Preparation of TYK2 inhibitors

Abstract

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

Description

[Technical Field]

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

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

[0003] Described herein is a process for synthesizing a TYK2 inhibitor compound, 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) or a pharmaceutically acceptable salt thereof.

[0004] One embodiment is the following process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1): A) The following structure

[0005] [ka] With t-butanol, triethylamine, and diphenylphosphoryl azide, a compound having the following structure is reacted to give

[0006] [ka] and producing a compound having the formula: B) Then, the following structure

[0007] [ka] with hydrochloric acid in ethyl acetate to give the compound having the following structure:

[0008] [ka] and producing a compound having the formula: C) The following structure

[0009] [ka] With nitric acid and sulfuric acid, a compound having the following structure is reacted to give

[0010] [ka] and producing a compound having the formula: D) Then, the following structure

[0011] [ka] By reacting a compound having the following structure with triethylamine,

[0012] [ka] and producing a compound having the formula: E) Then, the following structure

[0013] [ka] with potassium carbonate, palladium(II) acetate, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) to give the compound having the following structure:

[0014] [ka] and producing a compound having the formula: F) Then, the following structure

[0015] [ka] with palladium on carbon and hydrogen to give a compound having the following structure:

[0016] [ka] and producing a compound having the formula: G) Then, the following structure

[0017] [ka] By reacting a compound having the following structure with triethylamine,

[0018] [ka] and producing a compound having the formula: H) Then, the following structure

[0019] [ka] with triethylsilane and trifluoroacetic acid to give the compound having the following structure:

[0020] [ka] to produce 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (compound 1),

[0021] In some embodiments, the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) comprises reacting 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo The method further comprises reacting [1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) with adipic acid to produce 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate (Compound 1A).

[0022] Another embodiment is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1).

[0023] [ka] 1. A process for preparing The following structure

[0024] [ka] with triethylsilane 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.

[0025] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0026] [ka] The compound having the following structure:

[0027] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with a 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, and 2-methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide.

[0028] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0029] [ka] The compound having the following structure:

[0030] [ka] under reducing conditions in the presence of a solvent. In some embodiments, the reducing conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum on carbon and vanadium on carbon, platinum oxide, or a combination thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the reducing 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-methylpyrrolidone. In some embodiments, the solvent is dimethylformamide.

[0031] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0032] [ka] The compound having the following structure:

[0033] [ka] or a salt thereof with a base, a 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-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 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-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, THF, MeTHF, and acetonitrile. In some embodiments, the solvent is 1,4-dioxane.

[0034] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0035] [ka] The compound having the following structure:

[0036] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with 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 solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylacetamide (DMA), and N-methylpyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane.

[0037] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0038] [ka] The compound having the following structure:

[0039] [ka] with nitric acid and sulfuric acid.

[0040] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0041] [ka] or a salt thereof,

[0042] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with an 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-dimethoxyethane, and acetonitrile. In some embodiments, the solvent is ethyl acetate.

[0043] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0044] [ka] The compound having the following structure:

[0045] [ka] The compound having the formula: is prepared by a process comprising contacting a compound having the formula: with t-butanol, diphenylphosphoryl 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 solvent is selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, and 1,2-dimethoxyethane. In some embodiments, the solvent is toluene.

[0046] Incorporation by Reference 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

[0047] Large-scale production of clinically useful drug candidates typically requires good manufacturing practices. Provided herein are specific processes and methods for producing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), or a pharmaceutically acceptable salt or co-crystal thereof.

[0048] definition As used in this specification and the appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0049] As used in this specification and 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 cells) and equivalents thereof.

[0050] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0051] The term "about" when referring to a number or numerical range means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from 1% to 15% of the stated number or numerical range.

[0052] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as, for example, any composition, composition, method, or process described herein, that "consist of" or "consist essentially of" the described features.

[0053] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals 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.

[0054] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventative benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient despite the patient still suffering from the underlying disease. For preventative benefit, the composition is administered to a patient at risk of developing a particular disease or to a patient who reports one or more physiological symptoms of the disease, even if a diagnosis of the disease has been made.

[0055] "Pharmaceutically acceptable salt" includes both acid addition salts 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.

[0056] "Pharmaceutically acceptable acid addition salt" refers to salts that retain the biological effectiveness and properties of the free base and are biologically or otherwise undesirable and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including 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, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, adipate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Salts of amino acids, such as arginate, gluconate, and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)) are also contemplated. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0057] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines (e.g., 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, such as 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, etc. See Berge et al., supra.

[0058] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of multiple active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients are 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 simultaneously, concurrently, or sequentially, without any specific intervening time limit, such that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0059] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include treatment regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0060] As used herein, the term "activator" is used to refer to any molecular species that results in activation of the indicated receptor, whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered locally. Thus, an activator can be a ligand of the receptor, or it can be an activator that is metabolized to a ligand of the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

[0061] As used herein, the term "antagonist" refers to a small molecule agent that binds to a nuclear hormone receptor and subsequently reduces the agonist-induced transcriptional activity of the nuclear hormone receptor.

[0062] As used herein, the term "agonist" 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.

[0063] As used herein, the term "inverse agonist" refers to a small molecule drug that binds to a nuclear hormone receptor and subsequently reduces the basal level of nuclear hormone receptor transcriptional activity that exists in the absence of a known agonist.

[0064] As used herein, the term "modulate" means to interact either directly or indirectly with a target protein to alter the activity of the target protein, including, by way of example only, inhibiting the activity of the target or limiting or reducing the activity of the target.

[0065] As used herein, the term "modulator" refers to a compound that changes the 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 that reduces the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

[0066] compound In some embodiments, the TYK2 inhibitor compound described herein is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) or a pharmaceutically acceptable salt or co-crystal thereof. Compound 1 has the following structure:

[0067] [ka] In some embodiments, the starting material for the synthesis of Compound 1 is

[0068] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0069] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0070] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0071] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0072] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0073] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0074] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0075] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0076] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0077] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0078] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0079] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0080] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0081] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0082] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0083] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0084] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0085] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0086] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0087] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0088] [ka] In some embodiments, the starting material in the synthesis of Compound 1 is:

[0089] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0090] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0091] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0092] [ka] In some embodiments, an intermediate in the synthesis of Compound 1 is

[0093] [ka] is.

[0094] Further forms of the compound The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by forming diastereomers and separating them by recrystallization, or by chromatography, or any combination thereof (see Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates And Resolutions", John Wiley and Sons, Inc., 1981). Stereoisomers can also be obtained by stereoselective synthesis.

[0095] In some situations, compounds may exist as tautomers, and all tautomers are included within the formulae described herein.

[0096] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present 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.

[0097] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. 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 the purified compound in its free form with the appropriate acid or base and isolating the salt thus formed.

[0098] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is acetate, adipate, benzoate, besylate, tartrate, carbonate, citrate, fumarate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, nitrate, phosphate, salicylate, succinate, sulfate, or tartrate. 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 monohydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an adipate salt.

[0099] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0100] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. 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 aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein exist in both unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0101] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. 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 listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein that contain the above isotopes and / or other isotopes of other atoms, as well as pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, are within the scope of the present invention. Certain isotopically labeled compounds, such as 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2Substitution with heavy isotopes such as H provides certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Increased levels of deuterium incorporation result in a detectable kinetic isotope effect (KIE) that can affect the pharmacokinetic, pharmacological, and / or toxicological parameters of Compound 1 compared to Compound 1 with naturally occurring deuterium levels. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt thereof is prepared by any suitable method.

[0102] 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.

[0103] Process for preparation In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0104] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics. In further embodiments, the compounds described herein, and other related compounds with different substituents, can be synthesized using techniques and materials described herein, as well as other methods and methods described in, for example, 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 Supplementals (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 disclosures. General methods for the preparation of the compounds disclosed herein can be derived from reactions, which can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein.

[0105] Some embodiments are the following process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1): A) The following structure

[0106] [ka] With t-butanol, triethylamine, and diphenylphosphoryl azide, a compound having the following structure is reacted to give

[0107] [ka] and producing a compound having the formula: B) Then, the following structure

[0108] [ka] with hydrochloric acid in ethyl acetate to give the compound having the following structure:

[0109] [ka] and producing a compound having the formula: C) The following structure

[0110] [ka] With nitric acid and sulfuric acid, a compound having the following structure is reacted to give

[0111] [ka] and producing a compound having the formula: D) Then, the following structure

[0112] [ka] By reacting a compound having the following structure with triethylamine,

[0113] [ka] and producing a compound having the formula: E) Then, the following structure

[0114] [ka] with potassium carbonate, palladium(II) acetate, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) to give the compound having the following structure:

[0115] [ka] and producing a compound having the formula: F) Then, the following structure

[0116] [ka] with palladium on carbon and hydrogen to give a compound having the following structure:

[0117] [ka] and producing a compound having the formula: G) Then, the following structure

[0118] [ka] By reacting a compound having the following structure with triethylamine,

[0119] [ka] and producing a compound having the formula: H) Then, the following structure

[0120] [ka] with triethylsilane and trifluoroacetic acid to give the compound having the following structure:

[0121] [ka] to produce 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (compound 1),

[0122] In some embodiments, the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) comprises reacting 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo The method further comprises reacting [1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) with adipic acid to produce 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate (Compound 1A).

[0123] Some embodiments include 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1).

[0124] [ka] 1. A process for preparing The following structure

[0125] [ka] with triethylsilane 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, dimethoxyethane, 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 dimethoxyethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent is trifluorotoluene.

[0126] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0127] [ka] The compound having the following structure:

[0128] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with a 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 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.

[0129] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0130] [ka] The compound having the following structure:

[0131] [ka] with diphenylphosphoryl azide and a base in the presence of a solvent, followed by

[0132] [ka] 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-methyltetrahydrofuran.

[0133] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0134] [ka] The compound having the following structure:

[0135] [ka] under reducing conditions in the presence of a solvent. In some embodiments, the reducing conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum on carbon, and vanadium on carbon, platinum oxide, or a combination thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the hydrogenation catalyst is platinum on carbon and vanadium on carbon. In some embodiments, the hydrogenation catalyst is platinum oxide. In some embodiments, the reducing 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-methylpyrrolidone. 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-dimethoxyethane. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is N-methylpyrrolidone.

[0136] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0137] [ka] The compound having the following structure:

[0138] [ka] or a salt thereof with a base, a 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 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 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.

[0139] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0140] [ka] The compound having the following structure:

[0141] [ka] The compound is prepared by a process comprising contacting a compound having the formula: with 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 tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylacetamide (DMA), and N-methylpyrrolidone (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-dimethoxyethane. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP).

[0142] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0143] [ka] The compound having the following structure:

[0144] [ka] with nitric acid and sulfuric acid.

[0145] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0146] [ka] or a salt thereof,

[0147] [ka] with an 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-dimethoxyethane, 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.

[0148] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0149] [ka] The compound having the following structure:

[0150] [ka] The compound having the formula: is prepared by a process comprising contacting a compound having the formula: with t-butanol, diphenylphosphoryl 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-dimethoxyethane. 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-dimethoxyethane.

[0151] Some embodiments include 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1).

[0152] [ka] 1. A process for preparing The following structure

[0153] [ka] 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, dimethoxyethane, 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 dimethoxyethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent is trifluorotoluene.

[0154] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0155] [ka] The compound having the following structure:

[0156] [ka] 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-methyltetrahydrofuran.

[0157] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0158] [ka] The compound having the following structure:

[0159] [ka] with diphenylphosphoryl azide and a base in the presence of a solvent, followed by

[0160] [ka] 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-dimethyloxybenzyl 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-methyltetrahydrofuran.

[0161] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0162] [ka] The compound having the following structure:

[0163] [ka] 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-dimethyloxybenzyl protecting group. In some embodiments, PG is a 3,4,5-trimethyloxybenzyl protecting group. In some embodiments, the reducing conditions are hydrogen and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from palladium on carbon, platinum on carbon and vanadium on carbon, platinum oxide, or a combination thereof. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments, the hydrogenation catalyst is platinum on carbon and vanadium on carbon. In some embodiments, the hydrogenation catalyst is platinum oxide. In some embodiments, the reducing 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-methylpyrrolidone. 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-dimethoxyethane. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is N-methylpyrrolidone.

[0164] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0165] [ka] The compound having the following structure:

[0166] [ka] or a salt thereof with a base, a 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 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.

[0167] In some embodiments of the process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), the compound has the following structure:

[0168] [ka] The compound having the following structure:

[0169] [ka] 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-dimethyloxybenzyl 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-dimethoxyethane, dimethylacetamide (DMA), and N-methylpyrrolidone (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-dimethoxyethane. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP).

[0170] Some embodiments include:

[0171] [ka] or a pharmaceutically acceptable salt thereof.

[0172] Pharmaceutical Compositions and Methods of Administration Administration of Compound 1 described herein can be in any pharmacological form containing a therapeutically effective amount of Compound 1, alone or in combination with a pharmaceutically acceptable carrier.

[0173] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compounds into pharmaceutically usable preparations.Suitable formulation depends on the route of administration selected.More details about the excipients suitable for the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0174] As used herein, a pharmaceutical composition refers to a mixture of Compound 1 described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The 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 alone or in combination with one or more therapeutic agents as components of a mixture (as in combination therapy).

[0175] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. Furthermore, the pharmaceutical compositions described herein, including 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-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate-release and controlled-release formulations.

[0176] 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 a powder-in-capsule dosage form. In some embodiments, Compound 1 is formulated as a powder-in-bottle for reconstitution as a suspension.

[0177] Pharmaceutical compositions containing the compounds described herein may be manufactured in a conventional manner, such as by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0178] Dose administration may be repeatable depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0179] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate compositions in dosage unit form. As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary dosage for the mammalian subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier. The specifications of the dosage unit are determined by and directly depend on (a) the unique characteristics of Compound 1 and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technical field of compounding such active compounds for the treatment of susceptibility in individuals. Specific dosages can be easily calculated by those skilled in the art, for example, according to the approximate body weight or body surface area of ​​the patient or the volume of the body cavity to be occupied. Dosages are also calculated depending on the specific route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by those skilled in the art. The exact dosage is determined in conjunction with standard dose-response tests. It will be understood that the amount of composition actually administered will be determined by the physician in light of the relevant circumstances, including the disease(s) being 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. [Example]

[0180] All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification.

[0181] Standard abbreviations and acronyms are used herein as defined in J. Org. Chem. 2007 72(1):23A-24A. Other abbreviations and acronyms used herein are as follows:

[0182] [Table 1]

[0183] Example 1: Synthesis of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine hydrochloride (Compound C)

[0184] [ka] Toluene (471 kg) and Compound A (76 kg) were heated to 60°C and stirred for 1 hour. The solvent was partially evaporated under vacuum, cooled to 25°C, and allowed to stand for at least 10 minutes. tert-Butanol (64 kg) was added under nitrogen, followed by triethylamine (52 kg). The reaction mixture was heated to 80°C, and diphenylphosphoryl azide (99 kg) was added. The reaction mixture was stirred at 80°C for 3 hours and then cooled to 25°C. Toluene (176 kg) and 5% aqueous NaOH (214 kg) were added. The mixture was stirred at 25°C for 30 minutes 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 combined organic phase was washed with 5% aqueous NaOH (212 kg) and 10.0% aqueous citric acid (531 kg) until the aqueous phase reached a pH of 4-5. Water (204 kg) was added to the organic phase, and the mixture was stirred for 30 minutes. 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 hours. The mixture was filtered, and the wet filter cake was washed with toluene (118 kg) and collected to give compound C (36 kg).

[0185] Water (182 kg) and compound C (34 kg) were stirred at 25° C. for 30 minutes. 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 minutes. The phases were separated, and the aqueous phase was extracted with dichloromethane (243 kg). The combined organic phases were washed with 5% aqueous NaCl solution (116 kg), dried over sodium sulfate (18 kg), and filtered. The filtrate was concentrated and diluted with ethyl acetate (197 kg). A 4.0 M HCl-ethyl acetate solution (81 kg) was added to the organic solution and stirred for 1 hour. The solid was collected by filtration, washed with ethyl acetate (66 kg), and dried under vacuum to give compound C (27.8 kg). 1 H NMR (300MHz, DMSO-d6) δ 8.61 (br s, 3H), 6.70 (d, 1H), 6.59 (d, 1H), 4.29 (s, 4H).

[0186] Example 2: Synthesis of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1)

[0187] [ka] Nitric acid (11.4 L, 70%) was added dropwise to sulfuric acid (34 L, concentrated) in a 100 L reactor at -10 °C over 2 hours, and then D (5.68 kg) was added portionwise (the temperature was maintained below 5 °C). The mixture was stirred at 0 °C for 2 hours. The mixture was divided into three portions, each of which was poured into ice water (50 L) and extracted with DCM (30 L × 2). The combined organic layer was washed with saturated NaHCO (25 L) and brine (15 L), dried over Na SO , and the filtrates from three batches 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 give compound E (5.63 kg) as a brown solid. 1H NMR (400MHz, CDCl3) δ 8.84 (s, 1H), 7.35 (s, 1H).

[0188] To a solution of compound E (3.00 kg, 12.33 mol, 1.00 equiv.) in dioxane (45 L) was added 1-(4-methoxyphenyl)-N-methylmethanamine (1.86 kg, 12.33 mol, 1.00 equiv.) and TEA (2.50 kg, 24.66 mol, 2.00 equiv.). 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 min. The solid was collected by filtration, dissolved in DCM (60 L), and washed with brine (3 × 15 L). The organic phase was dried over Na SO and concentrated in vacuo to give compound F (3.68 kg) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=2.1Hz,1H),7.06-6.95(m,2H),6.73(dd,J=8.6,2.0Hz,2H),6.12 (d,J=2.1Hz,1H),5.08(s,2H),3.64(d,J=2.2Hz,3H),3.06(d,J=2.0Hz,3H).

[0189] To a solution of compound F (3.64 kg, 10.05 mol, 1.00 equiv.) and compound C (2.14 kg, 12.06 mol, 1.20 equiv.) in 1,4-dioxane (73 L) was added K2CO3 (2.78 kg, 20.10 mol, 2.00 equiv.), Pd(OAc)2 (180.48 g, 0.804 mol, 0.08 equiv.), and BINAP (1.00 kg, 1.61 mol, 0.16 equiv.) under an 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 HO (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 give compound G (4.08 kg) as a pale yellow solid. 1H NMR(400MHz,DMSO)δ 9.20(s,1H),8.72(s,1H),8.48(dd,J=12.2,2.8Hz,1H),7.21(d,J=8.5Hz,2H),6.90(d,J=8.5H z,2H),6.57-6.43(m,2H),5.02(s,2H),4.33(dd,J=9.4,4.6Hz,4H),3.73(s,3H),2.99(s,3H).

[0190] To a solution of compound G (4.80 kg, 9.79 mol, 1.00 equiv) in DMF (72 L) was added 10% Pd / C (0.48 kg) at 25 °C, the mixture was evacuated and flushed with N followed by H (3 times), and the mixture was warmed to 80 °C and stirred for 24 h. Upon completion of the reaction, the reaction mixture was cooled to 50 °C. The Pd / C was filtered, and HO (114 L) was added to the filtrate. The mixture was triturated and filtered. The filter cake was washed with HO (30 L) and EtOH (10 L), collected, and dried to give compound H (4.25 kg) as a brown solid. 1 H NMR(400MHz,DMSO)δ 8.30(dd,J=13.0,3.9Hz,2H),7.60(s,1H),7.10(d,J=8.5Hz,2H),6.86(d,J=8.6Hz,2H),6.35(d d,J=9.6,3.0Hz,1H),6.07(s,1H),5.08(s,2H),4.30(q,J=4.6Hz,4H),3.71(s,5H),2.87(s,3H).

[0191] To a solution of compound H (50.0 g, 1.0 equiv.) in DMF (150 mL) was added N-((1R,2S)-2-fluorocyclopropyl)benzamide (23.9 g, 1.1 equiv.). Triethylamine (13.5 g, 1.2 equiv.) was then added dropwise. The reaction mixture was heated at 60° C. and stirred for 3 hours. The mixture was cooled. Water (280 mL) was added dropwise, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed with water (2×100 mL). The filter cake was dried at 50° C. for 16 hours to give compound I (58.9 g). 1H NMR(400MHz,DMSO):8.49(d,J=1.4Hz,1H),8.18(dd,J=11.7,3.0Hz,1H),8.12(s,1H),7.80(s,1H),7.20-7.1 0(m,2H),6.92-6.83(m,2H),6.71-6.65(m,1H),6.38(dd,J=9.6,3.0Hz,1H),6.18(s,1H),5.10(s,2H),4.81(t d,J=5.8,3.0Hz,0.5H),4.65(td,J=5.7,3.0Hz,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=14.6,8.1,6.1Hz,1H),0.83(dddd,J=25.3,8.1,5.7,3.0Hz,1H);MSESI+:552.10[M+H] + .

[0192] To a solution of compound I (25.0 g, 1.0 equiv.) in DCM (125 mL) at −10° C., EtSiH (9.0 g, 1.7 equiv.) was added dropwise. TFA (62.5 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at −10° C. for 1 hour. Trifluoromethanesulfonic acid (12.5 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at −10° C. for 3 hours. 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 hours. The mixture was filtered, and the filter cake was washed with water (2×50 mL) and EtOH (2×25 mL). The filter cake was dried at 50° C. for 12 hours to give compound 1 (12.2 g). 1H NMR(400MHz,DMSO):8.32(d,J=1.4Hz,1H),8.18(dd,J=11.8,3.1Hz,1H),8.03(s,1H),7.77(d,J=2.2Hz,1H),7.5 7(q,J=4.9Hz,1H),6.63(d,J=3.7Hz,1H),6.35(dd,J=9.6,3.0Hz,1H),5.95(s,1H),4.80(td,J=5.7,3.0Hz,0.5H ),4.63(td,J=5.8,3.0Hz,0.5H),4.36-4.26(m,4H),2.89(d,J=4.8Hz,3H),2.69-2.58(m,1H),1.03(dtd,J=14.5 MSESI+:432.10[M+H] + .

[0193] Example 3: Synthesis of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate (Compound 1A)

[0194] [ka] To a solution of adipic acid (6.8 g, 2.0 equivalents) in water (8 mL) and acetone (152 mL) was added compound 1 (10.0 g, 1.0 equivalents). The reaction mixture was stirred at 25° C. for 24 hours and then filtered. The filter cake was washed with 5% water / acetone (2×20 mL). The filter cake was dried at 25° C. for 24 hours to give compound 1A (9.8 g). 1H NMR(400MHz,DMSO):12.02(s,1H),8.32(s,1H),8.18(dd,J=11.8,3.1Hz,1H),8.03(s,1H),7.76(s,1H),7.5 7(q,J=4.8Hz,1H),6.63(d,J=3.7Hz,1H),6.35(dd,J=9.6,3.0Hz,1H),5.95(s,1H),4.80(td,J=5.7,3.0Hz, 0.5H),4.63(td,J=5.8,3.0Hz,0.5H),4.40-4.26(m,4H),2.89(d,J=4.8Hz,3H),2.64(dqd,J=11.0,3.9,1.8 C 24 H 29 HR-MS of F2N5O3: (calculated value): 432.1596, found value: 432.1603.

[0195] Example 4: Costimulation assays in lysed whole blood; JAK2:GM-CSF stimulated STAT5 phosphorylation and JAK1 / TYK2 stimulated STAT1 phosphorylation assays Human blood lysis using Abcam's RBC lysis buffer Dilute RBC lysis buffer to 1x in distilled water. Add 2 mL of blood to 38 mL of 1x RBC lysis buffer. Incubate for 15 min at RT in the dark. Spin at 300g for 5 min and collect the pellet. Resuspend if necessary in 5 mL of cRPMI.

[0196] Compound and cytokine treatment Dispense 80 μL of lysed human blood into wells of a 96-deep-well plate. Add 10 μL (10× conc.) of different concentrations of Compound 1 to each well, except for the controls (unstained and unstimulated), and mix using a 100 μL multichannel mixer. Add 10 μL of RPMI medium to the controls. See the Appendix for compound dilutions and dilution ranges. Incubate for 1 hour at 37°C in a water bath or CO2 incubator. Add 10 μL (10× conc.) of a cytokine mixture (GM-CSF and IFNa) (final concentrations: 10 ng / mL GM-CSF and 100 ng / mL IFNa) to each well, except for the unstimulated and unstimulated controls, and further incubate for 20 minutes at 37°C in a water bath.

[0197] RBC lysis and fixation Add 900 μL of preheated 1X Fix / Lyse Solution (Appendix), mix properly using the 1000 μL multichannel, and incubate for 10 minutes (including the addition time) in a water bath at 37°C. Centrifuge at 800 × g for 5 minutes at 40°C, remove 900 μL of the supernatant, and add 900 μL of 1X PBS. Centrifuge at 800 × g for 5 minutes at 40°C, remove 900 μL of the supernatant. Wash once more with 900 μL of PBS (optional), and resuspend the pellet in 100 μL of PBS.

[0198] Permeabilization Disrupt the pellet by gentle tapping, resuspend in 1000 μL of BD Phosflow Perm Buffer III, and incubate the plate on ice for 30 minutes. Centrifuge the plate at 800 × g for 5 minutes at 40 °C. Wash two more times with 1000 μL of BD Pharmingen Stain Buffer.

[0199] Antibody treatment Break up the pellet by gentle tapping. Resuspend the pellet in 100 μL of Stain Buffer and add 5 μL of pSTAT5_AF488 Ab and 5 μL of pSTATI_PE to all wells except the unstained control. Mix thoroughly using a 200 μL multichannel and incubate overnight at 40°C. Add 900 μL of wash buffer and centrifuge at 1800 rpm for 3 minutes at 40°C. Wash once more with 1000 μL of BD Pharmingen Stain Buffer. Finally, resuspend the pellet in 300 μL of BD Pharmingen Stain Buffer. Transfer the cells to a 96-well v-bottom plate and acquire them using a Beckman Coulter CytExpert. Acquire cells in the flow cytometer: maintain a threshold of 250 and the cell concentration should not exceed 100-500 cells / μL. Acquire at least 5,000-10,000 cells.

[0200] appendix Preparation of reagents RPMI1640 complete medium: RPMI1640 medium + 10% FBS.

[0201] Cytokine Dilutions: 1) 100 ug / mL GM-CSF stock. Prepare a 1 ug / mL intermediate dilution by adding 2 uL of stock to 198 uL of cRPMI. Further dilute to 100 ng / mL by adding 100 uL of intermediate stock to 900 uL of cRPMI. 2) 200 ug / mL IFNa stock. Dilute the IFNa stock 1:200 by adding 5 uL of stock to 1000 uL of the 100 ng / mL GM-CSF working stock above to obtain a combined working stock of 1000 ng / mL IFNa and 100 ng / mL GM-CSF (10x). Keep on ice until use.

[0202] Preparation of Lyse / Fix buffer: Dilute 5x Lyse / Fix buffer to 1x using MQ water and keep at 37°C until use.

[0203] BD Phosflow perm buffer III: Keep on ice / refrigerator.

[0204] [Table 2]

[0205] Compound 1 IFN-α / Jak1Tyk2 IC50 is less than 1 μM.

[0206] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or alterations are within the scope of the disclosure and the appended claims.

Claims

1. 1. A process for preparing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (compound 1), comprising: A) The following structure: 【Chemistry 1】 with t-butanol, triethylamine, and diphenylphosphoryl azide to give the compound having the following structure: 【Chemistry 2】 and producing a compound having the formula: B) Then, the following structure 【Transformation 3】 with hydrochloric acid in ethyl acetate to give the compound having the following structure: 【Chemistry 4】 and producing a compound having the formula: C) The following structure: 【Transformation 5】 With nitric acid and sulfuric acid, a compound having the following structure is reacted to give 【Transformation 6】 and producing a compound having the formula: D) Then, the following structure 【Transformation 7】 By reacting a compound having the following structure with triethylamine, 【Transformation 8】 and producing a compound having the formula: E) Then, the following structure 【Chemistry 9】 with potassium carbonate, palladium(II) acetate, and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) to give a compound having the following structure: 【Chemistry 10】 and producing a compound having the formula: F) Then, the following structure 【Chemistry 11】 with palladium on carbon and hydrogen to give a compound having the following structure: 【Chemistry 12】 and producing a compound having the formula: G) Then, the following structure 【Chemistry 13】 By reacting a compound having the following structure with triethylamine, 【Chemistry 14】 and producing a compound having the formula: H) Then, the following structure 【Chemistry 15】 with triethylsilane and trifluoroacetic acid to give the compound having the following structure: 【Chemistry 16】 and producing 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (compound 1), having the formula The process includes:

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

3. 4-Fluoro-3-(2-hydroxyethoxy)-N-(2-isobutoxy)-4-((2-isobutoxy)-4-(((1R,4R)-4-(quinolin-3-ylcarbamoyl)cyclohexyl)carbamoyl)phenyl)carbamoyl)phenyl)benzamide (Compound 1) 【Chemistry 17】 1. A process for preparing The following structure [Chemistry 18] contacting a compound having the formula: with triethylsilane and an acid in the presence of a solvent.

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

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

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

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

9. The following structure 【Chemistry 19】 The compound having the following structure: 【Chemistry 20】 9. The process of any one of claims 3 to 8, wherein the compound is prepared by a process comprising contacting a compound having the formula: with a base in the presence of a solvent.

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

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

14. The following structure 【Chemistry 21】 The compound having the following structure: 【Chemistry 22】 The process of any one of claims 3 to 13, wherein the compound is prepared by a process comprising contacting a compound having the formula:

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

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

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

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

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

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

21. The following structure 【Chemistry 23】 The compound having the following structure: 【Chemistry 24】 or a salt thereof with a base, a catalyst, and a phosphine ligand in the presence of a solvent.

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

24. 24. The process of any one of claims 21 to 23, wherein 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).

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

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

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

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

30. The following structure 【Chemistry 25】 The compound having the following structure: 【Chemistry 26】 30. The process of any one of claims 3 to 29, wherein the compound is prepared by a process comprising contacting a compound having the formula: with a base in the presence of a solvent.

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

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

33. 33. The process of any one of claims 30 to 32, wherein the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylacetamide (DMA), and N-methylpyrrolidone (NMP).

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

35. The following structure 【Chemistry 27】 The compound having the following structure: 【Chemistry 28】 35. The process of any one of claims 3 to 34, wherein the compound is prepared by a process comprising contacting a compound having the formula:

36. The following structure 【Chemistry 29】 or a salt thereof, 【Transformation 30】 36. The process of any one of claims 3 to 35, wherein the compound is prepared by a process comprising contacting a compound having the formula: with an acid in the presence of a solvent.

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

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

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

41. The following structure 【Chemistry 31】 The compound having the following structure: 【Chemistry 32】 The process of any one of claims 3 to 40, wherein the compound having the formula:

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

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

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

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

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