Intermediate salts for synthesis of a CDK2 inhibitor

Abstract

The present disclosure provides, in part, compounds of formula (A) and formula (D), which are intermediate compounds that can be used to prepare the compound N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4- b]pyrazin-6-amine (compound of formula (I)) and processes for the preparation of the compound of formula (I).

Description

Attorney Docket No.: BPM-6055WOINTERMEDIATE SALTS FOR SYNTHESIS OF A CDK2 INHIBITORBACKGROUND

[0001] This application claims priority to and the benefit of International Application No. PCT / CN2024 / 116385, filed on September 2, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Cyclin-Dependent Kinases (CDKs) are serine / threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs allows for the proper ordering of the steps in cell cycle progression. Activation of CDKs requires heterodimerization with regulatory subunits known as cyclins. Cell cycle deregulation is a common feature of human cancer.

[0003] Cyclin-dependent kinase 2 (CDK2) participates in a range of biological activities. CDK2 is a key cell cycle regulator, active from the late Gi-phase and throughout the S-phase. CDK2 is involved in DNA damage response (DDR) through the homologous recombination (HR) pathway. CDK2 also regulates aspects of apoptotic pathways. Cyclin El (CCNE1), cyclin E2 (CCNE2), cyclin Al (CCNA1), and cyclin A2 (CCNA2), along with p21Cipl / Wafl, p27Kipl and p57Kip2 (the cyclin dependent kinase inhibitors of the cyclin-CDK2 complex) are the main regulators of CDK2 activity. In cancer, dysregulation of the binding of CDK2 by cyclin El, E2, Al, or A2 or the activity of the cyclin-dependent kinase inhibitor proteins may occur. (S. Tadesse et al., Drug Discovery' Today, Volume 25, Number 2 February 2020)

[0004] The dysregulation of CDK2 can occur through several mechanisms. Amplification and / or overexpression of CCNE1 has been identified occurring in ovarian and breast cancer (Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011) and Etemadmoghadam, D. et al. Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013). Poor outcomes in gastric, endometrial, and other cancers have been associated with overexpression and / or amplification of CCNE1 (Ooi et al. Hum Pathol. (2017) 61:58-67, and Noske et al, Oncotarget (2017) 8: 14794- 14805).

[0005] While these findings indicate CDK2 is a potential target for cancers with deregulated CDK2 activity, no agents selectively targeting CDK2 have been approved to date. Therefore, there is a need to develop new CDK2 inhibitors.1IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0006] The structure of one CDK2 inhibitor, referred to herein as “a compound of formula (I)” or N-(5-(difluoromethoxy)-lH-pyrazol-3-yl)-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH- pyrazolo[3,4-b]pyrazin-6-amine is shown below:or a pharmaceutically acceptable salt thereof.

[0007] There is a need to develop processes for preparing a compound of formula (I) that are suitable to large scale manufacture, formulation, and commercialization.SUMMARY

[0008] In a first aspect, the present disclosure provides a compound represented by formula(D):

[0009] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (D):comprising:(i) contacting a compound of formula (C):21PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO with p-toluenesulfonic acid monohydrate in an organic solvent to provide a mixture having the compound of formula (D); and(ii) crystallizing the compound of formula (D) from the mixture, thereby providing the compound of formula (D).

[0010] In another aspect, the present disclosure provides a compound represented by formula (F):

[0011] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (I):or a pharmaceutically acceptable salt thereof, comprising preparing a compound of formula (F):

[0012] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (F):comprising:(i) contacting a compound of formula (E):1PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO with oxalic acid in an organic solvent to provide a mixture having the compound of formula (F); and(ii) crystallizing the compound of formula (F) from the mixture, thereby providing the compound of formula (F).BRIEF DESCRIPTION OF THE FIGURES

[0013] Figure 1 is a X-ray powder diffraction (XRPD) pattern obtained from the compound of formula (D) designated as crystalline solid Form A, from 3 to 40 degrees 2-theta.

[0014] Figure 2 is a differential scanning calorimetry (DSC) thermogram of the material analyzed in Figure 1 obtained from a sample of the compound of formula (D) designated as crystalline solid Form A.

[0015] Figure 3 is a XRPD pattern obtained from the compound of formula (F) designated as crystalline solid Form B, from 3 to 40 degrees 2-theta.

[0016] Figure 4 is a DSC thermogram of the material analyzed in Figure 3 obtained from a sample of the compound of formula (F) designated as crystalline solid Form B.DETAILED DESCRIPTIONCompounds and Processes for Preparation of Compounds of the Disclosure

[0017] Provided herein, in part, are intermediate compounds that can be used in processes for preparing N-(5-(difluoromethoxy)-lH-pyrazol-3-yl)-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-pyrazolo[3,4-b]pyrazin-6-amine (herein, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, represented by the following structural formula:

[0018] In one aspect, the present disclosure provides a salt, e.g., a pharmaceutically acceptable salt of a compound of formula (C):41PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0019] The phrase “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio.

[0020] In some embodiments, the pharmaceutically acceptable salt is formed by contacting the compound of formula (C) with an acid selected from camphorsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and phthalic acid. In some embodiments, the acid is methanesulfonic acid or p-toluenesulfonic acid. In some embodiments, the acid is p- toluenesulfonic acid.

[0021] In a one aspect, the present disclosure provides a compound represented by formula (D):

[0022] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (D) :comprising:(i) contacting a compound of formula (C):5IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO with p-toluenesulfonic acid in an organic solvent to provide a mixture having the compound of formula (D); and(ii) crystallizing the compound of formula (D) from the mixture, thereby providing the compound of formula (D).

[0023] In some embodiments of the process, the organic solvent is a polar aprotic solvent. In some embodiments, the organic solvent is selected from acetone, acetonitrile (MeCN), dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate (EtOAc), isopropyl acetate (IP Ac), methyl tert-butyl ether (MTBE), and tetrahydrofuran (THF). In some embodiments, the organic solvent is selected from MeCN, EtOAc, and IPAc. In some embodiments, the solvent is EtOAc.

[0024] In some embodiments of the process, the compound of formula (C) is in a concentrated reaction mixture from a previous step, e.g. , a previous reaction performed to provide the compound of formula (C).

[0025] In some embodiments of the process, the volume of the organic solvent is from about 4 times to about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (C). In some embodiments, the volume of organic solvent is about 4 times, about 5 times, or about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (C). In some embodiments, the volume of organic solvent is about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (C).

[0026] In some embodiments of the process, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments of the process, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1 .6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments of the process, the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents6IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, p- toluenesulfonic acid is anhydrous.

[0027] In some embodiments, the process further comprises reacting a compound of formula (A):with a compound of formula (B):O +Ck 1 -Na / \0F F(B), in a second solvent to form a compound of formula (C).

[0028] In some embodiments of the process, the second organic solvent is selected from cyclopentyl methyl ether (CPME), dimethylacetamide (DMA), DMF, DMSO, dioxane, MeCN, N-methyl-2-pyrrolidone (NMP), and a mixture of DMF and water. In some embodiments, the second solvent is DMF.

[0029] In another aspect, the present disclosure provides a compound represented by formula (F):

[0030] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (I):71PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO or a pharmaceutically acceptable salt thereof, comprising preparing a compound of formula (F):

[0031] In another aspect, the present disclosure provides a salt, e.g., a pharmaceutically acceptable salt of a compound of formula (E):

[0032] In some embodiments, the pharmaceutically acceptable salt is formed by contacting the compound of formula (E) with an acid selected from 2,4-dimethylbenzene sulfonic acid, benzenesulfonic acid, citric acid, diphenyl phosphate, hydrochloric acid, maleic acid, oxalic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, (R)-(-)-I,I’-binapthyl-2,2’-diyl- hydrogenphosphate, and succinic acid. In some embodiments, the acid is selected from 2,4- dimethylbenzene sulfonic acid, benzenesulfonic acid, citric acid, diphenyl phosphate, maleic acid, oxalic acid, p-toluenesulfonic acid, (R)-(-)-l,r-binapthyl-2,2’-diyl-hydrogenphosphate, and succinic acid. In some embodiments, the acid is selected from benzenesulfonic acid, diphenyl phosphate, hydrochloric acid, maleic acid, oxalic acid, p-toluenesulfonic acid, and (R)- (-)-l,l ’-binapthyl-2,2’-diyl-hydrogenphosphate. In some embodiments, the acid is oxalic acid.

[0033] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (F):comprising:(i) contacting a compound of formula (E):with oxalic acid in an organic solvent to provide a mixture having the compound of formula (F); and81PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO(ii) crystallizing the compound of formula (F) from the mixture, thereby providing the compound of formula (F).

[0034] In some embodiments of the process, the organic solvent is selected from EtOAc, isopropanol (IPA), IP Ac, MeCN, MTBE, and toluene. In some embodiments, the organic solvent is EtOAc.

[0035] In some embodiments of the process, the compound of formula (E) is in a concentrated reaction mixture from a previous step, e.g. , a previous reaction performed to provide the compound of formula (E), and the concentrated reaction mixture is a solution comprising the compound of formula (E). In some embodiments, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 1 volume to about 5 volumes. In some embodiments, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 1 volume, about 2 volumes, about 3 volumes, about 4 volumes, or about 5 volumes. In some embodiments, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 3 volumes.

[0036] In some embodiments of the process, the volume of the organic solvent is from about 1 time to about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 1 time, about 2 times, about 3 times, about 4 times, about 5 times, or about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 2 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 3 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 4 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (E).

[0037] In some embodiments of the process, the amount of oxalic acid that is contacted with the compound of formula (E) is from about 0.9 equivalents in mmol to about 1.6 equivalents in mmol of the amount of the compound of formula (E). In some embodiments of the process, the amount of oxalic acid that is contacted with the compound of formula (E) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (E). In some embodiments, the amount of oxalic acid that is contacted with the91PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO compound of formula (E) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (E).

[0038] In some embodiments, the process (e.g., of paragraph

[0032] ) further comprises: (hi) reacting a compound of formula (D):with an acid to provide a mixture, and(iv) treating the mixture of step (iii) with a base to provide a compound of formula (E).

[0039] In some embodiments of the process, the acid is selected from formic acid, hydrobromic acid (or hydrogen bromide in acetic acid), hydrochloric acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid (also known as triflic acid). In some embodiments, the acid is trifluoromethanesulfonic acid. In some embodiments, the acid is hydrochloric acid.

[0040] In some embodiments of the process, the volume of the acid is from about 2 times to about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (D). In some embodiments, the volume of acid is about 2 times, about 3 times, about 4 times, about 5 times, or about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (D). In some embodiments, the volume of acid is about 3 times the volume of the concentrated reaction mixture comprising the compound of formula (D).

[0041] In some embodiments of the process, the pH value of the reaction mixture of step (iv) (e.g., paragraph

[0037] ) is adjusted to a pH value from about 6.0 to about 10.0. In some embodiments, the pH value is adjusted to a pH value from about 6.5 to about 9.5. In some embodiments, the pH value is adjusted to a pH value from about 7.0 to about 9.0. In some embodiments, the pH is adjusted by adding a base. In some embodiments, the base is sodium hydroxide.

[0042] In another aspect, the present disclosure provides a process for the preparation of a compound of formula (I):101PTS / 20011 1698.1Attorney Docket No.: BPM-6055WOor a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula (E):with a compound of formula (G):thereby providing the compound of formula (I).

[0043] In one aspect, the present disclosure provides a process for preparation of a compound of formula (I) according to the following scheme:Scheme 1 : Synthesis of the Compound of Formula (I)111PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO ifluoromethylationCompound (I)

[0044] In some embodiments of Step 1 of Scheme 1 , a base is used in the reaction. In some embodiments of Step 1, the base is selected from N,N-diisopropylethyl-amine, potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide, sodium methoxide, sodium te -butoxide, triethylamine, and potassium phosphate tribasic. In some embodiments, the base is N,N-diisopropylethylamine.

[0045] In some embodiments, no base is added. In some embodiments, product isolation and salt formation was more efficient and higher yielding without the use of a base in Step 1 of Scheme 1.12IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0046] In some embodiments of Step 1 of Scheme 1 , a solvent is used in the reaction. In some embodiments of Step 1 of Scheme 1 , the solvent is selected from CPME, DMA, DMF, DMSO, dioxane, MeCN, NMP, and a mixture of DMF and water e.g., 10:1 DMF:H2O). In some embodiments, the solvent is DMF.

[0047] In some embodiments of Step 1 of Scheme 1 , the reaction temperature is maintained at temperatures ranging from about 60 °C to about 115 °C. In some embodiments, the reaction temperature is maintained at temperatures ranging from about 75 °C to about 105 °C until the reaction completion. In some embodiments, the reaction temperature is maintained at about 75 °C to about 85 °C until the reaction completion. In some embodiments, the reaction temperature is maintained at about 95 °C to about 105 °C until the reaction completion.

[0048] In some embodiments of Step 1 of Scheme 1, an organic solvent, e.g., a polar aprotic organic solvent, is used in the purification after the reaction completion. In some embodiments, the organic solvent is selected from acetone, MeCN, dichloromethane, DMF, DMSO, EtOAc, IP Ac, MTBE, and THF. In some embodiments, the organic solvent is selected from MeCN, EtOAc, and IPAc. In some embodiments, the organic solvent is ethyl acetate.

[0049] In some embodiments of the process of the Step 1 of Scheme 1 purification, the volume of the organic solvent is from about 2 times to about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (C). In some embodiments, the volume of organic solvent is about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, or about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (C). In some embodiments, the volume of organic solvent is about 2 times to about 3 times the volume of the concentrated reaction mixture comprising the compound of formula (C). In some embodiments, the volume of organic solvent is about 2.5 times the volume of the concentrated reaction mixture comprising the compound of formula (C).

[0050] In some embodiments of Step 1 of Scheme 1, an acid, e.g., p-toluenesulfonic acid, is used in a purification performed after the reaction completion. In some embodiments of the process of the Step 1 of Scheme 1 purification, the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1 .6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the p-toluenesulfonic acid is anhydrous. In some embodiments, the p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate. In some131PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO embodiments, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments of the process, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (C). In some embodiments, the amount of p-toluenesulfonic acid monohydrate that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (C).

[0051] In some embodiments, an acid is used in Step 2 of Scheme 1. In some embodiments of Step 2, the acid is selected from formic acid, hydrobromic acid (or hydrogen bromide in acetic acid), hydrochloric acid, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. In some embodiments, the acid is trifluoromethanesulfonic acid. In some embodiments, the acid is hydrochloric acid.

[0052] In some embodiments, a solvent is used in Step 2 of Scheme 1. In some embodiments of Step 2, the solvent is selected from 1-propanol, acetic acid, MeCN, anisole, DCM, 1,2- dimethoxyethane, 1,4-dioxane, ethanol (EtOH), EtOAc, formic acid, n-heptane, hydrochloric acid, hydrogen bromide, IPA, methanesulfonic acid, MeOH, MTBE, toluene, trifluoroacetic acid, trifluoromethanesulfonic acid, water, and mixtures thereof. In some embodiments, the solvent is EtOH. In some embodiments, the solvent is the acid. In some embodiments, the solvent is hydrochloric acid, optionally with water.

[0053] In some embodiments of Step 2 of Scheme 1 , the reaction temperature is maintained at temperatures ranging from about 0 °C to about 100 °C. In some embodiments, the reaction temperature is maintained at about 45 °C to about 55 °C until the reaction completion. In some embodiments, the reaction temperature is maintained at about 55 °C to about 60 °C until the reaction completion.

[0054] In some embodiments of Step 2 of Scheme 1 , an organic solvent is used in a purification performed after the reaction completion. In some embodiments of the Step 2 of Scheme 1 purification, the organic solvent is selected from EtOAc, IPA, IP Ac, MeCN, MTBE, and toluene. In some embodiments, the organic solvent is EtOAc.

[0055] In some embodiments of Step 2 of Scheme 1 , the pH value of the reaction mixture is adjusted in a purification performed after the reaction completion. In some embodiments of Step 2, the pH value of the reaction mixture is adjusted to a pH value from about 6.0 to about 10.0. In some embodiments, the pH value is adjusted to a pH value from about 6.5 to about 9.5. In some 14IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO embodiments, the pH value is adjusted to a pH value from about 7.0 to about 9.0. In some embodiments, the pH is adjusted by adding a base. In some embodiments, the base is sodium hydroxide.

[0056] In some embodiments of Step 2 of Scheme 1 , a solvent is used in a purification performed after the reaction completion. In some embodiments, the concentrated reaction mixture is a solution comprising the compound of formula (E). In some embodiments of the Step 2 purification, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 1 volume to about 5 volumes. In some embodiments, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 1 volume, about 2 volumes, about 3 volumes, about 4 volumes, or about 5 volumes. In some embodiments, the volume of the concentrated reaction mixture comprising the compound of formula (E) is about 3 volumes. In some embodiments of the Step 2 of Scheme 1 purification, the volume of the organic solvent is from about 1 time to about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 1 time, about 2 times, about 3 times, about 4 times, about 5 times, or about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 2 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 3 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 4 times the volume of the concentrated reaction mixture comprising the compound of formula (E). In some embodiments, the volume of organic solvent is about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (E).

[0057] In some embodiments of Step 2 of Scheme 1, an acid, e.g., oxalic acid is used in a purification performed after the reaction completion. In some embodiments of the Step 2 of Scheme 1 purification, the amount of oxalic acid that is contacted with the compound of formula (E) is from about 0.9 equivalents in mmol to about 1.6 equivalents in mmol of the amount of the compound of formula (E). In some embodiments, the amount of oxalic acid that is contacted with the compound of formula (E) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (E). In some embodiments, the amount of oxalic acid that is contacted with the compound of formula (E) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (E).151PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0058] In some embodiments of Step 2 of Scheme 1 , the reaction temperature is maintained at temperatures ranging from about 0 °C to about 70 °C in a purification performed after the reaction completion. In some embodiments, the reaction temperature is maintained at temperatures ranging from about 15 °C to about 70 °C. In some embodiments, the reaction temperature is maintained at about 20 °C to about 30 °C.

[0059] In some embodiments of Step 3 of Scheme 1, a base is used in the reaction. In some embodiments of Step 3, the base is selected from N-methyl morpholine, N,N- diisopropylethylamine, potassium carbonate, potassium dihydrogen phosphate, potassium hydroxide, potassium phosphate tribasic, sodium carbonate, sodium hydroxide, sodium methoxide, sodium rert-butoxide, 2,2,6,6-tetramethylpiperidine, and triethylamine. In some embodiments, the base is N-methyl morpoholine. In some embodiments of Step 3 of Scheme 1, the amount of base that is contacted with the compound of formula (F) is from about 0.9 equivalents in mmol to about 1.6 equivalents in mmol of the amount of the compound of formula (F). In some embodiments, the amount of base that is contacted with the compound of formula (F) is about 0.9 equivalents in mmol, about 1 equivalent in mmol, about 1.1 equivalents in mmol, about 1.2 equivalents in mmol, about 1.3 equivalents in mmol, about 1.4 equivalents in mmol, about 1.5 equivalents in mmol, or about 1.6 equivalents in mmol of the amount of the compound of formula (F). In some embodiments, the amount of oxalic acid that is contacted with the compound of formula (F) is from about 0.9 equivalents in mmol to about 1.2 equivalents in mmol of the amount of the compound of formula (F).

[0060] In some embodiments of Step 3 of Scheme 1, an anti-solvent is added. In some embodiments, the anti-solvent is selected from DCM, MTBE, n-heptane, and THF. In some embodiments, the anti-solvent is MTBE.

[0061] In some embodiments of Step 3 of Scheme 1 , the mixture was cooled to a temperature ranging from about -15 °C to about 25 °C. In some embodiments, the mixture was cooled to a temperature ranging from about -10 °C to about -5 °C. In some embodiments, the mixture was cooled to a temperature ranging from about 15 °C to about 25 °C.

[0062] In some embodiments of Step 4 of Scheme 1 , the reaction is an SNAr reaction. In some embodiments of Step 4 of Scheme 1 , the compound of formula (E) and the compound of formula (G) are combined in a solvent followed by an addition of a base. In some embodiments of Step 4, the base is selected from lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), or lithium diisopropylamide (LDA).

[0063] In some embodiments, synthesis of the compound of formula (I) using Scheme 1 and the intermediate compounds of formula (D) and formula (F) led to an improved overall impurity 16IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO profile, improved material handling and operational efficiencies, a decrease in waste generation, an increase in the overall yield of the synthetic route, and a decrease in the cost per kilogram of the compound of formula (I). For example, the intermediate compounds of formula (D) and formula (F) are isolated as high purity salts and provide a great control of process impurities. As a result, the compounds of formula (D) and formula (F) contribute to the process efficiencies in the subsequent steps, and impurity control of Compound (I). In some embodiments, use of the intermediate compound of formula (D) in Scheme 1, Step 1 compared to the free base compound of formula (C) in Scheme 2, Step 1 in Scheme 1 had advantages, including improved impurity control, improved material handling, improved material stability, and improved yield of the compound of Formula (I) .

[0064] In some embodiments, the compound of formula (D) can be directly used in Scheme 1, Step 2 without forming a free base first, and with the optimized deprotection conditions, hydrochloric acid was used as a reagent and solvent. In some embodiments, using the compound of formula (C), which is a free base, required the use of a co-solvent (e.g., EtOH) for solubility, which would have led to the formation of impurities, including alkyl chloride and alkyl sulfonates using EtOH and HC1. In some embodiments, Scheme 1 streamlined the work-up and isolation protocols compared to Scheme 2. For example, Scheme 2, Step 2 required formation of the compound of formula (F) as a precipitate followed by purification by silica column chromatography to isolate the compound of formula (E) for a final product that was a yellow or a brown oil. In contrast, Scheme 1 , Step 2 led to the isolation of the compound of formula (F) as a solid without further chromatography. In some embodiments, use of the intermediate compound of formula (D) in Scheme 1, Step 2 compared to the free base compound of formula (E) in Scheme 2, Step 2 had advantages, including increased impurity purging power, improved material handling, increased material stability, and improved yield of product by 25%.EXAMPLES

[0065] The following Examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generating tool provided in ChemBioDraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.Abbreviations:Solvents and Chemicals Name Abbreviation17IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO2-Propanol or isopropanol IPAAcetonitrile ACN or MeCNCyclopentyl methyl ether CPMEDichloromethane DCMDimethyl acetamide DMAcDimethylformamide DMFDimethyl sulfoxide DMSOEthanol EtOHEthyl acetate EtOAc or EAIsopropyl acetate IP AcLithium hexamethyldisilazane LiHMDSMethanol MeOHMethyl tert-butyl ether MTBEN-methyl-2-pyrrolidone NMP p-Toluenesulfonic acid pTsOH or TsOHTetrahydrofuran THFTrifluoroacetic acid TFAUnitsName AbbreviationAngstrom A or ang.Celsius CDegree0or deg.Equivalent(s) eq.Gram gHour hHertz (s’1) HzJoule JKilogram kgKilovolt kVLiter LMicrometer pmMicromole pmolMolar MMilliampere mAMilligram mgMilliliter mLMinute minParts-per million ppmVolume V or vol.InstrumentsName AbbreviationDifferential Scanning Calorimetry DSCHigh Performance Liquid Chromatography HPLCLiquid Chromatography-Mass Spectrometry LC-MSNuclear Magnetic Resonance NMRX-ray Powder Diffraction XRPDThermogravimetric Analysis TGA18IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WOOthersName AbbreviationAmorphous Am.Broad peak br.Low crystalline L.C.Overnight O / NRelative humidity RHRoom temperature (20-24 °C) RTAnalysis Conditions:1H-Nuclear Magnetic Resonance Spectroscopy i'H-NMRi

[0066] 1H NMR spectra were obtained with an Avance III 400 Broker 400 MHz NMR(acquisition time = 4.09 seconds with a 1 second delay; 16 scans) Unless otherwise indicated, all protons were reported in either DMSO-c / 6 or CDCh NMR solvent as parts-per million (ppm) with respect to residual undeuterated NMR solvent signals (DMSO (2.50 ±0.02 ppm) and CDCh (7.26 ±0.02 ppm)).Liquid Chromatography-Mass Spectrometry

[0067] The liquid chromatography-mass spectrometry (LC-MS) data (sample analyzed for purity and identity) were obtained with an Agilent product line 1290 Infinity II LC stack using an Agilent model G7129B LC / MSD XT spectrometer utilizing an ESI ionization fitted with a Waters XSelect HSS T3 column (C18, 3.5 pm particle size, 3.0 x 150 mm dimensions) reversephase column at 40 °C. The mobile phase consisted of a mixture of solvent 0.05% trifluoro acetic acid in water and acetonitrile. The respective acquisition method for each step was utilized.Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

[0068] DSC was performed using a Mettler Toledo DSC. The sample (3-5 mg) was weighed directly in a 40 pL hermetic aluminum pan with a pinhole. TGA was performed on the same sample simultaneously using a Mettler Toledo TGA. Protective and purge gas was nitrogen at a flowrate of 50 mL / min and 50-100 mL / min respectively. The desired amount of sample (5-10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed according to the parameters below:ParametersMettler Toledo DSC Mettler Toledo TGAMethod Ramp RampSample size 3-5 mg 5-10 mgHeating rate 10.0 °C / min 10.0 °C / min191PTS / 20011 1698.1Attorney Docket No.: BPM-6055WOTemperature range 20 to 350 °C 30 to 500 °CMethod gas N2 at 50.00 mL / minX-Ray Powder Diffraction (XRPD)

[0069] XRPD was performed using a Broker D2 X-ray. Samples were prepared on Si zeroreturn wafers. The parameters for XRPD methods used are listed below:Parameter Regular ScanX-ray wavelength Cu K-a, 1.54184 A,X-ray tube setting 30 kV, 10 mADivergence Slit (mm) 1.0 Detector ID modeSoller slit (mm) 2.5Detector Slit (mm) 0.5Anti-scattering Slit (mm) 8.0Scan mode Continuous PSD fastScan range (°20) -3 - 40Scan type Coupled Two Theta / ThetaScanning Time (s) 0.1 Step size (deg) 0.01Example 1. Salt Screening of the Compound of Formula (C)Exemplary Sall Screening:

[0070] About 50 mg or about 100 mg of the compound of Formula (C) was dissolved in about 0.25 mL or about 0.5 mL of solvent, and about 1.0 eq. of an acid was added. The reaction mixtures were maintained at temperatures ranging from about 0 °C to about 70 °C, including about 20 °C to about 25 °C for 16 h or at about 0 °C to about 5 °C for 2 h for the salt screen.

[0071] 20 different acids were used in a salt screen, and 4 solid salts were obtained. Solid salts were formed with camphorsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and phthalic acid. The purity of the solid salt was low with phthalic acid. The yields with camphorsulfonic acid were lower than with methanesulfonic acid and p-toluenesulfonic acid. The reaction product salt formed with methanesulfonic acid was hygroscopic. With fumaric acid, (R)-(-)-l,l’-Binapthyl-2,2’-diyl-hydrogenphosphate, and succinic acid, the obtained solid was the acid, not a salt of the reaction product. No or trace solids were formed under certain tested conditions with 2,4-dimethylbenzene sulfonic acid, 4-chlorobenzene sulfonic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, dihydrogen phosphate,20IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO maleic acid, malonic acid, oxalic acid, sulfuric acid, TFA, or trifluorosulfonic acid in any of the following solvents 4-methyl-2-pentanone, IP A, IP Ac, MeCN, MTBE, or THF.

[0072] Table 1. Selected salt screening of the compound of formula (C)N.D. means not determinedExample 2. Scheme 1, Step 1: Synthesis of the Compound of Formula (D) ifluoromethylationStep 1: Difluoromethylation Reaction, Synthesis of l-(tert-butyl)-3-(difluoromethoxy)-lH- pyrazol-5-amine, the Compound of Formula (C)

[0073] DMF (9.0 L, 3 V) was charged into a 50 L (Rl) glass jacketed reactor at 20 -25 °C. The compound of formula (A) (3.0 kg, 1.00 eq) was charged into Rl at 20-25 °C. A yellow suspension was obtained at this point. The mixture was heated to 95-105 °C to form a yellow solution. Sodium chlorodifluoroacetate (the compound of formula (B), 2.9 kg, 1.05 eq) was dissolved in DMF (9.0 L, 3 V) at 20-30 °C to form a cloudy solution. The latter was added to Rl at 95-105 °C over the course of 3 h; during addition, gas evolution was observed, and the21IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO reaction mixture changes from a yellow to a reddish brown coloration. The resulting mixture was stirred at 95-105 °C for 0.5 h. The reaction mixture was cooled to 20-25 °C over the course of 1 h. Water was charged (36.0 L, 12 V) to the reaction mixture at 20-25 °C; a mild exotherm was observed. The resulting mixture was extracted with MTBE (21.0 L, 7 V) twice. The combined organic phases were washed with 25% brine (15.0 L, 5 V) twice. The organic phase was concentrated under reduced pressure at 45-50 °C to ~ 2 V. EtOAc (3.0 L, 1 V) was added to the mixture, followed by concentration under reduced pressure at 45-50 °C to ~ 2 V.Step 1: Purification, Synthesis of Tosylate Salt of 1 -(teri-lHiiyl)-S-(difhioromethoxy)-l H-pyraz.ol- 5-amine, the Compound of Formula (D)

[0074] The mixture comprising the compound of formula (C) from Step 1 was then diluted with EtOAc (15.0 L, 5 V) at 20-30 °C. TsOH»H2O (3.5 kg, 1.0 eq) was charged to the mixture at 20-30 °C; a yellow solid is observed forming during addition. The mixture was stirred at 20-30 °C for 4 h. The resulting slurry was filtered, and the filter cake was washed with EtOAc (6.0 L, 2 V). The filter cake was dried under reduced pressure at 45-50 °C. The desired compound of formula (D) was obtained as a yellow solid (5.69 kg) with 98.8% HPLC purity and 77.5% yield. LC-MS: m / z = 206.2 [M+H]+. ’H NMR: (400 MHz, CDCh): 5 ppm 7.51 (d, 2H), 7.14 (d, 2H), 7.09 (t, 1H), 6.00 (s, 3H), 5.14 (s, 1H), 2.29 (s, 3H), 1.48 (s, 9H).

[0075] The XRPD of crystalline Form A of the compound of formula (D) is shown in Figure 1. The DSC of crystalline Form A of the compound of formula (D) has two broad endotherms with onset peaks at about 157.0 ± 2 °C and about 179.7 ± 2 °C with enthalpies of about -171.2 ± 2 J / g and about -23.7 ± 2 J / g, respectively, and two broad exotherms with onset peaks at about 265.2 ± 2 °C and about 301.7 ± 2 °C with enthalpies of about 125.3 ± 2 J / g and about 29.9 ± 2 J / g, respectively (Figure 2).Alternate synthesis

[0076] The compound of formula (C) (2.0 g, 1 eq) was dissolved in EtOAc (10 mL). TsOH monohydrate (1.15 eq) was added, and the mixture was stirred at about 20 °C to about 25 °C for 4 h. 93.9% yield. 'H NMR: (400 MHz, CDCh): 5 ppm 7.51 (d, 2H), 7.14 (d, 2H), 7.09 (t, 1H), 6.00 (s, 3H), 5.14 (s, 1H), 2.29 (s, 3H), 1.48 (s, 9H).Example 3. Salt Screening of the Compound of Formula (E)

[0077] About 50 mg or about 100 mg of the compound of Formula (E) was dissolved in about 0.25 mL or about 0.5 mL of solvent, and about 1.0 eq. of acid was added. The reaction mixtures were maintained at temperatures ranging from about 0 °C to about 70 °C, including about 20 °C to about 25 °C for 16 h or at about 0 °C to about 5 °C for 2 h for the salt screen.221PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0078] 22 different acids were used in the salt screen, and 9 solid salts were obtained. Solid salts were formed with 2,4-dimethylbenzene sulfonic acid, benzenesulfonic acid, citric acid, diphenyl phosphate, maleic acid, oxalic acid, p-toluenesulfonic acid, (R)-(-)-l,l’-binapthyl-2,2’- diyl-hydrogenphosphate, and succinic acid. With fumaric acid and phthalic acid, the obtained solid was the acid, not a salt of the reaction product. No or trace solids were formed under certain tested conditions with (lS)-(+)-10-camphorsulfonic acid, 4-chlorobenzene sulfonic acid, benzoic acid, cyclic (2-ethylhexyl)phosphate, diethyl phosphate, monophenyl phosphate, malonic acid, phosphoric acid, sulfuric acid, TFA, or trifluoromethanesulfonic acid in any of the following solvents 4-methyl-2-pentanone, IPA, IP Ac, MeCN, MTBE, or THF.

[0079] Table 2. Selected salt screening of the compound of formula (C)N / A is not applicableAlternate Exemplary' Salt Screening:

[0080] About 60 - 70 mg of the compound of Formula (E) was dissolved in about 0.5 mL of solvent, and 1.0 eq. of an acid was added. The reaction mixtures were maintained at temperatures ranging from about 0 °C to about 70 °C, including about 20 °C to about 25 °C for 16 h.

[0081] 8 different acids were used in the salt screen, and 4 solid salts were obtained. Solid salts were formed with hydrochloric acid, maleic acid, oxalic acid, and p-toluenesulfonic acid. With adipic acid, the obtained solid was the acid, not a salt of the reaction product. No or trace solids were formed under certain tested conditions with fumaric acid, citric acid and methanesulfonic acid in any of the following solvents IPA, IP Ac, MeCN, or toluene.

[0082] Table 3. Selected salt screening of the compound of formula (E)23IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO*N.I. means not isolated; N.D. means not determinedExample 4. Scheme 1, Step 2: Synthesis of the Compound of Formula (F)Step 2: Deprotection Reaction,. Synthesis of 5-(difluoromelhoxy)-lH-pyrazol-3-amine, the Compound of Formula (E)

[0083] 12 M aq. HC1 (15.0 L, 3 V) was charged into a 50 L (Rl) glass jacketed reactor at20-25 °C. The compound of formula (D) (5.00 kg, 1.0 eq) was charged into Rl at 20-25 °C. A yellow solution was formed upon dissolution with no observable exotherm. The resulting mixture was heated to 45-55 °C and stirred at temperature for 1 h. The reaction mixture was cooled to 15-25 °C and pH adjusted to 7-8 with 30% aq. NaOH (22.6 kg) while maintaining temperature. The mixture was then diluted with EtOAc (20.0 L, 4 V). The resulting biphasic mixture was filtered to remove solid particulates. The filtered solid was rinsed with EtOAc (5.0 L, 1 V). The aqueous phase was re-extracted with EtOAc (25.0 L, 5 V). The combined organic phases were washed with 25% brine (25 kg). The organic phase was concentrated under reduced pressure to ~ 3 V.24IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WOStep 2: Purification, Synthesis of Oxalate Salt of 5-(difluoromethoxy)-lH-pyraz.ol-3-amine, the Compound of Form ula (F)

[0084] Oxalic acid (1.12 kg, 1.00 eq) was charged into the mixture from Step 2 at 20-25 °C; during addition, a yellow solid is observed forming. The resulting slurry was stirred at 20-25 °C for 4 h. The resulting slurry was filtered, and the filter cake was washed with EtOAc (5.0 L, 1 V). The filter cake was dried under reduced pressure at 40-50 °C. The desired compound of formula (F) was obtained as a light yellow solid (2.46 kg) with 99.2% HPLC purity and 79.3% yield. LC-MS: m / z = 150.1 [M+H]+. ’H NMR: (400 MHz, CDCh): 5 ppm 7.14 (t, 1H), 4.95 (s, 1H).

[0085] The XRPD of crystalline Form B of the compound of formula (F) is shown in Figure 3. The DSC of crystalline Form B of the compound of formula (F) has one broad endotherm with an onset peak at about 130.9 ± 2 °C with an enthalpy of about -245.6 ± 2 J / g and one broad exotherm with an onset peak at about 219.2 ± 2 °C with an enthalpy of about 482.0 ± 2 J / g (Figure 4).Example 5. Scheme 1, Step 3: Synthesis of the Compound of Formula (E)

[0086] The compound of formula (F) (12.3 g, 1.0 eq) was added to a 400 mL reactor and diluted with THF (120 mL, 10 V) at ambient temperature. The stirring was set to 200 rpm. The resulting suspension was adjusted to 50 - 55 °C. The suspension became a homogeneous solution after stirring for 30 minutes at temperature. N-methyl morpholine (6.2 mL, 1.1 eq) was added neat in small portions at 50 - 55 °C over the course of 15 minutes; a slight exotherm is observed during addition. A well-mixed slurry was observed forming after adding 10-15% of the base. Once addition was completed, the resulting suspension was stirred at 50 - 55 °C for 30 minutes. The mixture was cooled down slowly over the course of 60 minutes to -10 to -5 °C.The mixture was stirred at temperature for 2 h and then warmed to 20 °C; the slurry was filtered, and the filtration was very fast (<1 minute). The filter cake was washed with THF (2 x 24 mL, 2 x 2 V). The filtrate was concentrated via distillation to ~ 5 V and then polish filtered (to remove solid particulates) into a clean reactor. The prior vessel and the polish filtration assembly were rinsed forward with THF (12 mL, 1 V). The solution comprising the compound of formula (E)25IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO free-base solution was set aside for use in the reaction described in Example 6 (—60 mL, ~7.6 g theoretical mass).Alternate Synthesis of the Compound of Formula (E):

[0087] The compound of formula (F) (10.0 g, 1.0 eq) was added to a 400 mL reactor and diluted with THF (100 mL, 10 V) at ambient temperature. The stirring was set to 200 rpm. The resulting suspension was adjusted to 50 - 55 °C. The suspension became a homogeneous solution after stirring for 30 minutes at temperature. N-methyl morpholine (6.0 mL, 1.3 eq) was added neat in small portions at 50 - 55 °C over the course of 15 minutes; a slight exotherm is observed during addition. A well-mixed slurry was observed forming after adding 10-15% of the base. Once addition was completed, the resulting suspension was stirred at 50 - 55 °C for 30 minutes. The mixture was cooled slowly over the course of 60 minutes to 20 - 25 °C. MTBE (50 mL, 5 V) was added over 10 minutes; the slurry appears well-stirred. The mixture was cooled slowly over the course of 60 minutes to -10 to -5 °C. The mixture was stirred at temperature for 2 h and then warmed to 20 °C; the slurry was filtered, and the filtration was very fast (<1 minute). The filter cake was washed with 1 : 1 THF:MTBE (2 x 20 mL, 2 x 2 V). The filtrate was set aside for further manipulation, e.g., use in Scheme 1, Step 4.Example 6. Scheme 1, Step 4: Synthesis of the Compound of Formula (I)Compound (I)

[0088] The compound of formula (G) (10.0 g, 1.0 eq) was added to the THF solution of the compound of formula (E) (6 V THF, ~7.6 g, 1.3 eq, see Example 5) in a 400 mL reactor. The stirring was set to 200 rpm. The resulting mixture was cooled down to 0 - 5 °C. While maintaining temperature, lithium hexamethyldisilazane (LiHMDS) as a 1.25 M solution in THF (120 mL, 3.8 eq) was added over a period of 1 hour. The reaction mixture was stirred at 0 - 5 °C for 2 hours.

[0089] While maintaining temperature at 0 - 5 °C, 3 M hydrochloric acid (90 mL, 9 V) was added over a period of 30 minutes. The temperature was then adjusted to 20 - 25 °C. The pH was 7-8; an additional 0.5 V of 3 M HC1 was required to adjust the pH to 0-2. The aqueous layer 261PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO was discarded. While maintaining temperature, 5% aqueous sodium carbonate (50 mL, 5 V) was added; the biphasic mixture was stirred for 10 minutes, and the aqueous layer was discarded. While maintaining temperature, 5% aqueous sodium carbonate (50 mL, 5 V) was added once more; the biphasic mixture was stirred for 10 minutes, and the aqueous layer was discarded. The resulting mixture was concentrated via distillation to ~5 V and the temperature was set to 20 - 25 °C.

[0090] The resulting mixture appeared as a homogeneous orange / brown solution at this stage and no nucleation was observed. The stirring was set to 200 rpm. The mixture was cooled down to 10 - 15 °C and stirred at temperature for 60 minutes; no nucleation was observed. A spatula tip of seed crystals was added, and a thin slurry was formed. The resulting slurry was treated with water (93 mL, 9.3 V) over the course of 60 minutes. The resulting thick slurry was stirred at temperature for 60 minutes before filtration. The resulting filter cake was washed with 3:7 THF:water (3 x 20 mL, 3 x 2 V). The filter cake was dried in a vacuum oven at 45 - 50 °C until constant weight. The compound of formula (I) was obtained as an off-white solid (13.2 g) with a 92.0% yield and 99.2% HPLC purity.Example 7. Synthesis of the Compound of Formula (I) based on Scheme 2

[0091] The compound of formula (I) may be synthesized according to the following synthetic scheme 2: ifluoromethylationStep 2: DeprotectionReactionStep 3: SNAr ReactionStep 1. Synthesis of l-(tert-butyl)-3-(difluoromethoxy)-lH-pyrazol-5-amine, Compound ofFormula (C)27IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO

[0092] DMF (480 L, 6 V) was charged into a 1500 L (Rl) reactor at 20 -25 °C. The compound of formula (A) (80 kg, 1.00 eq) was charged into Rl at 20-25 °C. Diisopropyl ethylamine (33 kg, 0.50 eq) was charged into Rl at 20-30 °C. A clear solution was obtained at this point. The compound of formula (B) (83 kg, 1.05 eq) was charged into Rl at 20-30 °C. A clear solution was still present at this point. The resulting mixture was heated to 80-85 °C and stirred at temperature for 3 h; a large exotherm and aerogenesis was observed. The reaction mixture was cooled to 20-25 °C over the course of 1 h. Water (1440 L, 18 V) was charged to the reaction mixture at 20-25 °C; a mild exotherm was observed. The resulting mixture was extracted with MTBE (800 L, 10 V) twice. The combined organic phases were washed with 25% brine (635 L, 8 V) twice. The organic phase was dried over NaiSO4 and filtered; the filter cake was washed with MTBE (50 L, 0.6 V). The combined organics were then concentrated to dryness to obtain the compound of formula (C) as a brown oil (84 kg, 93.4% HPLC purity) with a 56.7% crude recovery taking potency into account.Step 2. Synthesis of 5 -(difluoromethoxy)- 1 H-pyrazol-3 -amine, Compound of Formula (E)

[0093] EtOH (200 L, 1 V) was charged into a 3000 L (Rl) reactor at 20-25 °C. The compound of formula (C) (200 kg, 1.00 eq) was charged into Rl at 20-25 °C. 12 M aq. HC1 (1000 L, 5 V) was charged into Rl at 20-25 °C. A clear solution was obtained at this point. The resulting mixture was heated to 70-80 °C and stirred at temperature for 3 h; a large aerogenesis was observed. The reaction mixture was cooled to 20-25 °C, and the pH was adjusted to 7-8 with 30% aq. NaOH (1440 kg) while maintaining temperature. A black solid powder was observed forming during the quench; the powder was filtered, and the filter cake was washed with water (100 L, 0.5 V). The mixture was then diluted with EtOAc (1000 L, 5 V) and extracted twice. The organic phase was dried over NaiSO4 and concentrated down to dryness to obtain a crude brown oil. The resulting residue was dissolved in EtOAc (1000 L, 5 V) and treated with oxalic acid (82 kg, 1.00 eq). The resulting slurry was stirred at 20-25 °C for 3 h. The slurry was filtered, and the filter cake was washed with EtOAc (100 L, 0.5 V) twice. The filter cake was diluted with water (1000 L, 5 V), and the pH was adjusted to 7-8 with 30% aq. NaOH (110 kg) while maintaining temperature. The resulting suspension was filtered, and the filter cake was washed with EtOAc (50 L, 0.25 V). The aqueous filtrate was extracted with EtOAc (500 L, 2.5 V) twice. The combined organics were dried over Na SOi and concentrated down to dryness to obtain a crude brown oil. The residue was purified by column chromatography (silica gel: 1,200 kg, DCM: 17,880 kg, EtOAc: 4,050 kg) to obtain the desired compound as a yellow oil (74 kg) with a 54.7% yield and 99.9% HPLC purity.28IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WOStep 3. Synthesis ofN-(5-(difluoromethoxy)-lH-pyraz.ol-3-yl)-l-((tetrahydro-2H-pyran-4- yl )methyl )-lH-pyrazolo[ 3,4-b ]pyraz,in-6-amine, Compound (I)

[0094] The compound of formula (G) (61 .6 kg, 1.0 eq), the compound of formula (E) (40.0 kg, 1.1 eq), and anhydrous tetrahydrofuran (THF) (367 L) were combined to form a solution. The temperature was adjusted to 0 - 5 °C. While maintaining temperature, LiHMDS as a 24% solution in THF (597 kg, 3.3 eq) was added over a period of 7 hours. The reaction mixture was stirred at -5 to 5 °C for 2 hours.

[0095] The temperature of the mixture was adjusted to -10 - 10 °C. While maintaining temperature, 3 M hydrochloric acid (518 L) was added over a period of 9 hours. The temperature was adjusted to 15 - 25 °C and the aqueous layer was discarded. While maintaining temperature, 5% aqueous sodium bicarbonate (308 kg) was added; the biphasic mixture was stirred for one hour and the aqueous layer was discarded. While maintaining temperature, 5% aqueous sodium bicarbonate (308 kg) was added once more; the biphasic mixture was stirred for one hour and the aqueous layer was discarded. The resulting mixture was distilled down to a total volume of -308 L at < 66 °C. DCM (185 L) was then added, and the resulting mixture was distilled down to a total volume of -308 L at < 66 °C. The solvent swap cycle was repeated 8 additional times. The reaction mixture was then distilled down to a total of volume of -246 L and the temperature was adjusted to 25 - 35 °C. DCM (60 L) was added, and the temperature was adjusted to 35 - 45 °C. While maintaining temperature, n-heptane (108 L) was added. The reaction mixture was slowly cooled down to 10 - 25 °C over a period of 10.5 hours, and then slowly cooled down to 5 - 10 °C over a period of 2.5 hours. The resulting suspension was stirred at temperature for 3.5 hours. The suspension was filtered, and the cake was washed with cold (5 - 10 °C) 1 :1 dichloromethane: n-heptane (2 x 124 L). The material was dried at 45 - 55 °C under vacuum for 6 hours. The dry cake was slurried on the filter with water (308 L) at 35 - 45 °C. After deliquoring, the wet cake was washed with n-heptane (2 x 126 L) at 15 - 30 °C. The material was dried at 45 - 55 °C under vacuum for 12.5 hours to give the desired compound (78.4 kg, 88.0% yield) with 99.8% AUC purity.Comparison of Synthesis of the Compound of Formula (I) using Scheme 1 versus Scheme 2

[0096] Synthesis of the compound of formula (I) using Scheme 1 and the intermediate compounds of formula (D) and formula (F) led to higher yields in each synthetic step, higher product purity in each synthetic step, higher overall yields, and decreased waste generation compared to synthesis of the compound of formula (I) using Scheme 2. The overall yield for the Step 2 compound for the synthetic route using Scheme 1 was increased by 91% compared to291PTS / 20011 1698.1Attorney Docket No.: BPM-6055WOScheme 2. The overall yield of the compound of formula (I) based on the synthetic route using Scheme 1 was increased by 106.9% compared to Scheme 2.Table 4. Comparison of Compound (I) prepared using Scheme 1 (using intermediate compounds of formula (D) and formula (F)) vs. Scheme 2aCrude yield

[0097] Claims or descriptions that include “or” or “and / or” between at least one members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0098] Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the30IPTS / 20011 1698.1Attorney Docket No.: BPM-6055WO art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0099] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.311PTS / 20011 1698.1

Claims

Attorney Docket No.: BPM-6055WOCLAIMS1. A compound represented by formula (D):

2. A process for the preparation of a compound of formula (D):comprising:(i) contacting a compound of formula (C):with p-toluenesulfonic acid in an organic solvent to provide a mixture having the compound of formula (D); and(ii) crystallizing the compound of formula (D) from the mixture, thereby providing the compound of formula (D).

3. The process of claim 2, wherein the organic solvent is a polar aprotic solvent.

4. The process of claim 2 or 3, wherein the organic solvent is ethyl acetate.

5. The process of any one of claims 2 to 4, wherein the compound of formula (C) is in a concentrated reaction mixture from a previous step.321PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO6. The process of claim 5, wherein the volume of the organic solvent is from about 2 times to about 5 times the volume of the concentrated reaction mixture comprising the compound of formula (C).

7. The process of any one of claims 2 to 6, wherein the amount of p-toluenesulfonic acid that is contacted with the compound of formula (C) is from about 0.9 equivalents in mmol to about 1 .6 equivalents in mmol of the amount of the compound of formula (C).

8. The process of any one of claims 2 to 7, further comprising:(iii) contacting a compound of formula (A):with a compound of formula (B):in a second organic solvent to form a compound of formula (C).

9. The process of claim 8, wherein the second organic solvent is selected from the group consisting of acetonitrile, cyclopentyl methyl ether (CPME), dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, and N-methyl-2- pyrrolidone (NMP).

10. A compound represented by formula (F):

11. A process for the preparation of a compound of formula (I):331PTS / 20011 1698.1Attorney Docket No.: BPM-6055WOor a pharmaceutically acceptable salt thereof, comprising preparing a compound of formula (F):

12. A process for the preparation of a compound of formula (F):comprising:(i) contacting a compound of formula (E):with oxalic acid in an organic solvent to provide a mixture having the compound of formula (F); and(ii) crystallizing the compound of formula (F) from the mixture; thereby providing the compound of formula (F).

13. The process of claim 12, wherein the organic solvent is ethyl acetate.

14. The process of claim 12 or 13, wherein the compound of formula (E) is in a concentrated reaction mixture from a previous step.341PTS / 20011 1698.1Attorney Docket No.: BPM-6055WO15. The process of claim 14, wherein the volume of the organic solvent is from about 4 times to about 6 times the volume of the concentrated reaction mixture comprising the compound of formula (E).

16. The process of any one of claims 12 to 15, wherein the amount of oxalic acid that is contacted with the compound of formula (E) is from about 0.9 equivalents in mmol to about 1 .6 equivalents in mmol of the amount of the compound of formula (E).

17. The process of any one of claims 12 to 16, further comprising:(iii) reacting a compound of formula (D):with an acid to provide a mixture, and(iv) treating the mixture of step (iii) with a base to provide a compound of formula (E).

18. The process of claim 17, wherein the acid is hydrochloric acid and the base is sodium hydroxide.351PTS / 20011 1698.1

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