolidin-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.

[0869] In some embodiments, the carbonyl equivalent is phenyl chloroformate.

[0870] In some embodiments, 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. In some embodiments, R’ is phenyl. In some embodiments, R’ is paranitrophenyl. In some embodiments, contacting pyrimidine- 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base; the salt is a hydrochloride salt.

[0871] In some embodiments, contacting pyrimidine- 2,5-diamine to form Compound 1 comprises: combining R’OC(O)C1 with a base; wherein

[0872] In some embodiments, combining R’OC(O)C1 with a base comprises combining the base with a solvent, then adding the R’OC(O)C1. In some embodiments, 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.

[0873] In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0874] In some embodiments, 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

[0875] 5 °C, or about 0 °C). In some embodiments, adding the mixture of

[0876] 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.

[0877] In some embodiments, added to the mixture of R’OC(O)C1 and the base as a solution in a solvent. In some embodiments, 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. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a combination of tetrahydrofuran and water.

[0878] In some embodiments, 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).

[0879] In some embodiments, adding the mixture of R’OC(O)C1 and the base forms mixture 3. In some embodiments, mixture 3 is agitated for about 15 minutes to about 48 hours (e.g., about 15 minutes to about 2 hours, about 18 hours to about 30 hours, about 18 hours to about 24 hours, about 15 minutes to about 24 hours, about 1 hour to about 7 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 3 hours to about 7 hours, about 24 hours, about 21 hours, about 18 hours, about 16 hours, about 12 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour). In some embodiments, mixture 3 is agitated at about 0 to about 10 °C (e.g., about 0 °C to about 5 °C, about 0 °C to about 5 °C, or about 0 °C).

[0880] In some embodiments, agitating mixture 3 forms a biphasic mixture comprising an organic phase and an aqueous phase. In some embodiments, the organic phase is separated from the aqueous phase. In some embodiments, the organic phase was washed with an aqueous base. In some embodiments, the aqueous base is aqueous sodium bicarbonate. In some embodiments, the organic phase is concentrated at a pressure lesser than atmospheric pressure. In some embodiments, after concentrating the organic phase, an anti-solvent is added to the concentrated organic phase to form mixture 4. In some embodiments, the anti-solvent is hexane or heptane. In some embodiments, the anti-solvent is heptane. In some embodiments, after adding the 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

[0881] (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

[0882] °C to about 50 °C, or about 45 °C). In some embodiments, °C. In some embodiments, drying comprises drying

[0883] (e.g., under nitrogen).

[0884] In some embodiments, the molar ratio of the about

[0885] 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

[0886] 1.0 to about 1.4, about 1.0 to about 1.1, about 1.2 to about 1.4, about 1.05, about 1.1, about 1.2, about 1.3, about 2.0). In some embodiments, the molar ratio of the R’OC(O)C1 to about 1.05. In some embodiments, the molar ratio of the R’OC(O)C1 to about 1.3. In some embodiments, the molar ratio of the R’OC(O)C1 to about 2.0. In some embodiments, 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 2.2, about 3.0, or about 3.5. In some embodiments, the molar ratio of the sodium

[0887] In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, trimethylamine, and citric acid. In some embodiments, the base is sodium bicarbonate.

[0888] In some embodiments, contacting pyrimidine¬

[0889] 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. In some embodiments, 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. In some embodiments, the third base is triethylamine. In some embodiments, the third base is N,N-diisopropylethylamine. absence of a base. In some embodiments, 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

[0890] 2,5-diamine to form Compound 1 is performed under nitrogen. In some embodiments, 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.

[0891] In some embodiments, after adding after adding pyrimidine-2,5-diamine mixture 5 is formed. 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

[0892] 30 minutes to about 1.5 hours, about 8 hours to about 24 hours, about 12 hours to about 13 hours, about 3 hours, or about 1 hour). In some embodiments, mixture 5 is 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

[0893] 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

[0894] 1%, about 1.3%, about 0.05%, or no detectable amount) of Impurity 1 is present as an impurity with Compound 1.

[0895] In some embodiments, less than 10% (e g., less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.6%, about 1%, about 1.3%, about 0.05%, or no detectable amount) of Impurity 2 is present as an impurity with Compound 1.

[0896] In some embodiments, the acid is a protic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, nitric acid, aluminum chloride, zinc chloride, trimethylaluminum, iron (III) bromide, and boron trifluoride (e.g., boron trifluoride dietherate).

[0897] In some embodiments, the acid is acetic acid.

[0898] In some embodiments, contacting acid comprises adding

[0899] F OEt the acid. In some embodiments, contacting an acid comprises contacting the acid in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N- di methyl acetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, , ,

[0900] 90 °C to about 150 °C, about 100 °C to about 140 °C, about 110 °C to about 130 °C, about 115 °C to about 125 °C, or about 120 °C). In some embodiments, after adding the acid, 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.

[0901] In some embodiments, after agitating mixture 11, water is added to mixture 11. In some embodiments, after adding water to mixture 11, a solvent is added to mixture 11 to form mixture 12. In some embodiments, mixture 12 is biphasic. In some embodiments, mixture 12 comprises an organic phase and an aqueous phase. In some embodiments, the organic phase is isolated and washed with an aqueous base. In some embodiments, the aqueous base is aqueous potassium carbonate (e.g., 15% aqueous potassium carbonate by weight). In some embodiments, after washing the organic phase with the aqueous base, the organic phase is agitated with water and Na2S2O4. In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 5 minutes to about 2 days (e.g., about 1 hour to about 24 hours, about 4 hours to about 18 hours, about 6 hours to about 10 hours, or about 8 hours). In some embodiments, the organic phase is agitated with water and Na2S2O4 for about 8 hours. In some embodiments, agitating the organic phase with water and Na2S2Ch forms a solid. In some embodiments, the solid is separated from the solvent and water. In some embodiments, the solid is combined with ethyl acetate to form a solution, and the pH of the solution is adjusted to about 8 to about 11 (e.g., about 9 to about 10, about 9, or about 10) and then agitated for about 5 minutes to about 1 day (e.g., about 1 hour to about 10 hours, about 3 hours to about 7 hours, about 4 hours to about 6 hours, or about 5 hours) to form a biphasic mixture. In some embodiments, the biphasic mixture comprises an organic phase and an aqueous phase. In some embodiments, the organic phase concentrated under at a pressure lesser than atmospheric pressure to provide

[0902] In some embodiments, the process comprises preparing

[0903] OEt contacting witl - wherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.

[0904] In some embodiments, contacting comprises contacting base. In some embodiments, the base is selected from sodium bicarbonate, potassium carbonate, potassium phosphate, sodium carbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, and citric acid. In some embodiments, the base is potassium carbonate.

[0905] In some embodiments, contacting and a base is performed in a solvent. In some embodiments, the solvent is acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, contacting base comprises contacting base, and sodium iodide.

[0906] In some embodiments, 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).

[0907] In some embodiments, contacting base, and sodium iodide is performed at about 120 °C.

[0908] In some embodiments, adding base, and sodium iodide forms mixture 13. In some embodiments, 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.

[0909] In some embodiments, 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. In some embodiments, the acid is sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, or hydrogen bromide. In some embodiments, the acid is sulfuric acid.

[0910] In some embodiments, contacting the acid is performed in a solvent. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, water, or any combination thereof. In some embodiments, 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. In some embodiments, the solvent is methyl tert-butyl ether.

[0911] In some embodiments, 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.

[0912] In some embodiments, the process comprises preparing the compound of Formula (I-viii) some embodiments, Z is O. In some embodiments,

[0913] R2is C1-C6 alkyl. In some embodiments, R2is 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.

[0914] In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropyl alcohol, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, water, or any combination thereof. In some embodiments, 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. In some embodiments, the solvent is methyl tert-butyl ether.

[0915] In some embodiments, contacting 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). In some embodiments, contacting base is performed at about 25 °C.

[0916] Some embodiments provide a process of preparing Compound 1, having the structure: comprising contacting form wherein R” is C1-C6 alkyl; and reacting

[0917] Some embodiments provide Compound 1, having the structure: salt and / or solvate thereof; prepared by a process comprising contacting form , wherein R” is C1-C6 alkyl; and reacting

[0918]

[0919] (i) a carbonyl equivalent; and (ii) pyrimidine-2,5-diamine having the structure ; to form Compound 1.

[0920] Some embodiments provide a process of preparing Compound 1, having the structure: salt and / or solvate thereof; comprising: pyrimidine-2,5-diamine having the structure to form Compound 1. Some embodiments provide Compound 1, having the structure: salt and / or solvate thereof; prepared by a process comprising: pyrimidine-2,5-diamine having the structure to form Compound 1.

[0921] Some embodiments provide a process of preparing Compound 1, having the structure: salt and / or solvate thereof; comprising: wherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; (f) contacting carbonyl equivalent; and (ii) pyrimidine-2,5-diamine having the structure ; to form Compound 1.

[0922] Some embodiments provide Compound 1, having the structure: salt and / or solvate thereof; prepared by a process comprising: wherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; wherein R” is C1-C6 alkyl;

[0923] pyrimidine-2,5-diamine having the structure ; to form Compound 1.

[0924] Some embodiments provide a process of preparing Compound 1, having the structure: salt and / or solvate thereof; comprising: wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; ed from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl -6 alkoxy; and (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0925] Some embodiments provide Compound 1, having the structure: wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl;

[0926] 10 from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl -6 alkoxy; and (ii) pyrimidine-2,5-diamine having the structure to form Compound 1.

[0927] In some embodiments, the process comprises preparing pyrimidine-2,5-diamine by contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen. In some embodiments, the palladium on carbon is palladium adsorbed to carbon. In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen forms mixture 14. In some embodiments, In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen is performed at a pressure of about 15 to about 90 psi (e.g., about 25 to about 70 psi, about 55 to about 75 psi, about 60 to about 70 psi, about 35 to about 55 psi, about 40 to about 50 psi, about 60 to about 80 psi, about 65 to about 75 psi, about 40 psi, about 50 psi, about 60 psi, about 70 psi, or about 80 psi). In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen is performed at a pressure of about 40 to about 50 psi. In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen is performed at a pressure of about 60 to about 70 psi. In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen is performed at a pressure of about 70 psi.

[0928] In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen comprises contacting 5-nitropyrimidine-2-amine with palladium on carbon in a solvent under an atmosphere of hydrogen. In some embodiments, the solvent comprises acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, or any combination thereof. In some embodiments, the solvent is acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, or any combination thereof. In some embodiments, the solvent comprises tetrahydrofuran and methanol.

[0929] In some embodiments, the palladium on carbon comprises water. In some embodiments, the palladium on carbon comprises about 40% to about 60% water (e.g., about 45% to about 55% water or about 50% by weight water). In some embodiments, the palladium on carbon comprises water. In some embodiments, the palladium on carbon comprises about 50% by weight water. In some embodiments, the palladium on carbon is about 5% to about 20% (e.g., about 5%, about 8% to about 12%, about 9% to about 11%, about 10%, about 13% to about 17%, about 14% to about 16%, about 15%, or about 20%) weight / weight palladium on carbon. In some embodiments, the palladium on carbon is about 10% weight / weight palladium on carbon. In some embodiments, the palladium on carbon is about 15% weight / weight palladium on carbon.

[0930] In some embodiments, the weight percentage of the palladium in the palladium on carbon to the 5-nitropyrimidine-2-amine is about 1% to about 50% (e.g., about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 5% to about 25%, about 10% to about 50%, about 8% to about 12%, about 13% to about 17%, about 10%, about 15%, or about 20%. In some embodiments, the weight percentage of the palladium in the palladium on carbon to the 5- nitropyrimidine-2-amine is about 10%. In some embodiments, the weight percentage of the palladium in the palladium on carbon to the 5-nitropyrimidine-2-amine is about 20%.

[0931] In some embodiments, contacting 5-nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen comprises agitating the 5-nitropyrimidine-2-amine with the palladium on carbon under the atmosphere of hydrogen. In some embodiments, the agitating is performed for about 1 minute to about 48 hours (e.g., about 1 minute to about 12 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 6 hours, about 1 hour to about 4 hours, about 2.5 hours to about 3.5 hours, about 3.5 hours to about 4.5 hours, about 1 hour to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours). In some embodiments, the agitating is performed for about 1 hour. In some embodiments, the agitating is performed for about 2 hours. In some embodiments, the agitating is performed for at least about 4 hours.

[0932] In some embodiments, the agitating is performed at about 20 °C to about 90 °C (e.g., about 30 °C to about 80 °C, about 40 °C to about 70 °C, about 35 °C to about 55 °C, about 40 °C to about 55 °C, about 40 °C to about 50 °C, about 50 °C to about 60 °C, about 60 °C to about 70 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, or about 70 °C).

[0933] In some embodiments, the process comprises filtering mixture 14 (e.g., through a layer of diatomaceous earth) to form a filtrate. In some embodiments, the process comprises reducing the volume of the filtrate at a pressure lesser than atmospheric pressure to form a concentrate. In some embodiments, the process comprises adding a solvent to the concentrate to form mixture 14’. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the process comprises cooling mixture 14’ to about -10 °C to about 20 °C (e.g., about -5 °C to about 5 °C, about 0 °C to about 10 °C, about 0 °C to about 5 °C, about 0 °C to about 2 °C, or about 0 °C). In some embodiments, a precipitate forms in mixture 14’ after cooling. In some embodiments, the process comprises filtering mixture 14’ to provide pyrimidine-2,5-diamine.

[0934] In some embodiments, the process comprises dissolving the pyrimidine-2,5-diamine in a solvent to form a slurry. In some embodiments, the solvent comprises methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, water, or any combination thereof. In some embodiments, the solvent is methyl tert-butyl ether, acetone, chloroform, ethyl acetate, dichloromethane, isopropanol, methanol, ethanol, tetrahydrofuran, acetonitrile, water, or any combination thereof. In some embodiments, the solvent comprises isopropanol and water. In some embodiments, the solvent is isopropanol and water. In some embodiments, the solvent comprises about 40% to about 99% isopropanol and about 1% to about 40% water (e.g., about 70% to about 97% isopropanol and about 3% to about 30% water; about 80% to about 95% isopropanol and about 5% to about 20% water; or about 90% isopropanol and about 10% water). In some embodiments, the solvent comprises about 90% isopropanol and about 10% water. In some embodiments, the slurry is heated at about 30 °C to about 90 °C (e.g., about 40 °C to about 90 °C, about 50 °C to about 80 °C, about 55 °C to about 75 °C, about 60 °C to about 70 °C, about 50 °C to about 60 °C, about 70 °C to about 80 °C, about 60 °C, about 65 °C, or about 70 °C). In some embodiments, the slurry is heated at about 60 °C to about 70 °C. In some embodiments, the slurry is heated for about 1 minute to about 48 hours (e.g., about 1 minute to about 36 hours, about 1 minute to about 24 hours, about 1 minute to about 2 hours, about 1 hour to about 12 hours, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, or about 1 hour). In some embodiments, the slurry is heated for about 1 hour. In some embodiments, the process comprises cooling the slurry after heating the slurry. In some embodiments, cooling the slurry comprises cooling the slurry at about -20 °C to about 30 °C (e.g., about -10 °C to about 20 °C, about -5 °C to about 15 °C, about 0 °C to about 10 °C, about 0 °C, about 5 °C, or about 10 °C). In some embodiments, cooling the slurry comprises cooling the slurry to about 0 °C to about 10 °C. In some embodiments, cooling the slurry comprises cooling the slurry for about 1 minute to about 72 hours (e.g., about 1 minute to about 48 hours, about 1 hour to about 36 hours, about 2 hours to about 24 hours, about 3 hours to about 18 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, about 7.5 hours to about 8.5 hours, about 8 hours, at least 1 hour, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, or at least 12 hours). In some embodiments, cooling the slurry comprises cooling the slurry for at least 8 hours. In some embodiments, the process comprises filtering the slurry after cooling the slurry to provide recrystallized pyrimidine-2,5-diamine. In some embodiments, the process comprises drying the recrystallized pyrimidine-2,5-diamine at a pressure lesser than atmospheric pressure. In some embodiments, the process comprises heating the recrystallized pyrimidine-2,5-diamine at a temperature of about 20 °C to about 70 °C (e.g., about 30 °C to about 60 °C, about 40 °C to about 50 °C, about 40 °C, or about 50 °C). In some embodiments, the process comprises heating the recrystallized pyrimidine-2,5-diamine at a temperature of about 40 °C to about 50 °C.

[0935] In some embodiments of the compounds, methods, and processes described herein, Formula (I) is present in the form of a salt. In some embodiments of the compounds, methods, and processes described herein, Formula (I) is present in the form of a solvate. In some embodiments of the compounds, methods, and processes described herein, Formula (I) is present in the form of a salt of a solvate. In some embodiments of the compounds, methods, and processes described herein, Compound 1 is present in the form of a salt. In some embodiments of the compounds, methods, and processes described herein, Compound 1 is present in the form of a solvate. In some embodiments of the compounds, methods, and processes described herein, Compound 1 is present in the form of a salt of a solvate. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the solvate is a pharmaceutically acceptable solvate.

[0936] In some embodiments, Compound 1 is present in the form of a solvate. In some embodiments, Compound 1 is present in the form of a free base solvate. In some embodiments, Compound 1 is present in the form of a hydrate. In some embodiments, Compound 1 is present in the form of a free base hydrate. In some embodiments, Compound 1 is present in the form of a hemihydrate. In some embodiments, Compound 1 is present in the form of a free base hemihydrate.

[0937] Compounds

[0938] Some embodiments provide a compound of Formula (I-i): wherein:

[0939] Z is O or NRX;

[0940] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0941] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; and

[0942] R3is 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.

[0943] In some embodiments, the compound of Formula (I-i) is a compound of Formula (I-i-i):

[0944] Some embodiments provide a compound of Formula (I-i-a) wherein:

[0945] Z is O or NRX;

[0946] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0947] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0948] R3is 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; and R’ is selected from C1-C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl -6 alkoxy.

[0949] In some embodiments, the compound of Formula (I-i-a) is a compound of Formula (I-i-a- i)

[0950] Some embodiments provide a compound of Formula (I-iii) wherein:

[0951] Z is O or NRX;

[0952] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1 -C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0953] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;

[0954] R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with

[0955] 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; and

[0956] R” is C1-C6 alkyl.

[0957] In some embodiments, the compound of Formula (I-iii) is a compound of Formula (I-iii-i)

[0958] Some embodiments provide a compound of Formula (I-iv) wherein:

[0959] Z is O or NRX;

[0960] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0961] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; and

[0962] R” is C1-C6 alkyl.

[0963] In some embodiments, the compound of Formula (I-iv) is a compound of Formula (I-iv-i) ide a compound of Formula (I-v) wherein:

[0964] Z is O or NRX;

[0965] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; and

[0966] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro.

[0967] In some embodiments, the compound of Formula (I-v) is a compound of Formula (I-v-i)

[0968] In some embodiments, In some embodiments,

[0969] In some embodiments, In some embodiments,

[0970] Some embodiments provide a compound of Formula (I-vi) wherein:

[0971] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro.

[0972] In some embodiments, the compound of Formula (I-vi) is a compound of Formula (I-vi-i) wherein:

[0973] Z is O or NRX;

[0974] Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;

[0975] R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; and

[0976] Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.

[0977] In some embodiments, the compound of Formula (I-viii) is a compound of Formula (I-viii-

[0978] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, each R1is an independently selected halogen. In some embodiments, each R1is independently selected from fluoro and chloro. In some embodiments, each R1is independently selected from fluoro and bromo. In some embodiments, each R1is fluoro. In some embodiments, at least one R1is an independently selected halogen. In some embodiments, at least one R1is independently selected from fluoro and chloro. In some embodiments, at least one R1is fluoro.

[0979] In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R1is C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R1is hydroxymethyl. In some embodiments, at least one R1is unsubstituted C1-C6 alkyl. In some embodiments, at least one R1is methyl. In some embodiments, at least one R1is C3-C6 cycloalkyl. In some embodiments, at least one R1is cyclopropyl.

[0980] In some embodiments, m is 2; one R1is halogen; and the other R1is C 1-C6 alkyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is methyl In some embodiments, m is 2; one R1is halogen; and the other R1is C3-C6 cycloalkyl. In some embodiments, m is 2; one R1is halogen; and the other R1is cyclopropyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is cyano. In some embodiments, m is 2; one R1is halogen; and the other R1is halogen. In some embodiments, m is 2; one R1is fluoro; and the other R1is fluoro.

[0981] In some embodiments, R2is hydroxyl. In some embodiments, R2is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R2is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R2is C1-C3 alkyl substituted with hydroxyl. In some embodiments, R2is hydroxymethyl. In some embodiments, R2is an unsubstituted C1-C6 alkyl. In some embodiments, R2is unsubstituted C1-C3 alkyl. In some embodiments, R2is methyl.

[0982] In some embodiments, R2is a C1-C6 haloalkyl. In some embodiments, R2is a C1-C3 haloalkyl. In some embodiments, R2is difluoromethyl. In some embodiments, R2is tri fluoromethyl.

[0983] In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0984] In some embodiments, R2is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is an unsubstituted C3-C6 cycloalkyl.

[0985] In some embodiments, R3is a C1-C6 alkyl. In some embodiments, R3is a C1-C3 alkyl. In some embodiments, R3is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0986] In some embodiments, R3is a C1-C6 haloalkyl. In some embodiments, R3is a C1-C3 haloalkyl. In some embodiments, R3is difluorom ethyl. In some embodiments, R3is trifluorom ethyl.

[0987] In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R3is C3- C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is an unsubstituted C3-C6 cycloalkyl. In some embodiments, the R3C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0988] In some embodiments, R’ is C1-C6 alkyl. In some embodiments, R’ is C1-C4 alkyl. In some embodiments, R’ is C1-C3 alkyl. In some embodiments, R’ is isopropyl. In some embodiments, R’ is methyl. In some embodiments, R’ is ethyl. In some embodiments, R’ is n- propyl.

[0989] In some embodiments, 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.

[0990] In some embodiments, R” is C1-C6 alkyl. In some embodiments, R” is C1-C4 alkyl. In some embodiments, R” is C1-C3 alkyl. In some embodiments, R” is isopropyl. In some embodiments, R” is methyl. In some embodiments, R” is ethyl. In some embodiments, R” is n- propyl.

[0991] In some embodiments, 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.

[0992] Some embodiments provide a process of preparing Compound 1, having the structure: salt and / or solvate thereof; comprising: from chloro, bromo, iodo, and trifluoromethanesulfonyl; and wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; (f) contacting carbonyl equivalent; and (ii) pyrimidine-2,5- diamine having the structure ; to form Compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5- nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen.

[0993] Some embodiments provide a process of preparing Compound 1, having the structure:

[0994] LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl;

[0995] (b) contacting

[0996] (c) contacting wherein R” is C1-C6 alkyl; diamine having the structure to form Compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5- nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen.

[0997] Some embodiments provide a process of preparing Compound 1, having the structure: selected from chloro, bromo, iodo, and trifluoromethanesulfonyl; (b) contacting

[0998] (c) contacting wherein R” is C1-C6 alkyl; wherein R’ is selected from Cl-

[0999] C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl-

[1000] 6 alkoxy; and (ii) pyrimidine-2,5-diamine having the structure ; to form Compound 1; wherein the pyrimidine-2,5-diamine is formed by contacting 5- nitropyrimidine-2-amine with palladium on carbon under an atmosphere of hydrogen. Some embodiments provide a compound having the structure

[1001] Some embodiments provide a compound having the structure . Some embodiments provide a compound having the structure Some embodiments provide a compound having the structure

[1002] Some embodiments provide a compound having the structure

[1003] Some embodiments provide a compound having the structure

[1004] Some embodiments provide a compound having the structure

[1005] EXAMPLES

[1006] Compound Preparation

[1007] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.

[1008] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[1009] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt and / or solvate thereof.

[1010] Materials and Methods

[1011] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[1012] The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[1013] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1st Ed., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).

[1014] X-ray Powder Diffraction (XRPD):

[1015] XRPD analysis was carried out on a PANalytical X’pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 29. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Mylar polymer fdm to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (al X = 1.54060 A; a2 = 1.54443 A; 0 = 1.39225 A; al : a2 ratio = 0.5) running in transmission mode (step size 0.0130° 29, step time 18.87s) using 40 kV / 40 mA generator settings. XRPD analysis that used the longer basic batch method was carried out on a PANalytical X’pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 29. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (al X= 1.54060 A; a2 = 1.54443 A; 0 = 1.39225 A; al : a2 ratio = 0.5) running in transmission mode (step size 0.0130° 20, step time 68.595s) using 40 kV / 40 mA generator settings. Data were visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[1016] Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC):

[1017] Material (3 - 10 mg of mg) was added into a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC and held at room temperature. The sample was then heated at a rate of 10 °C / min from 30 - 400 °C during which time the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas, at a flow rate of 200 cm3 / min.

[1018] Differential Seaming Calorimetry (DSC): Material (1 - 5 mg) was weighed into an aluminum DSC pan and sealed non-hermetically with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with a RC90 cooler. The sample and reference were heated to 210 °C at a scan rate of 10°C / min and the resulting heat flow response monitored. The sample was cooled to -80°C and then reheated again to 210 °C all at 10 °C / min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3 / min.

[1019] Abbreviations

[1020] Introduction

[1021] An improved route for the synthesis of Compound 1 was developed in order to ensure higher standards for Identity, Strength, Quality, and Purity of Active Pharmaceutical Ingredient (API) according to Good Manufacturing practices (cGMP). The route in Scheme 1 below, was executed on a 300 g scale and the cGMP route, which is shown in Scheme 2 below, was executed on about 11 kg scale.

[1022] The specification for Compound 1, Form 1 hemihydrate (the “API” as referred to herein) were : > 97.0 % (area / area or “a / a”), 97.0-103.0 % (weight / weight, “w / w”), unknown individual impurity < 0.15 % (a / a), total impurities < 3.0 % (a / a) by UPLC and the chiral purity > 98.0 % (a / a) by HPLC. The cGMP scale up campaign was successfully executed over 3 months to deliver 10.87 kg API with purity of 99.9 % (a / a), 99.6 % (w / w) and 0.1 % Impurity 2 as a single impurity by UPLC. The chiral purity was 100.0% (a / a) by HPLC.

[1023] Several challenges were overcome in order to successfully execute a multi -kilogram synthesis of Compound 1, Form 1 hemihydrate that adhered to cGMP requirements and guidance standards. These included:

[1024] 1. Production of Intermediate VI (see Scheme 1). The main issue was the capacity of the hydrogenator required to run the reaction in a single batch run. An alternative approach to catalytic hydrogenation was explored to reduce of 5-nitropyrimidin-2-amine via the hydrogen transfer from formic acid (see Example 1). While it was found that the hydrogen transfer conditions successfully transformed V into VI, the removal of salts and extraction of VI from the aqueous work up was difficult due to the high solubility of VI in water. Accordingly, it was decided to use hydrogenation with hydrogen gas for the production ...

Claims

WHAT IS CLAIMED IS:

1. A process of preparing a compound of Formula (I):salt and / or solvate thereof; comprising contacting a compound of Formula (I-i):with(i) a carbonyl equivalent; and(ii) a compound of Formula (I-ii)to form the compound of Formula (I), wherein:Z is O or NRX;Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3;R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro;R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with1 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 R4is independently selected from the group consisting of:(i) halogen,(ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB,(iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,(iv) C1-C6 haloalkyl,(v) hydroxyl,(vi) cyano,(vii) -CO2H,(viii) -NRARB,(ix) =NRA2,(x) -C(=O)NRCRD,(xi) -SO2(NRERF),(xii) -SO2(C1-C6 alkyl),(xiii) -S(=O)(=NH)(C1-C6 alkyl),(xiv) -C(=O)(C1-C6 alkyl),(xv) -CO2(C1-C6 alkyl),(xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and(xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently(i) hydrogen,(ii) hydroxyl,(iii) 4-6 membered heterocyclyl,(iv) C1-C6 haloalkyl,(v) -C(=O)(C1-C6 alkyl),(vi) -C(=O)O(C1-C6 alkyl),(vii) -SO2(C1-C6 alkyl),(viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or(ix) C1 -C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SC>2(C1-C6 alkyl), -CO2H, and -SO2CNH2); orRcand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1Rcl, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRclRD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

2. A process of preparing Compound 1, having the structure:(i) a carbonyl equivalent; and(ii) pyrimidine-2,5-diamine having the structureto form Compound 1.

3. The process of claim 2, wherein the process comprises preparingThe process of claim 3, wherein the process comprises preparing5. The process of claim 3 or 4, wherein the process comprises preparingclaim 5, wherein the process comprises preparing7. The process of claim 6, wherein the process comprises preparingwherein LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.

8. The process of claim 5, wherein the process comprises preparingacid; wherein Hal is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl.

9. The process of claim 8, wherein the process comprises preparing10. A process of preparing Compound 1, having the structure:Compound 1 comprises contactingform; wherein R” is C1-C6 alkyl.

13. The process of claim 12,formCompound 1 comprises contactingform14. The process of claim 10, wherein reactingformCompound 1 comprises contacting(i) a carbonyl equivalent; and(ii) pyrimidine-2,5-diamine having the structureto form Compound 1.

15. A process of preparing Compound 1, having the structure:

16. The process of claim 15, wherein reactingform Compoundtrifluoromethylating reagent to form; wherein R” is C1-C6 alkyl.The process of any one of claims 15-16, wherein reacting18. The process of any one of claims 15-17, wherein reactingform Compound 1 comprises contacting(i) a carbonyl equivalent; and(ii) pyrimidine-2,5-diamine having the structureto form Compound 1.

19. A process of preparing Compound 1, having the structure:(a) contactingform, whereinR” is C1-C6 alkyl;(c) contactingform(d) contactingcarbonyl equivalent; and (ii) pyrimidine-2,5- diamine having the structureto form Compound 1.

20. A process of preparing Compound 1, having the structure:LG is selected from chloro, bromo, iodo, and trifluoromethanesulfonyl;(b) contacting(c) contactingwherein R” is C1-C6 alkyl;(e) contactingform(f) contactingcarbonyl equivalent; and (ii) pyrimidine-2,5- diamine having theto form Compound 1 .

21. A process of preparing Compound 1, having the structure:salt and / or solvate thereof; comprising:selected from chloro, bromo, iodo, and trifluoromethanesulfonyl;(e) contactingform(f) contactingwherein R’ is selected from Cl -C6 alkyl and C6-C10 aryl optionally substituted with 1-3 independently selected Cl -6 alkyl or Cl-6 alkoxy; and (ii) pyrimidine-2,5-diamine having the structureto form Compound 1.

22. The process of any one of claims 1-21, wherein 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.

23. The process of any one of claims 1-22, wherein the carbonyl equivalent is selected from the group consisting of: phenyl chloroformate, phosgene, trichloromethyl chloroformate (i.e., diphosgene), bis(trichloromethyl) carbonate (i.e., triphosgene), 4-nitrophenyl chloroformate, bis(2,5-dioxopyrrolidin-l-yl) carbonate, l,l'-carbonyl diimidazole, 2,2,2-trifluoroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, dimethyl carbonate, carb onochlori die acid, and 1 -methylethenyl ester.

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

25. The process of any one of claims 3-24, wherein the acid is HC1.

26. The process of any one of claims 4-25, wherein the trifluoromethylating reagent is TMSCFs.

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