WO2024151992A1

WO2024151992A1 - Preparation of a tyk2 inhibitor

Info

Publication number: WO2024151992A1
Application number: PCT/US2024/011464
Authority: WO
Inventors: Venkat BOLLU; John Nuss; Shendong Yuan; Scott Alan Wolckenhauer
Original assignee: Ventyx Biosciences Inc
Current assignee: Ventyx Biosciences Inc
Priority date: 2023-01-13
Filing date: 2024-01-12
Publication date: 2024-07-18
Anticipated expiration: 2025-07-13
Also published as: CN120897919A; EP4649082A1

Abstract

Described herein is the preparation of a TYK2 inhibitor and chemical intermediates used in the synthetic process.

Description

PREPARATION OF A TYK2 INHIBITOR

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No. 63/479,917, filed on January 13, 2023, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The four JAK family members are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2) and have been shown to be key components of cytokine-mediated effects. Unlike JAK1 deficient mice, TYK2 deficient mice are viable and the TYK2 deficiency has been shown to be protective in various models of autoimmunity.

SUMMARY OF THE INVENTION

[0003] Described herein are processes for the synthesis of a TYK2 inhibitor compound, wherein the compound is l-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-

(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), or a pharmaceutically acceptable salt thereof.

[0004] In one aspect is a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-

((lR,2S)-2-fluorocyclopropyl)urea (Compound 1):

A) the reaction of compound with the structure: butanol, triethylamine, and diphenyl phosphoryl azide to produce a tructure:

B) followed by the reaction of the compound with the structure: hydrochloric acid in ethyl acetate to produce a compound with the f the compound with the structure: nitric acid and sulfuric acid to produce a compound with the structure:

D) followed by the reaction of the compounds with the structures:

E) followed by the reaction of the compounds with the structures:

potassium carbonate, palladium(II) acetate, and 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl (BINAP) to produce a compound with the structure:

F) followed by the reaction of the compound with the structure:

G) followed by the reaction of the compounds with the structures:

H) followed by the reaction of the compound with the structure:

tri ethylsilane and trifluoroacetic acid to produce l-(5- ((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5- a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea (Compound 1) having the structure:

(Compound 1).

[0005] In some embodiments, the process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1) further comprises the reaction of l-(5-((7- fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin- 3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea(Compound 1) with adipic acid to produce l-(5-((7- fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin- 3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea adipic acid salt (Compound 1 A).

[0006] In another aspect is a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1):

(Compound 1), comprising contacting a compound with the structure:

triethyl silane and an acid in the presence of a solvent.

In some embodiments, the acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. In some embodiments, the acid is trifluoromethanesulfonic acid and trifluoroacetic acid. In some embodiments, the acid is trifluoromethanesulfonic acid. In some embodiments, the solvent is selected from dichloromethane, 1,2-dichloroethane, 1,4- dioxane, tetrahydrofuran, dimethoxyethane, chlorobenzene, and trifluorotoluene. In some embodiments, the solvent is dichloromethane.

[0007] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

base in the presence of a solvent. In some embodiments, the base is triethylamine, diisopropylethylamine (DIPEA), N- methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, tri-n-propylamine, and triisopropylamine. In some embodiments, the base is triethylamine. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. [0008] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

un er re uc ve con ons n e presence o a so ven . n some embodiments, the reductive conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum and vanadium on carbon, platinum oxide, or combinations thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the reductive conditions are ammonium formate and formic acid. In some embodiments, the solvent is selected from dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2- dimethoxy ethane, dimethylacetamide, and N-methyl pyrrolidone. In some embodiments, the solvent is dimethylformamide.

[0009] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihy drobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[l ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

salt thereof, with a base, catalyst, and a phosphine ligand in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and potassium tert-butoxide. In some embodiments, the base is potassium carbonate. In some embodiments, the catalyst is selected from palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), [1 , 1 '-Bis(di-/c/7- butylphosphino)ferrocene]dichloropalladium(II), Bis(triphenylphosphine)palladium(II) dichloride, Tetrakis(triphenylphosphine)palladium(0), and Tris(dibenzylideneacetone)dipalladium(0). In some embodiments, the catalyst is palladium(II) acetate. In some embodiments, the phosphine ligand is selected from BINAP, triphenylphosphine, tert-BuXPhos, CyJohnPhos, DavePhos, JohnPhos, Sphos, Xphos, DPPF, and BrettPhos. In some embodiments, the phosphine ligand is BINAP. In some embodiments, the solvent is selected from 1,4-di oxane, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, THF, MeTHF, and acetonitrile. In some embodiments, the solvent is 1,4- dioxane.

[0010] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 -

((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

base in the presence of a solvent. In some embodiments, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N- methylmorpholine, N-methylpyrrolidine, and N-methylpiperidine. In some embodiments, the base is triethylamine. In some embodiments, the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimeth oxy ethane, dimethylacetamide (DMA), andN- methyl pyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. [0011] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting a compound with the structure:

nitric acid and sulfuric acid.

[0012] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-

((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure: hereof is prepared by a process comprising contacting a compound with

acid in the presence of a solvent. In some embodiments, the acid is selected from hydrochloric acid, trifluoroacetic acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the solvent is selected from ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, methanol, 1,2-dimethoxy ethane, and acetonitrile. In some embodiments, the solvent is ethyl acetate.

[0013] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting a compound with the structure:

solvent. In some embodiments, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, and N-methylpiperidine. In some embodiments, the base is triethylamine. In some embodiments, the solvent is selected from toluene, acetonitrile, 1 ,4-dioxane, tetrahydrofuran, dichloromethane, and 1,2-dimethoxy ethane. In some embodiments, the solvent is toluene.

INCORPORATION BY REFERENCE

[0014] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Good manufacturing practices are usually required for large scale manufacture of clinically useful drug candidates. Provided herein are certain processes and methods for the manufacture of l-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7- (methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), or a pharmaceutically acceptable salt or co-crystal thereof.

Definitions

[0016] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0017] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof.

[0018] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. [0019] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range.

[0020] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0021] The term “subject” or “patient” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of nonmammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0022] As used herein, “treatment” or “treating “ or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has been made.

[0023] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0024] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, adipic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, adipates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0025] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0026] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0027] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0028] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0029] The term “antagonist” as used herein, refers to a small -molecule agent that binds to a nuclear hormone receptor and subsequently decreases the agonist induced transcriptional activity of the nuclear hormone receptor.

[0030] The term “agonist” as used herein, refers to a small-molecule agent that binds to a nuclear hormone receptor and subsequently increases nuclear hormone receptor transcriptional activity in the absence of a known agonist.

[0031] The term “inverse agonist” as used herein, refers to a small-molecule agent that binds to a nuclear hormone receptor and subsequently decreases the basal level of nuclear hormone receptor transcriptional activity that is present in the absence of a known agonist.

[0032] The term “modulate,” as used herein, means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.

[0033] As used herein, the term “modulator” refers to a compound that alters an activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

Compounds

[0034] In some embodiments, the TYK2 inhibitor compound described herein is l-(5-((7-fluoro- 2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), or a pharmaceutically acceptable salt or cocrystal thereof. Compound 1 has the structure:

In some embodiments, the starting material for the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

embodiments, an intermediate in the synthesis of Compound 1

embodiments, a starting material in the synthesis of Compound

embodiments, an intermediate in the synthesis of Compound

embodiments, a starting material in the synthesis of Compound 1 is

embodiments, an intermediate in the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

In some embodiments, an intermediate in the synthesis of Compound

In some embodiments, an intermediate in the synthesis of Compound 1 is

C

ompoun s . n some em o mens, an nerme ae n e syn ess of

Compound

some embodiments, an intermediate in the synthesis of

Compound

some embodiments, an intermediate in the synthesis of

synthesis of Compound 1 is

. In some embodiments, an intermediate in the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

some embodiments, a starting material in the synthesis of Compound 1 is

. In some embodiments, an intermediate in the synthesis of Compound

some embodiments, an intermediate in the synthesis of Compound

embodiments, an intermediate in the synthesis of Compound

embodiments, an intermediate in the synthesis of Compound

Further Forms of Compounds

[0035] The compounds described herein may in some casesexist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by the forming diastereomeric and separation by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0036] In some situations, compounds may exist as tautomers. All tautomers are included within the formulas described herein.

Pharmaceutically acceptable salts

[0037] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0038] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0039] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate, adipate, benzoate, besylate, bitartrate, carbonate, citrate, fumarate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, nitrate, phosphate, salicylate, succinate, sulfate, or tartrate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a monohydrochloride salt. In further embodiments, the pharmaceutically acceptable salt of Compound 1 is a mono-hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an adipic acid salt.

Solvates

[0040] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0041] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Labeled compounds

[0042] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ¹⁴C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, z.e., ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Increased levels of deuterium incorporation produce a detectable kinetic isotope effect (KIE) that may affect the pharmacokinetic, pharmacologic and/or toxicologic parameters of Compound 1 in comparison to Compound 1 having naturally occurring levels of deuterium. In some embodiments, the isotopically labeled compound, or a pharmaceutically acceptable salt thereof, is prepared by any suitable method.

[0043] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Process for Preparation

[0044] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0045] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics. In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3^rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. [0046] In some embodiments is a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-

((lR,2S)-2-fluorocyclopropyl)urea (Compound 1):

A) the reaction of compound with the structure:

O OH

O

⁰ t F with t-butanol, triethylamine, and diphenyl phosphoryl azide to produce a compound with the structure: he reaction of the compound with the structure:

hydrochloric acid in ethyl acetate to produce a compound with the f the compound with the structure: nitric acid and sulfuric acid to produce a compound with the structure:

D) followed by the reaction of the compounds with the structures:

E) followed by the reaction of the compounds with the structures:

potassium carbonate, palladium(II) acetate, and 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl (BINAP) to produce a compound with the

F) followed by the reaction of the compound with the structure:

G) followed by the reaction of the compounds with the structures:

H) followed by the reaction of the compound with the structure:

tri ethyl silane and trifluoroacetic acid to produce l-(5-

((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5- a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea (Compound 1) having the structure:

[0047] In some embodiments, the process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1) further comprises the reaction of l-(5-((7- fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin- 3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea(Compound 1) with adipic acid to produce l-(5-((7- fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin- 3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea adipic acid salt (Compound 1A). [0048] In some embodiments is a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1):

(Compound 1), comprising contacting a compound with the structure:

triethyl silane and an acid in the presence of a solvent.

In some embodiments, the acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. In some embodiments, the acid is trifluoromethanesulfonic acid and trifluoroacetic acid. In some embodiments, the acid is trifluoromethanesulfonic acid. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is p-toluenesulfonic acid. In some embodiments, the acid is benzenesulfonic acid. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the solvent is selected from dichloromethane, 1,2- dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is dimethoxy ethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent is trifluorotoluene.

[0049] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

some embodiments, the base is triethylamine, diisopropylethylamine (DIPEA), N- methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, tri-n-propylamine, and triisopropylamine. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N- methylpiperidine. In some embodiments, the base is tri-n-propylamine. In some embodiments, the base is triisopropylamine. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP). In some embodiments, the solvent is

1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0050] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 -

prepared by a process comprising contacting the compounds with the structures:

with diphenyl phosphoryl azide, and a base in the presence of a solvent followed

the presence of a solvent. In some embodiments, the base is triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N- methylpyrrolidine, N-methylpiperidine, tri-n-propylamine, and triisopropylamine. In some embodiments, the base is tri ethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N- methylpiperidine. In some embodiments, the base is tri-n-propylamine. In some embodiments, the base is triisopropylamine. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0051] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting a compound with the structure:

under reductive conditions in the presence of a solvent. In some embodiments, the reductive conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum and vanadium on carbon, platinum oxide, or combinations thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the hydrogenation catalyst is platinum and vanadium on carbon. In some embodiments, the hydrogenation catalyst is platinum oxide. In some embodiments, the reductive conditions are ammonium formate and formic acid. In some embodiments, the solvent is selected from dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, dimethylacetamide, and N-methyl pyrrolidone. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is 1,4- dioxane. In some embodiments, the solvent is 1,2-dimethoxy ethane. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is N-methyl pyrrolidone. [0052] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

phosphine ligand in the presence of a solvent. In some embodiments, the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and potassium tert-butoxide. In some embodiments, the base is potassium carbonate. In some embodiments, the base is cesium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is tri ethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the catalyst is selected from palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), [1 , 1 '-Bis(di-te/7- butylphosphino)ferrocene]dichloropalladium(II), Bis(triphenylphosphine)palladium(II) dichloride, Tetrakis(triphenylphosphine)palladium(0), and Tris(dibenzylideneacetone)dipalladium(0). In some embodiments, the catalyst is palladium(II) acetate. In some embodiments, the catalyst is Bis(dibenzylideneacetone)palladium(0). In some embodiments, the catalyst is [1,1 '-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). In some embodiments, the catalyst is Bis(triphenylphosphine)palladium(II) dichloride. In some embodiments, the catalyst is Tetrakis(triphenylphosphine)palladium(0). In some embodiments, the catalyst is Tris(dibenzylideneacetone)dipalladium(0). In some embodiments, the phosphine ligand is selected from BINAP, triphenylphosphine, tert-BuXPhos, CyJohnPhos, DavePhos, JohnPhos, Sphos, Xphos, DPPF, and BrettPhos. In some embodiments, the phosphine ligand is BINAP. In some embodiments, the phosphine ligand is triphenylphosphine. In some embodiments, the phosphine ligand is tert-BuXPhos. In some embodiments, the phosphine ligand is tert-BuXPhos. In some embodiments, the phosphine ligand is CyJohnPhos. In some embodiments, the phosphine ligand is DavePhos. In some embodiments, the phosphine ligand is JohnPhos. In some embodiments, the phosphine ligand is Sphos. In some embodiments, the phosphine ligand is Xphos. In some embodiments, the phosphine ligand is DPPF. In some embodiments, the phosphine ligand is BrettPhos. In some embodiments, the solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, THF, MeTHF, and acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, the solvent is N,N- dimethylacetamide. In some embodiments, the solvent is N-methylpyrrolidone. In some embodiments, the solvent is THF. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is acetonitrile.

[0053] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

presence of a solvent. In some embodiments, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N- methylmorpholine, N-methylpyrrolidine, and N-methylpiperidine. In some embodiments, the base is tri ethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N- methylpyrrolidine. In some embodiments, the base is N-methylpiperidine. In some embodiments, the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4- dioxane, 1,2-dimethoxy ethane, dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran (THF). In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is 1,2-dimethoxy ethane. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methyl pyrrolidone (NMP). [0054] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting a compound with the structure:

nitric acid and sulfuric acid.

[0055] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure: hereof is prepared by a process comprising contacting a compound with t

acid in the presence of a solvent. In some embodiments, the acid is selected from hydrochloric acid, trifluoroacetic acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is p-toluenesulfonic acid. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the acid is benzenesulfonic acid. In some embodiments, the solvent is selected from ethyl acetate, 1,4- dioxane, tetrahydrofuran, dichloromethane, ethanol, methanol, 1,2-dimethoxy ethane, and acetonitrile. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is methanol. In some embodiments, the solvent is 1,2- dimethoxyethane. In some embodiments, the solvent is acetonitrile.

[0056] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure: epared by a process comprising contacting a compound with the structure:

butanol, diphenyl phosphoryl azide, and a base in the presence of a solvent. In some embodiments, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, and N-methylpiperidine. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N- methylpiperidine. In some embodiments, the solvent is selected from toluene, acetonitrile, 1,4- dioxane, tetrahydrofuran, dichloromethane, and 1,2-dimethoxy ethane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is 1,2- dimethoxy ethane.

[0057] In some embodiments is a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1):

(Compound 1), comprising contacting a compound with the structure:

tri ethyl silane and an acid in the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2, 4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3, 4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethoxybenzyl protecting group. In some embodiments, the acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. In some embodiments, the acid is trifluoromethanesulfonic acid and trifluoroacetic acid. In some embodiments, the acid is trifluoromethanesulfonic acid. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is p-toluenesulfonic acid. In some embodiments, the acid is benzenesulfonic acid. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the solvent is selected from dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is dimethoxy ethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent is trifluorotoluene.

[0058] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

with a base in the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethoxybenzyl protecting group. In some embodiments, the base is triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, N- methylpiperidine, tri-n-propylamine, and triisopropylamine. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N- methylpyrrolidine. In some embodiments, the base is N-methylpiperidine. In some embodiments, the base is tri-n-propylamine. In some embodiments, the base is triisopropylamine. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and 2- methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N- methylpyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2- m ethy Itetrahy drof uran .

[0059] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzofb] [ 1 ,4]dioxin-5 -yl)amino)-7 -(methylamino)pyrazolo[ 1 ,5 -a]pyrimidin-3 -y l)-3 -

prepared by a process comprising contacting the compounds with the structures:

the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3, 4-dimeth oxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethoxybenzyl protecting group. In some embodiments, the base is triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, tri-n-propylamine, and triisopropylamine. In some embodiments, the base is tri ethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N- methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N-methylpiperidine. In some embodiments, the base is tri-n- propylamine. In some embodiments, the base is triisopropylamine. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0060] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-

((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure: prepared by a process comprising contacting a compound with the

under reductive conditions in the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3, 4-dimeth oxybenzyl protecting group. In some embodiments, PG is a 3,4,5- trimeth oxybenzyl protecting group. In some embodiments, the reductive conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum and vanadium on carbon, platinum oxide, or combinations thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the hydrogenation catalyst is platinum and vanadium on carbon. In some embodiments, the hydrogenation catalyst is platinum oxide. In some embodiments, the reductive conditions are ammonium formate and formic acid. In some embodiments, the solvent is selected from dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, dimethylacetamide, and N-methyl pyrrolidone. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is 1,4- dioxane. In some embodiments, the solvent is 1,2-dimethoxy ethane. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is N-methyl pyrrolidone. [0061] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

salt thereof, with a base, catalyst, and a phosphine ligand in the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2,4- dimethoxybenzyl protecting group. In some embodiments, PG is a 3,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethoxybenzyl protecting group. In some embodiments, the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and potassium tert-butoxide. In some embodiments, the base is potassium carbonate. In some embodiments, the base is cesium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the catalyst is selected from palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), [1 , 1 '-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II), Bis(triphenylphosphine)palladium(II) dichloride, Tetrakis(triphenylphosphine)palladium(0), and Tris(dibenzylideneacetone)dipalladium(0). In some embodiments, the catalyst is palladium(II) acetate. In some embodiments, the catalyst is Bis(dibenzylideneacetone)palladium(0). In some embodiments, the catalystis [1,1 '-Bis(di-/c/7-butylphosphino)ferrocene]dichloropalladium(II). In some embodiments, the catalystis Bis(triphenylphosphine)palladium(II) dichloride. In some embodiments, the catalystis Tetrakis(triphenylphosphine)palladium(0). In some embodiments, the catalystis Tris(dibenzylideneacetone)dipalladium(0). In some embodiments, the phosphine ligand is selected from BINAP, triphenylphosphine, tert-BuXPhos, CyJohnPhos, DavePhos, JohnPhos, Sphos, Xphos, DPPF, and BrettPhos. In some embodiments, the phosphine ligand is BINAP. In some embodiments, the phosphine ligand is triphenylphosphine. In some embodiments, the phosphine ligand is tert-BuXPhos. In some embodiments, the phosphine ligand is tert-BuXPhos. In some embodiments, the phosphine ligand is CyJohnPhos. In some embodiments, the phosphine ligand is DavePhos. In some embodiments, the phosphine ligand is JohnPhos. In some embodiments, the phosphine ligand is Sphos. In some embodiments, the phosphine ligand is Xphos. In some embodiments, the phosphine ligand is DPPF. In some embodiments, the phosphine ligand is BrettPhos. In some embodiments, the solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, THF, MeTHF, and acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, the solvent is N,N- dimethylacetamide. In some embodiments, the solvent is N-methylpyrrolidone. In some embodiments, the solvent is THF. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is acetonitrile.

[0062] In some embodiments of a process for the preparation of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- cyclopropyl)urea (Compound 1), the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

base in the presence of a solvent, wherein PG is an amine protecting group. In some embodiments, PG is a 4-methoxybenzyl protecting group. In some embodiments, PG is a 2,4-dimethoxybenzyl protecting group. In some embodiments, PG is a 3, 4-dimeth oxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethoxybenzyl protecting group. In some embodiments, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, and N- methylpiperidine. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is N-methylmorpholine. In some embodiments, the base is N-methylpyrrolidine. In some embodiments, the base is N- methylpiperidine. In some embodiments, the solvent is selected from tetrahydrofuran (THF), 2- methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, dimethylacetamide (DMA), and N- methyl pyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran (THF). In some embodiments, the solvent is 2- methyltetrahydrofuran. In some embodiments, the solvent is 1,2-dimethoxy ethane. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N- methyl pyrrolidone (NMP).

[0063] In some embodiments is a compound selected from:

pharmaceutically acceptable salt thereof.

Pharmaceutical compositions and methods of administration

[0064] Administration of Compound 1 described herein can be in any pharmacological form including a therapeutically effective amount of Compound 1 alone or in combination with a pharmaceutically acceptable carrier.

[0065] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0066] A pharmaceutical composition, as used herein, refers to a mixture of Compound 1 described herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. Compound 1 can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).

[0067] The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. Moreover, the pharmaceutical compositions described herein, which include Compound 1 described herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tab lets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0068] In some embodiments, Compound 1 is formulated in a tablet dosage form. In some embodiments, Compound 1 is formulated in a capsule dosage form. In some embodiments, Compound 1 is formulated in a suspension dosage form. In some embodiments, Compound 1 is formulated as powder-in-capsule dosage form. In some embodiments, Compound 1 is formulated as a powder-in -bottle for reconstitution as a suspension.

[0069] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [0070] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0071] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of Compound 1 and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration.

EXAMPLES

[0072] All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification.

[0073] Standard abbreviations and acronyms as defined in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreviations and acronyms used herein are as follows:

Example 1: Synthesis of 7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-amine hydrochloride

(Compound C)

[0074] Toluene (471 kg) and compound A (76 kg) were heated to 60 °C and stirred for 1 h. The solvent was partially evaporated under vacuum, cooled down to 25 °C and allowed to stand for at least 10 min. tert-Butanol (64 kg) was added under nitrogen, followed by triethylamine (52 kg). The reaction mixture was heated to 80 °C and add diphenyl phosphoryl azide (99 kg) was added. The reaction mixture was stirred for 3 h at 80 °C and then cooled to 25 °C. Toluene (176 kg) and 5% aq. NaOH (214 kg) solution were added. The mixture was stirred for 30 min at 25 °C and then filtered through celite (68 kg). The wet filter cake was washed with toluene (119 kg). The organic phase was collected and the aqueous phase was extracted with toluene (176 kg). The combine organic phases were washed with 5% aq. NaOH solution (212 kg) and 10.0% aq. citric acid solution (531 kg) until the aqueous phasepH = 4-5. Water (204 kg) was added to the organic phase and the mixture was stirred for 30 min. The mixture was filtered through celite (17 kg) and the wet filter cake was washed with toluene (119 kg). The organic solution was collected and concentrated under vacuum. HCl-ethyl acetate solution (4.0 M, 314 kg) was added at 25 °C and the mixture was stirred for 4 h. The mixture was filtered and the wet filter cake was washed with toluene (118 kg) and collected to afford compound C (36 kg).

[0075] Water (182 kg) and compound C (34 kg) were stirred at 25 °C for 30 min. The mixture was filtered and washed with water (73 kg). The filtrate was combined with dichloromethane (245 kg) and sodium bicarbonate (18 kg) and stirred for 15 min. The phases were separated and the aqueous phase was extracted with dichloromethane (243 kg). The combined organic phases were washed with 5% aq NaCl (116 kg), dried over sodium sulfate (18 kg) and filtered. The filtrate was concentrated and diluted with ethyl acetate (197 kg). An HCl-ethyl acetate solution (4.0 M, 81 kg) was added to the organic solution and stirred for 1 h. Solids were collected by filtration, washed with ethyl acetate (66 kg), and dried under vacuum to afford compound C (27.8 kg). 'HNMR (300 MHz, DMSO-d₆) 8 8.61 (br s, 3H), 6.70 (d, 1H), 6.59 (d, 1H), 4.29 (s, 4H).

Example 2: Synthesis of l-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7- (methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea

Compound 1

[0076] To sulfuric acid (34 L, concentrated) in a 100 L reactor was added nitric acid (11.4 L, 70%) dropwise over 2 h at -10 °C, and then D (5.68 kg) was added in portions (the temperature was kept below 5 °C). The mixture was stirred at 0 °C for 2 h. The mixture was divided into 3 portions and each was poured into ice-water (50 L) and extracted with DCM (30 L * 2). The combined organic layers were washed by saturated NaHCO₃ (25 L) and brine (15 L), dried over Na2SO4, and 3 batches of filtrate were combined and concentrated. The residue was triturated with Heptane/EtOAc (25 L, 5/1, V/V). The solid was collected by filtration and dried under vacuum to afford compound E (5.63 kg) as a brown solid. ^JH NMR (400 MHz, CDC1₃) 5 8.84 (s, 1H), 7.35 (s, 1H).

[0077] To a solution of compound E (3.00 kg, 12.33 mol, 1.00 eq) in dioxane (45 L) was added l-(4-methoxyphenyl)-N-methylmethanamine (1.86 kg, 12.33 mol, 1.00 eq) and TEA (2.50 kg, 24.66 mol, 2.00 eq). After stirring at 90 °C for 1 h, the mixture was cooled to 40 °C, diluted with Hep/EtOAc = 10:1 (45 L, V/V) and stirred at 25 °C for 30 mins. The solid was collected by filtration, dissolved with DCM (60 L) and washed by brine (3 x 15 L). The organic phase was dried over Na₂SO₄ and concentrated under vacuum to afford compound F (3.68 kg) as a yellow solid. ^JH NMR (400 MHz, CDC1₃) 88.45 (d, J= 2.1 Hz, 1H), 7.06 - 6.95 (m, 2H), 6.73 (dd, J = 8.6, 2.0 Hz, 2H), 6.12 (d, J=2.1 Hz, 1H), 5.08 (s, 2H), 3.64 (d, J = 2.2 Hz, 3H), 3.06 (d, J= 2.0 Hz, 3H).

[0078] To a solution of compound F (3.64 kg, 10.05 mol, 1.00 eq) and compound C (2.14 kg, 12.06 mol, 1.20 eq) in 1,4-dioxane (73 L) was added K2CO3 (2.78 kg, 20.10 mol, 2.00 eq), Pd(OAc)₂ (180.48 g, 0.804 mol, 0.08 eq) and BINAP (1.00 kg, 1.61 mol, 0.16 eq) under argon atmosphere at 25 °C. The mixture was warmed to 100 °C and stirred for 3 h. The reaction mixture was cooled to 25±5 °C, and diluted with heptane (36.4 L). The mixture was filtered, and the filter cake was triturated with a mixture of ACN (18 L), MeOH (18 L) and H₂O (36 L) for 30 min. The mixture was filtered, and the filter cake was washed with H₂O (18 L) and ACN (18 L), and dried under vacuum to afford compound G (4.08 kg) as a light-yellow solid. 'H NMR (400 MHz, DMSO) 5 9.20 (s, 1H), 8.72 (s, 1H), 8.48 (dd, J = 12.2, 2.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.57 - 6.43 (m, 2H), 5.02 (s, 2H), 4.33 (dd, J = 9.4, 4.6 Hz, 4H), 3.73 (s, 3H), 2.99 (s, 3H).

[0079] To a solution of compound G (4.80 kg, 9.79 mol, 1.00 eq) in DMF (72 L) was added 10% Pd/C (0.48 kg) at 25 °C, and the mixture was evacuated and flushed with N₂ followed by H₂ (3 times), and the mixture was warmed to 80 °C and stirred for 24 h. Upon reaction completion, the reaction mixture was cooled to 50 °C. Pd/C was filtered and H₂O (114 L) was added to the filtrate. The mixture was triturated, and filtered. The filter cake was washed with H₂O (30 L) and EtOH (10 L), collected and dried to give compound H (4.25 kg) as a brown solid. ^XH NMR (400 MHz, DMSO) 5 8.30 (dd, J = 13.0, 3.9 Hz, 2H), 7.60 (s, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 6.07 (s, 1H), 5.08 (s, 2H), 4.30 (q, J = 4.6 Hz, 4H), 3.71 (s, 5H), 2.87 (s, 3H). [0080] To a solution of compound H (50.0 g, 1.0 eq) in DMF (150 mL) was added N-((1R,2S)- 2-fluorocyclopropyl)benzamide (23.9 g, 1.1 eq). Triethylamine (13.5 g, 1,2 eq) was then added dropwise. The reaction mixture was heated at 60 °C and stirred for 3 h. The mixture was cooled. Water (280 mL) was added dropwise and the mixture was stirred for 2 h. The mixture was filtered and the filter cake was washed with water (2 x 100 mL). The filter cake was dried at 50 °C for 16 h to afford compound I (58.9 g). 'HNMR (400 MHz, DMSO): 8.49 (d, J = 1.4 Hz, 1H), 8.18 (dd, J = 11.7, 3.0 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.20-7.10 (m, 2H), 6.92-6.83 (m, 2H), 6.71-6.65 (m, 1H), 6.38 (dd, J = 9.6, 3.0 Hz, 1H), 6.18 (s, 1H), 5.10 (s, 2H), 4.81 (td, J = 5.8, 3.0 Hz, 0.5H), 4.65 (td, J = 5.7, 3.0 Hz, 0.5H), 4.35-4.25 (m, 4H), 3.71 (s, 3H), 2.90 (s, 3H), 2.70-2.60 (m, 1H), 1.05 (dtd, J = 14.6, 8.1, 6.1 Hz, 1H), 0.83 (dddd, J = 25.3, 8.1, 5.7, 3.0 Hz, 1H); MS ESI+: 552.10 [M + H]+.

[0081] To a solution of compound I (25.0 g, 1.0 eq) in DCM (125 mL) at -10 °C was added Et₃SiH (9.0 g, 1.7 eq) dropwise. To the reaction mixture was added TFA (62.5 mL) dropwise and the reaction mixture was stirred 1 h at -10 °C. To the reaction mixture was added trifluoromethanesulfonic acid (12.5 mL) dropwise and the reaction mixture was stirred 3 h at - 10 °C. The reaction mixture was warmed to 10 °C and a solution of potassium carbonate (75 g) in water (250 mL) was added dropwise to the reaction mixture. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was filtered and the filter cake was washed with water (2 x 50 mL) and EtOH (2 x 25 mL). The filter cake was dried at 50 °C for 12 h to afford compound 1 (12.2 g). ¹H NMR (400 MHz, DMSO): 8.32 (d, J= 1.4 Hz, 1H), 8.18 (dd, J = 11.8, 3.1 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.57 (q, J = 4.9 Hz, 1H), 6.63 (d, J = 3.7 Hz, 1H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 5.95 (s, 1H), 4.80 (td, J = 5.7, 3.0 Hz, 0.5 H), 4.63 (td, J = 5.8, 3.0 Hz, 0.5 H), 4.36-4.26 (m, 4H), 2.89 (d, J = 4.8 Hz, 3H), 2.69-2.58 (m, 1H), 1.03 (dtd, J = 14.5, 8.1, 6.1 Hz, 1H), 0.85 (ddd, J = 8.1, 5.7, 3.0 Hz, 0.5 H), 0.78 (ddd, J = 8.0, 5.6, 3.0 Hz, 0.5 H); MS ESI+: 432.10 [M + H]⁺.

Example 3: Synthesis of l-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7- (methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3-((lR,2S)-2-fluorocyclopropyl)urea adipic acid salt (Compound 1A)

Compound 1 Compound 1A [0082] To a solution of adipic acid (6.8 g, 2.0 eq) in water (8 mL) and acetone (152 mL) was added compound 1 (10.0 g, 1.0 eq). The reaction mixture was stirred at 25 °C for 24 h and then filtered. The filter cake was washed with 5% water/acetone (2 x 20 mL). The filter cake was dried at 25 °C for 24 h to afford compound 1 A (9.8 g). ^JH NMR (400 MHz, DMSO): 12.02 (s, 1H), 8.32 (s, 1H), 8.18 (dd, J= 11.8, 3.1 Hz, 1H), 8.O3 (s, 1H), 7.76 (s, 1H), 7.57 (q, J = 4.8 Hz, 1H), 6.63 (d, J = 3.7 Hz, 1H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 5.95 (s, 1H), 4.80 (td, J = 5.7, 3.0 Hz, 0.5 H), 4.63 (td, J = 5.8, 3.0 Hz, 0.5 H), 4.40-4.26 (m, 4H), 2.89 (d, J = 4.8 Hz, 3H), 2.64 (dqd, J = 11.0, 3.9, 1.8 Hz, 1H), 2.26-2.16 (m, 2H), 1.56-1 .44 (m, 2H), 1.10 -0.96 (m, 1H), 0.81 (dddd, J = 25.3, 8.0, 5.6, 2.9 Hz, 1H); HR-MS for C24H29F2N5O3: (calc.): 432.1596, Found: 432.1603.

Example 4: Co-Stimulation Assay in Lysed Whole Blood; JAK2: GM-CSF Stimulated STAT5 Phosphorylation and JAK1/TYK2 Stimulated STAT1 Phosphorylation Assay Human Blood Lysis using abcam’s RBC lysis buffer

[0083] Dilute RBC lysis buffer to IX in distilled water. Add 2 mL blood to 38 mL of IX RBC- lysis buffer. Incubate for 15 mins atRT, in dark. Spin at 300g, 5 mins, to collect the pellet. Relyse if necessary. Re-suspend pellet in 5 mL of cRPMI.

Compound and Cytokine treatment

[0084] Aliquot 80 pL of lysed human blood in to wells of 96 deep-well plate. Add 10 pL of (lOX conc.) of different concentrations of compound 1 to wells except controls (unstained and unstimulated) and mix it with the help of 100 uL multichannel. Add 10 uL of RPMI media in controls. For dilution of compounds and dilution range please refer Appendix. Incubate on water bath or CO₂ incubator for 1 hour at 37°C. Add 10 pL of (10X cone.) of cytokine mix (GM-CSF and IFNa) (final conc. lOng/mL of GM-CSF and 100 ng/mL of IFNa) to each well except unstimulated and unstained controls and incubate further for 20 minutes on water bath at 37°C. RBC Lysis and Fixation

[0085] Add 900 pL of prewarmed IX Fix/Lyse solution (Appendix) and mix it properly using 1 OOOpl multichannel, incubate further on water bath at 37°C for 10 minutes (which includes time of addition). Centrifuge at 800 x g for 5 minutes at 40°C; remove 900 uL of supernatant and add 900 pL of IX PBS. Centrifuge at 800 x g for 5 minutes at 40°C, remove 900 pL of supernatant. Wash one more time with 900 pL of PBS (optional) and resuspend pellets in 100 uL of PBS. Permeabilization

[0086] Disrupt the pellet by gentle tapping and resuspend in 1000 pL of BD Phosflow Perm Buffer III and incubate plate on ice for 30 minutes. Centrifuge plate at 800 x g for 5 minutes at 40°C. Wash two more times with 1000 pL of BD Pharmingen Stain Buffer. Antibody treatment

[0087] Disrupt the pellet by gentle tapping. Resuspend pellets in 100 uL of Stain Buffer and add 5 pL of pSTAT5_AF488 Ab and 5 uL of pSTATI PEin all wells except unstained control and mix properly using 200pl multichannel, incubate overnight at 40°C. Add 900 pL of wash buffer and centrifuge at 1800 rpm for 3 minutes at 40°C. Wash one more time with 1000 pL of BD Pharmingen Stain Buffer. Finally resuspend the pellet in 300 uL of BD Pharmingen Stain Buffer. Transfer the cells to 96-well v-bottom plate and acquire the cells in Beckman Coulter CytExpert. Acquiring cells in Flow Cytometer: Keep the threshold value to 250 and cell concentration should not exceed 100-500 cells/pL. Acquire at least 5,000-10,000 cells. Appendix

Preparation of Reagents

[0088] RPMI 1640 Complete Medium: RPMI 1640 media + 10% FBS.

[0089] Cytokine dilution: 1) GM-CSF Stock at 100 ug/mL. Prepare an intermediate dilution of 1 ug/mL by adding 2 uL of stock into 198 uL of cRPMI. Further dilute to 100 ng/mL by adding 100 uL of the intermediate stock to 900 uL of cRPMI. 2) IFNa Stock at 200 ug/mL. Dilute IFNa stock 1 :200 by adding 5 uL of stock into the 1000 uL of 100 ng/mL GM-CSF working stock as above to give a combined working stock of 1000 ng/mL of IFNa and 100 ng/mL GM-CSF (lOx). Keep it on ice until used.

[0090] Lyse/Fix buffer preparation: Dilute 5XLyse/Fix bufferto IXusing MQ water and keep at 37°C until used.

[0091] BD Phosflow perm buffer III: Keep on ice/fridge.

Compound dilution

[0092] Compound 1 IFN-a/JaklTyk2 IC50 is less than 1 pM.

[0093] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A process for the preparation of l-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5- yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3-((lR,2S)-2- fluorocyclopropyl)urea (Compound 1), comprising:

B) followed by the reaction of the compound with the structure: hydrochloric acid in ethyl acetate to produce a compound with the

C) the reaction of the compound with the structure: nitric acid and sulfuric acid to produce a compound with the structure:

D) followed by the reaction of the compounds with the structures:

E) followed by the reaction of the compounds with the structures:

F) followed by the reaction of the compound with the structure:

G) followed by the reaction of the compounds with the structures:

H) followed by the reaction of the compound with the structure:

tri ethyl silane and trifluoroacetic acid to produce l-(5-

(Compound 1).

2. The process of claim 1, further comprising the reaction of l-(5-((7-fluoro-2,3- dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-3- ((lR,2S)-2-fluorocyclopropyl)urea (Compound 1) with adipic acid to produce l-(5-((7-fluoro- 2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[l,5-a]pyrimidin-3 -yl)-3 - ((lR,2S)-2-fluorocyclopropyl)urea adipic acid salt (Compound 1 A).

3. A process for the preparation of 4-fluoro-3-(2 -hydroxyethoxy )-N-(2 -isobutoxy -4-((2- isobutoxy -4 -(((lR,4R)-4-(quinolin-3- ylcarbamoyl)cyclohexyl)carbamoyl)phenyl)carbamoyl)phenyl)benzamide (Compound 1):

comprising contacting the compound with the structure:

tri ethyl silane and an acid in the presence of a solvent.

4. The process of claim 3, wherein the acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, p- toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid.

5. The process of claim 3 or claim 4, wherein the acid is trifluoromethanesulfonic acid and trifluoroacetic acid.

6. The process of any one of claims 3-5, wherein the acid is trifluoromethanesulfonic acid.

7. The process of any one of claims 3-6, wherein the solvent is selected from dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene.

8. The process of any one of claims 3-7, wherein the solvent is dichloromethane.

9. The process of any one of claims 3-8, wherein the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

with a base in the presence of a solvent.

10. The process of claim 9, wherein the base is triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, tri-n-propylamine, and triisopropylamine

11. The process of claim 9 or claim 10, wherein the base is triethylamine.

12. The process of any one of claims 9-11, wherein the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.

13. The process of any one of claims 9-12, wherein the solvent is dimethylformamide.

14. The process of any one of claims 3-13, wherein the compound with the structure:

un er re uc ve con ons n e presence o a so ven .

15. The process of claim 14, wherein the reductive conditions are hydrogen and a hydrogenation catalyst.

16. The process of claim 15, wherein the hydrogenation catalyst is selected from palladium on carbon, platinum and vanadium on carbon, platinum oxide, or combinations thereof.

17. The process of claim 14 or claim 15, wherein the hydrogenation catalyst is palladium on carbon.

18. The process of claim 14, wherein the reductive conditions are ammonium formate and formic acid.

19. The process of any one of claims 14-18, wherein the solvent is selected from dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, dimethylacetamide, and N-methyl pyrrolidone.

20. The process of any one of claims 14-19, wherein the solvent is dimethylformamide.

21. The process of any one of claims 3-20, wherein the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

phosphine ligand in the presence of a solvent.

22. The process of claim 21, wherein the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and potassium tert-butoxide.

23. The process of claim 21 or claim 22, wherein the base is potassium carbonate.

24. The process of any one of claims 21-23, wherein the catalyst is selected from palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), [1 , 1 '-Bis(di-/c77- butylphosphino)ferrocene]dichloropalladium(II), Bis(triphenylphosphine)palladium(II) dichloride, Tetrakis(triphenylphosphine)palladium(0), and Tris(dibenzylideneacetone)dipalladium(0).

25. The process of any one of claims 21-24, wherein the catalyst is palladium(II) acetate.

26. The process of any one of claims 21-25, wherein the phosphine ligand is selected from BINAP, triphenylphosphine, tert-BuXPhos, CyJohnPhos, DavePhos, JohnPhos, Sphos, Xphos, DPPF, and BrettPhos.

27. The process of any one of claims 21-26, wherein the phosphine ligand is BINAP.

28. The process of any one of claims 21-27, wherein the solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, THF, MeTHF, and acetonitrile.

29. The process of any one of claims 21-27, wherein the solvent is 1,4-dioxane.

30. The process of any one of claims 3-29, wherein the compound with the structure:

prepared by a process comprising contacting the compounds with the structures:

presence of a solvent.

31. The process of claim 30, wherein the base is selected from triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, and N- methylpiperidine.

32. The process of claim 30 or claim 31, wherein the base is triethylamine.

33. The process of any one of claims 30-32, wherein the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-di oxane, 1 ,2-dimeth oxyethane, dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP).

34. The process of any one of claims 30-33, wherein the solvent is 1,4-dioxane.

35. The process of any one of claims 3-34, wherein the compound with the structure:

prepared by a process comprising contacting a compound with the structure:

nitric acid and sulfuric acid.

36. The process of any one of claims 3-35, wherein the compound with the structure:

or a salt thereof is prepared by a process comprising contacting a compound with the structure:

acid in the presence of a solvent.

37. The process of claim 36, wherein the acid is selected from hydrochloric acid, trifluoroacetic acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid.

38. The process of claim 36 or claim 37, wherein the acid is hydrochloric acid.

39. The process of any one of claims 36-38, wherein the solvent is selected from ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, ethanol, methanol, 1,2-dimethoxy ethane, and acetonitrile.

40. The process of any one of claims 36-39, wherein the solvent is ethyl acetate.

41. The process of any one of claims 3-40, wherein the compound with the structure: repared by a process comprising contacting a compound with the structure:

butanol, diphenyl phosphoryl azide, and a base in the presence of a solvent.

42. The process of claim 41, wherein the base is selected from triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, and N- methylpiperidine.

43. The process of claim 41 or claim 42, wherein the base is triethylamine.

44. The process of any one of claims 41-43, wherein the solvent is selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, and 1,2-dimethoxy ethane.

45. The process of any one of claims 41-44, wherein the solvent is toluene.