PROCESSES FOR PREPARING A JANO KINASE 1 (JAK1) INHIBITOR

Abstract

The present application provides processes for preparing 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, and phosphoric acid salt thereof, which is useful as a selective inhibitor of JAK1 (Jano kinase 1), as well as salt forms and related intermediates thereof.

Description

PROCESSES FOR PREPARING A JANO KINASE 1 (JAK1) INHIBITOR FIELD OF INVENTION The present application provides processes for preparing 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-lH,l'H-4,4'bipyrazol-l-yl)azetidin-l-yl]-2,5-difluoro-N-[(13)-2,2,2-trifluoro-l-methylethyl]benzamide, and phosphoric acid salt thereof, which is useful as a selective inhibitor of JAK1 (Jano kinase 1), as well as salt forms and related intermediates thereof. BACKGROUND OF THE INVENTION Protein kinases (PKs) regulate diverse biological processes, including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, and tissue repair and regeneration, among others. Protein kinases also play specialized roles in a wide range of human diseases, including cancer. Cytokines, low-molecular-weight polypeptides or glycoproteins, regulate many pathways involved in the host's inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation, and activation, and can modulate pro-inflammatory and anti-inflammatory responses to enable the host to react appropriately to pathogens. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Ref. 340283 Signaling of a wide range of cytokines involves the Janus kinase (JAK) family of protein tyrosine kinases and signal transducers and activators of transcription (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (also known as leukocyte Janus kinase; JAKL; and L-JAK), and TYK2 (protein tyrosine kinase 2). Cytokine-stimulated immune and inflammatory responses contribute to the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune / inflammatory response contributes to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis) and diseases such as scleroderma and osteoarthritis (Ortmann, RA, T. Cheng, et al. (2000) Arthritis Res 2(1): 16-32). Deficiencies in JAK expression are associated with many disease states. For example, Jakl- / - mice are delayed at birth, do not nurse, and die perinatally (Rodig, SJ, MA Meraz, et al. (1998) Cell 93(3): 373-83). Jak2- / - mouse embryos are anemic and die around day 12.5 after mating due to the absence of definitive erythropoiesis. It is believed that the JAK / STAT pathway, and in particular the The four JAK pathways L77C ίΠ / ZZΖ / E / YΙΛΙ play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. Multiple cytokines that signal via JAK have been linked to inflammatory diseases / conditions of the upper respiratory tract, such as those affecting the nose and sinuses (e.g., rhinitis and sinusitis), whether classic allergic reactions or not. The JAK / STAT pathway has also been implicated in inflammatory eye diseases / conditions and chronic allergic responses. JAK / STAT activation in cancers can occur through stimulation by cytokines (e.g., IL-6 or GM-CSF) or by a reduction in endogenous suppressors of JAK signaling, such as SOCS (suppressor of cytokine signaling) or PIAS (activated STAT protein inhibitor) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355. 2002). Activation of STAT signaling, as well as other pathways upstream of JAK (e.g., Akt), has been correlated with poor prognosis in many cancers (Bowman, T., et al. Oncogene 19:2474-2488. 2000). Elevated levels of circulating cytokines that signal via JAK / STAT play a causal role in cachexia and / or chronic fatigue. As such, JAK inhibition may be beneficial for cancer patients for reasons that extend beyond potential antitumor activity. The JAK2 tyrosine kinase may be beneficial for patients with myeloproliferative disorders, such as polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) (Levin et al., Cancer Cell, vol. 7, 2005: 387–397). Inhibition of the JAK2V617F kinase decreases hematopoietic cell proliferation, suggesting that JAK2 is a potential target for pharmacological inhibition in patients with PV, ET, and MMM. JAK inhibition may benefit patients with immunological skin disorders such as psoriasis and skin sensitization. Psoriasis maintenance is thought to depend on several inflammatory cytokines, as well as various chemokines and growth factors (JCI, 113:1664-1675), many of which signal via JAK (Adv Pharmacol. 2000;47:113-74). Therefore, new or improved agents that inhibit kinases, such as JAKs, are continually needed to develop new and more effective pharmaceuticals intended to augment or suppress immune and inflammatory pathways (such as immunosuppressive agents for organ transplantation), as well as agents for the prevention and treatment of autoimmune diseases, diseases involving a hyperactive inflammatory response (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (e.g., skin rash or contact dermatitis, or diarrhea) caused by other therapies. JAK inhibitors are currently under development.Although JAK inhibitors and processes for their preparation exist in the literature, there remains a need for new processes to prepare these inhibitors with suitable properties for manufacturing effective, high-quality pharmaceutical products for sale. The present description addresses this need. SUMMARY OF THE INVENTION The present description provides processes for preparing a selective JAK1 inhibitor, 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4.4'-bipyrazol-1-yl)azetidin-1-yl]-2.5-difluoro-N-[(15)-2.2.2-trifluoro-1-methylethyl]benzamide, or salt forms thereof, including phosphoric acid salt of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4.4'-bipyrazol-1-yl)azetidin-1-yl]-2.5-difluoro-N-[(15)-2.2.2-trifluoro-1-methylethyl]benzamide and related intermediates thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a representative differential scanning calorimetry (DSC) plot for phosphoric acid from compound 1, prepared according to the process described in Example 1. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Figure 2 shows a representative thermogravimetric analysis (TGA) plot for phosphoric acid from compound 1, prepared according to the process described in Example 1. Figure 3 shows a representative X-ray powder diffraction (XRPD) plot for phosphoric acid of compound 1, prepared according to the process described in Example 1, superimposed with an XRPD plot of phosphoric acid of compound 1 prepared according to a process described in U.S. Patent No. 9,382,231. DETAILED DESCRIPTION OF THE INVENTION This description provides processes for preparing a selective JAK1 inhibitor, 4-[3-(cyanomethyl)-3(3',5'-dimethyl-IH,l'H-4,4'-bipyrazol-l-yl)azetidin-l-yl]-2,5-difluoro-N-[(13)-2,2,2-trifluoro-l-methylethyl]benzamide (see below), referred to herein as "compound 1". The free base of the compound is shown below. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ \ / / HN-N Free base of compound 1 This description also provides a process for preparing the phosphoric acid salt of the free base of compound 1 (see below), phosphoric acid salt of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-lH,1'H-4,4' bipyrazol-l-yl)azetidin-l-yl]-2,5-difluoro-N-[(13)-2,2,2-trifluoro-l-methylethyl]benzamide, referred to in this description as "phosphoric acid salt of compound 1", "phosphate of compound 1" or "phosphate salt of compound 1". L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Phosphoric acid salt of compound 1 An example process for preparing compound 1 and its phosphoric acid salt is described in US2014 / 0343030, which is incorporated herein by reference in its entirety. The processes for preparing the free base of compound 1 and its phosphoric acid salt provided herein have several advantages over the process described in US2014 / 0343030, making them more suitable for scale-up manufacturing. For example, one example process described herein is a convergent synthesis that provides high yields, increasing the efficiency of a multi-step synthesis compared to the linear synthesis in US2014 / 0343030.The yields of intermediate products such as those shown in Reaction Scheme 2 (see below) range from approximately 93% to approximately 94% on a scale ranging from approximately 670 grams to approximately 2000 grams. Furthermore, the yields of the free base of compound 1 and its phosphoric acid salt, as shown in Reaction Scheme 5 (see below), range from approximately 90% to approximately 97% on a scale ranging from 430 grams to approximately 5800 grams. The overall process yield provided herein is from the preparation of (S)-2,4,5-trifluoro-N-[1,1,1-trifluoropropan-2-yl]benzamide (compound 1, reaction scheme 2).(see below) for the free base of compound 1 is approximately between 68% and approximately 70% in a five-step synthesis, whereas the overall yield using the process in US2014 / 0343030 is less than 5%, requiring six steps from the preparation of (S)-2,4,5-trifluoro-N-[1,1,1-trifluoropropan-2-yl]benzamide for the free base of compound 1. The processes described herein provide good product purity and high yields on a large scale. For example, in US2014 / 0343030 the Suzuki coupling reaction of 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-IH-pyrazol-l-yl]azetidinL77C ίΠ / ZZΖηZ / E / YΙΛΙ The coupling of (S)4-(3-(cyanomethylene)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide with 4-bromo-3,5-dimethyl-1H-pyrazole in the presence of a palladium catalyst to generate the free base of compound 1 results in a low yield (less than 10% yield, Example 7) and requires the removal of palladium contaminants from the product. In an example process provided herein, the Suzuki coupling step involving a palladium catalyst is carried out in a separate parallel synthesis to generate a bipyrazole compound (compound 2x, reaction scheme 1, see below), which is then coupled with (S)4-(3-(cyanomethylene)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide to generate the free base of compound 1 (Reaction scheme 5, see below). Compound 2x can be easily purified as the highly crystalline HC1 salt.The crystallization process allows compound 2x to be purified more easily to remove palladium impurities than the freebase compound 1, which contains multiple nitrogens. This is an advantage over the previous process, which required low-throughput column chromatography separation. Furthermore, placing the palladium coupling step earlier in the synthesis process improved the overall yield. Furthermore, the use of the bipyrazole compound (compound 2x) in a Michael addition reaction with compound lx unexpectedly resulted in a high degree of regioselectivity. In some embodiments, the regioselectivity was approximately 20:1 or greater in favor of the desired regioisomer, the free base of compound 1, over the undesired regioisomer (compound R, shown below). Based on electronic effects, the regioisomer of compound R was the expected product because the two electron-donating methyl groups make the 1H-NH group of compound 2x more nucleophilic than the l'H-NH group. Without limiting ourselves to a particular theory, it is believed that spherical hindrance in the 1H-NH group results in an unexpectedly high degree of regioselectivity. HN-N HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Free base of compound 1 Compound R In some forms, this description refers to a process for preparing or a salt thereof, which involves reacting F (Compound lx) L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ with HN^\ Z^NH i 7-----< I \^N / (Compound 2x) to form the free base of compound 1. or a salt of the same. In some embodiments, the reaction of compound lx with compound 2x is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and an organic solvent component. In some embodiments, the organic solvent component comprises dimethylformamide (DMF). In some embodiments, the reaction of compound lx with compound 2x is carried out at a temperature of approximately 40°C to approximately 70°C, approximately 45°C to approximately 65°C, or approximately 50°C to approximately 60°C. In some embodiments, the temperature is approximately 50°C to approximately 60°C. For example, the temperature is approximately 60°C. In some embodiments, the process for preparing the free base of compound 1 further includes treatment after the reaction is complete. For example, the treatment may involve adding water to the reaction mixture and collecting the free base solid of compound 1 by filtration, which may then be washed with water. In some embodiments, this description provides a process for preparing the phosphoric acid salt of compound 1, comprising reacting the free base of compound 1, prepared by a process described herein, with phosphoric acid. In some embodiments, the salt of compound 1 is a phosphoric acid salt of compound 1 prepared by a process comprising reacting the free base of compound 1 with phosphoric acid. In some embodiments, the reaction of the free base of compound 1 with phosphoric acid is carried out in the presence of the solvent component. In some embodiments, the solvent component comprises methanol, isopropanol, or a mixture thereof. In some embodiments, the reaction of the free base of compound 1 with phosphoric acid is carried out at a temperature of approximately 40 °C to approximately 70 °C or from approximately 45 °C to approximately 55 °C. For example, the temperature is approximately 50 °C. In some embodiments, phosphoric acid is an aqueous solution of approximately 85% phosphoric acid by weight. In some embodiments, the free base reaction The reaction of compound 1 with phosphoric acid with L77C iΠ / ZZΖηZ / E / YΙΛΙ further comprises adding a second solvent component to the reaction mixture. L77C ίΠ / ZZΖηZ / E / YΙΛΙ example, the second solvent component comprises n-heptane. This description also provides a process for preparing the intermediate compounds, for example, In some embodiments, the present description provides a process for preparing compound lx comprising: Me H la) react 2 ^r3 with of a base to form f (Compound la); 2a) to make the react presence of DBU to form compound (Compound Ib); 3a) react compound Ib with diacetate of f5Q f V—\ / N\Z0oviodobenzene and TEMPO to form F (Compound le) ; and 4a) react compound le with diethyl cyanomethylphosphonate in the presence of a base to form compound Ix. In operation 1, (2S)1,1,1-trifluoropropan-2-amine can be reacted with 2,4,5-trifluorobenzoyl chloride in the presence of a base to form the compound 1. In some embodiments, the base is N,N-diisopropylethylamine or aqueous sodium hydroxide solution. In some embodiments, the base is aqueous sodium hydroxide. In some embodiments, the reaction is carried out in the presence of an organic solvent component (e.g., toluene). In some embodiments, the reaction is carried out at a temperature of approximately 0 °C to approximately 10 °C or from approximately 0 °C to approximately 5 °C. In some embodiments, a salt of (2S)-1,1,1-trifluoropropan-2-amine (e.g., an HCl salt) is converted into its base. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ free before reaction with F. For example, in some embodiments, the (2S)-1,1,1-trifluoropropan-2-amine salt (e.g., an HCl salt) is converted to its free base in situ. In some embodiments, the operation further comprises a treatment to obtain the compound after the reaction is considered complete, for example, by HPLC. For example, the treatment may comprise separating the phases of the reaction mixture and washing the organic phase with, for example, a 0.5 M aqueous sodium hydroxide solution. In some embodiments, the solid of the compound can be suspended in n-heptane at approximately 50 °C for approximately 1 h. The solids can be collected by filtration and washed with n-heptane. In operation 2a, compound Ia can be reacted with azetidin-3-ol hydrochloride in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form compound Ib. In some embodiments, the reaction is carried out in an organic solvent component, including, for example, acetonitrile. In some embodiments, DBU can be added to the reaction mixture of compound Ia and azetidin-3-ol hydrochloride in portions. In some embodiments, the reaction is carried out at a temperature of approximately 50 °C to approximately 75 °C or from approximately 55 °C to approximately 70 °C. For example, the temperature is approximately 58 °C to approximately 68 °C. In some embodiments, operation 2a further comprises a treatment to obtain compound Ib after the reaction is considered complete, for example, by HPLC. The treatment may comprise adding aqueous hydrochloric acid solution 1.Add 0 M to the mixture of compound Ib with azetidin-3-ol hydrochloride and DBU, stir the mixture with hydrochloric acid solution at room temperature, add water to the stirred mixture and stir the mixture to which the water has been added. The treatment may further comprise isolating the solid from compound Ib and rinsing the solid with water. In operation 3a, compound Ib can react with iodobenzene diacetate and the 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO) free radical to form compound le. In some embodiments, the reaction is carried out in an organic solvent component, including, for example, methylene chloride. In some embodiments, the reaction is carried out at a temperature of approximately 0 °C to approximately 20 °C or approximately 5 °C to approximately 15 °C. For example, the temperature is approximately 10 °C to approximately 12 °C. In some embodiments, operation 3a further comprises a treatment to obtain compound le after the reaction is considered complete, for example, by HPLC. The treatment may comprise inactivating the reaction with an aqueous solution of sodium thiosulfate and potassium phosphate. Two phases can be separated, and the organic phase can be washed with water.The organic solution can be concentrated under reduced pressure to provide the compound as a solid. The solid compound can be resuspended in n-heptane at room temperature for approximately 30 minutes and washed with n-heptane. In operation 4a, the compound can be reacted with diethyl cyanomethylphosphonate in the presence of a base to form compound lx. The base includes, for example, potassium tert-butoxide. In some embodiments, the reaction is carried out in the presence of an organic solvent component, including, for example, THE, ethanol, or a mixture thereof. In some embodiments, diethyl cyanomethylphosphonate can be added to a 1.0 M solution of potassium tert-butoxide in THE at a temperature of approximately 5°C to approximately 25°C. In some embodiments, the molar equivalents of the potassium tert-butoxide solution in THE for compound lx are approximately 0.95. In some forms, the molar equivalents of potassium tert-butoxide solution in THE to the compound are less than approximately 0.95 (e.g., approximately 0.94, approximately 0.93, approximately 0.92, approximately 0.91 or approximately 0.90).In some embodiments, the compound can be dissolved in a mixture of organic solvent components (e.g., ethanol and tetrahydrofuran). In some embodiments, the mixture of diethyl cyanomethylphosphonate and potassium tert-butoxide 1.0. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ M can be added to the mixture containing compound le. In some embodiments, step 4a further comprises a treatment to obtain compound lx after the reaction is considered complete, for example, by HPLC. The treatment may comprise the addition of water to the reaction mixture. The solid can be collected by filtration and washed with water and n-heptane. In some embodiments, the solid can be resuspended in terebutyl methyl ether, collected by filtration, and washed with MTBE. In some embodiments, the process for preparing the free base of compound 1, or a salt thereof, further comprises preparing compound lx, wherein compound lx can be prepared by a process comprising reacting compound le with diethyl cyanomethylphosphonate in the presence of a base. In some embodiments, the process further comprises preparing compound le, wherein compound le can be prepared by a process comprising reacting compound Ib with iodobenzene diacetate and TEMPO. In some embodiments, the process further comprises preparing compound Ib, wherein compound Ib can be prepared by a process comprising reacting compound la with azetidin-3-ol hydrochloride in the presence of DBU. In some embodiments, the process further comprises preparing compound la, wherein compound la can be prepared by a process comprising reacting (23)-1,1,1 L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ trifluoropropan-2-amine with 2,4,5-trifluorobenzoyl chloride in the presence of a base. In some embodiments, the present description provides a process for preparing the 2x compound that L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ includes: (Compound 2a) with Ib) do 2b) react compound 2b with hydrochloric acid to form HN'<\ zT'NH-HCI । V—v \^n / (HC1 of compound 2x); and 3b) react HC1 from compound 2x with a base to form compound 2x. In operation Ib, compound 2a can be reacted with 4-bromo-3,5-dimethylpyrazole to form compound 2b. In some embodiments, the reaction is carried out in the presence of K₂HPO₄, a solvent component, and a palladium complex. For example, the solvent component comprises 1-propanol, water, or a mixture thereof. In some embodiments, the palladium complex is [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (11) (Pd-118). In some embodiments, the reaction is carried out at a temperature of approximately 80 °C to approximately 100 °C or from approximately 90 °C to approximately 100 °C. For example, the temperature is approximately 90 °C. In some embodiments, operation Ib further comprises a treatment to obtain compound 2a. The treatment may include cooling the reaction mixture to approximately 17 °C and separating the phases.The organic phase can be mixed with activated carbon, heated to approximately 70 °C, stirred for about 4 hours, and cooled to approximately 21 °C. The mixture comprising compound 2a can be filtered through Celite. In some embodiments, operation Ib further comprises mixing the crude compound 2a with ethyl acetate and an aqueous solution of NaHSO₄, where the resulting mixture is heated to approximately 65 °C to approximately 70 °C for approximately 2.5 h. The phases can be separated, and the organic phase can be mixed with an aqueous solution of NaHSO₄, where the resulting mixture is heated to approximately 65 °C to approximately 70 °C for approximately 3.5 h. The phases can be separated, and the phase comprising compound 2a can be purified by column chromatography using ethyl acetate as the eluent. In some embodiments, the purified compound 2a is further mixed with methylene chloride and Si-thiol, where it is filtered. L77C ΙΠ / ΖΖηΖ / Ε / ΥΙΙΛΙ the resulting mixture. In operation 2b, compound 2b can react with hydrochloric acid to form HCl of compound 2x. In some embodiments, the reaction is carried out in the presence of an organic solvent component. For example, the organic solvent component comprises 2-propanol. In some embodiments, the reaction of compound 2b with hydrochloric acid is carried out at a temperature of approximately 50°C to approximately 75°C or from approximately 55°C to approximately 70°C. For example, the temperature is approximately 60°C to approximately 65°C. In some embodiments, operation 2b further comprises a treatment to obtain compound 2b after the reaction is considered complete, for example, by HPLC. For example, the reaction mixture is cooled to room temperature and stirred for approximately 1 hour. The solid of compound 2b can be collected by filtration and washed with 2-propanol. In operation 3b, the HCl of compound 2x can react with a base to form compound 2x. This description also refers to a process for preparing compound 2x comprising reacting the HCl of compound 2x with a base. Example bases include KOH, LiOH, K2CO3, Na2O3, and other bases that can neutralize the HCl of compound 2x to its free base. In some embodiments, the base is NaOH. In some embodiments, the reaction of HCl of The reaction of compound 2x with a base is carried out at a temperature of approximately 10 °C to approximately 20 °C or approximately 15 °C to approximately 20 °C. For example, the temperature is approximately 15 °C to approximately 18 °C. In some embodiments, operation 3b further comprises a treatment to obtain compound 2x after the reaction is complete. For example, the solid of compound 2x may be collected by filtration and washed with water and nheptane. In some embodiments, the process for preparing the free base of compound 1, or a salt thereof, further comprises preparing compound 2x, wherein compound 2x can be prepared by a process comprising reacting the HCl of compound 2x with a base. In some embodiments, the process further comprises preparing the HCl of compound 2x, wherein the HCl of compound 2x is prepared by a process comprising reacting compound 2b with hydrochloric acid. In some embodiments, the process further comprises preparing compound 2b, wherein compound 2b is prepared by a process comprising reacting compound 2a with 4-bromo-3,5-dimethylpyrazole. In some embodiments, this application also provides a process for preparing a compound with formula A: HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ TO. In some embodiments, the process for preparing the compound with formula A comprises reacting 3,5-dimethyl-1H,1'H-4,4'-bipyrazole with a compound with formula B: B in which Pg1 is an amine protecting group. In some embodiments, Pg1 is tert-butoxycarbonyl. In some embodiments, the reaction of 3,5-dimethyl-1H, 1Ή-4,4'-bipyrazole with a compound of formula B is carried out in the presence of ,8-diazabicclo[5.4.0]undec-7-ene. In some forms, less than 1 equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene is used on a basis of 1 equivalent of the compound with formula B. In some forms, approximately 0.2 to approximately 0.3 equivalents of 1,8diazabicyclo[5.4.0]undec-7-ene are used on a basis of 1 equivalent of the compound with formula B. In some forms, more than approximately 1 equivalent of 3,5-dimethyl-1H,1Ή-4,4'-bipyrazole is used based on 1 equivalent of the compound with formula B. In some formulations, approximately 1.0 to approximately 2.0 equivalents of 3,5-dimethyl-1H,1'H-4,4'bipyrazole are used based on 1 equivalent of the compound with formula B. In some formulations, approximately 1.0 to approximately 1.1 equivalents of 3,5-dimethyl-1H,1'H-4,4'bipyrazole are used based on 1 equivalent of the compound with formula B. In some formulations, approximately 1.0 to approximately 1.1 equivalents of 3,5-dimethyl-1H,1'H-4,4'bipyrazole are used based on 1 equivalent of the compound with formula B. In some embodiments, the reaction of 3,5-dimethyl1H, 1 Ή-4, 4'-bipyrazole with a compound having the formula B is carried out at approximately room temperature. In some embodiments, the reaction of 3,5-dimethyl-1H,1-4,4'-bipyrazole with the compound of formula B is carried out in the presence of a solvent component. In some embodiments, the solvent component comprises dimethyl sulfoxide. In some embodiments, the solvent component comprises dimethyl sulfoxide and methylene chloride. In some forms, the process provided in this description also includes deprotecting the compound L77C ίΠ / ZZΖηZ / E / YΙΛΙ with formula A to form a compound with formula C: HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ C or a salt of the same. In some embodiments, the deprotection of the compound with formula A involves reacting the compound with formula A in the presence of a strong acid (e.g., hydrochloric acid). In some embodiments, the deprotection of the compound with formula A comprises reacting the compound with formula A in the presence of a trialkylsilyl halide. In some forms, the trialkylsilyl halide is trimethylsilyl iodide. In some embodiments, the deprotection of the compound with formula A is carried out in the presence of a solvent component. In some embodiments, the solvent component comprises methylene chloride. In some embodiments, the solvent component comprises methylene chloride and methanol. In some forms, the deprotection of the compound with formula A is carried out at approximately room temperature. In some embodiments, the process provided in the present description further comprises reacting the compound with formula C, or a salt thereof, with a base, to form the free base form of the compound with formula C. In some embodiments, the process provided in the present description further comprises reacting the compound with formula C, or a salt thereof, with an amine base, to form the free base form of the compound with formula C. In some forms, the base is a tri(Ci6 alkyl)amine. In some forms, the base is triethylamine. In some embodiments, the reaction of the compound with formula C, or a salt thereof, with an amine base is carried out in the presence of a solvent component. In some embodiments, the solvent component comprises methylene chloride. In some embodiments, the process provided in the present description further comprises reacting the free base form of the compound with formula C with compound la: F CF3la. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ to form compound 1: L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ or a salt thereof. In some embodiments, the free base form of the compound with formula C is reacted with compound la in the presence of a base and an alkali metal halide to form compound 1: or a salt of it. In some forms, the base is a bicarbonate base. In some forms, the base is sodium bicarbonate. In some forms, the alkali metal halide is lithium chloride. In some forms, the reaction of the free base form of the compound with formula C with the compound la is carried out at a temperature of approximately 80 °C to approximately 90 °C. In some embodiments, the reaction of the free-base form of the compound with formula C with the compound is carried out in the presence of a solvent component. In some embodiments, the solvent component comprises dimethyl sulfoxide. In some embodiments, the solvent component comprises dimethyl sulfoxide and isopropyl acetate. In some embodiments, the process provided in the present description further comprises reacting compound 1 with a strong acid to form a salt form of compound 1. In some embodiments, the process provided in the present description further comprises reacting compound 1 with hydrochloric acid to form the hydrochloric acid salt of compound 1: L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some forms, more than 1 equivalent of hydrochloric acid is used based on 1 equivalent of compound 1. In some forms, the reaction of compound 1 with hydrochloric acid is carried out at approximately room temperature. In some forms, hydrochloric acid is an alcoholic solution of hydrochloric acid. In some forms, hydrochloric acid is an isopropanol solution of hydrochloric acid. In some embodiments, the process provided in the present description further comprises reacting the hydrochloric acid salt of compound 1 with a base to form the free base form of compound 1: HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some embodiments, the process provided in the present description further comprises reacting the hydrochloric acid salt of compound 1 with a bicarbonate base to form the free base form of compound 1: HN-N In some forms, the base is potassium bicarbonate. In some forms, potassium bicarbonate is an aqueous solution of potassium bicarbonate. In some embodiments, the process provided in the present description further comprises reacting the free base form of compound 1 with phosphoric acid to form the phosphoric acid salt of compound 1: HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ The process according to claim 69, wherein the reaction of the free base form of compound 1 with phosphoric acid is carried out at approximately room temperature. In some embodiments, the reaction of the free base form of compound 1 with phosphoric acid is carried out in the presence of a solvent component. In some embodiments, the solvent component comprises water. In some embodiments, the solvent component comprises water and isopropyl alcohol. In some embodiments, the process provided in the present description also includes isolating the phosphoric acid salt from compound 1. In some forms, the phosphoric acid salt of compound 1 is isolated by recrystallization. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising methanol. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising isopropanol. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising methylcyclohexane. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising one or more of methanol, isopropanol, and methylcyclohexane. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising methanol, isopropanol, and methylcyclohexane. In some embodiments, the phosphoric acid salt of compound 1 is isolated by recrystallization from a solvent component comprising methanol, isopropanol, and methylcyclohexane; and subsequently recrystallized from a solvent component comprising methanol and isopropanol. In some embodiments, this application also provides a process for preparing the phosphoric acid salt of compound 1: HN-N L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Phosphoric acid salt of compound 1 comprising: react 3,5-dimethyl-1H,1Ή-4,4'-bipyrazole with 3-(cyanomethylene)azetidine-l-carboxylate of tere-butyl in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to form the compound with the formula Al: To the; L77C ίΠ / ZZΖηZ / E / YΙΛΙ deprotect the compound with the formula Al to form the compound with the formula Cl: Cl or a salt of it; react the compound with the formula Cl with triethylamine to form the free base form of the compound with the formula Cl; react the free base form of the compound with the formula Cl with the compound la: L77C ίΠ / ZZΖηZ / E / YΙΛΙ in the presence of sodium bicarbonate and lithium chloride to form compound 1: HN-N react compound 1 with hydrochloric acid to form the hydrochloric acid salt of compound 1: HN-N react the hydrochloric acid salt of compound 1 with potassium bicarbonate to form the free base form of compound 1; and react the free base form of compound 1 with phosphoric acid to form the phosphoric acid salt of compound 1. In some embodiments, the present description provides a compound that is 3,5-dimethyl-1H, 1 Ή [4,4']bipyrazolyl (compound 2x) , 3,5-dimethyl-1H, 1 Ή-4 , 4 '-bipyrazole hydrochloride (HC1 of compound 2x) , l-(l-ethoxyethyl)3',5'-dimethyl-lH,1' H-4,4'-bipyrazole (compound 2b), or 1-(1ethoxyethyl)-4 - (4,4,5,5-tetramethyl-1-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (compound 2a), or a salt of any of the above. In some embodiments, the present description provides a compound that is 3,5-dimethyl-1H,1'H[4,4']bipyrazolyl (compound 2x) or a salt thereof. In some embodiments, the present description provides a compound that is (3)-4-(3(cyanomethylene)azetidin-l-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound lx), (3)-2,5-difluoro-4-(3-oxoazetidin-l-yl)-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound le), (3)-2,5-difluoro-4-(3hydroxyazetidin-l-yl)-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound Ib), or (3)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound la), or a salt of any of the above. In some forms, the term "approximately" refers to roughly 10% of the value. As used herein, the term "react" is used as it is known in the art and generally refers to combining chemical reactants in such a way as to allow them to interact at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reaction involves at least two reactants. In some embodiments, the reacting step or operation of a synthetic process may involve one or more substances in addition to the reactants, such as a solvent and / or a catalyst. The reaction steps or operations of the processes described herein can be carried out for a time and under conditions suitable for preparing the identified product. The terms "combine" and "mix" with respect to the reactants in a chemical reaction are used interchangeably with the term "react" herein.The term "couple" can also be considered interchangeable with "make react," but it can be used in conjunction with a reaction step or operation that involves the joining of two organic fragments. The processes described herein can be controlled by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., o13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography. The compounds obtained from the reactions can be purified by any suitable method known in the art. For example, chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina, and the like), preparative HPLC or thin-layer chromatography; distillation; sublimation; trituration; or recrystallization.The purity of compounds is generally determined by physical methods such as measuring the melting point (in the case of a solid), obtaining an NMR spectrum, or performing HPLC separation. If the melting point decreases, if unwanted signals in the NMR spectrum diminish, or if extraneous peaks are eliminated in an HPLC trace, the compound can be considered purified. In some cases, compounds are substantially purified. The preparation of the compounds described may involve the protection and deprotection of various chemical groups. A person skilled in the art can readily determine the need for protection and deprotection, and the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New York, 2006, which is incorporated herein by reference in its entirety. The reactions of the processes described herein can be carried out at appropriate temperatures that can be easily determined by an expert in the L77C iP / ZZΖ / E / YILI technical. Reaction temperatures will depend, for example, on the melting and boiling points of the reactants and the solvent, if present; the thermodynamics of the reaction (for example, it may be necessary to carry out vigorously exothermic reactions at reduced temperatures); and the kinetics of the reaction (for example, a high activation energy barrier may require elevated temperatures). “Elevated temperature” refers to temperatures above room temperature (approximately 22°C). The reactions of the compounds described herein can be carried out in suitable solvents that can be readily selected by someone skilled in organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, for example, temperatures ranging from the solvent's freezing point to its boiling point. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the reaction step or operation, suitable solvents can be selected for that particular step or operation. Appropriate solvents include water, alkanes (such as pentanes, hexanes, heptanes, cyclohexane, etc., or a mixture thereof), and aromatic solvents (such as L77C ίΠ / ZZΖηZ / E / YΙΛΙ benzene, toluene, xylene, etc.), alcohols (such as methanol, ethanol, isopropanol, etc.), ethers (such as dialkyl ethers, tert-butyl methyl ether (MTBE), tetrahydrofuran (THE), dioxane, etc.), esters (such as ethyl acetate, butyl acetate, etc.), halogenated hydrocarbon solvents (such as dichloromethane (DCM), chloroform, dichloroethane, tetrachloroethane), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, acetonitrile (ACN), hexamethylphosphoramide (HMPA), and N-methylpyrrolidone (NMP). The solvents can be used in their wet or anhydrous forms. The resolution of racemic mixtures of compounds can also be carried out using any of several methods in the art. For example, racemic mixtures can be resolved by elution in a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A person skilled in the art can determine the appropriate elution solvent composition. Methods The compounds provided in this description (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1) are JAK inhibitors, more specifically selective JAK1 inhibitors. A selective JAK1 inhibitor is a compound that inhibits JAK1 activity preferentially over other Janus kinases. For example, the compounds provided in this description L77C iP / ZZΖ / E / YILI preferentially inhibit JAK1 over one or more of JAK2, JAK3, and TYK2. In some embodiments, the compounds preferentially inhibit JAK1 over JAK2 (e.g., they have an IC50 ratio >1 with respect to JAK2 / JAK1). In some embodiments, the compounds are approximately 10 times more selective for JAK1 than for JAK2. In some embodiments, the compounds are approximately 3 times, approximately 5 times, approximately 10 times, approximately 15 times, or approximately 20 times more selective for JAK1 over JAK2 as calculated by measuring IC50 at 1 mM ATP (e.g., see Example A). JAK1 plays a central role in a number of cytokine and growth factor signaling pathways that, when dysregulated, can cause or contribute to pathological states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease in which it has been suggested to have detrimental effects (Fonesca, JE et al., Autoimmunity Reviews, 8:538-42. 2009). Because IL-6 signals, at least in part, through JAK1, direct or indirect antagonism of IL-6 through JAK1 inhibition is expected to provide clinical benefit (Guschin, D.N., et al., Embo J 14:1421. 1995; Emolen, JS, et al., Lancet 371:987. 2008). Furthermore, in some cancers, JAK1 is mutated, leading to constitutive undesirable tumor cell growth and survival (Mullighan CG, Proc Nati L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Acad Sel USA. 10 6:9414-8. 2009; Flex E., et al. J Exp Med. 205:751-8. 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to the disease and / or associated symptoms. Therefore, patients with these diseases may benefit from JAK1 inhibition. Selective JAK1 inhibitors can be effective while avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases. Selective JAK1 inhibitors, in relation to other JAK kinases, may have multiple therapeutic advantages over less selective inhibitors. Regarding selectivity for JAK2, several important cytokines and growth factors signal through JAK2, including, for example, erythropoietin (Epo) and thrombopoietin (Tpo) (Parganas E, et al. Cell. 93:385-95. 1998). Epo is a key growth factor for red blood cell production; therefore, a deficiency in Epo-dependent signaling can lead to a reduced red blood cell count and anemia (Kaushansky K, NEJM 354:2034-45. 2006). Tpo is another example of a JAK2-dependent growth factor. It plays a central role in controlling the proliferation and maturation of megakaryocytes, the cells from which platelets are produced (Kaushansky K, NEJM 354:2034-45. 2006). As such, reduced signaling L77C ίΠ / ZZΖ / E / YΙΛΙ of Tpo would decrease the number of megakaryocytes (megakaryocytopenia) and decrease the circulating platelet count (thrombocytopenia). This can lead to unwanted and / or uncontrollable bleeding. Reduced inhibition of other JAKs, such as JAK3 and Tyk2, may also be desirable, as humans lacking a functional version of these kinases have been shown to suffer from numerous diseases, such as severe combined immunodeficiency or hyperimmunoglobulin E syndrome (Minegishi, Y, et al. Immunity 25:74555. 2006; Macchi P, et al. Nature. 377:65-8. 1995). Therefore, a JAK1 inhibitor with reduced affinity for other JAKs would have significant advantages over a less selective inhibitor with respect to reduced side effects involving immunosuppression, anemia, and thrombocytopenia. Another aspect of this description relates to methods for treating a JAK-associated disease or disorder in an individual (e.g., a patient) by administering to the individual in need of treatment a therapeutically effective amount or dose of a compound of this description or a pharmaceutical composition thereof. A JAK-associated disease may include any disease, disorder, or condition that is directly or indirectly related to JAK expression or activity, including overexpression and / or abnormal activity levels. A JAK-associated disease may also include any disease, disorder, or condition that can be prevented, improved, or cured by modulating JAK activity. Examples of JAK-associated diseases include diseases that affect the immune system, including, for example, organ transplant rejection (e.g., allograft rejection and graft-versus-host disease). Other examples of diseases associated with JAK include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type 1 diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, autoimmune thyroid disorders, chronic obstructive pulmonary disease (COPD), and similar conditions. In some forms, the autoimmune disease is an autoimmune blistering skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (PA). Other examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, sclerotic dermatitis, contact dermatitis, atopic dermatitis (atrophic eczema), and rhinitis. Other examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV). Other examples of diseases associated with JAK include diseases associated with cartilage turnover, for example, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome, costal atrophy, endemic deforming osteoarthritis, Mseleni disease, Handigodu disease, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis. Other examples of JAK-associated diseases include congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias, and pseudochondrodysplasias (e.g., microtia, enotia, and metaphyseal chondrodysplasia). Other examples of diseases or conditions associated with JAK include skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, and skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, when applied topically, can cause skin sensitization. In some regimens, co-administration or sequential administration of at least one JAK inhibitor from the description along with the agent causing the unwanted sensitization may be helpful in treating the unwanted sensitization or dermatitis. In some regimens, the skin disorder is treated by topical administration of at least one JAK inhibitor from the description. In additional modalities, JAK-associated disease is cancer, which includes those characterized by solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman disease, uterine leiomyosarcoma, melanoma, etc.), hematologic cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example CTCLs include Sézary syndrome and mycosis fungoides. In some formulations, the JAK inhibitors described herein, or in combination with other JAK inhibitors, such as those reported in US publication 20070135461, which is incorporated herein by reference in its entirety, may be used to treat cancers associated with inflammation. In some formulations, the cancer is associated with inflammatory bowel disease. In some formulations, the inflammatory bowel disease is ulcerative colitis. In some formulations, the inflammatory bowel disease is Crohn's disease. In some formulations, the cancer associated with inflammation is a cancer associated with colitis. In some formulations, the cancer associated with inflammation is colon cancer or colorectal cancer.In some forms, the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small bowel cancer, or rectal cancer. JAK-associated diseases may also include those characterized by the expression of: JAK2 mutants such as those having at least one mutation in the pseudokinase domain (e.g., JAK2V617F); JAK2 mutants having at least one mutation outside the pseudokinase domain; JAK1 mutants; JAK3 mutants; erythropoietin receptor (EPOR) mutants; or dysregulated expression of CRLF2. JAK-associated diseases may also include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and similar conditions. In some forms, the myeloproliferative disorder is myelofibrosis (e.g., primary myelofibrosis (PMF)) or post-polycythemia vera / essential thrombocythemia myelofibrosis (Post-PV / ET FM)). In some forms, the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF).In some forms, the myeloproliferative disorder is myelofibrosis following polycythemia vera (PMV). In some regimens, the JAK inhibitors described herein may also be used to treat myelodysplastic syndrome (MDS) in patients who require it. In some regimens, the patient is dependent on a red blood cell transfusion. As used in this description, myelodysplastic syndromes are intended to encompass heterogeneous, clonal hematopoietic disorders characterized by ineffective hematopoiesis in one or more of the major myeloid cell lineages. Myelodysplastic syndromes are associated with bone marrow failure, peripheral blood cytopenias, and a propensity to progress to acute myeloid leukemia (AML). In addition, clonal cytogenetic abnormalities can be detected in approximately 50% of cases with MDS. In 1997, the World Health Organization (WHO), together with the Society of Hematopathology (SH) and the European Association of Hematopathology (EAHP), proposed new classifications for hematopoietic neoplasms (Harris, et al., J Clin Oncol 1999;17:3835-3849; Vardiman, et al., Blood 2002; 100:2292-2302).For MDS, the WHO used not only the morphological criteria of the French-American-British (FAB) classification, but also incorporated available genetic, biological, and clinical characteristics to define subsets of MDS (Bennett, et al., Br J Haematol 1982;51:189-199). In 2008, the WHO MDS classification (Table 1) was further refined to allow for accurate and prognostically relevant subclassification of unilineage dysplasia by incorporating new clinical and scientific information (Vardiman et al., Blood 2009;114:937-951; Swerdlow et al., WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic syndromes / neoplasma” in Chapter 5. Swerdlow et al., eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (4th ed.). L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ edition): Lyon, France: IARC Press;2008:88-103). Table. 2008 QMS classification for the syndrome L77C de novo myelodysplastic ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Subtype Blood Bone marrow Refractory cytopenia with single-lineage dysplasia (RCUD) Single or Bicytopenia Dysplasia in 2-10% of 1 cell lineage, <5% blasts Refractory anemia with ring sideroblasts (RARS) Anemia, no blasts 1-15% of erythroid precursors with ring sideroblasts, erythroid dysplasia only, <5% blasts Refractory cytopenia with multi-lineage dysplasia Cytopenia(s), <1 x 10⁹ / L monocytes Dysplasia in >10% of cells in >2 hematopoietic lineages, ±15% ring sideroblasts, <5% blasts Refractory anemia with excess blasts-1 (RAEB-1) Cytopenia(s), 1-2% to 4% of blasts, < 1 × 10⁹ / L monocytes Unilineage or multilineage dysplasia, without Auer bodies, 5% to 9% blasts Refractory anemia with excess blasts-2 (RAEB-2) Cytopenia(s), < 5% to 19% blasts, < 1 × 10⁹ / L monocytes Unilineage or multilineage dysplasia,± Auer bodies, 10% to 9% of blasts, Cytopenia Syndrome, Unilineage or without, Myelodysplastic syndrome, unclassified (MDS-U) blood type: dysplasia, but cytogenetically characteristic of MDS, <5% blasts. MDS associated with isolated del(5q) cells. Anemia, normal or increased platelets. Erythroid unilineage. Isolated del(5q) cells, <5% blasts. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some forms, myelodysplastic syndrome is refractory cytopenia with single-lineage dysplasia (RCUD). In some forms, myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS). In some forms, myelodysplastic syndrome is refractory cytopenia with multilineage dysplasia. In some forms, myelodysplastic syndrome is refractory anemia with excess blast-1 (RAEB-1). In some forms, myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2). In some forms, myelodysplastic syndrome is myelodysplastic syndrome, unclassified (MDS-U). In some forms, myelodysplastic syndrome is a myelodysplastic syndrome associated with isolated del(5q). In some forms, myelodysplastic syndrome is refractory to erythropoiesis-stimulating agents. This description further provides methods for treating psoriasis or other skin disorders by administering a topical formulation containing a compound provided in this description. In some cases, the JAK inhibitors described in this description can be used to treat pulmonary arterial hypertension. This description also provides a method for treating the dermatological side effects of other pharmaceutical products by administering the compound provided herein. For example, numerous pharmaceutical agents produce undesirable allergic reactions that may manifest as acneiform rash or related dermatitis. Examples of pharmaceutical agents that have undesirable side effects include anticancer drugs such as gefitinib, cetuximab, erlotinib, and similar drugs. The compounds provided herein may be administered systemically or topically (e.g., localized near the dermatitis) in combination with (e.g., simultaneously or sequentially) the pharmaceutical agent that has the undesirable dermatological side effect.In some formulations, the compound provided herein may be administered topically in conjunction with one or more other pharmaceutical products, where the other pharmaceutical products, when applied topically in the absence of a compound provided herein, cause contact dermatitis, allergic contact sensitization, or a similar skin disorder. Accordingly, the compositions described herein include topical formulations containing the compound provided herein and an additional pharmaceutical agent that may cause dermatitis, skin disorders, or related side effects. Other diseases associated with JAK include inflammation and inflammatory conditions. Examples of inflammatory diseases include sarcoidosis, inflammatory eye diseases (e.g., iritis, uveitis, scleritis, conjunctivitis, or related conditions), inflammatory respiratory diseases (e.g., upper respiratory tract, including the nose and sinuses, such as rhinitis or sinusitis, or lower respiratory tract, including bronchitis, chronic obstructive pulmonary disease, and similar conditions), inflammatory myopathy such as myocarditis, and other inflammatory diseases. In some modalities, the inflammatory eye disease is blepharitis. The JAK inhibitors described herein can also be used to treat ischemic reperfusion injury or a disease or condition related to an inflammatory ischemic event, such as stroke or cardiac arrest. The JAK inhibitors described herein can also be used to treat pathological conditions caused by endotoxins (e.g., complications following bypass surgery or chronic endotoxin states contributing to chronic heart failure). The JAK inhibitors described herein can also be used to treat anorexia, cachexia, or fatigue, such as that resulting from or associated with cancer. The JAK inhibitors described herein can also be used to treat restenosis, scleroderma, or fibrosis. The JAK inhibitors described herein can also be used to treat conditions associated with hypoxia or astrogliosis, such as diabetic retinopathy, cancer, or neurodegeneration. See, for example, Dudley, AC et al. Biochem. J. 2005. 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004. 279(19):19936-47. Epub March 2, 2004.Both are incorporated herein by reference in their entirety. The JAK inhibitors described herein may be used to treat Alzheimer's disease. The JAK inhibitors described in this description can also be used to treat other inflammatory diseases such as systemic inflammatory response syndrome (SIRS) and septic shock. The JAK inhibitors described in this description can also be used to treat gout and enlarged prostate gland due, for example, to benign prostatic hyperplasia or benign prostatic hypertrophy. Other diseases associated with JAK include bone resorption diseases such as osteoporosis and osteoarthritis. Bone resorption can also be associated with other conditions such as hormonal imbalance and / or hormone therapy, autoimmune disease (e.g., sarcoidosis of bone), or cancer (e.g., myeloma). The reduction in bone resorption due to JAK inhibitors can be approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some formulations, the JAK inhibitors described herein may also be used to treat dry eye disorder. As used herein, “dry eye disorder” is intended to encompass the disease states summarized in a recent official report from the Dry Eye Workshop (DEWS), which defined dry eye as “a multifactorial disease of the tears and ocular surface that produces symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the retina.” L77C iP / ZZΖ / E / YILI the ocular surface. It is accompanied by increased tear film osmolarity and inflammation of the ocular surface." Lemp, The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop, The Ocular Surface, 5(2), 75-92 April 2007. This is incorporated into the present description by reference in its entirety. In some modalities, dry eye disorder is selected from aqueous tear deficiency dry eye (ADDE) or evaporative dry eye disorder, or appropriate combinations thereof. In some modalities, the dry eye disorder is Sjögren's dry eye syndrome (SSDE). In some forms, dry eye disorder is non-Sjogren's dry eye syndrome (NSSDE). In another aspect, the present description provides a method for treating conjunctivitis, uveitis (including chronic uveitis), chorioditis, retinitis, cyclitis, scleritis, episcleritis, or iritis; treating inflammation or pain related to corneal transplantation, LASIK (laser-assisted in situ keratomileusis), photorefractive keratectomy, or LASEK (laser-assisted subepithelial keratomileusis); inhibiting loss of visual acuity related to corneal transplantation, LASIK, photorefractive keratectomy, or LASEK; or inhibiting transplant rejection in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound provided in the present description, or a pharmaceutically acceptable salt thereof. In addition, the compounds provided in this description, or in combination with other JAK inhibitors, such as those reported in U.S. serial number 11 / 637.545, which is incorporated herein by reference in its entirety, may be used to treat respiratory dysfunction or failure associated with a viral infection, such as influenza and SARS. In some embodiments, this description provides the free base of compound 1 and the phosphoric acid salt of compound 1, as described in any of the embodiments herein, for use in a method for treating any of the diseases or disorders described herein. In some embodiments, this description provides the use of the free base of compound 1 and the phosphoric acid salt of compound 1, as described in any of the embodiments herein, to prepare a medicament for use in a method for treating any of the diseases or disorders described herein. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some embodiments, this description provides the free base of compound 1 and the phosphoric acid salt of compound 1 as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for modulating JAK1. In some embodiments, this description also provides the free base of compound 1 and the phosphoric acid salt of compound 1 as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for modulating JAK1. As used herein, the term “contacting” refers to the joining of the indicated residues in an in vitro or in vivo system. For example, “contacting” a JAK with a compound described herein includes administering a compound from this description to an individual or patient, such as a human, who has a JAK, as well as, for example, introducing a compound provided herein into a sample containing a cell or purified preparation containing the JAK. As used in the present description, the terms "individual" or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. As used in this description, the term "therapeutic effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human being sought by a researcher, veterinarian, physician, or other clinician. In some formulations, the therapeutically effective amount is approximately 5 mg to approximately 1000 mg, or approximately 10 mg to approximately 500 mg. As used in this description, the term "treat" or "treatment" refers to one or more of (1) inhibiting disease, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., stopping the further development of the pathology and / or symptoms); and (2) improving disease, for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), such as lessening the severity of the disease. As used in this description, the term "prevent" or "prevention" refers to, for example, L77C ίΠ / ZZΖηZ / E / YΙΛΙ prevent a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but who does not yet experience or show the pathology or symptomatology of the disease. Combined therapies The methods described herein may also include the administration of one or more additional therapeutic agents. These additional therapeutic agents may be administered to a patient simultaneously or sequentially. In some modalities, the method also includes administering an additional therapeutic agent selected from IMiD, an anti-IL-6 agent, an anti-TNF-α agent, a hypomethylating agent, and a biological response modifier (BRM). In general, a biologic agent (BA) is a substance derived from living organisms to treat diseases, which may occur naturally in the body or be manufactured in a laboratory. Examples of BAs include IL-2, interferon, various types of colony-stimulating factors (CSF, GM-CSF, G-CSF), monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trasturzumab, and high-dose ascorbate. In some forms, the anti-TNF-α agent is infliximab or etanercept. In some forms, the hypomethylating agent is a L77C ίΠ / ZZΖηZ / E / YΙΛΙ DNA methyltransferase inhibitor. In some formulations, the DNA methyltransferase inhibitor is selected from 5 azacitidine and decitabine. IMiDs are generally immunomodulatory agents. In some forms, the IMiD is selected from thalidomide, lenalidomide, pomalidomide, CC-11006, and CC-10015. In some modalities, the method also includes administering an additional therapeutic agent selected from antithymocyte globulin, recombinant human granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte CSF (GM-CSF), an erythropoiesis-stimulating agent (ESA), and cyclosporine. In some modalities, the method also involves administering an additional JAK inhibitor to the patient. In some modalities, the additional JAK inhibitor is tofacitinib or ruxolitinib. One or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, spheroids, immunosuppressants, as well as PI3K5, mTOR, Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors, such as those described in WO 2006 / 056399, which are incorporated herein by reference in their entirety, or other agents, may be used in combination with the compounds described herein for the treatment of L77C ίΠ / ZZΖηZ / E / YΙΛΙ diseases, disorders or conditions associated with JAK. One or more additional pharmaceutical agents may be administered to a patient simultaneously or sequentially. Examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like. Examples of spheroids include corticosteroids such as dexamethasone or prednisone. Examples of suitable Bcr-Abl inhibitors include the compounds, and their pharmaceutically acceptable salts, of the genera and species described in U.S. Patent No. 5,521,184, WO 04 / 005281 and U.S. Serial No. 60 / 578,491, which are incorporated herein by reference in their entirety. Examples of suitable Flt-3 inhibitors include pharmaceutically acceptable compounds and their salts, as described in patents WO 03 / 037347, WO 03 / 099771 and WO 04 / 046120, which are incorporated herein by reference in their entirety. Other examples of suitable RAF inhibitors include pharmaceutically acceptable compounds and their salts, as described in patents WO 00 / 09495 and L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ WO 05 / 028444. which are incorporated into the present description by means of this reference in their entirety. Other examples of suitable FAK inhibitors include pharmaceutically acceptable compounds and their salts, as described in patents WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595 and WO 01 / 014402, which are incorporated herein by reference in their entirety. In some formulations, the compounds provided in this description (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1) can be used in combination with one or more kinase inhibitors, including imatinib, particularly to treat patients with resistance to imatinib or other kinase inhibitors. In some modalities, a suitable chemotherapeutic agent may be selected from antimetabolite agents, topoisomerase 1 inhibitors, platinum analogues, taxanes, anthracyclines, and EGFR inhibitors and combinations thereof. In some forms, antimetabolite agents include capecitabine, gemcitabine, and fluorouracil (5-FU). In some forms, taxanes include paclitaxel, Abraxane® (paclitaxel protein-bound particles for injectable suspension) and Taxotere® (docetaxel). L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some forms, platinum analogues include oxaliplatin, cisplatin, and carboplatin. In some forms, topoisomerase 1 inhibitors include irinotecan and topotecan. In some forms, anthracyclines include doxorubicin or liposomal formulations of doxorubicin. In some regimens, the chemotherapy agent is FOLFIRINOX (5-FU, lecovorin, irinotecan, and oxaliplatin). In some regimens, the chemotherapy agent is gemcitabine and Abraxane® (paclitaxel protein-bound particles for injection). In some formulations, the compounds provided herein (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1) may be used in combination with a chemotherapeutic agent in the treatment of cancer, such as multiple myeloma, and may improve the response to treatment compared to the response to the chemotherapeutic agent alone, without exacerbating its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Other additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of this description with an additional agent.Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible with treatment using a JAK inhibitor as described herein. The agents may be combined with the compounds provided herein in a single or continuous dosage form, or the agents may be administered concurrently or sequentially as separate dosage forms. In some modalities, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor, in which the dexamethasone is administered intermittently rather than continuously. In some additional modalities, the combinations of compounds provided in this description with other therapeutic agents may be administered to a patient before, during and / or after a bone marrow or stem cell transplant. In some embodiments, the additional therapeutic agent is fluocinolone acetonide (Retisert®) or rimexolone (AL-2178. Vexol, Alcon). In some modalities, the additional therapeutic agent is cyclosporine (Restasis®). In some embodiments, the additional therapeutic agent is a corticosteroid. In some modalities, the L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ corticosteroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone or flumetholone. In some formulations, the additional therapeutic agent is selected from Dehidrex™ (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio / TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15-(S)hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemin, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio). CF101 (2S,3S,4R,5R)-3.4-dihydroxy-5 - [ 6— [ (3iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214. Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011.Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31 (Evolutec), Lacritin (Senju), rebamipida (Otsuka-Novartis), OT-551 (Othera), PAI-2 (Universidad de Pensilvania y Universidad del Temple), pilocarpine, tacrolimus, pimecrolimus (AMS981. Novartis), loteprednol etabonate, rituximab, tetrasodium diquafosol (INS365. Inspire), KLS-0611 (Kissei. Pharmaceuticals), dehidroepiandrosterona, anakinra, L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ efalizumab, micofenolato de sodio, etanercept (Embrel®), hidroxicloroquina, NGX267 (TorreyPines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginasa o talidomida. In some formulations, the additional therapeutic agent is an antiangiogenic agent, a cholinergic agonist, a TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, a MUGI stimulator, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, a Bcr-Abl kinase inhibitor, an Flt-3 kinase inhibitor, a RAF kinase inhibitor, and an FAK kinase inhibitor, such as those described in WO 2006 / 056399, which is incorporated herein by reference in its entirety. In some formulations, the additional therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycycline). In some formulations, the additional therapeutic agent is bound to FKBP12. In some modalities, the additional therapeutic agent is an alkylating agent or a DNA crosslinking agent; an antimetabolite / demethylating agent (e.g., 5-fluorouracil, capecitabine, or azacitidine); an antihormonal therapy (e.g., hormone receptor antagonists, SERMs, or an aromatase inhibitor); a mitotic inhibitor (e.g., vincristine or paclitaxel); a topoisomerase (I or II) inhibitor (e.g., mitoxantrone); or a topoisomerase inhibitor (I or II) (e.g., mitoxantrone). L77C iP / ZZΖ / E / YILI irinotecan); apoptosis inducers (e.g., ABT-737); a nucleic acid therapy (e.g., antisense or RNAi); nuclear receptor ligands (e.g., agonists and / or antagonists: all-trans retinoic acid or bexarotene); epigenetic targeting agents such as histone deacetylase inhibitors (e.g., vorinostat), hypomethylating agents (e.g., decitabine); regulators of protein stability such as Hsp90 inhibitors, ubiquitin and / or ubiquitin-like conjugating or deconjugating molecules; or an EGFR inhibitor (erlotinib). In some treatments, the additional therapeutic agent(s) are demulcent eye drops (also known as "artificial tears"), which include, among others, compositions containing polyvinyl alcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol (e.g., PEG400), or carboxymethylcellulose. Artificial tears can help treat dry eye by compensating for the reduced moisturizing and lubricating capacity of the tear film. In some treatments, the additional therapeutic agent is a mucolytic drug, such as N-acetylcysteine, which can interact with mucoproteins and thus decrease the viscosity of the tear film. In some modalities, the additional therapeutic agent includes antibiotic, antiviral, antifungal, anesthetic, and anti-inflammatory agents. L77C iP / ZZΖ / E / YILI steroidal and non-steroidal anti-inflammatory drugs and anti-allergics. Examples of suitable medicines include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naftiridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paromomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampicin and its derivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericin B; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; Cromolin; lodoxamide; levocabastine; naphazoline; antazoline; pheniramine; or azalide antibiotic. In some formulations, the compounds described herein can be used in combination with immune checkpoint inhibitors in the treatment of diseases such as cancer. Examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2. In some formulations, the L77C ίΠ / ZZΖ / E / YILI immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors. In some forms, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. In some therapies, the inhibitor of an immune checkpoint molecule is a PD-1 inhibitor, for example, an anti-PD-1 monoclonal antibody. In some therapies, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some therapies, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some therapies, the anti-PD-1 antibody is pembrolizumab. In some forms, the inhibitor of an immune checkpoint molecule is a PD-L1 inhibitor. L77C ίΠ / ZZΖηZ / E / YΙΛΙ, for example, an anti-PD-Ll monoclonal antibody. In some modalities, the anti-PD-Ll monoclonal antibody is BMS935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some modalities, the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736. In some therapies, the inhibitor of an immune checkpoint molecule is a CTLA-4 inhibitor, for example, an anti-CTLA-4 antibody. In some therapies, the anti-CTLA-4 antibody is ipilimumab. In some modalities, the inhibitor of an immune checkpoint molecule is a LAG3 inhibitor, for example, an anti-LAG3 antibody. In some modalities, the anti-LAG3 antibody is BMS-986016 or LAG525. In some therapies, the inhibitor of an immune checkpoint molecule is a GITR inhibitor, for example, an anti-GITR antibody. In some therapies, the anti-GITR antibody is TRX518 or MK-4166. In some formulations, the inhibitor of an immune checkpoint molecule is an OX40 agonist, for example, an OX40 agonist antibody or an OX40L fusion protein. In some formulations, an anti-OX40 antibody is MEDI0562. In some formulations, the OX40L fusion protein is MEDI6383. The compounds described herein may be used in combination with one or more agents for the treatment of L77C iP / ZZΖ / E / YILI diseases, for example, cancer. In some forms, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some forms, the proteasome inhibitor is carfilzomib. In some forms, the corticosteroid is dexamethasone (DEX). In some forms, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Pharmaceutical formulations and pharmaceutical forms When drugs are used, the compounds provided in this description can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is indicated and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucous membrane administration, including intranasal, vaginal, and rectal), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by means of a nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, injection or infusion, or intracranial, for example, by L77C iP / ZZΖ / E / YILI intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or, for example, by means of a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable. This description also includes pharmaceutical compositions containing, as an active ingredient, the free base of compound 1 and / or the phosphoric acid salt of compound 1, in combination with one or more pharmaceutically acceptable carriers (excipients). In some formulations, the composition is suitable for topical administration. When preparing the compositions described, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semisolid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Therefore, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, seals, elixirs, L77C iΠ / ZZΖηZ / E / YΙΛΙ suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. When preparing a formulation, a compound provided in this description (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1) may be milled to provide the appropriate particle size before combining it with the other ingredients. If the free base of compound 1 and the phosphoric acid salt of compound 1 are substantially insoluble, they may be milled to a particle size of less than 200 mesh. If the free base of compound 1 and the phosphoric acid salt of compound 1 are substantially soluble in water, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., approximately 40 mesh. The compounds described herein can be milled using known milling procedures such as wet milling to obtain a particle size suitable for tablet formation and other formulations. Very fine (nanoparticulate) preparations of the compounds described herein can be prepared by processes L77C ίΠ / ZZΖηZ / E / YΙΛΙ known in the art, see, for example, see International Application No. WO 2002 / 000196. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may additionally include lubricating agents such as magnesium stearate and mineral oil; wetting agents; suspending and emulsifying agents; preservatives such as methyl and propyl hydroxybenzoates; and sweetening or flavoring agents. The compositions described may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient using procedures known in the art. In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises approximately 98% microcrystalline cellulose and approximately 2% silicon dioxide (w / w). L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ In some embodiments, the composition is a sustained-release composition comprising the free base of compound 1 and / or the phosphoric acid salt of compound 1 and at least one pharmaceutically acceptable carrier. In some embodiments, the composition comprises the free base of compound 1 and / or the phosphoric acid salt of compound 1 described herein, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises the free base of compound 1 and / or the phosphoric acid salt of compound 1 and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises the free base of compound 1 and / or the phosphoric acid salt of compound 1 and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide.In some formulations, the composition also includes magnesium stearate or silicon dioxide. In some formulations, the microcrystalline cellulose is Avicel PH102™. In some formulations, the lactose monohydrate is Fast-flo 316™. In some formulations, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Metocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Metocel K4 M Premier™). L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ example, Methocel K00LV™). In some embodiments, the polyethylene oxide is WSR 1105 polyethylene oxide (e.g., Polyox WSR 1105™). In some forms, a wet granulation process is used to produce the composition. In some forms, a dry granulation process is used to produce the composition. The compositions can be formulated in a unit dosage form, wherein each dosage contains between approximately 1 and approximately 1000 mg, between approximately 1 mg and approximately 100 mg, between approximately 1 mg and approximately 50 mg, and between approximately 1 mg and 10 mg of the active ingredient (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1). Preferably, the dosage is between approximately 1 mg and approximately 50 mg or between approximately 1 mg and approximately 10 mg of the active ingredient. In some embodiments, each dosage contains approximately 10 mg of the active ingredient. In some embodiments, each dosage contains approximately 50 mg of the active ingredient. In some embodiments, each dosage contains approximately 25 mg of the active ingredient.The expression "unit dosage forms" refers to physically distinct units suitable as unit doses for human and other mammalian subjects, each unit containing a predetermined amount of the calculated active material to obtain the desired therapeutic effect, together with a suitable pharmaceutical excipient. In some forms, the compositions range from approximately 1 to approximately 1000 mg, between L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ approximately 1 mg and approximately 100 mg, between approximately 1 mg and approximately 50 mg, and between approximately 1 mg and 10 mg of active ingredient (e.g., the free base of compound 1 and the acid salt phosphoric acid of compound 1). Preferably, the compositions comprise between approximately 1 mg and approximately 50 mg or between approximately 1 mg and approximately 10 mg of the active ingredient. A person skilled in the art will appreciate that this includes compounds or compositions containing between approximately 1 mg and approximately 10 mg, between approximately 1 mg and approximately 20 mg, between approximately 1 mg and approximately 25 mg, and between approximately 1 mg and approximately 50 mg of the active ingredient. The active compound (e.g., the free base of compound 1 and the phosphoric acid salt of compound 1) may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It is understood, however, that the amount of compound actually administered will normally be determined by a physician, taking into account relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, the severity of the patient's symptoms, and similar factors. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from approximately 0.1 to approximately 1000 mg of the active ingredient described herein. The tablets or pills of the present invention may be coated or otherwise composed to provide a pharmaceutical form that offers the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being enveloped by the former. The two components may be separated by an enteric coating that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or delays its release. A variety of materials may be used for such enteric coatings or layers, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. Liquid forms in which the compounds and compositions provided in this description can be incorporated for oral administration or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some formulations, compositions are administered orally or nasally for a local or systemic effect. Compositions may be nebulized using inert gases. Nebulized solutions may be breathed directly from the nebulizer device, or the nebulizer device may be connected to a face mask tent or an intermittent positive pressure breathing machine. Compositions in solution, suspension, or powder form may be administered orally or nasally from devices that deliver the formulation appropriately. Topical formulations may contain one or more conventional carriers. In some forms, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. Cream carrier compositions may be water-based in combination with glycerol and one or more components, for example, glyceryl monostearate, PEG glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, appropriately in combination with other components such as, for example, glycerol, hydroxyethylcellulose, and the like. In some forms, topical formulations contain at least approximately 0.1, at least approximately 0.25, at least approximately 0.5, at least approximately 1, at least approximately 2, or at least approximately 5% by weight of L77C iP / ZZΖ / E / YILI compound provided in this description. Topical formulations can be conveniently packaged in tubes of, for example, 100 g, which may optionally include instructions for the treatment of the selected indication, for example, psoriasis or another skin condition. The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (such as prophylaxis or therapy), the patient's condition, the route of administration, and other factors. In certain therapeutic applications, compositions may be administered to a patient already suffering from a disease in a quantity sufficient to cure or at least partially halt the symptoms of the disease and its complications. Effective doses will depend on the stage of the disease being treated, as well as the judgment of the attending physician, taking into account factors such as the severity of the disease, the patient's age, weight, and overall health. The compositions administered to a patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized using conventional sterilization techniques or by filtration. Aqueous solutions may be packaged for use as is or lyophilized, combining the lyophilized preparation with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be between 3 and 11, more preferably between 5 and 9, and even more preferably between 7 and 8. It is understood that the use of certain excipients, carriers, or stabilizers mentioned above will result in the formation of pharmaceutical salts. The therapeutic dose of a compound described herein may vary depending on, for example, the specific use for which the treatment is administered, the route of administration, the patient's health and condition, and the prescribing physician's judgment. The ratio or concentration of the free base of compound 1 or the phosphoric acid salt of compound 1 in a pharmaceutical composition may vary depending on several factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds provided herein may be provided in an aqueous physiological buffer solution containing from approximately 0.1% to approximately 10% w / v of the compound for parenteral administration. Typical dosage ranges are from approximately 1 pg / kg to approximately 1 g / kg of body weight per day.In some forms, the dosage range is approximately 0.01 mg / kg to approximately 100. L77C ίΠ / ZZΖ / E / YILI mg / kg of body weight per day. The dosage is likely to depend on variables such as the type and stage of disease or disorder progression, the patient's overall health status, the relative biological efficacy of the selected compound, the excipient formulation, and the route of administration. Effective doses can be extrapolated from dose-response curves derived from test systems in animal models or in vitro. The compositions described may also include one or more additional pharmaceutical agents such as a chemotherapeutic compound, spheroid, anti-inflammatory or immunosuppressant, examples of which are listed above. In some embodiments, the free base of compound 1 or the phosphoric acid salt of compound 1 is administered as an ophthalmic composition. Accordingly, in some embodiments, the methods comprise the administration of the compound, or a pharmaceutically acceptable salt thereof, and an ophthalmic-acceptable carrier. In some embodiments, the ophthalmic composition is a liquid composition, a semisolid composition, an insert, a film, microparticles, or nanoparticles. In some formulations, the ophthalmic composition is a liquid composition. In some formulations, the composition L77C ίΠ / ZZΖ / E / YILI ophthalmic is a semisolid composition. In some forms, the ophthalmic composition is a topical composition. Topical compositions include, but are not limited to, liquid and semisolid compositions. In some forms, the ophthalmic composition is a topical composition. In some forms, the topical composition comprises an aqueous solution, an aqueous suspension, an ointment, or a gel. In some forms, the ophthalmic composition is applied topically to the front of the eye, under the upper eyelid, on the lower eyelid, and in the fornix. In some forms, the ophthalmic composition is sterilized. Sterilization may be achieved by techniques known as sterilizing filtration of the solution or by heating the solution in the ready-to-use ampoule. The ophthalmic compositions described may also contain pharmaceutical excipients suitable for the preparation of ophthalmic formulations.Examples of such excipients are preservatives, buffering agents, chelating agents, antioxidants, and salts to regulate osmotic pressure. As used in this description, the term "ophthalmologically acceptable carrier" refers to any material that can contain and release the compound, or a pharmaceutically acceptable salt thereof, and that is compatible with the eyes. In some formulations, the ophthalmicly acceptable carrier is water or an aqueous solution or suspension, but it also includes oils such as those used to make ointments and polymeric matrices such as those used in ocular inserts. In some formulations, the composition may be an aqueous suspension comprising the compound or a pharmaceutically acceptable salt thereof. Liquid ophthalmic compositions, including ointments and suspensions, may have a viscosity suitable for the selected route of administration. In some formulations, the ophthalmic composition has a viscosity in the range of approximately 1.000 to approximately 30,000 centipoise. In some formulations, ophthalmic compositions may also include one or more surfactants, adjuvants, buffers, antioxidants, tonicity adjusters, preservatives (e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaternium-1), thickeners or viscosity modifiers (e.g., carboxymethylcellulose, hydroxymethylcellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol, hydroxymethylcellulose, hydroxypropyl guar, hyaluronic acid, and hydroxypropylcellulose), and the like. Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ methylparaben, propylparaben, chlorhexidine, castor oil and sodium perborate. Aqueous ophthalmic compositions (solutions or suspensions) generally do not contain physiologically or ophthally harmful constituents. In some formulations, purified or deionized water is used. The pH can be adjusted by adding any physiologically and ophthally acceptable acid, base, or pH-adjusting buffer within the range of approximately 5.0 to 8.5. Ophthalmologically acceptable examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and similar acids, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, trihydroxymethylaminomethane, and similar compounds. Salts and buffers include citrate / dextrose, sodium bicarbonate, ammonium chloride, and mixtures of the aforementioned acids and bases. In some modalities, the methods involve forming or delivering a reservoir of the therapeutic agent in contact with the external surface of the eye. A reservoir refers to a source of therapeutic agent that is not rapidly removed through tears or other ocular cleansing mechanisms. This allows for continuous and sustained high concentrations of the therapeutic agent to be present. L77C iP / ZZΖ / E / YILI in the fluid on the external surface of the eye by a single application. Without wishing to limit oneself to any one theory, it is believed that absorption and penetration may depend on both the concentration of the dissolved drug and the duration of contact of the external tissue with the drug-containing fluid. As the drug is removed by clearance from the ocular fluid and / or absorption into the ocular tissue, more drug, for example, dissolved, is provided in the ocular fluid replenished from the depot. Consequently, the use of a depot may more easily facilitate loading the ocular tissue for more insoluble therapeutic agents. In some modalities, the depot may remain for up to eight hours or more. In some modalities, ophthalmic depot forms include, but are not limited to, aqueous polymeric suspensions, ointments, and solid inserts. In some formulations, the ophthalmic composition is an ointment or gel. In some formulations, the ophthalmic composition is an oil-based delivery vehicle. In some formulations, the composition comprises a petroleum or lanolin base to which the active ingredient, generally at a concentration of 0.1 to 2%, and excipients are added. Common bases may include, but are not limited to, mineral oil, petrolatum, and combinations thereof. In some formulations, the ointment is applied as a strip to the lower eyelid. In some formulations, the ophthalmic composition is an ophthalmic insert. In some formulations, the ophthalmic insert is biologically inert, soft, bioerodible, viscoelastic, stable to sterilization after exposure to therapeutic agents, resistant to airborne bacterial infections, bioerodible, biocompatible, and / or viscoelastic. In some formulations, the insert comprises an ophthally acceptable matrix, for example, a polymeric matrix. The matrix is ​​typically a polymer, and the therapeutic agent is generally dispersed within it or bound to the polymeric matrix. In some formulations, the therapeutic agent may be slowly released from the matrix by dissolution or hydrolysis of the covalent bond. In some formulations, the polymer is bioerodible (soluble), and the rate of dissolution of the polymer may control the rate of release of the therapeutic agent dispersed within it.In another form, the polymer matrix is ​​a biodegradable polymer that decomposes through hydrolysis to release the therapeutic agent bound to or dispersed within it. In additional embodiments, the matrix and the therapeutic agent can be surrounded by an additional polymer coating for further control of release. In some embodiments, the insert comprises a biodegradable polymer such as polycaprolactone (PCL), an ethylene / vinyl acetate (EVA) copolymer, polyalkyl cyanoacrylate, polyurethane, a nylon, or poly(dl-lactide-co-glycolide). L77C iP / ZZΖ / E / YILI (PLGA), or a copolymer thereof. In some embodiments, the therapeutic agent is dispersed in the matrix material or dispersed among the monomer composition used to manufacture the matrix material prior to polymerization. In some embodiments, the amount of therapeutic agent is approximately 0.1 to approximately 50%, or approximately 2 to approximately 20%. In additional embodiments, the biodegradable or bioerodible polymer matrix is ​​used so that the spent insert does not need to be removed. As the biodegradable or bioerodible polymer degrades or dissolves, the therapeutic agent is released. In additional embodiments, the ophthalmic insert comprises a polymer, including, but not limited to, those described in Wagh, et al., "Polymers used in ocular dosage form and drug delivery systems", Asian J. Pharm., pages 12-17 (January 2008), which is incorporated herein by reference in its entirety. In some embodiments, the insert comprises a polymer selected from polyvinylpyrrolidone (PVP), an acrylate or methacrylate polymer or copolymer (e.g., the Eudragit® polymer family from Rohm or Degussa), hydroxymethylcellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethylsiloxane), polyethylene oxide, poly(lactide-co-glycolide), poly(hydroxyethyl methacrylate), poly(vinyl alcohol), or poly(propylene fumarate). In some embodiments, the insert comprises Gelfoam® R. In some embodiments, the insert is a 450 kDa cysteine ​​conjugate polyacrylic acid. In some forms, the ophthalmic composition is an ophthalmic film. Suitable polymers for such films include, but are not limited to, those described in Wagh, et al. (ibid). In some forms, the film is a soft contact lens, such as those made of N,N-diethylacrylamide and methacrylic acid copolymers crosslinked with ethylene glycol dimethacrylate. In some embodiments, the ophthalmic composition comprises microspheres or nanoparticles. In some embodiments, the microspheres comprise gelatin. In some embodiments, the microspheres are injected into the posterior segment of the eye, into the choroid space, into the sclera, via the intravitreal or subretinal route. In some embodiments, the microspheres or nanoparticles comprise a polymer that includes, among others, those described in Wagh et al. (ibid.), which is incorporated herein by reference in its entirety. In some embodiments, the polymer is chitosan, a polycarboxylic acid such as polyacrylic acid, albumin particles, hyaluronic acid esters, polyitaconic acid, poly(butyl)cyanoacrylate, polycaprolactone, poly(isobutyl)caprolactone, poly(lactic acid-co-glycolic acid), or poly(lactic acid). In some forms, the microspheres or nanoparticles comprise solid lipid particles. In some formulations, the ophthalmic composition comprises an ionic intertambium resin. In some formulations, the ionic intertambium resin is an inorganic zeolite or a synthetic organic resin. In some formulations, the ionic intertambium resin includes, but is not limited to, those described in Wagh et al. (ibid.), which is incorporated herein by reference in its entirety. In some formulations, the ionic intertambium resin is a partially neutralized polyacrylic acid. In some formulations, the ophthalmic composition is an aqueous polymer suspension. In some formulations, the therapeutic agent or a polymer suspension agent is suspended in an aqueous medium. In some formulations, aqueous polymer suspensions may be formulated to retain the same or substantially the same viscosity in the eye as they had prior to administration. In some formulations, these may be formulated to exhibit increased gelation upon contact with tear fluid. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Kits This description also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer. These kits include one or more containers holding a pharmaceutical composition comprising a therapeutically effective amount of the free base of compound 1 or the phosphoric acid salt of compound 1. The kits may further include one or more components of conventional pharmaceutical kits, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either in the form of package inserts or labels, indicating the quantities of the components to be administered, administration guidelines, and / or guidelines for mixing the components may also be included in the kit. The invention will be described in greater detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. The compounds in the Examples have been found to be JAK inhibitors according to at least one assay described herein. And temples Intermediate 1. 3,5-Dimethyl-4,4'-bipyrazole (compound 2x) Reaction scheme 1. Suzuki coupling Pe 118 IPAJAgua li '. ON or ''Nl· HCI conc. NN 2b UN NH HCl NaOH ac. Nz- / \-N ► n-heptane 2x hydrochloride H\ ' NH Nl· / 7' :N r 2x Step 1. 1 ' - (1-ethoxy-ethyl)-3,5-dimethyl-lH, 1 Ή[4,4 ']bipyrazolyl (compound 2b) To a nitrogen-purged 100 L glass reactor, 1-propanol (5.0 L), potable water (6.0 L), K₂HPO₄ (1032 g), 4-bromo-3,5-dimethylpyrazole (1084 g), and l-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (compound 2a, 1502 g) were sequentially added. Nitrogen gas was bubbled through the reaction mixture for 18 minutes, then Pd-118 (55.07 g) was loaded into the reactor and nitrogen gas was bubbled through the reaction mixture for another 18 minutes. The reaction mixture was heated to approximately 90 °C and stirred for approximately 4 hours at approximately 90 °C. The reaction mixture was then cooled to approximately 17 °C and the phases were separated. The organic phase was treated with activated carbon (1500 g), heated to approximately 70 °C, stirred at approximately 70 °C for approximately 4 hours, and cooled to approximately 21 °C.The mixture was filtered through Celite (1500 g) and the filter cake was washed with 2-propanol (15.0 L). The combined filtrate and washings were concentrated under vacuum at approximately 58°C to obtain the desired crude product, 1'-(1-ethoxyethyl)-3,5-dimethyl-1H,1Ή[4,4']bipyrazolyl (2593 g), which was used in the subsequent treatment. The 1(1-ethoxyethyl)-3,5-dimethyl-1H,1'Hcrudo Crude [4,4']bipyrazolyl (2590 g) and ethyl acetate (EtOAc, 15.0 L) were loaded into a reactor. Separately, an aqueous NaHSO₄ solution was prepared by thoroughly mixing NaHSC₆ (1500 g) and potable water (8.0 L). The aqueous NaHSC₆ solution was added to the reaction mixture, heated to 65–70 °C, and stirred at 65–70 °C for approximately 2.5 hours. The phases separated, and the organic phase was retained in the reactor. L77C iP / ZZΖ / E / YILI thoroughly mixed NaHSOs (1500 g) and potable water (8.0 L). The aqueous NaHSOs solution was added to the reaction mixture, heated to 65–70 °C, and stirred at 65–70 °C for approximately 3.5 hours. The phases separated. A chromatography column was sequentially loaded with sea sand (3000 g), ethyl acetate (EtOAc, 15.0 L), and silica gel (SiO2, 4500 g). The silica gel and solvent were mixed, and the solvent eluted to the surface of the silica gel. Sea sand (3000 g) was loaded at the top of the column. The reaction mixture was loaded into the column and eluted with ethyl acetate (18.0 L). The desired fractions were combined and the combined solution was concentrated under vacuum at approximately 55 °C, yielding the column-purified product (1760 g), which was then loaded into the reactor with methylene chloride (16.0 L).Si-thiol (160 g) was loaded into the reactor and the reaction mixture was heated to 35–40 °C and stirred at 35–40 °C for approximately 2 hours. The mixture was filtered and the filter cake was washed with methylene chloride (3.5 1). The combined filtrate and wash solution were concentrated under vacuum to obtain the purified desired product, 1'-(1-ethoxyethyl)-3,5-dimethyl-1H,1'H[4,4']bipyrazolyl (1600 g), which contained residual solvent and was used directly in the subsequent reaction. NMRΧΗ (400 MHz, DMSO-cU δ 12.17 (s, 1H), 7.89 (s, 1H), 7.56 (s, 1H), 5.53 (q, J = 6.0 Hz, 1H), 3.41 (dq, J = 9.6. 7.0 Hz, 1H), 3.19 (dq,. J = 9.6. 7.0 Hz, 1H), 2.20 (s, 6H), 2.10. 1.60 (d, J = 6.0 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 145.7. 137.75. 135.9. 125.48. 114.94. 108.69. 86.84. 63.57. 21.84. 15.43. 13.86 ppm. Step 2. 3,5-Dimethyl-1H,1'H[4,4']bipyrazolyl hydrochloride (HC1 of compound 2x) HNAx. / AnH-HCI i 7-----2 । NV ysN A 100 L glass reactor was purged with nitrogen and charged with 1'-(1-ethoxyethyl)-3,5-dimethyl-1H, 1'H[4,4']bipyrazolyl (5723 g, based on theoretical yield), 2-propanol (IPA, 13.0 L), and concentrated hydrochloric acid (HCl, 4.08 L) at room temperature. The resulting reaction mixture was heated to approximately 60–65 °C and stirred at 60–65 °C for approximately 2 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature for approximately 1 hour. The solids were collected by filtration, and the filter cake was washed with 2-propanol (6.5 L). The product was air-dried to obtain the desired product, 3,5-dimethyl-1H,1'H-[4,4']bipyrazolyl hydrochloride (3088 g, 63.6% for two steps), in the form of white solids. 1H NMR (400 MHz, DMSO-de) δ 7.94 (s, 2H) , 2.38 (s, 6H) ppm; 13c NMR (101 MHz, DMSO-d6) δ L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 141.95. 132.75. 111.78. 109.70. 10.97 ppm. Step 3. 3,5-dimethyl-1H,1 Ή- [ 4,4 ' ]bipyrazolyl (compound 2x) A 100 L glass reactor was purged with nitrogen and charged with 3,5-dimethyl-1H,1'H[4,4']bipyrazolyl hydrochloride (3010 g) and potable water (24.1 L), and the reaction mixture was cooled to 0–5 °C. Separately, an aqueous NaOH solution was prepared by thoroughly mixing NaOH (1212 g) and potable water (6.0 L). The aqueous NaOH solution was added to the reaction mixture while maintaining the temperature at approximately 15 °C. The reaction mixture was heated to approximately 18 °C and stirred at approximately 18 °C for approximately 14 hours. The solids were collected by filtration, and the filter cake was sequentially washed with potable water (30.1 L) and n-heptane (13.5 L). The product was air-dried for approximately 16 hours and then vacuum-dried at approximately 50–60 °C, yielding 3,5-dimethyl-1H, 1'H-[4,4']bipyrazoly (2006 g, 81.6%) as a whitish powder. RMNXH (400 MHz, DMSO-dg) δ 7.65 (s, 2H) , 2.19 (s, 6H) ppm; RMN13C (101 MHz, DMSO-d6) δ 140.76. 131.92. 113.44. 109.16. 12.37 ppm. L77C ίΠ / ΖηΖ / Ε / ΙΛΙ Intermediate 2. (S)-4-(3-(cyanomethylene)azetidine-l-yl)2,5-difluoro-N-(1,1,l-trifluoropropane-2-yl)benzamide (compound lx) Reaction Scheme 2 A E. NaOH ac. ' id-:·,1 ________________1 -é Ó F , HN is IRc\ / in and i. X—NH 1—d Vn 0; F 1b Iodobenzene diacetate Time .'-BuCK F,C F. EtOuPiOjCFtCN X— NH ):—CN - j;—n .= / oλy i Step 1. (S)-2,4,5-trifluoro-N-(1,1,l-trifluoropropane-211)benzamide (the compound F A mixture of (2S)-1,1,1-trifluoropropan-2-amine (520.96 g, 4.61 mol) in toluene (9.7 L) was cooled to 0–5 °C before being added to a 1.0 M sodium hydroxide solution. Aqueous solution (6.92 L, 6.92 mol, 1.5 equivalents) was added at 0–8 °C. Then, 2,4,5-trifluorobenzoyl chloride (995.62 g, 5.07 mol, 1.1 equivalents) was added dropwise to the mixture at 0 °C. The reaction mixture was heated to -15 °C for 20 min. The cooling bath was removed, and the reaction mixture was warmed to room temperature and stirred for 1 h. The two phases of the reaction mixture were then separated. The organic phase was washed with 0.5 M aqueous sodium hydroxide solution (4.61) and concentrated under reduced pressure, yielding the crude product as a white solid. The solid was then suspended in n-heptane (2.31) at 50 °C for 1 h and subsequently cooled to room temperature. The solids were collected by filtration, washed with n-heptane (11), and vacuum dried for 2 days, yielding (5)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (1203.7 g, 93.2%) as a white powder. RMNXH (300 MHz, DMSO-dg) δ 9.00 (d, J = 8.09 Hz, 1H), 7.69 (m, 2H), 4.75 (m, 1H), 1.92 (d, J = 7.00 Hz, 3H) ppm. Step 2. (S)-2,5-difluoro-4-(3-hydroxyazetidin-l-yl)-N(1,1,1-trifluoropropan-2-yl)benzamide (compound Ib) F3CF\ F L77C ΙΠ / ΖΖηΖ / Ε / ΥΙΙΛΙ To a mixture of (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound I, 1807.5 g, 6.67 mol) and azetidin-3-ol hydrochloride (827.9 g, 7.56 mol, 1.13 equiv) in acetonitrile (3.6 I) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2335.2 g, 15.33 mol, 2.3 equiv) was added in portions. The exothermic reaction raised the internal temperature from 12 °C to 58 °C when the first 1000 g of DBU were charged for 25 minutes. The remaining DBU was added at 58–68 °C for 20 minutes, and the resulting reaction mixture was stirred at 58–68 °C for 1 h. The reaction mixture was then cooled to room temperature and treated with a 1.0 M aqueous hydrochloric acid solution (4.34 1). The mixture was stirred at room temperature for 15 minutes, and water was added (6 1). The resulting mixture was stirred for 1 h at room temperature.The solids are collected by filtration, washed with water (2 1) and dried in the vacuum for 4 days to obtain (S)2,5-difluoro-4-(3-hidroxiazetidin-l-yl)-N-(1,1,1trifluoropropan-2-yl)benzamida (2009.8 g, 93.0 %) in the form of white powder.1H-RMN (300 MHz, DMSO-dg) δ 8.38 (d, J = 8.71 Hz, 1H), 7.26 (dd, J = 12.91 Hz, 1H), 6.38 (dd, J = 12.29 Hz, 1H), 5.70 (d, J = 6.38. 1H) , 4.75 (m, 1H) , 4.56 (m, 1H) , 4.22 (m, 2H), 3.71 (m, 2H) , 1.28 (d, J = 7.16. 3H) ppm. Step 3. (S)-2.5-difluoro-4-(3-oxoazetidin-l-yl)-N(1.1.l-trifluoropropan-2-yl)benzamida (compound 1c) FsC F L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ F A solution of 2,5-difluoro-4-(3-hidroxiazetidin-1-yl)N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamida (compound Ib, 100 1672.6 g, 5.16 mol) and iodobenzene diacetate (1923.5 g, 5.98 mol, 1.16 equivalents) in methylene chloride (8.5 L) was added to the free radical 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO, 20.9 g, 0.13 mol, 0.025 equivalents) at 10–12 °C. The resulting reaction mixture was stirred at 10–12 °C, reaching an internal temperature of 36–38 °C within 30–60 minutes. An IPA cooling bath and dry ice were used to control the reaction temperature. Once the temperature of the internal mixture was reduced below 25 °C, the reaction mixture was heated to 35–38 °C and stirred at 35–38 °C for a further 2–3 hours. Afterward, the reaction mixture was cooled to room temperature and inactivated with an aqueous solution (8.0 L) of sodium thiosulfate (82.9 g, 0.52 mol) and potassium phosphate (950.0 g, 4.5 mol). Two phases separated, and the organic phase was washed with water (2 x 4 L).The organic solution was then concentrated under reduced pressure, yielding the desired crude product in solid form. The solid was suspended in n-heptane (10 1) at room temperature for 30 minutes. The solids were collected by filtration, washed with n-heptane (2 x 21) and vacuum dried overnight, yielding (S)2,5-difluoro-4-(3-oxoazetidin-l-yl)-N-(1,1,1-trifluoropropan2-yl)benzamide (1552.1 g, 93.4%) as a brown powder.XHRMN (300 MHz, DMSO-d6) δ 8.50 (d, J = 8.72 Hz, 1H), 7.35 (dd, J = 12.6 Hz, 1H) , 6.62 (dd, J = 12.1 Hz, 1H) , 4.81 (s, 4H) ,. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 101 4.56 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H) ppm. Step 4. (S)-4-(3-(cyanomethylene)azetidin-l-yl)-2,5difluoro-N-(1,1,l-trifluoropropan-2-ll)benzamide (compound lx) Diethyl cyanomethylphosphonate (422.6 g, 2.39 mol, 0.98 equiv) was added to a 1.0 M potassium tert-butoxide solution in THF (1996.6 g, 2.27 mol, 0.94 equiv) and nitrogen, for 10 min at 5 °C-25 °C. The resulting mixture was then heated to room temperature and stirred for 1 h to generate a clear solution (Solution A). In nitrogen, [2,5-difluoro-4-(3-oxoazetidin-l-yl)-N-[(1S)2,2,2-trifluoro-l-methylethyl]benzamide (compound l, 784.2 g, 2.43 mol) was added to a mixture of ethanol (EtOH, 0.75 L) and tetrahydrofuran (THF, 2.9 L) to form a solution (Solution B). The resulting Solution B was then cooled to -5 °C in an IPA bath on dry ice, and Solution A was added to Solution B for 30 minutes at -5 °C to 5 °C. The resulting mixture was stirred at 0 °C to 5 °C for 60 minutes. The reaction mixture was then inactivated by the addition of water (9.4 L) for 10 minutes.The resulting mixture was stirred for 60 minutes at room temperature. The solids were then collected by filtration and washed with water (2 1) and n-heptane (2.4 1), yielding a brown powder. The brown solids were suspended in pter-butyl methyl ether (MTBE, 4 1) overnight. 102 ambient temperature. The solids were collected by filtration, washed with MTBE (1 1) and vacuum dried for 3 days, yielding (S)-4-(3-(cyanomethylene)azetidin1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (671.1 g, 94%) as a whitish powder.1H-NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 9.95 Hz, 1H) , 7.31 (dd, J = 12.4 Hz, 1H) , 6.58 (dd, J = 12.0 Hz, 1H), 5.88 (m, 1H) , 4.86 - 4.75 (m, 5H), 1.31 (d, J = 7.0 Hz, 3H) ppm. Intermediate 3. 3-(cyanomethylene)azetidine-l-carboxylate of tere-butyl (ly compound) Reaction scheme 3 L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ or F< CN o' । --- MiO / decolorizer—0 / ü·, ' ► Λ N =O ~cj ΒυΟΚ / ΓΗΓ Ω ' CN iy Step 1. l-Benzhydrilazetidin-3-ol *hci hydrochloride A solution of diphenylmethanamine (2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 1) was treated with 2 103 (chloromethyl)oxirane (1330 g, 14.5 mol) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 days and then heated under reflux for a further 3 days. The reaction mixture was then cooled to room temperature and then to 0–5°C in an ice bath. The solids were collected by filtration and washed with acetone (4, 1), yielding the first harvest of the desired crude product (1516 g). The filtrate was concentrated under reduced pressure, and the resulting semi-solid was diluted with acetone (1, 1). This solid was then collected by filtration, yielding the second harvest of the desired crude product (221 g). The crude product, l-benzhydrylazetidin-3-ol hydrochloride (1737 g, 43.4% yield), was used in the subsequent reaction without further purification. NMRΧΗ (300 MHz, DMSOd6) δ 12.28 (br. d, 1H) , 7.7 (m, 5H) , 7.49 (m, 5H) , 6.38 (d, 1H) , 4.72 (br. s, 1H) , 4.46 (m, 1H) , 4.12 (m, 2H), 3.85 (m, 2H) ppm; CigHigCINO (MW 275.77; CigHivNO for the free base, MW, 239.31), LCMS (El) m / e 240 (M++ H) . Step 2. tere-butyl 3-hydroxyazetidine-l-carboxylate L77C ίΠ / ΖηΖ / Ε / ΥΙΛΙ A suspension of l-benzhydrilazetidin-3ol hydrochloride (625 g, 2.27 moles) in a 10 % solution of sodium carbonate (Na2COa. 5 1) and dichloromethane (CH2CI2. 5 1) was stirred a The mixture was heated at room temperature until all solids dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2). The combined organic extracts were dried in sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude 1-benzhydrylazetidin-3-ol free base was then dissolved in THF (6 1), and the solution was placed in a large Parr pump. Di-tere-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20% palladium (Pd) on carbon (125 g, 50% wet) were added to the Parr pump. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred in a constant hydrogen atmosphere (the vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. The reaction mixture was filtered through a layer of Celite and the Celite layer was washed with THF (4 1).The filtrates were concentrated under reduced pressure to remove the solvent, and the residue was loaded onto a Biotage 150 column with a minimal amount of dichloromethane (CH2C12). The column was eluted with 20–50% ethyl acetate in n-heptane, and the fractions containing the desired pure product, tere-butyl 3-hydroxyazetidine-L-carboxylate, were collected and combined. The solvents were removed under reduced pressure, yielding tere-butyl 3-hydroxyazetidine-L-carboxylate (357 g, 90.8% yield) as a colorless oil, which solidified upon standing at room temperature under vacuum. 1H NMR (300 MHz, 90.8% yield). 105 CDC13), δ 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm. Step 3. ptero-butyl 3-oxoazetidine-l-carboxylate L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ A solution of pter-butyl 3-hydroxyazetidine-l-carboxylate (50 g, 289 mmol) in ethyl acetate (400 ml) was cooled to 0 °C. The resulting solution was then treated with solid TEMPO (0.5 g, 3.2 mmol, 0.011 equiv) and a solution of potassium bromide (KBr, 3.9 g, 33.2 mmol, 0.115 equiv) in water (60 ml) at 0 °C–5 °C. Maintaining the reaction temperature between 0 °C and 5 °C, a saturated aqueous solution of sodium bicarbonate (NaHCO3, 450 ml) and an aqueous solution of sodium hypochlorite (NaClO, 10–13% available chlorine, 450 ml) were added. When additional sodium hypochlorite solution was added, the color of the reaction mixture gradually faded. Once the starting material was consumed, the color of the reaction mixture remained unchanged. The reaction mixture was then diluted with ethyl acetate (EtOAc, 500 mL), and two layers separated.The organic layer was washed with water (500 ml) and saturated aqueous sodium chloride solution (500 ml) and dried in sodium sulfate (Na2SO4). The solvent was then removed under reduced pressure, yielding the crude product, 3-oxoazetidine-l-carboxylate. 106 of tere-butyl (48 g, 49.47 g theoretical, 97% yield), which was used directly in the next step without further purification. NMR (CDC13. 300 MHz) δ 4.65 (s, 4H), 1.42 (s, 9H) ppm. Step 4. 3-(cyanomethylene)azetidine-l-carboxylate of ptero-butyl Diethylcyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) were added to a four-necked flask at room temperature. The solution was cooled to -14 °C using an ice-methanol bath, and a 1.0 M solution of potassium tert-butoxide (t-BuOK) was added to anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) over 20 min, maintaining the reaction temperature below -5 °C. The resulting reaction mixture was stirred for 3 hours at -10 °C, and a solution of 1-tert-butoxycarbonyl-3-azetidinone (600 g, 3.50 mol) was added to anhydrous tetrahydrofuran (THF, 2 L) over 2 h, maintaining the internal temperature below -5 °C. The reaction mixture was stirred from -5 °C to -10 °C for 1 h then slowly heated to room temperature and stirred at room temperature overnight. Next, the reaction mixture was diluted with water (4.5 1) and saturated aqueous solution of sodium chloride (NaCl, 4.51) and was extracted with ethyl acetate (EtOAc, 2 x 9 1). The combined organic layers were washed with brine (61) and dried in sulfate. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 107 of anhydrous sodium (Na2SO4). The solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2. 4 1) before being absorbed onto silica gel (SiO2. 1.5 kg). The crude product, which was absorbed onto silica gel, was purified by ultrafast column chromatography (SiO2. 3.5 kg, EtOAc at 0% - 25% and n-hexane elution gradient) yielding 3-(cyanomethylene)azetidine-l-carboxylate terebutyl (414.7 g, 61% yield) as white solids. NMRΧΗ (300MHz, CDC13) δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; CioH14N202 (MW, 194.23), LCMS (El) m / e 217 (M++ Na). Intermediate 4. Alternative synthesis of (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound la) L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Reaction scheme 4. F SCSI· FH0, ,1 2, (Jlt |)Mf E!. j / W; -------* i—1 — f íix-=< ebb π 1=, / F ' f Step 1. 2,4,5-Trifluorobenzoyl chloride F 108 A 100 L reactor was charged with SOCl₂ (34.9 kg), DMF (0.34 L), and 2,4,5-trifluorobenzoic acid (32.3 kg). The batch was heated to 80 °C and stirred at 80–90 °C for 9 hours. It was then cooled to 50–60 °C and vacuum distilled at 60 °C until distillation stopped. 14 kg of toluene were charged into the reactor, and the batch was continuously distilled at 60 °C, yielding the crude product, 2,4,5-trifluorobenzoyl chloride (46.28 kg, 88% by HPLC), which was used directly in the following reaction. Step 2. (S)-2.4.5~trifluoro-N-(lll-trifluoropropan-2yl)benzamide (compound la) An aqueous solution (158 L) containing (S)-1,1,1-trifluoropropan-2-amine hydrochloride (35 kg) was loaded into a 1000 L reactor, and toluene (198 kg) was added to the reactor, followed by the addition of K₂CO₃ (82 kg) in portions. 2,4,5-Trifluorobenzoyl chloride (36.1 kg) was dissolved in toluene (40 kg), and the toluene solution was loaded into the reactor with the toluene solution of the amine intermediate. The resulting mixture was stirred at 20°C for 2 hours. The batch was filtered, and the filter cake was washed with toluene (117 kg). The filtrate and washings were loaded into a 1000 L reactor, and a 1N aqueous NaOH solution (125 kg) was added to the reactor. The mixture was stirred for 2 hours and allowed to separate. The aqueous phase was discarded, and the organic phase was washed twice with water (135 kg) and stored in a container. 109 clean (solution 1). A separate portion (portion 2) was treated in the same way, yielding solution 2. Solution 1 and solution 2 were loaded into a 1000 L reactor, and 104 kg of Na₂SO₄ was added. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with 90 kg of toluene. The filtrate and washings were loaded into a 500 L reactor, and the batch was vacuum distilled at 50 °C. Toluene (14 kg) and heptane (166 kg) were then loaded into the 500 L reactor, and the batch was stirred at 80 °C until a solution was obtained. The solution was cooled to 25 °C and stirred for 2 hours. The product was isolated by vacuum filtration and the filter cake was washed with n-heptane (40 kg). The filter cake was vacuum dried at <50 °C, yielding the crude product, (S)-2,4,5-trifluoroN-(1,1,1-trifluoropropan-2-yl)benzamide (87.0 kg; 79.0 wt. by LOD, net weight: 68.7 kg; 68%; 69.4% by HPLC; 97.1 ee % by HPLC quinal), which was further purified from a mixture of IPA and n-heptane according to the following procedures. In a 500 L reactor, IPA (30.5 kg), heptane (213 kg), and crude (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (70 kg) were charged. The mixture was heated to 85 °C and stirred to form a clear solution. The batch was cooled to 20 °C and stirred for 12 hours. The batch was filtered, and the filter cake was washed with n-heptane (48 kg) and vacuum dried at 50 °C, yielding the purified product, (S)-2,4,5 L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 110 trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (37.5 kg, 54%; HPLC Purity: 98.8%; 99.7 ee% by chiral HPLC). !H NMR (300 MHz, CDC13) δ 7.96 (m, 1H), 7.01 (m, 1H), 6.71 (m, 1H), 4.93 (m, 1H), 1.44 (d, J= 8.00 Hz, 3H) ppm. Example 1. Synthesis of phosphoric acid salt of 4[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1Ή-4,4'-bipyrazol-1yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (phosphoric acid salt of compound 1) Reaction scheme 5. F-.C F. S—NH >—x CN 3—X —N —zO F 1x L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ F X N- <, X—1 Me NN '1—3 HN / < XF;'CI , DMF Step 1 F. >—··, or N 4 ¿—X Me hn / F '-CI • H3PÜ4 HN'__ \HN< / Ñ 2x NC- > h,po4 -----► NN IPA / / \ Step 2 | HÑ-Ñ F. Phosphoric acid salt of crude compound 1 recrystallization MeOH4PA''n-heptane Step 3 HN-N Free base of compound 1 NXX—Me \ N 1—% HN / < yf “Xi, •h-po4 HN N Phosphoric acid salt of compound 1 Step 1. 4-[3-(cyanomethyl)-3-(35′-dimethyl-lH, 1 Ή-4,4′ 111 bipyrazole-1-yl)azetidine-l-yl]-2,5-difluoro-N-[(1S)-2,2,2trifluoro-l-methylethyl]benzamide (free base of compound 1 L77C ίΠ / ΖηΖ / Ε / ΙΛΙ HN-N 3,5-Dimethyl-1H,1-[4,4']bipyrazolyl hydrochloride (HCl of compound 2x, 2002 g, 12.34 mol, 1.1 equiv), DMF (3.9 L) and DBU (0.201 L, 204.6 g, 1.34 mol, 0.12 equiv) were loaded into a 50 L reactor and the reaction mixture was heated to 50–60 °C and stirred for approximately 30 minutes. Separately, a solution was prepared by thoroughly mixing (5)-4-(3(cyanomethylene)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (compound lx, 3872 g, 11.21 mol) and DMF (11.6 L). Next, the solution of compound lx in DMF was added to the reaction mixture while maintaining the temperature at approximately 61 °C. The resulting reaction mixture was stirred at approximately 60 °C for approximately 3.5 hours. The reaction mixture was then cooled to room temperature, and water (77.4 L) was added to the reactor. The cooled reaction mixture was added to the water while maintaining the temperature at approximately 21 °C.The resulting mixture was stirred at room temperature for approximately 1.5 hours. The solids were collected by filtration and the filter cake was washed with water. 112 potable (38.7 1). The wet cake was air dried to obtain 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (free base of compound 1. 5849 g). A chromatography column was sequentially loaded with ethyl acetate (9.9 1), CH2CI2 (22.4 1) and silica gel (8000 g), mixed well and eluted to the surface of the silica gel. The crude freebase of compound 1 (1006 g), silica gel (4000 g), and CH2Cl2 (8.0 1) were loaded into a first rotary evaporator and spun at approximately 22 °C for approximately 45 minutes without solvent collection. The crude freebase of compound 1 (1008 g), silica gel (4002 g), and CH2Cl2 (8.0 1) were loaded into a second rotary evaporator and spun at approximately 23 °C for approximately 45 minutes without solvent collection. Both mixtures were then concentrated at approximately 34 °C under reduced pressure, and the residues were loaded into the column. Sea sand (5010 g) was loaded into the column. The column was sequentially eluted with the collected eluent (16 1), 30% (v / v) EtOAc-CH2Cl2 (prepared separately from 31.2 1 of EtOAc and 72.8% (v / v) MeOH-CH2Cl2 (prepared separately from 2.5% MeOH and 47.5% CH2Cl2), and 8% (v / v) MeOH-CH2C12 (prepared separately from 4.8% MeOH and 55.2% CH2C12). The combined fractions were concentrated under reduced pressure at approximately 45°C. 113 obtaining the free base of pure compound 1 (1824 g) . Four batches of the purification column were performed obtaining 5181 g of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl1H,1'H-4,4'-bipyrazol-1-yl)azetidin-l-yl]-2,5-difluoro-N[(1S)-2,2,2-trifluoro-l-methylethyl]benzamide pure (1% duty-free basis; yield 91%). RMN1H (400 MHz, DMSOd6) δ 12.22 (s, 1H) , 8.50 (d, J = 8.7 Hz, 1H) , 8.13 (s, 1H) , 7.72 (s, 1H) , 7.36 (dd, J = 15.3 Hz, 1Hz). 6.62 (dd, J = 11.9. 7.3 Hz, 1H) , 4.78 (m, 1H), 4.64 (d, J = 8.9 Hz, 2H) , 4.40 (d, J = 9.1 Hz, 2H) , 3.66 (s, 2H) , 2.23 Hz, 2H). 1.31 (d, J = 7.0 Hz, 3H) ppm; NMR «C (101 MHz, DMSO-d6) δ 162.8. 156.7 (d, J = 246.6 Hz), 146.9 (d, J = 236.9 Hz), 141.6 (t, J = 12.3 Hz), 135.5. 125.8 (q, J = 281.9 Hz), 117.2. 116.4 (d, J = 26.4 Hz), 111.3 (dd, J = 15.7. 5.8 Hz), 102.0 (d, J = 29.1 Hz), 62.4. 57.7. 45.8 (q, J = 30.8 Hz), 27.0. 13.3. 13.3. 10.4 ppm;19F NMR (282 MHz, DMSO-d6) δ -76.17 (d, J = 7.4 Hz), −116.89 (s), −139.71 (s) ppm. Step 2. Phosphoric acid salt of 4-[3- (cyanomethyl)-3(3 ', 5 '-dimethyl-lH, 1 Ή-4,4 '-bipyrazol-l-yl) azetidin-l-yl ] -2, 5difluoro-N-[(1bethyl-salt-trimethyl,2,2 phosphoric acid of compound 1 in gross) HN-N L77C ίΠ / ΖηΖ / Ε / ΙΛΙ 114 A clear solution of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoroN-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (compound free base 1, 405.0 g, 798.1 mmol) in methanol (MeOH, 520.0 mL) and 2-propanol (IPA, 2550.0 mL) at 50 °C was combined with phosphoric acid solution (85 wt% aqueous, 119.65 g, 1037.8 mmol, 1.3 equivalents) in isopropyl alcohol (IPA, 120.0 mL) for 18 minutes. The resulting suspension was stirred at 50 °C for 1 h. n-heptane (4050.0 ml) was added for 40 min while maintaining the internal temperature between 46 °C and 53 °C. After the addition of n-heptane, the suspension was cooled to room temperature and stirred for 19 h.The solids were collected by filtration, washed with a mixture of 2-propanol / n-heptane (3 to 10 per volume, 2 x 700 ml) followed by n-heptane (3 x 550 ml) and vacuum dried at room temperature to produce phosphoric acid salt of crude 4-[3-(cyanomethyl)-3(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl1]benzamide (phosphoric acid salt of crude compound 1, 434.6 g, 89.9% yield). Step 3. Phosphoric acid salt of 4-[3-(cyanomethyl)-3(3',5'-dimethyl-1H,1Ή-4,4'-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (phosphoric acid salt of compound 1, purified) 4-[3-(cyanomethyl) phosphoric acid salts were loaded 115 3-(3' , 5'-dimethyl-lH,1Ή-4 ,4'-bipyrazol-l-yl)azetidin-l-yl]2,5-difluoro-N-[(13)-2,2,2-trifluoro-l-methylethyl]benzamide (phosphoric acid salt of crude compound 1, 958.3 g, 1583 mmol) and methanol (MeOH, 9583.0 ml) in a 22 1 flask at room temperature. The resulting suspension was heated to 50 °C, yielding a clear, light orange solution. The solution was filtered thoroughly, transferred to a 22 L flask, and heated to remove the methanol for 70 min. Then, 2-Propanol (IPA, 7700 mL) was added to the flask over 30 min while maintaining the internal temperature between 50 °C and 65 °C. Next, n-Heptane (14400 mL) was added in portions while maintaining the distillation of the solvent mixture (MeOH, IPA, and n-heptane) for 2.5 h. A total of 10818 g (15000 mL) of the solvent mixture was distilled. The resulting suspension was cooled to room temperature and stirred for 17 h.The solids were collected by filtration, washed with a mixture of 2-propanol (IPA) and n-heptane (1 to 5 by volume, 3000 ml) followed by n-heptane (3 x 4000 ml) and dried under vacuum at room temperature, yielding phosphoric acid salt of 4—[3—(cyanomethyl)-3-(3',5'-dimethyl-1H,1Ή-4,4'-bipyrazol-lyl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (phosphoric acid salt of compound 1, 925.7 g, 96.6% yield) as a whitish crystalline powder. NMR (400 MHz, DMSO-dg) δ 9.35 (br. S, 4H) , 8.50. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 116 (d, J= 8.9 Hz, 1H) , 8.11 (s, 1H) , 7.70 (s, 1H) , 7.34 (dd, J = 12.5. 6.4 Hz, 1H), 6.61 (dd, J= 12.9 Hz, 4. 8.4). (m, 1H) , 4.61 (d, J = 8.9 Hz, 2H) , 4.38 (d, J= 8.9 Hz, 2H) , 3.64 (s, 2H), 2.21 (s, 6H), 1.30 (d, J = 3.1 Hz, pp, 2H). RMN13C (100 MHz, DMSO-d6) δ 162.8. 156.7 (d, JCf = 246.5 Hz), 146.9 (d, JCf = 236.1 Hz), 141.6 (dd, JCF= 13.0. 11.7 Hz), 140.3. 138.3. 125.8 (q, JCF= 281.8 Hz), 125.6. 117.2. 116.4 (dd, JCF= 22.3. 4.6 Hz), 115.1. 111.3 (dd, JCf = 15.7. 5.8 Hz), 107.7. 102.0 (dd, Jcf = 29.5. 4.5 Hz) , 62.3. 57.7. 57.7. 45.8 (q, JCF= 30.5 Hz), 27.0. 13.3 (d, JCF= 1.7 Hz), 11.7 ppm; C23H22F5N7O (MW 507.46), LCMS (El) m / e 508.1 (M++ H). The phosphoric acid salt ratio was measured by NMR at 1.01 phosphoric acid relative to the free base of compound 1. The same crystalline form of the pharmaceutical substance phosphoric acid salt of compound 1 was consistently prepared following the preparation and purification procedures described above. This form was confirmed by differential scanning calorimetry (DSC) as shown in Figure 1, thermogravimetric analysis (TGA) as shown in Figure 2, and powder X-ray diffraction (XRPD) as shown in Figure 3. Example 2. Alternative synthesis of phosphoric acid salt of 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1117 methylethyl]benzamide (phosphoric acid salt of compound 1) Reaction scheme 6. A Hix: M -=7rjDBU CMSC HN-N TMSI.OCM 2. r iEt.: NC ·, 1' NH rj-rí Htj-ri i rjHiicx);. Russian HCh'IPA MONKEY· Ά;ΟΗ.·:Ρ*· methylcyclohexane • H^POj Crude phosphoric acid salt recrystallization MeCH; PA F HC- ·, )- o >' Ni i -4 , Nn -l(·. / lJ' F CF. HÑ-Ñ Phosphoric acid salt of compound 1 Step 1. 3-(cyanomethyl)-3-(3', 5'-dimethyl-lH, 1 Ή-[4,4'bipyrazole]-1-11)azetidine-l-carboxylate of tere-butyl Anhydrous dimethyl sulfoxide (DMSO; 57.0 L) was loaded into a 250 L glass-lined dry reactor, which was heated to 32°C. Once the solvent was at temperature, 3-(cyanomethylene)azetidine-1 was loaded into the reaction vessel. 118 tere-butyl carboxylate (compound ly, 22.8 kg, 117.4 mol, 1.0 equiv), followed by 3,5-dimethyl-4,4'-bipyrazole (compound 2x, 20.0 kg, 123.3 mol, 1.05 equiv). The reaction mixture was cooled to 24 °C, DBU (4.4 1, 29.56 mol, 0.25 equiv) was loaded into the reaction vessel, and the resulting solution was stirred for at least 2 hours. The reaction mixture was then diluted with methylene chloride (116 1) and loaded into an aqueous solution of 10% citric acid and 10% NaCl (97 1). The lower organic layer was separated from the two-phase mixture, and the aqueous layer was extracted with methylene chloride (58 1). The combined organic layers were then washed twice with an aqueous solution of 10% citric acid and 10% NaCl (97 1). As part of the second wash, additional methylene chloride (DCM) was added to the organic layer (58 1).After washing, isopropyl acetate (465 1) was added to the reaction mixture while distillation was carried out at constant volume. White solids formed during the distillation. The resulting suspension was cooled to 20°C, stirred for at least 4 hours, filtered, and dried, yielding the desired product, tert-butyl 3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-[4,4'-bipyrazol]-1yl)azetidine-1-carboxylate (30.4 kg, 79%), as a white solid. NMR (400 MHz, DMSO-de) δ 12.19 (s, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 4.41 (d, J = 9.4 Hz, 2H), 4.18 (d, J = 9.3 Hz, 2H), 3.55 (s, 2H), 2.23 (d, J = 19.5Hz, 6H),. 119 1.41 (s, 9H) ppm; Ci8H24N6O2. (MW 356.42), LCMS (El) m / e 357.4 (M++H) . Step 2. 2-(3-(3',5'-Dimethyl-1H,1Ή-[4,4'-bipyrazol]-1yl)azetidin-3-yl)a ce ton ytrile L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ A 450 L glass-lined reactor was charged with methylene chloride (300 L) and 3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H[4,4'-bipyrazol]-1-yl)azetidine-1-tere-butyl carboxylate (30.0 kg, 84.17 mol, 1.000 equiv). TMSI (14.4 L, 101.45 mol, 1.205 equiv) was added, and the resulting solution was stirred for at least 2 hours at 25 °C. Methanol (4.3 L, 106.12 mol, 1.261 equiv) was then charged into the reactor, and the reaction mixture was stirred for a further 30 minutes. The reaction mixture was then heated to remove the methylene chloride (150 L) by Distillation. Once the distillation was complete, isopropyl acetate (IPAc, 150 1) was charged into the vessel at 25 °C and the reaction mixture was stirred for 1 hour. The resulting suspension was filtered and washed with IPAc to produce a crude mixture of 2-(3-(3',5'-dimethyl-1H,1'H-[4,4'-bipyrazole]-1-yl)azetidin-3-yl)acetonitrile and the hydroiodic acid salt 2-(3-(3',5'-dimethyl-1H,1'H-[4,4'-bipyrazole] 120 1-yl)azetidin-3-yl)acetonitrile in the form of yellow solids (68 kg) . The crude solids were then transferred to a 450 L glass-lined reactor charged with methylene chloride (360 L). Triethylamine (14 L, 100.80 mol, 1.198 equiv.) was charged into the reactor for 30 min and the resulting mixture was stirred at 25 °C for 12 h. The resulting suspension was filtered, washed once with methylene chloride and three times with IPAc, filtered again and dried, yielding the desired product, 2-(3-(3',5'-dimethyl-1H,1Ή-[4,4'-bipyrazol]-1-yl)azetidin-3-yl)acetonitrile (16.8 kg, 78%) ), as a white solid. iH NMR (600 MHz, DMSO-d6) δ 10.16 (q, J = 7.0 Hz, 1H), 9.90 (s, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 4.65 - 4.55 (m, 2H), 4.36 - 4.25 (m, 2H) , 3.88 (s, 2H) , 2.41 (s, 6H) ppm; Ci3H16N6. (MW 256.31), LCMS (El) m / e 257.2 (M++ H) . Step 3. Hydrochloric acid salt of (S) -4-(3(cyanomethyl)-3- (3 ',5'-dimethyl-lH,1 'H-[4,4' -bipyrazol]-1 il)azetidine-1-yl)-2,5-difluoride-pro-N-(trifluoro1,1)lpan-l HN-N L77C ίΠ / ΖηΖ / Ε / ΙΛΙ A 250 L glass-lined reactor was charged with 2-(3121 (3',5'-dimethyl-1H,1 Ή-[ 4 ,4'-bipyrazol]-1-yl)azetidin-Sil ) acetonitrile (12 kg, 46.8 mol, 1.00 equiv), (3)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (14.6 kg, 53.8 mol, 1.15 equiv), NaHCO3 (4.1 kg, 49.1 mol, 1.05 equiv), LiCl (4.0 kg, 93.6 mol, 2.00 equiv) and DMSO (96 L, 8 v). The resulting reaction mixture was heated to 85 °C for at least 7 hours and then the resulting solution was cooled to room temperature. The reaction mixture was diluted with isopropyl acetate (147 L, 12 v) and then with water (120 L, 10 v). The aqueous layer was separated, and the remaining organic layer was washed with a 1 wt% aqueous citric acid solution (88 L, 7.3 v) and water (88 L, 7.3 v) before concentrating it to approximately 133 L (11 v). Isopropyl acetate (147 L, 12.25 v) was then added to the mixture while distillation was carried out at constant volume. A solution of HCl in IPA (2) was then added.5 wt% (96 1.8 v) was charged into the reactor and the resulting solution was stirred at room temperature. After 1 hour, methylcyclohexane (220 1.18.1 v) was charged into the suspension and the resulting suspension was stirred at room temperature for a further 4 hours. The resulting suspension was filtered and the wet cake was washed with a mixture of methylcyclohexane and isopropyl acetate (3:1, 60 1.5 v), followed by methylcyclohexane (60 1.5 v). Finally, the wet cake was dried at 50–60 °C under vacuum, yielding the desired crude product, (S)-4-(3-(cyanomethyl)-3-(3',5') hydrochloride. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 122 dimethyl-lH,1 Ή-[4,4'-bipyrazol]-l-yl)azetidin-l-yl)-2,5difluoro-N-(1, 1,1-trifluoropropan-2-yl)benzamide (22.4 kg, 88 %). Step 4. Phosphoric acid salt of (S)-4-(3-(Cyanomethyl)3-(3',5'-dimethyl-lH,1 'H-[4,4'-bipyrazol]-l-yl)azetidin-l-yl)2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ A 450 L glass-lined reactor was charged with isopropyl acetate (286 L, 10% v) and hydrochloric acid salt (S)-4-(3-(cyanomethyl)-3-(3',5'-dimethyl-1H,1'H-[4,4'-bipyrazol]-lyl)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (28.6 kg), followed by KHCO3 (86 L, 10 wt% in water, 3 v). The suspension was stirred until a clear solution was obtained. The aqueous layer was then removed, and the organics were washed with water (86 L (3 v)) and subsequently filtered through charcoal into a second glass-lined reactor. The organic extracts were concentrated to remove 240 L (8.4 v) of solvent at 50 °C under a reduced pressure of 200–400 mbar. Isopropanol (163 L, 5.7 v) was added to the resulting residue at 50 °C and subsequently cooled to room temperature. Then, 14.9 kg (52 wt%) of 48 wt H3PO4 in IPA / water was added to the reactor for at least 2 hours, and the resulting solution was stirred at room temperature. 123 ambient for at least 1 hour. Methylcyclohexane (172 1.6 v) was charged at room temperature and the mixture was stirred for at least 1 hour. The suspension was filtered and the cake was washed with 1:1 IPA / methylcyclohexane (86 1.3 v), followed by methylcyclohexane (86 1.3 v). The wet cake was then dried at 50 °C under vacuum to produce crude phosphoric acid salt (3)-4-(3(cyanomethyl)-3-(3',5'-dimethyl-1H,1Ή-[4,4'-bipyrazol]-1-yl)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (28.0 kg (88%). In a 450 L glass-lined reactor, crude phosphoric acid salt (28.0 kg) and methanol (336 L (12 v)) were charged, and the resulting mixture was heated to 50 °C, yielding a clear solution. The solution was transferred to a separate reactor through a polishing filter. MeOH (28 L, 1 v) was used to rinse the first reactor and then transferred to the second reactor through a polishing filter. The filtrate was then concentrated to 7 v by distilling 196 L (7 v) of solvent at 45 °C under a reduced pressure of 300 mbar–400 mbar. Next, seeds of pure phosphoric acid salt of (S)-4-(3-(cyanomethyl)-3-(3',5'-dimethyl-1H, 1Ή[4,4'-bipyrazol]-1-yl)azetidin-1-yl)-2,5-difluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (28.0 g, 0.1 wt%) were charged into the reactor and the mixture was stirred at 45 °C for at least 15 min. Isoprapanol (196 1, 7 v) was charged and 196 1 (7 v) of solvent was distilled at around 45 °C under pressure L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙThe pressure was reduced from 100 mbar to 200 mbar. Isopropanol (196 1.7 v) was loaded into the reactor and 196 1 (7 v) of solvent was removed by distillation. IPC was performed to confirm that the methanol content was no more than 5% in the mixture. The mixture was then cooled to room temperature and the resulting suspension was filtered. The cake was washed twice with isopropanol (56 1, 2 v) and then dried at 50 °C under reducing pressure, yielding the phosphoric acid salt of (S)-4-(3-(cyanomethyl)-3-(3',5'-dimethyl1H,1'H-[4,4'-bipyrazol]-1-yl)azetidin-1-yl)-2,5-difluoro-N(1,1,1-trifluoropropan-2-yl)benzamide (24.1 kg (86.1%) as a white solid. RMNXH (500 MHz, DMSO-de) δ 8.53 - 8.43 (m, 1H) , 8.12 (d, J = 0.7 Hz, 1H), 7.72 (s, 1H) , 7.36 (dd, J = 12.5. 6.3 Hz, 1H), 6.63 (dd, J= 11.9. 7.2 Hz, 1H), 4.85 - 4.72 (m, J = 7.5 Hz, 1H), 4.64 (d, J = 9.0 Hz, 2H), 4.45 - 4.37 (m, 2H), 3.66 (s, 2H), 2.24 (s, 6H), 1.33 (d, J = 7.1 Hz, 3H) ppm; C23H25F5N7O5P (MW 605.45; C23H22F5N7O: MW 507.47), LCMS (El) m / e 508.2 (M++ H) . Example A. In vitro JAK kinase assay The compounds provided in the present description are tested for JAK target inhibitory activity according to the following in vitro assay described in Park et al., Analytic Biochemistry 1999. 269. 94-104. The catalytic domains of human JAK1 (aa 837-1142), JAK2 (aa 828-1132), and JAK3 (aa 781-1124) with an N-terminus His tag are expressed using baculovirus in cells of L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 125 insect enzymes were purified. The catalytic activity of JAK1, JAK2, or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by time-resolved homogeneous fluorescence (HTRF). The IC50 values ​​of the compounds were measured for each kinase in 40 microL reactions containing the enzyme, ATP, and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg / ml (0.01%) BSA. For IC50 measurements of 1 mM, the ATP concentration in the reactions was 1 mM. The reactions were carried out at room temperature for 1 hour and then stopped with 20 μL of 45 mM EDTA, 300 nM SA-APC, and 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the europium-labeled antibody took place over 40 minutes, and the HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA).The free base of compound 1 had an IC50 of d 300 nM with a JAK2 / JAK1 selectivity of > 10 to ATP 1 mM. Example B. Cell assays Cytokine-dependent cancer cell lines, and therefore those that rely on JAK / STAT signal transduction for growth, can be plateted at 6000 cells per well (96-well plate format) in RPMI 1640. The cells are then plated with 10% FBS and 1 nG / ml of the appropriate cytokine. The compounds described herein are added to the cells in DMSO / media (final DMSO concentration 0.2%) and then... L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ Cells 126 were incubated for 72 hours at 37 °C, 5% CO2. The effect of the compound on cell viability was assessed using the CellTiter-Glo luminescent cell viability assay (Promega) followed by TopCount quantification (Perkin Elmer, Boston, MA). Potential off-target effects of the compounds were measured in parallel using a non-JAK-driven cell line with the same assay readout. Experiments were performed in duplicate. The cell lines described above can also be used to examine the effects of the compounds provided herein on the phosphorylation of JAK kinases or potential upstream substrates such as STAT, Akt, Shp2, or Erk proteins. These experiments can be performed after an overnight cytokine starvation, followed by a brief pre-incubation with the compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. The proteins are then extracted from the cells and analyzed using techniques familiar to those skilled in the art, including immunoblotting or ELISA using antibodies that can differentiate between phosphorylated and total protein. These experiments can use normal or cancer cells to investigate the activity of compounds in humoral cell survival biology or in mediators of inflammatory diseases.For example, regarding the latter, cytokines such as IL-6, IL-12, IL-23 or IFN can be used. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 127 to stimulate JAK activation, resulting in phosphorylation of STAT protein(s) and potentially in transcriptional profiles (assessed by array or qPCR technology) or production and / or secretion of proteins, such as IL-17. The ability of compounds to inhibit these cytokine-mediated effects can be measured using common techniques for experts in the field. The compounds described herein can also be tested in cell models designed to evaluate their potency and activity against mutant JAKs, such as the JAK2V617F mutation found in myeloid proliferative disorders. These experiments often use cytokine-dependent cells of hematologic lineage (e.g., BaF / 3) in which mutant or wild-type JAK kinases are ectopically expressed (James, C., et al. Nature 434:1144-1148; Staerk, J., et al. JBC 280:41893-41899). Evaluation criteria include the effects of the compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins. The compounds provided in this description can be evaluated to determine their T-lymphocyte proliferation-inhibiting activity. Such an assay can be considered a second cytokine-driven proliferation assay (i.e., JAK) and also a simplified immunosuppression assay. L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 128 Inhibition of immune activation. The following is a brief summary of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human whole blood samples using the Ficoll Hipaque separation method, and T lymphocytes (fraction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T lymphocytes can be maintained in culture medium (RPMI 1640 supplemented with 10% fetal bovine serum, 100 U / ml penicillin, 100 pg / ml streptomycin) at a density of 2 x 10⁶ cells / ml at 37 °C for up to 2 days. For IL-2-stimulated cell proliferation assays, the T lymphocytes are first treated with phytohemagglutinin (PHA) at a final concentration of 10 μg / ml for 72 hours.After washing once with PBS, 6000 cells / wells were placed in 96-well plates and treated with the compounds provided in this description at different concentrations in the culture medium in the presence of 100 U / ml of human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates were incubated at 37 °C for 72 hours and the proliferation index was assessed using CellTiter-Glo luminescent reagents following the manufacturer's suggested protocol (Promega; Madison, WI). L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 129 Example C. In vivo antitumor efficacy The compounds described herein can be evaluated in human tumor xenograft models in immunocompromised mice. For example, a tumorigenic variant of the INA6 plasmacytoma cell line can be used to inoculate SCID mice subcutaneously (Burger, R., et al. Hematol J. 2:42-53. 2001). The tumor-bearing animals can then be randomized into drug- or vehicle-treated groups, and different doses of the compounds described herein can be administered via any number of common routes, including oral, intraperitoneal (IP), or continuous infusion using implantable pumps. Tumor growth is monitored over time using calibrators.Furthermore, tumor samples can be collected at any time after the start of treatment for analysis as described above (Example B) to assess the effects of the compound on JAK activity and upstream signaling pathways. Additionally, the compound's selectivity can be evaluated using xenograft tumor models driven by other known kinases (e.g., Bcr-Abl), such as the K562 tumor model. Example D. Murine skin contact delayed hypersensitivity response test The compounds provided in this description L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ 130 can also be tested for their efficacy (JAK target inhibition) in the murine T-cell-driven delayed-type hypersensitivity assay model. Murine skin contact delayed-type hypersensitivity (DTK) is considered a valid model of clinical contact dermatitis and other T-cell-mediated immune disorders of the skin, such as psoriasis (Iminunol Today. January 1998; 19(1):37-44). Murine DTK shares multiple features with psoriasis, including immune infiltration, concomitant increase in inflammatory cytokines, and keratinocyte hyperproliferation. In addition, many classes of agents that are effective in the treatment of psoriasis in the clinic are also effective inhibitors of the DTH response in mice (Agents Actions. January 1993; 38(1-2):116-21). On days 0 and 1, Balb / c mice are sensitized with the 2,4-dinitrofluorobenzene (DNFB) antigen by topical application to their shaved abdomens. On day 5, ear thickness is measured using an engineer's micrometer. This measurement is recorded and used as a reference. Both ears of the animals are subjected to topical application of DNFB totaling 20 µA (10 µA on the inner pinna and 10 µA on the outer pinna) at a concentration of 0.2%. Twenty-four to seventy-two hours post-exposure, the ears are measured again. Treatment with the The 131 compounds described herein are administered during the sensitization and exposure phases (day -1 to day 7) or before and during the exposure phase (generally the afternoon of day 4 to day 7). The test compound (at varying concentrations) is administered systemically or topically (topical application of the treatment to the ears). The efficacy of the test compound is indicated by a reduction in ear swelling compared to the untreated condition. A test compound that causes a 20% or greater reduction is considered effective. In some experiments, mice are challenged but not sensitized (negative control). The inhibitory effect (inhibiting the activation of the JAK-STAT pathways) of the compounds described herein can be confirmed by immunohistochemical analysis. Activation of the JAK-STAT pathway(s) results in the formation and translocation of functional transcription factors. Furthermore, the influx of immune cells and increased keratinocyte proliferation should also produce unique changes in the expression profile in the ear that can be investigated and quantified. Formalin-fixed, paraffin-embedded ear sections (collected after the challenge phase in the DTK model) are subjected to immunohistochemical analysis using 132 An antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). Mouse ears are treated with the compounds provided herein, vehicle, or dexamethasone (a clinically effective treatment for psoriasis), or without treatment, in the DTH model for comparison. The test compounds and dexamethasone can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and dexamethasone can reduce the number of infiltrating cells. Both systemic and topical administration of the test compounds can produce inhibitory effects, i.e., a reduction in the number of infiltrating cells and inhibition of transcriptional changes. Example E. In vivo anti-inflammatory activity The compounds described herein may be evaluated in rodent or non-rodent models designed to replicate a single or complex inflammatory response. For example, rodent arthritis models may be used to evaluate the therapeutic potential of compounds administered preventively or therapeutically. These models include, but are not limited to, mouse or rat collagen-induced arthritis, rat adjuvant-induced arthritis, and collagen antibody-induced arthritis. Autoimmune diseases, including multiple sclerosis, may also be evaluated. Multiple inflammatory conditions, type I diabetes mellitus, uveoretinitis, thyroiditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds provided in this description. These models are well established in the research community and are familiar to those skilled in the art (Current Protocols in Immunology, vol. 3, Coligan, JE et al., Wiley Press; Methods in Molecular Biology: vol. 225, Inflammatory Protocols, Winyard, PG and Willoughby, DA, Humana Press, 2003). Example F. Animal models for the treatment of dry eye, uveitis, and conjunctivitis The agents may be evaluated in one or more preclinical models of dry eye known to those skilled in the art, including, but not limited to, the rabbit concanavalin A (ConA) lacrimal gland model, the mouse scopolamine (subcutaneous or transdermal) model, the mouse botulinum lacrimal gland model, or any of a number of spontaneous rodent autoimmune models that cause ocular gland dysfunction (e.g., NOD-SCID, MRL / lpr, or NZB / NZW) (Barabino et al., Experimental Eye Research 2004. 79. 613-621 and Schrader et al., Developmental Ophthalmology, Karger 2008. 41. 298-312). Each of which is incorporated herein by this L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ (Reference 134 in its entirety). The assessment criteria in these models may include the histopathology of the ocular glands and the eye (cornea, etc.) and possibly the classic Schirmer test or modified versions thereof (Barabino et al.) that measure tear production. Activity can be assessed by dosing via multiple routes of administration (e.g., systemic or topical) that may begin before or after the onset of measurable disease. Agents can be evaluated in one or more preclinical models of uveitis known to those skilled in the art. These include, but are not limited to, experimental autoimmune uveitis (EAU) and endotoxin-induced uveitis (EIU) models. EAU experiments can be performed in rabbits, rats, or mice and may involve passive or active immunization. For example, any of a series of retinal antigens can be used to sensitize the animals to a relevant immunogen, after which the animals can be periodically exposed to the same antigen. The EIU model is more acute and involves the local or systemic administration of lipopolysaccharide at sublethal doses. Endpoints for the EIU and EAU models may include fundus examination, histopathology, and other assessments. These models are reviewed by Smith et al. (Immunology and Cell Biology 1998; 76:497-512). 135, which is incorporated herein by reference in its entirety. Activity is assessed by dosing via multiple routes of administration (e.g., systemic or topical), which may be initiated before or after the onset of a medial disease. Some of the models listed above may also develop scleritis / episcleritis, chorioditis, cyclitis, or iritis and are therefore useful for investigating the potential activity of the compounds for the therapeutic treatment of these diseases. Agents can also be evaluated in one or more preclinical models of conjunctivitis known to those skilled in the art. These include, but are not limited to, rodent models using guinea pigs, rats, or mice. Guinea pig models include those using active or passive immunization and / or immune-mediated exposure protocols with antigens such as ovalbumin or ragweed (reviewed in Groneberg, DA, et al., Allergy 2003; 58: 1101–1113, which is incorporated herein by reference in its entirety). Rat and mouse models are similar in general design to the guinea pig model (also reviewed by Groneberg). Activity can be assessed by dosing via multiple routes of administration (e.g., systemic or topical), which can be initiated before or after the onset of measurable disease. The endpoints for the studies may 136 include, for example, histological, immunological, biochemical or molecular analyses of ocular tissues such as the conjunctiva. Example G. In vivo bone protection The compounds provided in this description can be evaluated in various preclinical models of osteopenia, osteoporosis, or bone resorption known to experts in the technique. For example, ovariectomized rodents can be used to assess the ability of compounds to affect signs and markers of bone remodeling and / or density (WSS Jee and W. Yao, J Musculoskel. Neuron. Interact., 2001. 1(3), 193-207, whose description is incorporated herein in full by this reference). Alternatively, bone density and architecture can be assessed in control rodents or rodents treated with compounds in therapy-induced (e.g., glucocorticoid) osteopenia models (Yao, et al. Arthritis and Rheumatism, 2008. 58(6), 3485-3497; and id. 58(11), 1674-1686, both incorporated herein in full by this reference).Furthermore, the effects of the compounds provided in this description on bone resorption and density can be evaluated in the previously treated rodent arthritis models (Example E). The assessment criteria for all these models may vary, but often include histological and radiological evaluations as well. 137 such as immunohistology and appropriate biochemical markers of bone remodeling. Example H. S100A9 transgenic mouse model Previously, S100A9 transgenic mice were shown to exhibit an accumulation of multidrug-resistant stem cells (MDSCs) in the bone marrow, accompanied by the development of progressive multilineage cytopenias and cytologic dysplasia similar to MDS. Furthermore, forced early maturation of MDSCs by treatment with total trans-retinoic acid or active disruption of the adaptor protein (DAP12) based on the immunoreceptor tyrosine activation motif (ITAM carrier) of CD33 signaling rescued the hematologic phenotype and mitigated the disease. This system may be useful for testing the effects of JAK1 inhibition in MDS-like diseases in a preclinical model. J. Clin. Invest., 123(11):4595-4611 (2013). Accordingly, a selective JAK1 inhibitor was administered via oral gavage. The compound's ability to reduce the cytopenias and cytologic dysplasia observed in S100A9 transgenic mice was monitored. Several modifications to the description, in addition to those described herein, will be apparent to those skilled in the art from the preceding description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and L77C ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ The 138 publications cited in this application are incorporated herein in their entirety by means of this reference. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

1. A process for preparing HN-N (Free base of compound 1) or a salt thereof, characterized in that it comprises reacting F (Compound 1x) with HN^X / ^NH i \ । N^ / \^N / (Compound 2x) 20 to form the free base of compound 1, or a salt thereof.

2. The process according to claim 1, characterized in that the reaction of compound lx with compound 2x is carried out in the presence of ,8 2 5 diazabicyclo[5.4.0]undec-7-ene (DBU) an organic solvent component 140.

3. The process according to claim 2, characterized in that the organic solvent component comprises dimethylformamide (DMF).

4. The process of any of claims 1 to 3, characterized in that the reaction of compound lx with compound 2x is carried out at a temperature of between approximately 50 °C and approximately 60 °C.

5. The process according to claim 4, characterized in that the temperature is approximately 60 C.

6. The process of any of claims 1 to 5, characterized in that the salt of compound 1 is a phosphoric acid salt of compound 1 prepared by a process comprising reacting the free base of compound 1 with phosphoric acid to form L77C ίΠ / ZZΖηZ / E / YΙΛΙ HN-N (Phosphoric acid salt of compound 1) 7. The process according to claim 6, characterized in that the reaction of the free base of compound 1 with phosphoric acid is carried out in the presence of a solvent component.

8. The process according to claim 7, characterized in that the solvent component comprises methanol, isopropanol or a mixture thereof.

9. The process of any of claims 6 to 8, characterized in that the reaction of the free base of compound 1 with phosphoric acid is carried out at a temperature of between approximately 40 °C and approximately 70 °C.

10. The process according to claim 9, characterized in that the temperature is between approximately 45 °C and approximately 55 °C.

11. The process according to claim 10, characterized in that the temperature is approximately 50 C.

12. The process of any of claims 6 to 11, characterized in that the phosphoric acid is an aqueous solution of approximately 85% by weight of phosphoric acid.

13. The process of any of claims 6 to 12, characterized in that the reaction of the free base of compound 1 with phosphoric acid further comprises adding a second solvent component to the reaction mixture.

14. The process according to claim 13, characterized in that the second solvent component comprises n-heptane. L77C iΠ / ZZΖηZ / E / YILI 142 15. The process of any of claims 1 to 14, characterized in that it further comprises preparing compound 2x by a process comprising reacting HN^. / / NH-HCI I 7-----\ I / (HC1 of compound 2x) with a base.

16. The process according to claim 15, characterized in that the base is NaOH.

17. The process of claims 15 or 16, characterized in that the reaction of HC1 of compound 2x with a base is carried out at a temperature of between approximately 15 °C and approximately 18 °C.

18. The process of any of claims 15 to 17, characterized in that it further comprises preparing the HC1 of compound 2x by a process comprising reacting L77C ίΠ / ZZΖηZ / E / YΥΙΛΙ (Compound 2b) with hydrochloric acid.

19. The process according to claim 18, characterized in that the reaction of compound 2b with hydrochloric acid is carried out in the presence of an organic solvent component. 143 20. The process according to claim 19, characterized in that the organic solvent component comprises 2-propanol.

21. The process of any of claims 18 to 20, characterized in that the reaction of compound 2b with hydrochloric acid is carried out at a temperature between approximately 60 °C and approximately 65 °C. L77C iP / ZZΖηZ / E / YILI 22. The process of any of claims 18 to 21, characterized in that it further comprises preparing compound 2b by a process comprising reacting with 23. The process according to claim 22, characterized in that the reaction of compound 2a with 4-bromo3,5-dimethylpyrazole is carried out in the presence of K2HPO4, a solvent component and a palladium complex.

24. The process according to claim 23, characterized in that the solvent component comprises propanol, water, or a mixture thereof.

25. The process according to claim 23, 144 characterized in that the palladium complex is [l,l'-bis(ditert-butylphosphine)ferrocene]dichloropalladium(II) (Pd-118).

26. The process of any of claims 22 to 25, characterized in that the reaction of compound 2a with 4-bromo-3,5-dimethylpyrazole is carried out at a temperature of approximately 80 °C to approximately 100 °C.

27. The process according to claim 26, L77C iΠ / ZZΖηZ / E / YILI characterized in that the temperature is approximately 90 C.

28. The process of any of claims 1 to 14, characterized in that it further comprises preparing HN \\ ^nh iy—< । NV \^N / (Compound 2x) by a process comprising: reacting compound 2b with hydrochloric acid to form 145 (HC1 of compound 2x); and L77C ίΠ / ZZΖηZ� / E / YΙΛΙ reacting HC1 of compound 2x with a base to form compound 2x.

29. The process of any of claims 1 to 28, characterized in that it further comprises preparing F (Compound lx) wherein compound lx is prepared by a process comprising reacting F (Compound le) with diethyl cyanomethylphosphonate in the presence of a base.

30. The process according to claim 29, characterized in that the reaction of the compound le with diethyl cyanomethylphosphonate in the presence of a base is carried out in an organic solvent component.

31. The process according to claim 30, characterized in that the organic solvent component comprises tetrahydrofuran, ethanol or a mixture thereof.

32. The process of any of claims 29, 146 to 31, characterized in that it further comprises preparing compound le wherein compound le is prepared by a process comprising reacting L77C ίΠ / ZZΖηZ / E / YΙΛΙ F (Compound Ib) with iodobenzene diacetate and 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO).

33. The process according to claim 32, characterized in that it further comprises preparing compound Ib wherein compound Ib is prepared by a process comprising reacting F (Compound la) with OH in the presence of DBU.

34. The process according to claim 33, characterized in that it further comprises preparing compound la wherein compound la is prepared by a process comprising reacting 147 L77C ίΠ / ZZΖηZ / E / YΙΛΙ in the presence of a base.

35. The process of any of claims 1 to 28, characterized in that it further comprises preparing F (Compound lx) by a process comprising: reacting CF3 with F3C f. 5—NH / 1 or a base to form F; reacting compound F3C f 5—NH Yvx . / λ—CN ov DBU to form F F. c| y^ / v—fo F in the presence of (Compound la); OH NHH la with Cl in the presence of 1 (Compound Ib); reacting compound Ib with iodobenzene diacetate and TEMPO to form F (Compound le); and reacting compound le with diethyl cyanomethylphosphonate in the presence of a base to form compound lx.

36. A process for preparing a compound of formula A: HN-N A characterized in that it comprises reacting 3,5-dimethyl-1H,1'H-4,4'-bipyrazole with a compound of formula B: CN B wherein Pg1 is an amine protecting group.

37. The process according to claim 36, characterized in that Pg1 is tert-butoxycarbonyl.

38. The process according to claim 36 or 37, characterized in that the reaction is carried out in the presence 149 of 1,8-diazabicyclo[5.4.0]undec-7-ene.

39. The process according to claim 38, characterized in that less than 1 equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene is used on a basis of 1 equivalent of the compound with formula B.

40. The process according to claim 38, characterized in that approximately 0.2 to approximately 0.3 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene are used on a basis of 1 equivalent of the compound of formula B.

41. The process of any of claims 36 to 40, characterized in that approximately 1.0 to approximately 1.1 equivalents of 3,5-dimethyl-1H,1'H-4,4' bipyrazole are used on a basis of 1 equivalent of the compound with formula B.

42. Any process conforming to claims 36 to 41, characterized in that the reaction is carried out at approximately room temperature.

43. The process according to any of claims 36 to 42, characterized in that the reaction of 3,5-dimethyl-1H,1Ή-4,4'-bipyrazole with the compound of formula B is carried out in the presence of a solvent component.

44. The process according to claim 43, characterized in that the solvent component comprises dimethyl sulfoxide. L77C iP / ZZηZ / E / YILI 150 45. The process according to claim 43, characterized in that the solvent component comprises dimethyl sulfoxide and methylene chloride.

46. ​​The process according to any of claims 36 to 45, characterized in that it further comprises deprotecting the compound of formula A to form a compound of formula C: HN-N L77C ίΠ / ZZΖηZ / E / YΙΛΙ C or a salt thereof.

47. The process according to claim 46, characterized in that the deprotection comprises reacting the compound with formula A in the presence of a trialkylsilyl halide.

48. The process according to claim 47, characterized in that the trialkylsilyl halide is trimethylsilyl iodide.

49. The process of any of claims 47 to 49, characterized in that the deprotection is carried out in the presence of a solvent component.

50. The process according to claim 49, characterized in that the solvent component comprises 151 methylene chloride.

51. The process according to claim 49, characterized in that the solvent component comprises methylene chloride and methanol.

52. The process of any of claims 47 to 51, characterized in that the removal of the protective coating is carried out at approximately room temperature.

53. The process of any of claims 47 to 52, characterized in that it further comprises the reaction of the compound with formula C, or a salt thereof, with an amine base, to form the free base form of the compound with formula C.

54. The process according to claim 53, characterized in that the amine base is triethylamine.

55. The process according to claim 53 or 54, characterized in that the reaction of the compound with formula C, or a salt thereof, with an amine base is carried out in the presence of a solvent component.

56. The process according to claim 55, characterized in that the solvent component comprises methylene chloride.

57. The process according to any of claims 53 to 56, characterized in that it further comprises reacting the free base form of the compound with formula C with the compound la: L77C ίΠ / ZZΖηZ / E / YΙΛΙ 152 L77C ίΠ / ZZΖηZ / E / YΙΛΙ la in the presence of a base and an alkali metal halide to form compound 1: E NC^ „ / =\ 0 / VN L Λ / NN VM; HN—\ F CF3 HN-N or a salt thereof.

58. The process according to claim 57, characterized in that the base is a bicarbonate base.

59. The process according to claim 57, characterized in that the base is sodium bicarbonate.

60. The process according to any of claims 57 to 59, characterized in that the alkali metal halide is lithium chloride.

61. The process according to any of claims 57 to 60, characterized in that the reaction is carried out at a temperature of approximately 80 °C to approximately 90 °C.

62. The process according to any of claims 57 to 61, characterized in that the reaction of the free base form of the compound with formula C with the compound is carried out in the presence of a solvent component.

63. The process according to claim 62, characterized in that the solvent component comprises dimethyl sulfoxide.

64. The process according to claim 62, characterized in that the solvent component comprises dimethyl sulfoxide and isopropyl acetate.

65. The process according to any of claims 57 to 64, characterized in that it further comprises reacting compound 1 with a strong acid to form a salt form of compound 1.

66. The process according to any of claims 57 to 64, characterized in that it further comprises reacting compound 1 with hydrochloric acid to form the hydrochloric acid salt of compound 1: E NC - >—1 „0 L77C ίΠ / ZZΖηZ / E / YΙΛΙ F CF3 Jx - HCI HN-Ñ 67. The process according to claim 66, characterized in that it further comprises reacting the hydrochloric acid salt of compound 1 with a bicarbonate base to form the free base form of compound 1.

68. The process according to claim 67, characterized in that the bicarbonate base is potassium bicarbonate.

69. The process according to claim 67 or 68, characterized in that it further comprises reacting the free base form of compound 1 with phosphoric acid to form the phosphoric acid salt of compound 1: E NC-X or XN < ¿-X » NN A F CF3 •-.;J v- H3PO4 HN-Ñ 70. The process according to claim 69, characterized in that the reaction is carried out at approximately room temperature.

71. The process according to claim 69 or 70, characterized in that the reaction of the free base form of compound 1 with phosphoric acid is carried out in the presence of a solvent component.

72. The process according to claim 71, characterized in that the solvent component comprises water.

73. The process according to claim 71, L77C iΠ / ZZΖηZ / E / YΙΛΙ 155 characterized in that the solvent component comprises water and isopropyl alcohol.

74. The process according to any of claims 69 to 73, characterized in that it further comprises isolating the phosphoric acid salt from compound 1.

75. The process according to claim 74, characterized in that the phosphoric acid salt of compound 1 is isolated by recrystallization. L77C ίΠ / ZZΖηZ / E / YΙΛΙ 76. The process according to claim 74 or 75, characterized in that the phosphoric acid salt of compound 1 is isolated by recrystallization from a mixture of methanol, isopropanol and methylcyclohexane.

77. A process for preparing the phosphoric acid salt of compound 1: HN-N Phosphoric acid salt of compound 1 characterized in that it comprises: reacting 3,5-dimethyl-1H,1Ή-4,4'-bipyrazole with 3-(cyanomethylene)azetidine-1-tere-butyl carboxylate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to form the compound with the formula Al: 156 Al; L77C ίΠ / ZZΖηZ / E / YΙΛΙ deprotect the compound with the formula Al to form the compound with the formula Cl: Cl or a salt thereof; react the compound with the formula Cl with triethylamine to form the free base form of the compound with the formula Cl; react the free base form of the compound with the formula Cl with the compound la: la in the presence of sodium bicarbonate and lithium chloride to form compound 1: 157 HN-N L77C iP / ZZΖηZ / E / YILI react compound 1 with hydrochloric acid to form the hydrochloric acid salt of compound 1: react the hydrochloric acid salt of compound 1 with potassium bicarbonate to form the free base form of compound 1; and react the free base form of compound 1 with phosphoric acid to form the phosphoric acid salt of compound 1.

78. The process according to claim 77, characterized in that it further comprises isolating the phosphoric acid salt from compound 1.

79. The process according to claim 78, characterized in that the phosphoric acid salt of compound 1 is isolated by recrystallization.

80. The process according to claim 78 or 158 79, characterized in that the phosphoric acid salt of compound 1 is isolated by recrystallization from a mixture of methanol, isopropanol and methylcyclohexane.