Process for the preparation of substituted pyrazolopyrimidines

Abstract

The present disclosure provides compounds of formula I: The present disclosure also provides compounds having the formula (VI): A method for preparing the compound of JPEG2024545157000207.jpg5265 is provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 287,623, filed December 9, 2021, which is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods for the preparation of substituted pyrazolopyrimidines and substituted purines, which can be used as ubiquitin-specific-processing protease 1 (USP1) inhibitors. [Background technology]

[0003] Substituted pyrazolopyrimidines such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine are inhibitors of USP1.

[0004] Additionally, the isolation and commercial scale preparation of substituted pyrazolopyrimidines such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine presents several challenges. For example, methods requiring expensive purification methods such as chromatography are often not suitable for commercial scale manufacture, as they generate significant amounts of impurities or utilize large amounts of expensive and undesirable reagents.

[0005] The compound 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine is disclosed in International Publication No. WO2020 / 132269. Solid state forms of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, as well as pharma- ceutically acceptable salts and cocrystals thereof, are disclosed in International Application No. PCT / US2021 / 057072. Methods for treating cancer using 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine are disclosed in International Publication No. WO2021 / 163530. Methods for synthesizing 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine are disclosed in WO2020 / 132269 and illustrated below. [ka]

[0006] Although this method allows for the small-scale preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, it has poor selectivity in the alkylation reaction to form the compound of formula XIV, resulting in a significant loss of yield late in the synthesis. Separation of the resulting N1 and N2 regioisomers requires chromatography, a procedure that is time-consuming and inefficient on a large kg scale. Furthermore, intermediate XXII is not readily commercially available to support large kg scale preparations.

[0007] Therefore, there is an ongoing need for one or more methods for preparing substituted pyrazolopyrimidines, such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, that avoid the costly and undesirable challenges. Summary of the Invention

[0008] Disclosed herein is an improved process for the preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, and novel intermediates useful in its synthesis. These methods and novel intermediates allow efficient large scale production of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, up to kg scale.

[0009] Applicants have discovered reaction routes for the synthesis of substituted pyrazolopyrimidines, such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine, using intermediates and processes that significantly reduce the number of steps required for the synthesis of said substituted pyrazolopyrimidines. Additionally, Applicants have discovered several intermediate compounds (also referred to herein as compounds of the present disclosure) that enable more efficient processes for the preparation of these substituted pyrazolopyrimidines, such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine.

[0010] Moreover, Applicant has discovered that a compound of formula XIV: [ka] For preparing a compound of formula XVII: [ka] We have discovered a reaction pathway that results in minimal amounts of impurity compounds (eg, less than about 5% AUC compared to the area of ​​the compound of formula XIV).

[0011] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein:

[0012] R 1 is cyano, -CHO, -CHNR 2 R 3 and -CH2R 4 Selected from;

[0013] R 2 is selected from hydrogen, optionally substituted aryl, and optionally substituted heteroaryl;

[0014] R 3 is hydrogen, amino and -NR 5 R 6 Selected from;

[0015] R 4 Formula II and Formula III: [ka] is selected from

[0016] R 5 and R 6 are independently selected from hydrogen and an amine protecting group;

[0017] R 7 is selected from optionally substituted aryl, and optionally substituted heteroaryl;

[0018] R 8 is selected from carbonyl, alkoxy and sulfonate;

[0019] R 9 is selected from hydroxy, alkoxy, sulfonate and leaving groups; The present disclosure relates to compounds.

[0020] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 5 and R 6 One of the R 5 and R 6 is an amine protecting group selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc).

[0021] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 1 -CH2NR 2 R 3 and R 2 is hydrogen, and R 3 is an amino.

[0022] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 1 -CH2NR 2 R 3 and R 2 is an optionally substituted pyrimidinyl.

[0023] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R7 is expressed as Equation XIX: [ka] wherein R 12 and R 13 is independently selected from hydrogen, hydroxy, alkyl, alkoxy, and cycloalkyl. In some embodiments, R 12 is cyclopropyl, R 13 is methoxy.

[0024] In some embodiments, the compounds of the present disclosure are compounds having formula I, where the leaving group is selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate, and halogen, hi some embodiments, the leaving group is trifluoromethanesulfonate.

[0025] In some embodiments, the compounds of the present disclosure have formula I: [ka] wherein R 9 is a leaving group, and R 14 is an amine protecting group.

[0026] In some embodiments, the compounds of the present disclosure have formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0027] In another aspect, the present disclosure provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein:

[0028] R 10 teeth, [ka] and

[0029] R 11 is hydrogen or alkyl; The present disclosure relates to compounds.

[0030] In some embodiments, the compounds of the present disclosure have formula IV: [ka] The compound is selected from the group consisting of:

[0031] In another aspect, the present disclosure provides a compound of formula XIV: [ka] or a salt or solvate thereof.

[0032] In another aspect, the present disclosure provides a compound of formula XVII: [ka] or a salt or solvate thereof.

[0033] In another aspect, the present disclosure provides a compound of formula XX: [ka] or a salt or solvate thereof.

[0034] In another aspect, the present disclosure provides a compound of formula XXVIII: [ka] or a salt or solvate thereof.

[0035] In another aspect, the present disclosure provides a compound of formula XXVIV: [ka] or a salt or solvate thereof.

[0036] In another aspect, the present disclosure provides a compound of formula XXX: [ka] or a salt or solvate thereof.

[0037] In another aspect, the present disclosure provides a compound of formula VIb: [ka] A process for preparing a compound of formula Vb: [ka] wherein R 16 is selected from hydrogen, alkyl and amine protecting groups.

[0038] In some embodiments of the above process, R 16 is hydrogen. In some embodiments, R 16 is an amine protecting group. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is (C1-C5) alkyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl. In some embodiments, R 16 is n-propyl. In some embodiments, R 16 is isopropyl.

[0039] In some embodiments of the above process, Formula VIb is Formula VI: [ka] It is.

[0040] In some embodiments of the above process, Formula Vb is Formula V: [ka] It is.

[0041] In some embodiments, the reducing occurs in the presence of a palladium catalyst and a trialkylsilane.

[0042] In some embodiments, the reducing occurs in the presence of a palladium catalyst and triethylsilane.

[0043] In some embodiments, the reducing occurs in the presence of a palladium catalyst, triethylsilane, and a base. In some embodiments, the base is triethylamine.

[0044] In another aspect, the present disclosure provides a compound of formula VI, which is prepared by combining the compound of formula VI with gentisic acid in a solvent to produce a compound of formula XVIII: [ka] The present invention relates to a process comprising forming a compound of the formula:

[0045] In some embodiments, the compound of formula XVIII is a co-crystal.

[0046] In some embodiments, the compound of formula VI is mixed with gentisic acid in the presence of a solvent, hi some embodiments, the solvent is a mixture of isopropanol and heptane.

[0047] In some embodiments, the compound of formula XVIII is isolated from the solvent. In some embodiments, the compound of formula XVIII is isolated from the solvent by precipitation. In some embodiments, the compound of formula XVIII is isolated from the solvent by evaporation. In some embodiments, the compound of formula XVIII is isolated from the solvent by crystallization. In some embodiments, the compound of formula XVIII is recrystallized using one or more solvents.

[0048] In another aspect, the present disclosure provides a compound of formula Vab: [ka] A process for preparing a compound of formula 9 is a leaving group selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate; Formula VIIb: [ka] with toluenesulfonic anhydride, toluenesulfonyl chloride, methanesulfonic anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to form a compound of formula Vab.

[0049] In some embodiments, formula Vab has formula Va: [ka] It is.

[0050] In some embodiments, Formula VIIb is Formula VII: [ka] It is.

[0051] In some embodiments, the compound of formula VII is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride.

[0052] In another aspect, the present disclosure provides a compound of formula VIIb: [ka] A process for preparing a compound of formula VIIIb: [ka] or a salt thereof with an acid to form a compound of formula VIIb, wherein R 14 is an amine protecting group. In some embodiments, the acid is trifluoroacetic acid.

[0053] In some embodiments, Formula VIIIb has Formula VIII: [ka] It is.

[0054] In some embodiments, the reaction occurs in the presence of toluene as a solvent. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by precipitation. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by evaporation. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by crystallization.

[0055] In some embodiments, the reaction occurs at a temperature of about 20°C to about 55°C.

[0056] In another aspect, the present disclosure provides a compound of formula VIIIb: [ka] or a salt thereof, comprising a compound of formula IXb: [ka] or a salt thereof with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid to form a compound of formula VIIIb, wherein R 14 is an amine protecting group.

[0057] In some embodiments, formula IXb is formula IX: [ka] It is.

[0058] In some embodiments, the coupling occurs in the presence of a palladium catalyst and triethylsilane.

[0059] In some embodiments, the coupling occurs in the presence of a solvent selected from 1,4-dioxane, water, and mixtures thereof.

[0060] In some embodiments, the coupling occurs at a temperature of about 20°C to about 65°C.

[0061] In another aspect, the present disclosure provides a compound of formula IXb: [ka] or a salt thereof, comprising a compound of formula Xb: [ka] or a salt thereof with 2,4-dichloropyrimidine-5-carboxylic acid ester to form a compound of formula IXb, wherein R 14 is an amine protecting group.

[0062] In some embodiments, formula Xb is represented by formula X: [ka] It is.

[0063] In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is ethyl 2,4-dichloropyrimidine-5-carboxylate.

[0064] In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is isopropyl 2,4-dichloropyrimidine-5-carboxylate.

[0065] In some embodiments, the compound of formula X is reacted with 2,4-dichloropyrimidine-5-carboxylic acid ester in the presence of a base and a solvent. In some embodiments, the base is an amine base and the solvent is an alcohol solvent. In some embodiments, the amine base is 2,6-lutidine. In some embodiments, the solvent is isopropanol.

[0066] In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc).

[0067] In another aspect, the present disclosure provides a compound of formula Xb: [ka] or a salt thereof, comprising a compound of formula XIb: [ka] with tert-butyl carbazate and a reducing agent to form a compound of formula Xb.

[0068] In some embodiments, formula XIb is formula XI: [ka] It is.

[0069] In some embodiments, the compound of formula XI is reacted with tert-butyl carbazate in the presence of sodium cyanoborohydride.

[0070] In some embodiments, the compound of formula XI is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst.

[0071] In another aspect, the present disclosure provides a compound of formula XIb: [ka] A process for preparing a compound of formula XIIb: [ka] with a reducing agent to form a compound of formula XIb.

[0072] In some embodiments, formula XIIb is formula XII: [ka] It is.

[0073] In some embodiments, the reducing agent is diisobutylaluminum hydride.

[0074] In another aspect, the present disclosure provides a compound of formula XII: [ka] A process for preparing a compound of formula XIII: [ka] with an alkylating agent to form a compound of formula XII.

[0075] In some embodiments, the alkylating agent is selected from 2-iodopropane, 2-bromopropane, 2-isopropyl mesylate, and 2-isopropyl tosylate, hi some embodiments, the alkylating agent is 2-iodopropane.

[0076] In another aspect, the present disclosure provides a compound of formula XIVb: [ka] A process for preparing a compound of formula XVb: [ka] or a salt thereof, of formula XVI: [ka] with a compound of formula XIVb to form a compound of formula XIVb In the formula, R 16 is selected from hydrogen, alkyl and amine protecting groups.

[0077] In some embodiments of the above process, R 16 is hydrogen. In some embodiments, R 16 is an amine protecting group. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is (C1-C5) alkyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl. In some embodiments, R 16 is n-propyl. In some embodiments, R 16 is isopropyl.

[0078] In some embodiments of the above process, Formula XIVb is Formula XIV: [ka] It is.

[0079] In some embodiments of the above process, Formula XVb is Formula XV: [ka] It is.

[0080] In some embodiments, the compound of formula XV is reacted with the compound of formula XVI in the presence of a solvent and a base. In some embodiments, the solvent is selected from ethanol, isopropanol, and tetrahydrofuran. In some embodiments, the base is an amine base. In some embodiments, the base is selected from triethylamine and diisopropylethylamine.

[0081] In some embodiments, the compound of formula XV is reacted with the compound of formula XVI at a temperature between -20°C and 25°C.

[0082] In some embodiments, the reaction of a compound of formula XV with a compound of formula XVI provides a compound of formula XVII: [ka] also forms a compound of the formula:

[0083] In some embodiments, the compound of formula XVII forms an AUC of less than 5% of the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an AUC of less than 3% of the area of ​​the compound of formula XIV.

[0084] In some embodiments, the compound of formula XIV is isolated with an AUC of less than 1%, less than 0.5%, less than 0.25%, or less than 0.15% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an AUC of less than 0.15% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an undetectable amount of the AUC of the compound of formula XVII.

[0085] In another aspect, the present disclosure provides a compound of formula XIVb: [ka] A process for preparing a compound of formula Xb: [ka] or a salt thereof, of formula XVI: [ka] to form a compound of formula XIVb.

[0086] In some embodiments, formula Xb is represented by formula X: [ka] It is.

[0087] In some embodiments, formula XIVb is formula XIV: [ka] It is.

[0088] In another aspect, the present disclosure provides a compound of formula XIV having formula XXI: [ka] to form a compound of formula VI: [ka] The present invention relates to a process comprising obtaining a compound of formula (I).

[0089] In another aspect, the present disclosure provides a compound of formula VI, which is prepared by combining the compound of formula VI with gentisic acid in a solvent to produce a compound of formula XVIII: [ka] The present invention relates to a process comprising forming a compound of the formula:

[0090] In some embodiments, the compound of formula XVIII is a co-crystal.

[0091] In another aspect, the present disclosure provides a compound of formula XXX: [ka] A process for preparing a compound of formula XXVII: [ka] or a salt thereof, of formula XVI: [ka] with a compound of formula XXX to form a compound of formula XXX.

[0092] In some embodiments, the compound of formula XXVIV is reacted with the compound of formula XVI in the presence of a solvent and a base. In some embodiments, the solvent is selected from ethanol, isopropanol, or THF. In some embodiments, the base is an amine base. In some embodiments, the base is selected from triethylamine and diisopropylethylamine. In some embodiments, the reaction is carried out at a temperature between -20°C and 25°C.

[0093] In some embodiments, the above process comprises reacting a compound of formula XXX with a compound of formula XXI: [ka] to form a compound of formula XXXI: [ka] The method further comprises forming a compound of the formula:

[0094] In some embodiments, the above process comprises reacting a compound of formula XXXI with [ka] where X is a leaving group and R 15 is an alkyl group; to form a compound of formula XXXII: [ka] or a salt thereof.

[0095] In some embodiments, R 15 is an isopropyl group. In some embodiments, R 15 is a methyl group.

[0096] In another aspect, the present disclosure provides a compound of formula XXVIV: [ka] or a salt thereof, comprising the steps of: Formula XXVIII: [ka] with an acid to form a compound of formula XXVII, or a salt thereof.

[0097] In some embodiments, the acid is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, in some embodiments, the reaction is carried out at a temperature between 0° C. and 75° C.

[0098] In another aspect, the present disclosure provides a compound of formula XXVIII: [ka] or a salt thereof, comprising the steps of: Formula XXVII: [ka] with tert-butyl carbazate and a reducing agent to form a compound of formula XXVIII.

[0099] In some embodiments, the compound of formula XXVII is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst.

[0100] Additional embodiments and advantages of the disclosure are set forth in part in the description that follows and may be derived from the description or may be learned by the practice of the disclosure. The embodiments and advantages of the disclosure will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.

[0101] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein:

[0103] R 1 is cyano, -CHO, -CHNR 2 R 3 and -CH2R 4 Selected from;

[0104] R 2 is selected from hydrogen, optionally substituted aryl, and optionally substituted heteroaryl;

[0105] R 3 is hydrogen, amino and -NR 5 R 6 Selected from;

[0106] R 4 Formula II and Formula III: [ka] is selected from

[0107] R5 and R 6 are independently selected from hydrogen and an amine protecting group;

[0108] R 7 is selected from optionally substituted aryl, and optionally substituted heteroaryl;

[0109] R 8 is selected from carbonyl, alkoxy and sulfonate;

[0110] R 9 is selected from hydroxy, alkoxy, sulfonate, and leaving groups.

[0111] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 1 is cyano. In some embodiments, R 1 -CH2NR 2 R 3 In some embodiments, R 1 Ha-CH2R 4 It is.

[0112] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted aryl. In some embodiments, R 2 is an optionally substituted heteroaryl.

[0113] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 2 is an optionally substituted C aryl. In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl.

[0114] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 2is an optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted pyrimidinyl. In some embodiments, R 2 is an optionally substituted pyridyl. In some embodiments, R 2 is an optionally substituted pyrazinyl. In some embodiments, R 2 is an optionally substituted pyridazinyl. In some embodiments, R 2 is an optionally substituted pyrazolyl.

[0115] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 2 The above optional substituents are independently selected from hydrogen, halo, hydroxy, alkyl, alkoxy, alkoxycarbonyl, cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

[0116] In another embodiment, R 2 The above optional substituents are independently selected from hydrogen, halo, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C4) alkoxycarbonyl, optionally substituted C6 aryl, and optionally substituted 6-membered heteroaryl. In some embodiments, the optionally substituted C6 aryl and optionally substituted 6-membered heteroaryl are substituted with alkoxy and cycloalkyl. In some embodiments, the optionally substituted C6 aryl and optionally substituted 6-membered heteroaryl are substituted with methoxy and cyclopropyl.

[0117] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 3 In some embodiments, the compounds of the present disclosure are compounds having formula I, where R 3 In some embodiments, the compounds of the present disclosure are compounds having formula I, where R 3 Ha-NR 5 R6 It is.

[0118] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 1 -CH2NR 2 R 3 and R 2 is hydrogen, and R 3 is an amino.

[0119] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 1 -CH2NR 2 R 3 and R 2 is an optionally substituted pyrimidinyl.

[0120] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 4 is represented by formula II: [ka] It is.

[0121] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 4 is represented by formula III: [ka] It is.

[0122] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 5 is hydrogen. In some embodiments, R 5is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc). In some embodiments, the amine protecting group is fluorenylmethoxycarbonyl (Fmoc). In some embodiments, the amine protecting group is benzyloxycarbonyl (Cbz). In some embodiments, the amine protecting group is acetyl. In some embodiments, the amine protecting group is trifluoroacetamide. In some embodiments, the amine protecting group is phthalimide. In some embodiments, the amine protecting group is benzyl. In some embodiments, the amine protecting group is trityl. In some embodiments, the amine protecting group is benzylideneamine. In some embodiments, the amine protecting group is toluenesulfonate.

[0123] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 6 is hydrogen. In some embodiments, R 6is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc). In some embodiments, the amine protecting group is fluorenylmethoxycarbonyl (Fmoc). In some embodiments, the amine protecting group is benzyloxycarbonyl (Cbz). In some embodiments, the amine protecting group is acetyl. In some embodiments, the amine protecting group is trifluoroacetamide. In some embodiments, the amine protecting group is phthalimide. In some embodiments, the amine protecting group is benzyl. In some embodiments, the amine protecting group is trityl. In some embodiments, the amine protecting group is benzylideneamine. In some embodiments, the amine protecting group is toluenesulfonate.

[0124] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 5 and R 6 One of the R 5 and R 6 is an amine protecting group selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc).

[0125] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 5 and R 6 is hydrogen. In some embodiments, R 5 and R 6is an amine protecting group. In some embodiments, R 5 is hydrogen, and R 6 is an amine protecting group. In some embodiments, R 6 is hydrogen, and R 5 is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc).

[0126] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 7 is an optionally substituted aryl. In some embodiments, R 7 is an optionally substituted heteroaryl.

[0127] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 7 is an optionally substituted C aryl. In some embodiments, R 7 is an optionally substituted 6-membered heteroaryl.

[0128] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 7 The above optional substituents are independently selected from hydrogen, halo, hydroxy, alkyl, alkoxy and cycloalkyl.

[0129] In another embodiment, R 7 The above optional substituents are independently selected from hydrogen, halo, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy and (C1-C6) cycloalkyl.

[0130] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R7 is expressed as Equation XIX: [ka] has.

[0131] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 8 is carbonyl. In some embodiments, R 8 is alkoxy. In some embodiments, R 8 is a sulfonate. In some embodiments, R 8 is (C1-C6)alkoxy.

[0132] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 9 is hydroxy. In some embodiments, R 9 is alkoxy. In some embodiments, R 9 is a sulfonate. In some embodiments, R 9 is a leaving group. In some embodiments, R 9 is (C1-C6)alkoxy. 9 Compounds of formula I where R is hydroxy are 8 is a tautomer of the compound of formula I where R is a carbonyl. 8 Compounds of formula I where R is carbonyl are 9 is a tautomer of the compound of formula I where is hydroxy.

[0133] In some embodiments, R 9 is a leaving group selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate, and a halogen. In some embodiments, the leaving group is trifluoromethanesulfonate. In some embodiments, the leaving group is toluenesulfonate. In some embodiments, the leaving group is methanesulfonate. In some embodiments, the leaving group is a halogen.

[0134] R9 Hydroxy is R as carbonyl 8 It is a tautomer of the formula:

[0135] In some embodiments, the compounds of the present disclosure are compounds having formula I, wherein R 12 and R 13 is independently selected from hydrogen, hydroxy, alkyl, alkoxy, and cycloalkyl.

[0136] In some embodiments, R 12 and R 13 is independently selected from hydrogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) cycloalkyl. 12 and R 13 In some embodiments, one of R 12 and R 13 In some embodiments, one of R 12 and R 13 One of the groups is cyclopropyl, and the other is R 12 and R 13 The other is methoxy.

[0137] In some embodiments, the compounds of the present disclosure have formula I: [ka] is selected from the group consisting of:

[0138] In some embodiments, the compounds of the present disclosure have formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0139] In some embodiments, R 9is a leaving group. In some embodiments, the leaving group is selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate, and halogen. In some embodiments, R 9 is trifluoromethanesulfonate.

[0140] In some embodiments, R 14 is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc).

[0141] In some embodiments, the compounds of the present disclosure have formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0142] In another aspect, the present disclosure provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0143] In some embodiments, the compounds of the present disclosure are compounds having formula IV, wherein R 10 teeth, [ka] It is. In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] It is.

[0144] In some embodiments, the compounds of the present disclosure are compounds having formula IV, wherein R 11 is hydrogen or alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is alkyl. In some embodiments, R 11 is (C1-C6) alkyl. In some embodiments, R 11 is methyl.

[0145] In some embodiments, the compounds of the present disclosure have formula IV: [ka] The compound is selected from the group consisting of:

[0146] In some embodiments, the compound is [ka] It is.

[0147] In some embodiments, the compound is [ka] It is.

[0148] In another aspect, the present disclosure provides a compound of formula XIV: [ka] or a salt or solvate thereof.

[0149] In another aspect, the present disclosure provides a compound of formula XVII: [ka] or a salt or solvate thereof.

[0150] In another aspect, the present disclosure provides a compound of formula XX: [ka] or a salt or solvate thereof.

[0151] In another aspect, the present disclosure provides a compound of formula XXVIII: [ka] or a salt or solvate thereof.

[0152] In another aspect, the present disclosure provides a compound of formula XXVIV: [ka] or a salt or solvate thereof.

[0153] In another aspect, the present disclosure provides a compound of formula XXX: [ka] or a salt or solvate thereof.

[0154] In another aspect, the present disclosure provides a compound of formula VIb: [ka] A process for preparing a compound of formula Vb: [ka] wherein R 16is selected from hydrogen, alkyl and amine protecting groups.

[0155] In some embodiments of the above process, R 16 is hydrogen. In some embodiments, R 16 is an amine protecting group. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is (C1-C5) alkyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl. In some embodiments, R 16 is n-propyl. In some embodiments, R 16 is isopropyl.

[0156] In some embodiments of the above process, Formula VIb is Formula VI: [ka] It is.

[0157] In some embodiments of the above process, Formula Vb is Formula V: [ka] It is.

[0158] In some embodiments, the process for preparing a compound of formula VI comprises reducing a compound of formula V in the presence of a palladium catalyst and a trialkylsilane or dialkylsilane. In some embodiments, the palladium catalyst is (dppf)PdCl2. In some embodiments, the palladium catalyst is (dppf)Pd(OAc)2. In some embodiments, the palladium catalyst is Pd(PPh3)4. In some embodiments, the palladium catalyst is (dba)3Pd2 using XPhos. In some embodiments, the trialkylsilane or dialkylsilane is selected from triethylsilane, trimethylsilane, and diethylsilane. In some embodiments, the trialkylsilane is triethylsilane.

[0159] In some embodiments, the process for preparing a compound of formula VI comprises reducing a compound of formula V in the presence of a palladium catalyst and an ammonium compound, in some embodiments, the palladium catalyst is Pd / C and the ammonium compound is ammonium formate.

[0160] In some embodiments, the process for preparing a compound of formula VI comprises reducing a compound of formula V in the presence of a palladium catalyst and triethylsilane. In some embodiments, the process for preparing a compound of formula VI comprises reducing a compound of formula V in the presence of (dppf)PdCl2 and triethylsilane.

[0161] In some embodiments, the process for preparing a compound of formula VI comprises reducing a compound of formula V in the presence of a palladium catalyst, a trialkylsilane, and a base. In some embodiments, the palladium catalyst is (dppf)PdCl2. In some embodiments, the trialkylsilane is selected from triethylsilane and trimethylsilane. In some embodiments, the trialkylsilane is triethylsilane. In some embodiments, the base is an amine base. In some embodiments, the amine base is selected from, but not limited to, triethylamine, tributylamine, 2,6-lutidine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the amine base is a tertiary amine base, such as triethylamine or N,N-diisopropylethylamine. In some embodiments, the amine base is triethylamine.

[0162] In another aspect, the present disclosure provides a compound of formula VI, which is prepared by combining the compound of formula VI with gentisic acid in a solvent to produce a compound of formula XVIII: [ka] The present invention relates to a process comprising forming a compound of the formula:

[0163] In some embodiments, the compound of formula XVIII is a co-crystal.

[0164] In some embodiments, the compound of formula VI is mixed with gentisic acid in the presence of a solvent. In some embodiments, the solvent is selected from, but not limited to, ethyl acetate, heptane, acetone, isopropanol, and combinations thereof. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is heptane. In some embodiments, the solvent is a mixture of isopropanol and heptane.

[0165] In some embodiments, the compound of formula XVIII is isolated from the solvent. In some embodiments, the compound of formula XVIII is isolated from the solvent by precipitation. In some embodiments, the compound of formula XVIII is isolated from the solvent by evaporation. In some embodiments, the compound of formula XVIII is isolated from the solvent by crystallization. In some embodiments, the compound of formula XVIII is recrystallized using one or more solvents.

[0166] In some embodiments, the compound of formula VI can be mixed with gentisic acid using the methods disclosed in U.S. Application Publication No. 2022 / 0162213, the disclosure of which is incorporated herein by reference.

[0167] In another aspect, the present disclosure provides a compound of formula Vab: [ka] A process for preparing a compound of formula 9 is a leaving group selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate; Formula VIIb: [ka] with a sulfonating agent to form a compound of formula Vab.

[0168] In some embodiments, formula Vab is represented by formula Va: [ka] It is.

[0169] In some embodiments, Formula VIIb is Formula VII: [ka] It is.

[0170] In some embodiments, the sulfonating agent is selected from toluenesulfonic anhydride, toluenesulfonyl chloride, methanesulfonic anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride. In some embodiments, the sulfonating agent is toluenesulfonic anhydride. In some embodiments, the sulfonating agent is toluenesulfonyl chloride. In some embodiments, the sulfonating agent is methanesulfonic anhydride. In some embodiments, the sulfonating agent is methanesulfonyl chloride. In some embodiments, the sulfonating agent is trifluoromethanesulfonic anhydride. In some embodiments, the sulfonating agent is trifluoromethanesulfonyl chloride.

[0171] In some embodiments, the compound of formula VII is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to form a compound of formula V. In some embodiments, the compound of formula VII is reacted with trifluoromethanesulfonic anhydride to form a compound of formula V. In some embodiments, the compound of formula VII is reacted with trifluoromethanesulfonyl chloride to form a compound of formula V.

[0172] In some embodiments, the compound of formula VII is reacted with a sulfonating agent and a base to form a compound of formula Va. In some embodiments, the base is an amine base. In some embodiments, the amine base is selected from, but not limited to, triethylamine, tributylamine, 2,6-lutidine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0173] In another aspect, the present disclosure provides a compound of formula VIIb: [ka] A process for preparing a compound of formula VIIIb: [ka] or a salt thereof with an acid to form a compound of formula VIIb. In some embodiments, the acid is selected from, but not limited to, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, and trifluoromethanesulfonic acid. In some embodiments, the acid is trifluoroacetic acid.

[0174] In some embodiments, Formula VIIIb has Formula VIII: [ka] It is.

[0175] In some embodiments, R 14 is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc). In some embodiments, the amine protecting group is fluorenylmethoxycarbonyl (Fmoc). In some embodiments, the amine protecting group is benzyloxycarbonyl (Cbz). In some embodiments, the amine protecting group is acetyl. In some embodiments, the amine protecting group is trifluoroacetamide. In some embodiments, the amine protecting group is phthalimide. In some embodiments, the amine protecting group is benzyl. In some embodiments, the amine protecting group is trityl. In some embodiments, the amine protecting group is benzylideneamine. In some embodiments, the amine protecting group is toluenesulfonate.

[0176] In some embodiments, the compound of formula VIII has formula VIIIa: [ka] It is a compound of the formula:

[0177] In some embodiments, the compound of formula VIII or a salt thereof is reacted with an acid in the presence of a solvent to form a compound of formula VII. In some embodiments, the solvent is selected from, but not limited to, toluene, xylene, dimethylsulfoxide (DMSO), acetonitrile, dioxane, N-methylpyrrolidone (NMP), and dichloromethane (DCM). In some embodiments, the solvent is toluene. In some embodiments, the solvent is xylene. In some embodiments, the solvent is DMSO. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is dioxane. In some embodiments, the solvent is NMP. In some embodiments, the solvent is DCM.

[0178] In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by precipitation. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by evaporation. In some embodiments, the compound of formula VII or formula VIIb is isolated from the solvent by crystallization.

[0179] In some embodiments, the compound of formula VIII or a salt thereof is reacted with an acid at a temperature of about 0° C. to about 100° C. to form a compound of formula VII. In some embodiments, the temperature is about 10° C. to about 75° C. In some embodiments, the temperature is about 20° C. to about 55° C. In some embodiments, the temperature is about 25° C. to about 50° C. In some embodiments, the temperature is about 30° C. to about 45° C. In some embodiments, the temperature is about 0° C., about 10° C., about 20° C., about 30° C., about 40° C., about 50° C., about 60° C., about 70° C., about 80° C., about 90° C., about 100° C., or any range of temperatures therein.

[0180] In another aspect, the present disclosure provides a compound of formula VIIIb: [ka] or a salt thereof, comprising a compound of formula IXb: [ka] or a salt thereof with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid to form a compound of formula VIIIb.

[0181] In some embodiments, formula IXb is formula IX: [ka] It is.

[0182] In some embodiments, R 14 is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc). In some embodiments, the amine protecting group is fluorenylmethoxycarbonyl (Fmoc). In some embodiments, the amine protecting group is benzyloxycarbonyl (Cbz). In some embodiments, the amine protecting group is acetyl. In some embodiments, the amine protecting group is trifluoroacetamide. In some embodiments, the amine protecting group is phthalimide. In some embodiments, the amine protecting group is benzyl. In some embodiments, the amine protecting group is trityl. In some embodiments, the amine protecting group is benzylideneamine. In some embodiments, the amine protecting group is toluenesulfonate.

[0183] In some embodiments, the compound of formula VIII has formula VIIIa: [ka] is a compound of The compound of formula IX may be represented by formula IXa: [ka] It is a compound of the formula:

[0184] In some embodiments, the compound of formula IX is coupled with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid in the presence of a palladium catalyst to form a compound of formula VIII. In some embodiments, the palladium catalyst is (dppf)PdCl2.

[0185] In some embodiments, the compound of formula IX is coupled with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid in the presence of a solvent to form a compound of formula VIII. In some embodiments, the solvent is selected from, but not limited to, 1,4-dioxane, water, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is water. In some embodiments, the solvent is THF. In some embodiments, the solvent is 2-methyl-tetrahydrofuran. In some embodiments, the solvent is a mixture of 1,4-dioxane and water.

[0186] In some embodiments, the compound of formula IX is coupled with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid at a temperature of about 0° C. to about 100° C. to form a compound of formula VIII. In some embodiments, the temperature is about 10° C. to about 80° C. In some embodiments, the temperature is about 20° C. to about 65° C. In some embodiments, the temperature is about 20° C. to about 55° C. In some embodiments, the temperature is about 25° C. to about 50° C. In some embodiments, the temperature is about 30° C. to about 45° C. In some embodiments, the temperature is about 0° C., about 10° C., about 20° C., about 30° C., about 40° C., about 50° C., about 60° C., about 70° C., about 80° C., about 90° C., about 100° C., or any range of temperatures therebetween.

[0187] In some embodiments, the compound of formula IX is coupled with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid in the presence of a base to form a compound of formula VIII. In some embodiments, the base is selected from sodium carbonate, potassium carbonate, and cesium carbonate. In some embodiments, the base is cesium carbonate.

[0188] In another aspect, the present disclosure provides a compound of formula IXb: [ka] or a salt thereof, comprising a compound of formula Xb: [ka] or a salt thereof with 2,4-dichloropyrimidine-5-carboxylic acid ester to form a compound of formula IXb.

[0189] In some embodiments, formula Xb is represented by formula X: [ka] It is.

[0190] In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is selected from, but not limited to, methyl 2,4-dichloropyrimidine-5-carboxylate, ethyl 2,4-dichloropyrimidine-5-carboxylate, and isopropyl 2,4-dichloropyrimidine-5-carboxylate. In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is methyl 2,4-dichloropyrimidine-5-carboxylate. In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is ethyl 2,4-dichloropyrimidine-5-carboxylate. In some embodiments, the 2,4-dichloropyrimidine-5-carboxylic acid ester is isopropyl 2,4-dichloropyrimidine-5-carboxylate.

[0191] In some embodiments, R 14 is an amine protecting group. In some embodiments, the amine protecting group is selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate. In some embodiments, the amine protecting group is t-butyloxycarbonyl (Boc). In some embodiments, the amine protecting group is fluorenylmethoxycarbonyl (Fmoc). In some embodiments, the amine protecting group is benzyloxycarbonyl (Cbz). In some embodiments, the amine protecting group is acetyl. In some embodiments, the amine protecting group is trifluoroacetamide. In some embodiments, the amine protecting group is phthalimide. In some embodiments, the amine protecting group is benzyl. In some embodiments, the amine protecting group is trityl. In some embodiments, the amine protecting group is benzylideneamine. In some embodiments, the amine protecting group is toluenesulfonate.

[0192] In some embodiments, the compound of formula X is reacted with 2,4-dichloropyrimidine-5-carboxylic acid ester in the presence of a base and a solvent to form a compound of formula IX.

[0193] In some embodiments, the base is an amine base. The amine base is selected from, but not limited to, triethylamine, tributylamine, 2,6-lutidine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,4-diazabicyclo[2.2.2]octane (DABCO). In some embodiments, the amine base is 2,6-lutidine.

[0194] In some embodiments, the solvent is an alcohol solvent. In some embodiments, the alcohol solvent is selected from, but not limited to, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol. In some embodiments, the solvent is isopropanol.

[0195] In some embodiments, the solvent is an organic solvent, in some embodiments, the organic solvent is selected from, but not limited to, toluene, methyl tert-butyl ether (MTBE), acetonitrile, and THF.

[0196] In another aspect, the present disclosure provides a compound of formula Xb: [ka] or a salt thereof, comprising a compound of formula XIb: [ka] with tert-butyl carbazate and a reducing agent to form a compound of formula Xb.

[0197] In some embodiments, formula XIb is formula XI: [ka] It is.

[0198] In some embodiments, the compound of formula XI is reacted with tert-butyl carbazate in the presence of a reducing agent selected from, but not limited to, sodium cyanoborohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride, and sodium bis(2-methoxyethoxy)aluminum hydride to form a compound of formula X. In some embodiments, the reducing agent is sodium cyanoborohydride.

[0199] In some embodiments, the compound of formula XI is reacted with tert-butyl carbazate in the presence of hydrogen or sodium formate and a transition metal catalyst to form a compound of formula X. In some embodiments, the transition metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C).

[0200] In another aspect, the present disclosure provides a compound of formula XIb: [ka] A process for preparing a compound of formula XIIb: [ka] with a reducing agent to form a compound of formula XI.

[0201] In some embodiments, formula XIIb is formula XII: [ka] It is.

[0202] In some embodiments, the compound of formula XII is reacted with a reducing agent selected from, but not limited to, diisobutylaluminum hydride and lithium aluminum hydride to form a compound of formula XI, in some embodiments, the reducing agent is diisobutylaluminum hydride.

[0203] In another aspect, the present disclosure provides a compound of formula XII: [ka] A process for preparing a compound of formula XIII: [ka] with an alkylating agent to form a compound of formula XII.

[0204] In some embodiments, the alkylating agent is selected from 2-iodopropane, 2-bromopropane, 2-chloropropane, 2-isopropyl mesylate, and 2-isopropyl tosylate. In some embodiments, the alkylating agent is 2-iodopropane. In some embodiments, the alkylating agent is 2-bromopropane. In some embodiments, the alkylating agent is 2-chloropropane. In some embodiments, the alkylating agent is 2-isopropyl mesylate. In some embodiments, the alkylating agent is 2-isopropyl tosylate.

[0205] In another aspect, the present disclosure provides a compound of formula XIVb: [ka] A process for preparing a compound of formula XVb: [ka] or a salt thereof, of formula XVI: [ka] with a compound of formula XIVb to form a compound of formula XIVb In the formula, R 16 is selected from hydrogen, alkyl and amine protecting groups.

[0206] In some embodiments of the above process, R 16 is hydrogen. In some embodiments, R 16 is an amine protecting group. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is (C1-C5) alkyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl. In some embodiments, R 16 is n-propyl. In some embodiments, R 16 is isopropyl.

[0207] In some embodiments of the above process, Formula XIVb is Formula XIV: [ka] It is.

[0208] In some embodiments of the above process, Formula XVb is Formula XV: [ka] It is.

[0209] In some embodiments, the compound of formula XV reacts with the compound of formula XVI in the presence of a solvent and a base to form a compound of formula XIV. In some embodiments, the solvent is selected from, but not limited to, methanol, ethanol, isopropanol, and tetrahydrofuran. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is tetrahydrofuran.

[0210] In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine, tributylamine, 2,6-lutidine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the base is triethylamine. In some embodiments, the base is N,N-diisopropylethylamine.

[0211] In some embodiments, the compound of formula XV is reacted with the compound of formula XVI at a temperature of about -50°C to about 50°C to form a compound of formula XIV. In some embodiments, the temperature is about -30°C to about 30°C. In some embodiments, the temperature is about -20°C to about 25°C. In some embodiments, the temperature is about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, or any range of temperatures therebetween.

[0212] In some embodiments, the reaction of a compound of formula XV with a compound of formula XVI provides a compound of formula XVII: [ka] also forms a compound of the formula:

[0213] In some embodiments, the compound of formula XVII forms an amount of AUC less than 10% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC less than 10%, or less than 9%, or less than 8%, or less than 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC less than 5% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC less than 3% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC less than 1% compared to the area of ​​the compound of formula XIV.

[0214] In some embodiments, the compound of formula XVII forms an amount of AUC of 0.1% to 10% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC of 0.1% to 5% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC of 0.1% to 3% compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms an amount of AUC of 0.1%, or 0.15%, or 0.25%, or 0.5%, or 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or any range thereof compared to the area of ​​the compound of formula XIV. In some embodiments, the compound of formula XVII forms a trace amount.

[0215] In some embodiments, the compound of formula XV is reacted with the compound of formula XVI to provide a compound of formula XIV, and the compound of formula XIV is isolated with an AUC of less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.25%, or less than 0.15%, or any range of values ​​therebetween, of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an AUC of less than 1% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an AUC of less than 0.5% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an AUC of less than 0.25% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an AUC of less than 0.15% of the compound of formula XVII. In some embodiments, the compound of formula XIV is isolated with an undetectable amount of the AUC of the compound of formula XVII.

[0216] In another aspect, the present disclosure provides a compound of formula XIVb: [ka] A process for preparing a compound of formula Xb: [ka] or a salt thereof, of formula XVI: [ka] to form a compound of formula XIVb.

[0217] In some embodiments, the compound of formula Xb reacts with the compound of formula XVI in the presence of a solvent and a base to form a compound of formula XIVb. In some embodiments, the solvent is selected from, but not limited to, methanol, ethanol, isopropanol, and tetrahydrofuran. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is tetrahydrofuran.

[0218] In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine, tributylamine, 2,6-lutidine, N,N-diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the base is triethylamine. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is 2,6-lutidine.

[0219] In some embodiments, formula XIVb is formula XIV: [ka] It is.

[0220] In some embodiments, formula Xb is represented by formula X: [ka] It is.

[0221] In another aspect, the present disclosure provides a compound of formula XIV having formula XXI: [ka] to form a compound of formula VI: [ka] The present invention relates to a process comprising obtaining a compound of formula (I).

[0222] In some embodiments, a compound of formula XIV reacts with a compound of formula XXI in the presence of a palladium catalyst to form a compound of formula VI. In some embodiments, the palladium catalyst is (dppf)PdCl2. In some embodiments, the palladium catalyst is P(t-Bu)3Pd. In some embodiments, the palladium catalyst is PdCl2(dtbpf). In some embodiments, the palladium catalyst is Pd(OAc)2 with A-PHOS. In some embodiments, the palladium catalyst is Pd-168.

[0223] In some embodiments, a compound of formula XIV reacts with a compound of formula XXI in the presence of a solvent to form a compound of formula VI. In some embodiments, the solvent is selected from, but not limited to, 1,4-dioxane, water, THF, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is water. In some embodiments, the solvent is THF. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is a mixture of 1,4-dioxane and water.

[0224] In some embodiments, the compound of formula XIV reacts with the compound of formula XXI in the presence of a base to form a compound of formula VI. In some embodiments, the base is selected from sodium carbonate, potassium carbonate, and cesium carbonate. In some embodiments, the base is cesium carbonate.

[0225] In some embodiments, a compound of formula XV is reacted with a compound of formula XVI to form a compound of formula XIV, a compound of formula XIV is reacted with a compound of formula XXI to form a compound of formula VI, and the compound of formula VI contains a trace amount of a compound of formula XX. In some embodiments, a compound of formula XIV is reacted with a compound of formula XXI to form a compound of formula VI, and the compound of formula VI contains a trace amount of a compound of formula XX.

[0226] In another aspect, the present disclosure provides a compound of formula VI, which is prepared by combining the compound of formula VI with gentisic acid in a solvent to produce a compound of formula XVIII: [ka] The present invention relates to a process comprising forming a compound of the formula:

[0227] In some embodiments, the compound of formula XVIII is a co-crystal.

[0228] In some embodiments, the compound of formula VI is mixed with gentisic acid in the presence of a solvent to provide a compound of formula XVIII. In some embodiments, the solvent is selected from, but not limited to, ethyl acetate, heptane, acetone, isopropanol, and combinations thereof. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is heptane. In some embodiments, the solvent is a mixture of isopropanol and heptane.

[0229] In some embodiments, the compound of formula XVIII is isolated from the solvent. In some embodiments, the compound of formula XVIII is isolated from the solvent by precipitation. In some embodiments, the compound of formula XVIII is isolated from the solvent by evaporation. In some embodiments, the compound of formula XVIII is isolated from the solvent by crystallization. In some embodiments, the compound of formula XVIII is recrystallized using one or more solvents.

[0230] In some embodiments, the compound of formula VI can be mixed with gentisic acid using the methods disclosed in U.S. Application Publication No. 2022 / 0162213, the disclosure of which is incorporated herein by reference.

[0231] In another aspect, the present disclosure provides a compound of formula XXX: [ka] A process for preparing a compound of formula XXVII: [ka] or a salt thereof, of formula XVI: [ka] to form a compound of formula XXX.

[0232] In some embodiments, the compound of formula XXVIV is reacted with the compound of formula XVI in the presence of a solvent and a base. In some embodiments, the solvent is selected from ethanol, isopropanol, or THF. In some embodiments, the base is an amine base. In some embodiments, the base is selected from triethylamine and diisopropylethylamine. In some embodiments, the reaction is carried out at a temperature between -20°C and 25°C.

[0233] In some embodiments, the above process comprises reacting a compound of formula XXX with a compound of formula XXI: [ka] to form a compound of formula XXXI: [ka] The method further comprises forming a compound of the formula:

[0234] In some embodiments, the above process comprises reacting a compound of formula XXXI: [ka] where X is a leaving group and R 15 is an alkyl group; to form a compound of formula XXXII: [ka] or a salt thereof.

[0235] In some embodiments, R 15 is an isopropyl group. In some embodiments, R 15 is a methyl group.

[0236] In another aspect, the present disclosure provides a compound of formula XXVIV: [ka] or a salt thereof, comprising the steps of: Formula XXVIII: [ka] with an acid to form a compound of formula XXVII, or a salt thereof.

[0237] In some embodiments, the acid is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, in some embodiments, the reaction is carried out at a temperature between 0° C. and 75° C.

[0238] In another aspect, the present disclosure provides a compound of formula XXVIII: [ka] or a salt thereof, comprising the steps of: Formula XXVII: [ka] with tert-butyl carbazate and a reducing agent to form a compound of formula XXVIII.

[0239] In some embodiments, the compound of formula XXVII is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst. definition

[0240] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. The use of the term "or" herein does not imply mutual exclusion of alternatives.

[0241] In this application, the use of "or" means "and / or" unless expressly stated or understood by one of ordinary skill in the art. The use of "or" in the context of a multiple dependent claim refers back to two or more preceding independent or dependent claims.

[0242] As used herein, the term "about" includes ±10% of the stated number. Thus, "about 10" means 9 to 11. As will be understood by one of ordinary skill in the art, reference herein to "about" a value or parameter includes (and describes) an example that is directed to the value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0243] For purposes of this disclosure, the term "leaving group" or "LG" refers to an atom or group of atoms that becomes separated during a particular reaction from an atom or group of atoms that is considered to be the remainder or major part of a molecule. Non-limiting exemplary leaving groups include -Cl, -I, -Br, -OTf, -OMs, and -OTs.

[0244] For purposes of this disclosure, the term "halo" when used by itself or as part of another group refers to a halogen atom. Non-limiting exemplary halo groups include fluoro, chloro, bromo, and iodo.

[0245] For purposes of this disclosure, the term "cyano," when used by itself or as part of another group, refers to --CN.

[0246] For purposes of this disclosure, the term "hydroxy" when used by itself or as part of another group refers to --OH.

[0247] For purposes of this disclosure, the term "amino," when used by itself or as part of another group, refers to --NH.sub.2.

[0248] For purposes of this disclosure, the term "alkyl," when used by itself or as part of another group, refers to an alkyl group having 1 to 12 carbon atoms (i.e., C 1~12 alkyl) or a specified number of carbon atoms (i.e., C1 alkyl, such as methyl, C2 alkyl, such as ethyl, C3 alkyl, such as propyl or isopropyl). An alkyl group refers to a straight-chain or branched-chain aliphatic hydrocarbon. 1~10 Alkyl group, branched chain C 3~10 Alkyl group, linear C 1~6 Alkyl group, branched chain C 3~6 Alkyl group, linear C 1~4 Alkyl group, branched chain C 3~4 Alkyl group, linear or branched C 3~4 The alkyl group can be suitably selected from alkyl groups. The alkyl group can be partially or fully deuterated, i.e., one or more hydrogen atoms of the alkyl group can be replaced with deuterium. Non-limiting exemplary C 1~10 Alkyl groups include methyl (including -CD3), ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3 pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~4Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0249] For purposes of this disclosure, the term "alkoxy," when used by itself or as part of another group, refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom. An alkoxy group is one selected from the group consisting of C 1~4 Alkoxy groups, as well as C attached to terminal oxygen atoms 1~4 Alkyl may be selected from, for example, methoxy, ethoxy and tert-butoxy.

[0250] For purposes of this disclosure, the term "aryl," when used by itself or as part of another group, refers to a monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms (i.e., C 6~14 The bicyclic aromatic ring system may be fused. The aryl group is 6~14 Aryl groups and C 6~10 The aryl group can be selected from phenyl or naphthyl. The aryl group can be phenyl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl. The aryl group can be selected from phenyl or naphthyl. The aryl group can be phenyl.

[0251] For purposes of this disclosure, the term "optionally substituted aryl," when used by itself or as part of another group, means that aryl, as defined above, is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkoxycarbonyl, cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. The optional substituents can be alkoxy and cycloalkyl.

[0252] For purposes of this disclosure, the term “heteroaryl” or “heteroaromatic” refers to heteroaryls having 5 to 14 ring atoms (i.e., C 5~14 Heteroaryl refers to monocyclic and bicyclic aromatic ring systems having a ring atom (heteroaryl) and 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. Heteroaryl groups are C 5~14 Heteroaryl groups and C 3~6Heteroaryl groups can be selected from heteroaryl groups. Heteroaryl can have 3 heteroatoms, 2 heteroatoms or 1 heteroatom. Heteroaryl can be C5 heteroaryl or C6 heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indyl, and aryl. These include zolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, triazolyl, tetrazolyl and phenoxazinyl.Heteroaryl includes thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl), pyrimidine (e.g., pyrimidin-4-yl, pyrimidin-5-yl), pyrimidine (e.g., pyrimidin-5-yl, pyrimidin-6-yl, pyrimidin-7-yl), pyrimidine (e.g., pyrimidin-8-yl, pyrimidin-9-yl), pyrimidine (e.g., pyrimidin-10-yl, pyrimidin-11-yl, pyrimidin-12-yl), pyrimidine (e.g., pyrimidin-13-yl, pyrimidin-14-yl), pyrimidine (e.g., pyrimidin-15-yl, pyrimidin-16-yl), pyrimidine (e.g., pyrimidin-17-yl, pyrimidin-18-yl), pyrimidine (e.g., pyrimidin-19-yl, pyrimidin-20-yl), pyrimidine (e.g., pyrimidin-21-yl, pyrimidin-22-yl), pyrimidine (e.g., pyrimidin-23-yl, pyrimidin-2 The heteroaryl group may be selected from the group consisting of 1,2,4-triazolyl and 1,2,3-triazolyl. The term "heteroaryl" is also intended to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxides.

[0253] For purposes of this disclosure, the term "optionally substituted heteroaryl," when used by itself or as part of another group, means that heteroaryl, as defined above, is unsubstituted or substituted with 1 to 4 substituents, e.g., 1 or 2 substituents, independently selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkoxycarbonyl, cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. The optional substituents can be alkoxy and cycloalkyl.

[0254] For purposes of this disclosure, the term "alkoxycarbonyl," when used by itself or as part of another group, refers to a carbonyl group substituted with an alkoxy group, i.e., -C(=O)-. Non-limiting exemplary alkoxycarbonyl groups are -CO2Me and CO2Et.

[0255] For purposes of this disclosure, the term "cycloalkyl," when used by itself or as part of another group, refers to an alkyl group having 3 to 12 carbon atoms (i.e., C 3~12 Cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having the specified number of carbons. Cycloalkyl groups can have two rings or one ring. Cycloalkyl groups include those listed in the C 3~8 Cycloalkyl groups and C 3~6 The cycloalkyl group can be selected from cycloalkyl groups. The cycloalkyl group can contain one or more carbon-carbon double bonds, or one carbon-carbon double bond. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0256] For purposes of this disclosure, the term "amine protecting group" as used herein refers to a group that blocks or protects an amine functionality while reactions occur with other functional groups or moieties of the molecule. Those skilled in the art will be familiar with the selection, attachment and cleavage of amine protecting groups and will understand that a variety of amine protecting groups are known in the art and that the suitability of one amine protecting group or another will depend on the particular synthetic scheme planned. Articles on this subject, such as Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Ed., J. Wiley & Sons, Inc., NY, 2014, are available for reference. Suitable amine protecting groups include, but are not limited to, t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, and toluenesulfonate.

[0257] For purposes of this disclosure, the term "base" as used herein refers to an organic proton acceptor. Non-limiting bases include "amine bases" such as non-nucleophilic tertiary amines, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and nitrogen-containing heteroaromatic groups, such as pyridine, and pyridine derivatives, such as 2,4,6-collidine and 2,6-lutidine.

[0258] For purposes of this disclosure, the term "coupling" or "coupled" as used herein refers to a chemical reaction in which two fragments or compounds are joined together via a carbon-carbon bond, optionally with the aid of a catalyst such as a metal catalyst (e.g., a palladium catalyst). The coupling reactions disclosed herein can occur in the presence of a palladium catalyst.

[0259] For the purposes of this disclosure, the term "sulfonating agent" as used herein refers to a reagent or combination of reagents used to form a bond between the oxygen atom and the sulfur atom in a sulfonate group. The sulfonating agent can be used to form a leaving group such as a triflate group, a mesylate group, or a tosylate group. A triflate group refers to -SO3CF3 or -OTf. A mesylate group refers to -SO3CH3 or -OMs. A tosylate group refers to -SO3C6H4CH3 or -OTs. Sulfonating agents are well known in the art. Any sulfonating agent known in the art can be used to form a leaving group in the compounds of the present disclosure and in the processes disclosed herein. Non-limiting exemplary sulfonating agents include toluenesulfonic anhydride, toluenesulfonyl chloride, methanesulfonic anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride.

[0260] For purposes of this disclosure, the term "alkylating agent" as used herein refers to a reagent or combination of reagents used to replace hydrogen with an alkyl group. An alkylating agent can be used to replace the hydrogen attached to a nitrogen with an alkyl group. Non-limiting exemplary alkylating agents include 2-iodopropane, 2-bromopropane, 2-isopropyl mesylate, and 2-isopropyl tosylate.

[0261] For purposes of this disclosure, the terms "reduce", "reduced" or "reduction", as used herein, refer to a chemical process that results in an increase in electrons or a decrease in the oxidation number of an atom or atoms in a compound. One example of "reduce" occurs when a triflate group (-OTf) is removed from a compound of formula V to form a compound of formula VI, as disclosed herein. Another example of "reduce" occurs when a cyano group in a compound of formula XII is converted to an aldehyde group in a compound of formula XI. The compound can be reduced, for example, in the presence of a palladium catalyst.

[0262] For purposes of this disclosure, the term "reducing agent" as used herein refers to a reagent or combination of reagents used to donate electrons to an electron acceptor. Reducing agents can be used, for example, to convert a cyano group in a compound of formula XII to an aldehyde group in a compound of formula XI. Reducing agents can also be used, for example, to remove a triflate group from a compound of formula V to form a compound of formula VI. Non-limiting exemplary reducing agents include sodium cyanoborohydride, diisobutylaluminum hydride, palladium and trialkylsilanes, hydrogen and palladium catalysts, lithium aluminum hydride, sodium borohydride, and sodium bis(2-methoxyethoxy)aluminum hydride.

[0263] For purposes of this disclosure, the term "palladium catalyst" as used herein refers to a reagent or combination of reagents containing palladium that is used to speed up chemical reactions, such as hydrogenation, dehydrogenation, and carbon-carbon bond formation, such as in coupling reactions. Palladium catalysts can be used to catalyze or speed up the reaction of removing a triflate group from a compound of formula V to form a compound of formula VI. Palladium catalysts can also be used to catalyze or speed up the coupling reaction between a compound of formula XIV and a compound of formula XXI, or between a compound of formula IX and a compound of formula XXI. Non-limiting exemplary palladium catalysts include (dppf)PdCl2, Pd2(dba)3, and Pd(PPh3)4.

[0264] For the purposes of this disclosure, the term "% AUC" as used herein means percent area under the curve. % AUC refers to a method of determining the relative amount of a particular product, as indicated by the area under the curve obtained from purification and / or measurement by high performance liquid chromatography (HPLC) after a chemical reaction. For example, a reaction that results in a compound of formula XVII having an AUC of less than 5% compared to a compound of formula XIV means that, after normalizing the integrals of the peaks corresponding to formula XVII and formula XIV, the compound of formula XVII is formed in an amount of less than 5% of the amount of the compound of formula XIV formed, as indicated by the area under the curve.

[0265] In another aspect, the present disclosure relates to a process for preparing a compound of formula XVIII, as shown in Scheme 1 below. [ka]

[0266] In another aspect, the present disclosure relates to a process for preparing a compound of formula XVIII, as shown in Scheme 2 below. [ka]

[0267] In another aspect, the present disclosure relates to a process for preparing a compound of formula XI, as shown in Scheme 3 below. [ka] EXAMPLES

[0268] Example 1: Synthesis of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XIII) The 100 L reactor was degassed and refilled with N2 three times. Water (61.8 kg) and NaOAc (18.8 kg, 246.3 mol, 4.0 equiv) were charged. Agitation was started and 1,1-dibromo-3,3,3-trifluoroacetone (30.9 kg, 258.6 mol, 2.0 equiv) was added. The batch was heated to reflux and stirred for 40 minutes, then cooled to 20-25 °C. The resulting pale yellow solution was added to a solution of 4-formylbenzonitrile (7.5 kg, 57.2 mol) and 25% aqueous NH4OH (35.0 kg, 514.7 mol, 9.0 equiv) in MeOH (88.9 kg, 15.0 vol) in a 300 L reactor while maintaining an internal temperature of ≦45 °C. The mixture was cooled to 20-25 °C and stirred for 16 hours. Water (24.5 kg) was carefully added to the mixture and stirred for 1 h. The resulting slurry was filtered and rinsed with 50% MeOH / H2O. The wet cake was dried under vacuum at 40°C to give 9.3 kg of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XIII) as a yellow solid (68.6% yield, 98.9% HPLC purity). LC-MS (ESI+): m / z 238.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.49 (br, 1H), 8.19 - 8.11 (m, 2H), 8.06 (q, J = 1.3 Hz, 1H), 8.01 - 7.93 (m, 2H).

[0269] Example 2: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XII) The 200 L reactor was degassed and refilled with N2 three times, followed by charging 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XIII, 10.4 kg, 43.8 mol) and acetonitrile (66.4 kg, 8.0 vol). Stirring was started and to the resulting solution was added Cs2CO3 (42.9 kg, 131.5 mol, 3.0 equiv) and 2-iodopropane (37.3 kg, 219.2 mol, 5.0 equiv). The batch was heated to 74-77 °C and stirred for 4 hours. The batch was then cooled to 20 °C and filtered. The filtrate was concentrated under vacuum at 40-45 °C to the minimum stirrable volume. The batch was then diluted with ethyl acetate (75.6 kg, 8.0 vol) and washed successively with water (21.0 kg) and brine (14.3 kg). The solvent was removed under reduced pressure at 40-45° C., followed by trituration of the resulting solid with n-heptane (35.7 kg, 5.0 vol) for 1 h and filtration. The filter cake was dried in a vacuum oven at 45° C. to give 10.6 kg of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XII) as a yellow solid (86.6% yield, 96.9% HPLC purity). LC-MS (ESI+): m / z 280.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.75 (m, 2H), 7.75 - 7.66 (m, 2H), 7.48 (q, J = 1.2 Hz, 2H), 4.55 (hept, J = 6.7 Hz, 1H), 1.50 (d, J = 6.7 Hz, 6H).

[0270] Example 3: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (XI) The 200 L reactor was evacuated and refilled with N2 three times. The reactor was charged with 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (XII, 10.4 kg, 37.2 mol) followed by dichloromethane (137.8 kg, 10.0 vol). Agitation was started and the resulting solution was cooled to -15°C. To this batch was added 1.0 M DIBAL-H solution in hexanes (38.4 kg, 55.9 mol, 1.5 equiv) over 2 hours while maintaining an internal temperature ≦0°C. After addition was complete the batch was stirred at -10°C for 1 hour. The reaction was then slowly quenched into a 500 L reactor with cold (0-5° C.) 5% aqueous H2SO4 (10.4 kg, 106.0 mol, 2.85 eq., water: 197.6 kg) while maintaining the internal temperature at <15° C. The batch was then heated to 30° C. for 24 hours and allowed to settle. The organic layer was separated and retained, and the aqueous layer was further extracted with dichloromethane (137.8 kg, 10.0 vol). The organic layers were combined, dried over Na2SO4 (15.0 kg), and filtered. The filtrate was concentrated under vacuum at 35-40° C. to a minimum volume and then diluted with EtOH (71.0 kg). The resulting solution (81.5 kg of solution containing 10.5 kg of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (XI, 99.9% yield, 93.3% HPLC purity) was taken directly to the next step. LC-MS (ESI+): m / z 283.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.98 - 7.89 (m, 2H), 7.72 - 7.65 (m, 2H), 7.41 (q, J = 1.2 Hz, 1H), 4.53 (hept, J = 6.7 Hz, 1H), 1.43 (d, J = 6.7 Hz, 6H).

[0271] Example 4: Synthesis of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (X) The 300 L reactor was evacuated and refilled with N2 three times, then charged with 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (XI, 17.3 kg, 61.3 mol) as a solution in EtOH (72.1 kg). tert-Butyl carbazate (8.5 kg, 64.3 mol, 1.05 eq) and AcOH (0.37 kg, 6.16 mol, 0.1 eq) as a solution in ethanol (81.8 kg) were added to the batch. The batch was stirred at 25° C. for 2 hours to allow the intermediate hydrazone to form, followed by the addition of triethylamine (0.62 kg, 6.13 mol, 0.1 eq). The batch was stirred for 30 minutes, then charged with 10% Pd / C (2.3 kg) under N2. The reactor was purged with hydrogen gas three times and the internal pressure was maintained at 0.002-0.008 MPa. The reaction was stirred at 25°C for 17 hours. The reactor was purged with N2 three times and the reaction mixture was filtered through Celite and washed with EtOH (27.3 kg, 2.0 vol). The filtrate was concentrated to a minimum volume under vacuum at 40-45°C, followed by charging ethyl acetate (138.1 L, 8.0 vol) and washing the batch with water (17.3 kg, 1.0 vol). The layers were separated and the organic layer was concentrated to a minimum volume under vacuum at 40-45°C. Ethyl acetate (31.1 kg, 2.0 vol) was then charged and the batch heated to 50-55°C. n-Heptane (138.4 L, 8.0 vol) was carefully added to the resulting solution while maintaining the internal temperature above 50°C. The mixture was cooled to 20-25° C. over 2 hours, followed by further cooling to 0-5° C. The resulting slurry was stirred at 0-5° C. for 1 hour, filtered, and washed with 20% v / v ethyl acetate / n-heptane (17.6 kg). The wet cake was dried under vacuum at 40-45° C. to give 19.4 kg of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (X) (79.4% yield, 99.2% HPLC purity) as an off-white solid. LC-MS (ESI+): m / z 399.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 7.55 - 7.44 (m, 4H), 7.42 (q, J = 1.2 Hz, 1H), 6.02 (s, 1H), 4.57 (hept, J = 6.7 Hz, 1H), 4.27 (s, 1H), 4.06 (s, 2H), 1.49 - 1.43 (m, 15H).

[0272] Example 5: Synthesis of ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl)-2-chloropyrimidine-5-carboxylate (IXa) To a slurry of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (X, 27 kg, 1 eq) in isopropanol (129.6 L, 4.8 vol) at 30±5° C. was added 2,6-lutidine (1.1 eq). The addition line was flushed with isopropanol (5.4 L, 0.2 vol). A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (16.5 kg, 1.1 eq) in isopropanol (135 L, 5 vol) was then added while maintaining the temperature at 30±5° C. The clear solution was stirred for 3 hours and then sampled for reaction completion by HPLC.

[0273] Upon completion of the reaction, the batch was heated to 50±5° C. and water (270 L, 10 vol) was then added over at least 1 hour while maintaining the batch temperature at 50±5° C. After water addition was complete, the batch was stirred at this temperature for at least 20 minutes while solids were allowed to settle. The batch was then cooled to 30±5° C. and stirred for an additional 4 hours, followed by filtration. The wet cake was washed with 50% isopropanol / water (81 L, 3 vol) and then dried under vacuum at 55-65° C. for 8-10 hours to give ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl)-2-chloropyrimidine-5-carboxylate (IXa) (34.3 kg, 86% yield, 99.4% HPLC purity) as an off-white solid. LC-MS (ESI+): m / z 583.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.32 (br s, 0.24H), 8.33 (s, 1H), 8.17 (s, 1H), 7.57 - 7.36 (m, 4H), 5.20 - 4.96 (m, 1H), 4.87 - 4.64 (m, 1H), 4.54 - 4.31 (m, 1H), 4.24-4.22 (m, 2H), 1.51 - 1.18 (m, 18H).

[0274] Example 6: Synthesis of ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl-4'-cyclopropyl-6'-methoxy-[2,5'-bipyrimidine]-5-carboxylate (VIIIa) To a mixture of ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl)-2-chloropyrimidine-5-carboxylate (IXa) (34 kg, 1 eq.) and cesium carbonate (56.8 kg, 3 eq.) in 1,4-dioxane (544 L, 16 vol.) and water (136 L, 4 vol.) at 30±5° C. was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid XXI (22.6 kg, 2 eq.). The batch was stirred for 15 minutes to produce a clear solution, and then the batch was purged with nitrogen / argon for 30 minutes. Under an inert atmosphere, (dppf)PdCl2 (3.2 kg, 7.5 mol %) was charged as a solid and the batch was purged with nitrogen / argon for an additional 15 minutes. The batch was then heated to 60-65°C for 2 hours and subsequently sampled periodically for reaction completion.

[0275] Upon completion of the reaction, the batch was cooled to 30±5° C. and filtered onto a bed of hyflow prepared with ethyl acetate. The filter cake was washed with ethyl acetate (68 L, 2 vol) and the combined filtrate was then distilled to 3.5±0.5 volumes while maintaining the temperature below 60° C. The batch was cooled to 30±5° C., followed by the addition of ethyl acetate (340 L, 10 vol) and water (340 L, 10 vol) and stirring the batch for at least 30 minutes. The layers were allowed to settle and separate, followed by washing the organic layer twice with 5% brine solution (340 L, 10 vol×2).

[0276] Charcoal (Norit CGP super, 6.8 kg, 0.2 wt eq.) was charged to the organic layer as a slurry in ethyl acetate (102 L, 3 vol) at 30±5° C. and the batch was stirred for not less than 2 hours. The batch was then filtered through a bed of hyflow prepared with ethyl acetate and the filter cake was washed with ethyl acetate (102 L, 3 vol). The combined filtrate was distilled to 4.0±0.5 volumes while maintaining the temperature below 60° C. Once distillation was complete, n-heptane (340 L, 10 vol) was added to the batch and the batch was heated to 60±5° C. to produce a clear solution. The batch was then cooled to 5±5° C. over a period of at least 4 hours, during which time the batch was allowed to crystallize. The batch was stirred at this temperature for at least 12 hours, then filtered and washed with n-heptane (102 L, 3 vol). The solid was dried under vacuum at 45-55° C. for 8 hours to give ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl-4'-cyclopropyl-6'-methoxy-[2,5'-bipyrimidine]-5-carboxylate (VIIIa) (34.3 kg, 84%, HPLC purity 97.5%) as a light brown solid. 1 Note that it appears as a rotamer by H NMR. LC-MS (ESI+): m / z 697.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 0.61H), 9.23 (s, 0.18H), 8.72 - 8.64 (m, 1H), 8.60 - 8.43 (m, 1H), 8.17 (s, 1H), 7.61 - 7.19 (m, 4H), 5.32 - 5.20 (m, 0.50H), 5.06-5.02 (m, 0.22H), 4.90 - 4.72 (m, 0.22H), 4.72 - 4.55 (m, 0.50H), 4.48 - 4.36 (m, 1H), 4.34 - 4.19 (m, 2H), 3.86 (s, 3H), 1.76 - 1.63 (m, 1H), 1.44 - 1.37 (m, 12H), 1.34-1.31 (m, 3H), 1.08 - 0.98 (m, 4.76H), 0.94 - 0.81 (m, 2H).

[0277] Example 7: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (VII) To a mixture of ethyl 4-(2-(tert-butoxycarbonyl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazineyl-4'-cyclopropyl-6'-methoxy-[2,5'-bipyrimidine]-5-carboxylate (VIIIa) (34.3 kg, 1 eq.) and toluene (343 L, 10 vol) at 30±10° C. was added TFA (56.2 kg, 10 eq.) while maintaining the temperature below 40° C. The batch was then heated to 50-55° C. and stirred at that temperature for at least 1 hour. The batch was then sampled periodically for reaction completion.

[0278] Upon completion of the reaction, the batch was cooled to 30-35°C and diluted with ethyl acetate (412L, 12vol). Aqueous sodium carbonate (31.3kg Na2CO3 in 6vol water) was then carefully added over time while maintaining the batch temperature at 30-35°C. After addition was complete, the batch was stirred for a further 30 minutes and then the layers were allowed to separate. The aqueous layer was back extracted with ethyl acetate (172L, 5vol) and then the combined organic layers were washed with 10% aqueous sodium chloride (172L, 5vol). The batch was then distilled under vacuum to 3.0±0.5vol while maintaining an internal temperature below 60°C. The batch was then cooled to 30±5°C and n-heptane (343L, 10vol) was added to produce a slurry. The batch was then stirred at this temperature for at least 4 hours, filtered and washed with n-heptane (69L, 2vol). The wet cake was dried under vacuum at 50-60° C. for 8 hours to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (VII) (23.2 kg, 86%, HPLC purity 96.8%) as a light brown solid. LC-MS (ESI+): m / z 551.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ12.31-11.43 (m, 1H), 9.28 (s, 1H), 8.69 (s, 1H), 8.16 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 5.52 (s, 2H), 4.50 - 4.30 (m, 1H), 3.86 (s, 3H), 1.77 - 1.62 (m, 1H), 1.38 (d, J = 6.7 Hz, 6H), 1.08 - 0.99 (m, 2H), 0.88-0.86 (m, 2H).

[0279] Example 8: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl trifluoromethanesulfonate (V) To a solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (VII) (7.46 kg, 1 eq.) in dichloromethane (75 L, 10 vol) at 30±5° C. was added triethylamine (2.8 kg, 1.5 eq.) and the clear solution was cooled to 0±5° C.

[0280] Trifluoromethanesulfonic anhydride (5.74 kg, 1.5 eq) was then carefully added to the batch while maintaining the temperature between 0±5°C. The clear reaction mixture was stirred at that temperature for at least 1 hour and then sampled periodically for reaction completion. Once the reaction was complete, water (75 L, 10 vol) was then carefully added over time while maintaining the batch temperature between 0±5°C. The batch was then warmed to 30±5°C and stirred at this temperature for at least 15 minutes and the layers were allowed to separate. The aqueous layer was extracted with dichloromethane (37.3 L, 5 vol) and then the combined organic layers were washed with water (75 L, 10 vol). The solvent was then distilled under vacuum to 3.0±0.5 volumes while maintaining the temperature below 40°C. The batch was then carefully added to pre-cooled (0-5°C) n-heptane (149 L, 20 vol) over at least 3 hours. The resulting slurry was stirred at this temperature for at least 2 hours, then warmed to 30±5° C. and stirred for an additional 3 hours. The slurry was then filtered and dried under vacuum at 40-45° C. for 8 hours to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl trifluoromethanesulfonate (V) (8.5 kg, 92%, HPLC purity 93%) as a light brown solid. LC-MS (ESI+): m / z 683.2 [M+H] + ;δ 9.69 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 7.59-7.52 (m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 5.81 (s, 2H), 4.45-4.40 (m, 1H), 3.87 (s, 3H), 1.76-1.74 (m, 1H), 1.38 (d, J = 6.6 Hz, 6H), 1.17 - 1.05 (m, 2H), 1.00 - 0.80 (m, 2H).

[0281] Example 9: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) from 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl trifluoromethanesulfonate (V). To a stirred solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl trifluoromethanesulfonate (V) (7.2 kg, 1 equiv.) in 1,4-dioxane (72 L, 10 vol.) was added (dppf)PdCl2 (230 g, 3 mol %) at 30±5° C. The batch was heated to 75-85° C., and subsequently a solution of triethylsilane (3.74 kg, 2.5 equiv.) and triethylamine (1.3 kg, 1.2 equiv.) in dioxane (14 L, 2 vol.) was added to the reaction mixture while maintaining the temperature at 75-85° C. The batch was heated at temperature for 2 hours and then sampled periodically for reaction completion.

[0282] Upon completion of the reaction, the batch was distilled under vacuum to 2-3 volumes followed by the addition of MTBE (144 L, 20 vol) and water (72 L, 10 vol). The temperature of the batch was adjusted to 30±5°C and stirred at that temperature for 30 minutes followed by filtration through a bed of hyflow. The resulting layers were then separated and the organic layer washed with water (72 L, 10 vol). The organic layer was treated with activated carbon (1.4 kg, 20% w / w) and the resulting slurry was held at 30±5°C for at least 4 hours. The batch was filtered through a bed of hyflow followed by distillation under vacuum to 5 volumes. The temperature of the batch was adjusted to 45-55°C followed by the addition of n-heptane (108 L, 15 vol) and maintaining the temperature within that range throughout the addition. After addition was complete, the batch was stirred at that temperature for 30 minutes followed by cooling to 30±5°C. The batch was stirred at temperature for an additional 2-3 hours, then filtered and the wet cake washed with n-heptane (14 L, 2 vol.) The wet cake was dried under vacuum at 45-50° C. to give the crude product (4.25 kg).

[0283] The crude product was then recrystallized using the following process: The volumes and equivalents used are for the crude product and not the initial charge, Formula V.

[0284] The crude product of formula (VI) (4.25 kg, 1 equiv.) was dissolved in methanol (34 L, 8 vol) and dichloromethane (8.5 L, 2 vol) followed by the addition of activated carbon (0.72 kg, 10% w / w). The batch was stirred at 30±5° C. for not less than 2 hours and then filtered through a bed of hyflow. The batch was distilled under vacuum to 2.5 volumes followed by the addition of methanol (10.6 L, 2.5 vol) and triethylamine (4.2 L, 1 vol) and the temperature adjusted to 50±5° C. To this clear solution was added water (21.2 L, 5 vol) over at least 1 hour. The batch was stirred at temperature for 30 minutes and then cooled to 0-5° C. over at least 4 hours. The resulting solid was filtered, washed with 50% methanol:water (8.5 L, 2 vol), and then dried at 45-55° C. to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) (3.5 kg, 62%, HPLC purity 98.8%) as a pale yellow solid. LC-MS (ESI+): m / z 535.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 5.77 (s, 2H), 4.45-4.34 (m, 1H), 3.83 (s, 3H), 1.60-1. 67 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.04 (m, 2H), 0.83 (m, 2H).

[0285] Example 10: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine gentisic acid cocrystal (XVIII) To a slurry of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) (5.0 kg, 1 equiv.) in isopropanol (30 L, 6 vol.) at 30±5° C. was added gentisic acid (1.44 kg, 1 equiv.). The resulting slurry was heated to 72.5±2.5° C. for 30 minutes to produce a clear solution. To this solution was charged n-heptane (50 L, 10 vol.) over at least 2 hours. After addition of n-heptane was complete, the batch was stirred at 72.5±2.5° C. for 30 minutes and then cooled to 30±5° C. over 2-4 hours. The batch was stirred at that temperature for 16-20 hours, then filtered, washed with n-heptane (10 L, 2 vol) and dried under vacuum at 60±5° C. for 8 hours to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine gentisic acid cocrystal (XVIII) (5.82 kg, 90%, HPLC purity 99.1%) as a white solid. LC-MS (ESI+): m / z 535.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.736 (s, 1H), 10.642 (s, 1H), 9.509 (s, 1H), 9.131 (s, 1H), 8.709 (s, 1H), 8.520 (s, 1H), 8.156 (s, 1H), 7.528 (d, J = 8 Hz, 2H), 7.425 (d, J = 8 Hz, 2H), 7.153 (d, J = 3.2 Hz, 1H), 6.956 (dd, J = 8.8, 2.8 Hz, 1H), 6.780 (d, J = 8 Hz, 1H), 5.792 (s, 2H), 4.409 (sept, J = 6.8 Hz, 1H), 3.853 (s, 3H), 1.660 (m, 1H), 1.373 (d, J = 6.8 Hz, 6H), 1.060 (m, 2H), 0.850 (m, 2H).

[0286] Example 11: Synthesis of 2-(4-(hydrazineylmethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole dihydrochloride (XV) A 20 L 4-neck flask was purged 3 times with N2. tert-Butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (X) (1.25 kg, 3.14 mol) and isopropanol (6.25 L, 5.0 vol) were charged. Agitation was started and the batch was heated to 75-80°C. 4M HCl in isopropanol (3.14 L, 12.56 mol, 4.0 equiv) was carefully added over 2 hours. The batch was held at 75-80°C with stirring for an additional 3 hours. Once the reaction was complete, the batch was cooled to 25-30°C over 4 hours. The resulting slurry was filtered and the solids were rinsed with isopropanol (2.5 L, 2 vol). The solid was collected and dried under vacuum at 40-45° C. for 22 hours to give 2-(4-(hydrazineylmethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole dihydrochloride (XV) (1.10 kg, 94% yield, 98.6% AUC by HPLC) as an off-white solid. LC-MS (ESI+): m / z 298.8 (C 14 H 17 F3N4+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (q, J = 1.2 Hz, 1H), 7.59 (s, 4H), 6.89 (br, 5H), 4.48 (hept, J = 6.5 Hz, 1H), 4.16 (s, 2H), 1.42 (d, J = 6.6 Hz, 6H).

[0287] Example 12: Synthesis of 6-chloro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XIV) A suitable reactor was charged with 2-(4-(hydrazineylmethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole dihydrochloride (XV) (72 g, 1 eq) and absolute ethanol (20 vol). The reaction mixture was cooled to -10°C and inerted with argon gas. Triethylamine (81.2 mL, 3 eq) was added to the reactor while maintaining the temperature below -5°C. After addition was complete, the mixture was cooled to -10°C. To the cooled batch was added 2,4-dichloropyrimidine-5-carboxaldehyde XVI (41.2 g, 1.2 eq) as a solid in small portions over 30-40 minutes. The batch was stirred at -10°C until the reaction was complete as monitored by HPLC.

[0288] After completion of the reaction, the batch was allowed to warm to room temperature and the solvent was removed under vacuum on a rotovap (60° C.) All volume references below are for the crude solid obtained after concentration.

[0289] Crude compound XIV was dissolved in DCM (5 vol) and washed with water (5 vol x 2) followed by 2% aqueous HCl (5 vol). The organic layer was dried over sodium sulfate followed by removal of the solvent under vacuum at 35°C. Crude compound was dissolved in ethanol (7 vol) and refluxed for 2 hours, then the batch was cooled to 75°C and water (3 vol) was added at the same temperature over 1 hour. The batch was then cooled to 20-25°C over 4 hours followed by further cooling to -10°C. The resulting slurry was stirred at -10°C for 12 hours. The solid was filtered and washed with cold 1:1 ethanol / water mixture (1 vol). The solid was dried under vacuum at 50-55° C. to give 6-chloro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XIV) as a yellow solid (71.1 g, 87.1% yield, 94.7% AUC by HPLC, containing <0.1% AUC of N2 isomer formula XVII). LC-MS (ESI+): m / z 420.9 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.19 (s, 1H), 7.54 - 7.50 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 5.69 (s, 2H), 4.51 (hept, J = 6.7 Hz, 1H), 1.43 (d, J = 6.7 Hz, 6H).

[0290] Example 13: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) from 6-chloro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XIV) A suitable reactor was charged with 6-chloro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XIV) (50 g, 1.0 eq.), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid XXI (27.7 g, 1.2 eq.), and (dppf)PdCl2 (6.52 g, 7.5 mol %) followed by degassed 1,4-dioxane (16 vol) at 20-25° C. under nitrogen atmosphere. The resulting mixture was further degassed using three vacuum / nitrogen cycles. The reaction mixture was heated to 35-40° C., followed by dropwise addition of Cs2CO3 (3 eq.) in degassed DI water (4 vol). The reaction temperature was increased to 75° C. and stirring was continued until the reaction was complete.

[0291] After completion of the reaction, the reaction mixture was cooled to 20-25° C., filtered through a pad of Celite, and washed successively with ethyl acetate (2 vol). The solvent was then removed under reduced pressure. All volume references below are for crude compound VI obtained after concentration.

[0292] Crude compound (VI) was dissolved in ethyl acetate (10 vol) and the organic layer was washed with water (10 vol x 2) followed by brine (10 vol). Activated carbon (Acticarbone® ENO-PC, 10% w / w) was charged as a slurry in ethyl acetate (3 vol) and the reaction mixture was stirred at 30±5° C. for 2 hours. The reaction mixture was filtered through a Celite pad and rinsed with ethyl acetate (3 vol). The carbon treatment was then repeated.

[0293] After the second carbon treatment, the solvent was removed at 60° C. to give a solid. The solid was recrystallized by adding ethyl acetate (3 vol) and heating to 78° C. for 1 h. In batches, n-heptane (7 vol) was slowly added to the reaction mixture at 70-75° C. and the resulting mixture was stirred at that temperature for 1 h. The mixture was cooled to 25° C. over 3-4 h and then stirred at that temperature for 12 h. The slurry was filtered, washed with n-heptane (2 vol), and then dried under vacuum at 50-55° C. overnight to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) (43 g, 67.7% yield; 98.8% AUC by HPLC) as a pale yellow solid. LC-MS (ESI+): m / z 535.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.69 (s, 1H), 8.24 (s, 1H), 7.57 - 7.47 (m, 4H), 7.40 (d, J = 1.4 Hz, 1H), 5.77 (s, 2H), 4.50 (hept, J = 6.7 Hz, 1H), 3.94 (s, 3H), 1.69 (tt, J = 8.3, 4.6 Hz, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.30 - 1.20 (m, 2H), 0.89 (dt, J = 8.1, 3.4Hz, 2H).

[0294] Example 14: Synthesis of 6-cyclopropyl-5-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-ol (XXV) A solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) (10 g, 1 equiv.) in 2N HCl (10 vol) was heated to 65-70° C. and stirred for 3 h. After completion, the reaction was cooled to 20-25° C. and washed with EtOAc (5 vol). The pH of the aqueous layer was adjusted to 7.5-8.0 with 10% aqueous sodium carbonate (5 vol) followed by extraction of the product with EtOAc (2×10 vol). The organic layer was distilled under vacuum at 50° C. and the solid was suspended in ethyl acetate (1 vol) and n-heptane (2 vol). The resulting slurry was heated to 50-55° C. and stirred for 1 h followed by cooling to room temperature. The solid was filtered and subsequently dried under vacuum at 55-60° C. to give 6-cyclopropyl-5-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrimidin-4-ol (XXV) (7 g, 72%, 97.4% AUC by HPLC). LC-MS (ESI+): m / z 521.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6):δ 12.61 (br s, 1H), 9.47 (s, 1H), 8.49 (s, 1H), 8.16 (d, J = 4.9 Hz, 2H), 7.53-7.51 (m, 2H), 7.42-7.40 (m, 2H), 5.78 (s, 2H), 4.45-4.39 (m, 1H), 1.59 - 1.46 (m, 1H), 1.37 (d, J = 6.7 Hz, 6H), 1.01-0.99 (m, 2H), 0.78-0.75 (m, 2H).

[0295] Example 15: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (XXVI) To a solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (VI) (10 g, 1 eq.) in THF (5 vol.) was charged sodium borohydride (5 eq.) and stirred for 15 min. The reaction mixture was cooled to 0-5° C. and acetic acid (0.1 vol.) was added dropwise. After completion of the reaction, the batch was basified with sodium bicarbonate and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 vol.) followed by the organic layers being combined and washed with brine (10 vol.). The solvent was removed under vacuum and the resulting crude was purified by column chromatography over neutral alumina (80-90% EtOAc / n-heptane). The product obtained from column chromatography was slurried in ethyl acetate (1 vol) and n-heptane (2 vol) at 50-55° C. and stirred for 1 hour, followed by cooling to room temperature. The solid was filtered and dried under vacuum to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (XXVI) (9 g, 89%, 98% AUC by HPLC). LC-MS (ESI+): m / z 537.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6):δ 8.62 (s, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.15 (s, 1H), 5.25 (s, 2H), 4.74 (s, 2H), 4.44-4.41 (m, 1H), 3.93 (s, 3H), 2.18 - 2.08 (m, 1H), 1.47 - 1.32 (m, 6H), 1.03-1.01 (m, 2H), 0.98 - 0.87 (m, 2H).

[0296] Example 16: Synthesis of 6-chloro-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine (XVII) [ka] Step 1: To a solution of aldehyde (XI) (5 g, 1.0 equiv.) in methanol (10 vol.) was added sodium borohydride (3.35 g, 5 equiv.) at 0° C. and the reaction progress was monitored by TLC (ethyl acetate / hexane=1:1). After completion of the reaction, the batch was poured into water (20 vol.) and left under stirring for 3 hours. The precipitated solid was filtered and dried under vacuum at 60° C. to give alcohol (XXIII) (4.5 g, 89.3% yield, 96.3% AUC by HPLC).

[0297] Step 2: To a mixture of alcohol (XXIII) (4 g, 1 eq.) in 1,2-dichloroethane (8 vol.) was added thionyl chloride (3 eq.) at room temperature and the reaction was stirred at that temperature for 4 h. Once the reaction was complete, n-heptane (10 vol.) was added to the reaction mixture and left to stir for 2 h. The precipitated solid was filtered and dried under vacuum at room temperature to give benzylic chloride (XXIV) (4.25 g, 99%, HPLC purity 97.8%).

[0298] Step 3: To a solution of benzylic chloride (XXIV) (1 g, 1 eq.) in DMF (10 mL, 10 vol), 6-chloropyrazolopyrimidine (2.06 g, 1.05 eq.) and K2CO3 (1.37 g, 3.0 eq.) were added. After stirring at room temperature for 8 h, the mixture was quenched with water and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 8:3) to give both regioisomers of formula (XIV) and (XVII) in a ratio of 1.2:1.

[0299] Characterization data for formula XVII: LC-MS (ESI+): m / z 421.3 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 9.06 (s, 1H), 8.18 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 5.85 (s, 2H), 4.43 (hept, 1H), 1.36 (d, 6H).

[0300] Example 17: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine (XX) [ka] To a solution of formula (XVII) (20 g, 1 eq) in 1,4-dioxane (16 vol) and water (4 vol) was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (XXI, 2 eq) and the batch was purged with argon gas for 45 minutes. The batch was charged with cesium carbonate (3 eq) followed by Pd(dppf)Cl2 (0.075 eq) at room temperature and the batch was purged with argon gas for 15 minutes.

[0301] The batch was heated to 65±5° C. for 2 hours. After consumption of the starting material, the batch was cooled to room temperature. The reaction mixture was filtered through a hyflo bed and the bed was washed with ethyl acetate (3 vol). The filtrate was concentrated under reduced pressure at ≦60° C. to 2.5±0.5 volumes. The batch was diluted with ethyl acetate (10 vol) and washed with water (10 vol). The aqueous layer was re-extracted with ethyl acetate (10 vol). The combined organic layers were washed with 10% sodium chloride solution (10 vol) and subsequently concentrated to dryness. The crude product was purified by column chromatography using neutral alumina and eluting the product with 50-80% ethyl acetate / n-heptane to give formula (XX) (10 g, 40%, 99.2% AUC by HPLC) as a pale yellow solid. LC-MS (ESI+): m / z 535.0 [M+H] + .

[0302] Example 18: Synthesis of 6-chloro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XIV) from tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (X). [ka] Formula (X) (10.0 g, 1.0 equiv), isopropanol (200 mL, 20 vol) and 2,6-lutidine (3.0 g, 1.1 equiv) were charged to a round bottom flask to form a reaction mixture which was cycled with nitrogen / vacuum three times. Formula (XVI) (4.9 g, 1.1 equiv) was added as a small portioned solid to the reaction mixture at 20-25°C. The reaction mixture was then heated to 50-55°C and stirred for 16 hours. HPLC was used to monitor the progress of the reaction. Concentrated HCl (4.9 g, 2.0 equiv) was then added to the mixture and stirred for an additional 4 hours to complete the Boc deprotection and condensation to form the pyrazolopyrimidine core.

[0303] The reaction mixture was cooled to 20-25°C and subsequently concentrated to dryness under reduced pressure at 40-45°C using a rotary evaporator. The crude compound was fractionated using ethyl acetate (100 mL) and water (100 mL) and stirred for 30 min. The aqueous phase was further extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine and dried under reduced pressure at 40-45°C to give a solid (11.9 g). The solid was purified by column chromatography (silica gel; hexane / ethyl acetate, 3:1) to give formula (XIV) (3.5 g, 33.2% yield) as a pale yellow solid (96.5% by HPLC).

[0304] Example 19: Synthesis of tert-butyl 2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (XXVIII) [ka]

[0305] A 500 mL flask was purged with N2 and then charged with Formula XXVII (20 g, 1.0 equiv) and EtOH (200 mL, 10 vol) and stirring was started. tert-Butyl carbazate (11.5 g, 1.05 equiv) and acetic acid (0.5 g, 0.1 equiv) were charged. The reaction was then stirred at 25°C for 2 hours. Triethylamine (0.84 g, 0.1 equiv) and 10% Pd / C (2.5 g, 12.5% ​​w / w) were then charged. The flask was then flushed with H2 gas three times and stirred at 25-30°C under 1 atm of H2 for approximately 6 hours. Upon completion of the reaction, the mixture was filtered through Celite and rinsed with EtOH (60 mL, 3 vol). The filtrate was collected and concentrated under vacuum at approximately 45°C. The resulting material was dissolved in ethyl acetate (200 mL, 10 vol) followed by washing with water (20 g, 1 vol). The phases were separated. The organic phase was concentrated at about 45° C. and charged with n-hexane (100.0 mL, 5 vol). The mixture was stirred at 20-25° C. for 1 hour. The mixture was filtered and the solid was rinsed with n-hexane (20 mL, 1 vol). The solid was dried under vacuum at 45-45° C. to give Formula XXVIII (28.4 g, 96% yield, 98.3% HPLC purity) as a white solid.

[0306] 1 H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.93 - 7.87 (m, 3H), 7.46 - 7.39 (m, 2H), 4.87 - 4.80 (m, 1H), 3.91 (d, J = 4.2 Hz, 2H), 1.38 (s, 9H)

[0307] Example 20: Synthesis of 2-(4-(hydrazineylmethyl)phenyl)-4-(trifluoromethyl)-1H-imidazole hydrochloride (XXVIV) from tert-butyl 2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)hydrazine-1-carboxylate (XXVIII) [ka] A 250 mL flask was purged with nitrogen and then charged with Formula XXVIII (5 g, 1.0 equiv) and isopropanol (50 mL, 10 vol). The resulting solution was heated to 70-75° C. and HCl (4 M in isopropanol, 14.0 mL, 4.0 equiv) was added dropwise over at least 30 min. The reaction was allowed to stir at 70-75° C. for at least 2 h and then cooled slowly to 20-25° C. The mixture was filtered and the solid was rinsed with isopropanol (30 mL, 6 vol). The solid was dried under vacuum at 45-50° C. to give Formula XXVIV (3.6 g, 78% yield, 99.2% HPLC purity) as a white solid.

[0308] 1 H NMR (400 MHz, DMSO) δ 13.43 (s, 1H), 8.05 - 7.98 (m, 2H), 7.92 (m, 1H), 7.55 - 7.49 (m, 2H), 4.10 (s, 2H)

[0309] Example 21: Synthesis of 6-chloro-1-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine (XXX) from 2-(4-(hydrazineylmethyl)phenyl)-4-(trifluoromethyl)-1H-imidazole hydrochloride (XXVIV) [ka] A 250 mL flask was purged with nitrogen and then charged with Formula XXVIV (3 g, 1.0 equiv) and ethanol (60 mL, 20 vol) and stirring was initiated. The solution was cooled to approximately -10°C. Triethylamine (2.8 g, 3.0 equiv) was added dropwise. Formula XVI (1.94 g, 1.2 equiv) was then added portionwise while maintaining the internal temperature below -5°C. The reaction was stirred for 4 hours and then warmed to 20-25°C. The mixture was concentrated to dryness at 60°C and the residual material was charged with dichloromethane (30 mL, 10 vol) and water (15 mL, 5 vol). The biphasic mixture was filtered and the phases were then separated. The organic phase was concentrated under vacuum at 40°C to give a yellow solid (2.9 g, 82.9% yield, 87.1% HPLC purity). An analytical sample (HPLC purity 99%) can be prepared by trituration with 10 vol MeOH at 20-25 °C.

[0310] 1 H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.32 (s, 1H), 8.52 (s, 1H), 7.98 - 7.89 (m, 3H), 7.40 - 7.33 (m, 2H), 5.69 (s, 2H)

[0311] It is to be understood that the foregoing embodiments and examples are not intended to limit the scope of the disclosure in any way, and that the claims presented herein are intended to encompass all embodiments and examples, whether or not expressly presented herein.

[0312] All patents and publications cited herein are incorporated by reference in their entirety.

Claims

1. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is cyano, -CHO, -CH ２ NR ２ R ３ and -CH ２ R ４ Selected from: R ２ is selected from hydrogen, optionally substituted aryl, and optionally substituted heteroaryl; R ３ represents hydrogen, amino, and —NR ５ R ６ Selected from: R ４ is represented by Formula II and Formula III: 【Chemistry 2】 is selected from R ５ and R ６ are independently selected from hydrogen and an amine protecting group; R ７ is selected from optionally substituted aryl, and optionally substituted heteroaryl; R ８ is selected from carbonyl, alkoxy and sulfonate; R ９ is selected from hydroxy, alkoxy, sulfonate and leaving groups, or a pharmaceutically acceptable salt thereof.

2. (i) R 3 is —NR 5 R 6 , and R ５ and R ６ One of the groups is hydrogen and the other R ５ and R ６ is an amine protecting group selected from t-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine and toluenesulfonate; preferably the amine protecting group is t-butyloxycarbonyl (Boc); or (ii) R 1 is —CH 2 NR 2 R 3 , R 2 is hydrogen, and R 3 is amino; or (iii) R 1 is CH 2 NR 2 R 3 and R 2 is an optionally substituted pyrimidinyl; or (iv) R 7 is a group represented by formula XIX: 【Transformation 3】 and During the ceremony, R 12 and R 13 are independently selected from hydrogen, hydroxy, alkyl, alkoxy and cycloalkyl; preferably R 12 is cyclopropyl and R 13 is methoxy; or (v) the leaving group is selected from trifluoromethanesulfonate, toluenesulfonate, methanesulfonate, and halogen; preferably the leaving group is trifluoromethanesulfonate.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound 【Chemistry 4】 is selected from the group consisting of During the ceremony, R ９ is the leaving group, R １４ is an amine protecting group; or The compound 【Transformation 5】 selected from the group consisting of 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. Formula IV: 【Transformation 6】 or a pharmaceutically acceptable salt thereof; During the ceremony, R １０ but, 【Transformation 7】 and R １１ is hydrogen or alkyl; Preferably, the compound is 【Transformation 8】 Selected from: The compound or a pharmaceutically acceptable salt thereof.

5. Formula VI: 【Chemistry 9】 1. A process for preparing a compound of formula (I), comprising: Formula V: 【Chemistry 10】 and optionally reducing a compound of formula (I) (i) the reducing occurs in the presence of a palladium catalyst and a trialkylsilane, preferably in the presence of a palladium catalyst and triethylsilane; or (ii) the process comprises mixing the compound of formula VI with gentisic acid in a solvent to produce a compound of formula XVIII: 【Chemistry 11】 Preferably, said compound of formula VI is mixed with gentisic acid in the presence of a solvent, more preferably said solvent is a mixture of isopropanol and heptane. The process.

6. Formula Va: 【Chemistry 12】 wherein R ９ is a leaving group selected from trifluoromethanesulfonate, toluenesulfonate, and methanesulfonate; Formula VII: 【Chemistry 13】 with toluenesulfonic anhydride, toluenesulfonyl chloride, methanesulfonic anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to form a compound of formula Va; Preferably, the compound of formula VII is reacted with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride. The process.

7. Formula VII: 【Chemistry 14】 1. A process for preparing a compound of formula (I), comprising: Formula VIII: 【Chemistry 15】 or a salt thereof with an acid to form a compound of formula VII, In the formula, R １４ is an amine protecting group; preferably (i) the acid is trifluoroacetic acid; or (ii) the reaction occurs in the presence of toluene as a solvent; (iii) the reaction occurs at a temperature of about 20°C to about 55°C; and / or (iv) the amine protecting group is t-butyloxycarbonyl (Boc); The process.

8. Formula VIII: 【Chemistry 16】 or a salt thereof, comprising: Formula IX: 【Chemistry 17】 or a salt thereof, (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid to form a compound of formula VIII; In the formula, R １４ is an amine protecting group; preferably (i) the coupling occurs in the presence of a palladium catalyst; or (ii) the coupling occurs in the presence of a solvent selected from 1,4-dioxane, water, and mixtures thereof; or (iii) the coupling occurs at a temperature of about 20°C to about 65°C; and / or (iv) the amine protecting group is t-butyloxycarbonyl (Boc); The process.

9. Formula IX: [Chemistry 18] or a salt thereof, comprising: Formula X: 【Chemistry 19】 or a salt thereof with 2,4-dichloropyrimidine-5-carboxylic acid ester to form a compound of formula IX, In the formula, R １４ is an amine protecting group; preferably (i) the 2,4-dichloropyrimidine-5-carboxylic acid ester is ethyl 2,4-dichloropyrimidine-5-carboxylate; or (ii) the 2,4-dichloropyrimidine-5-carboxylic acid ester is isopropyl 2,4-dichloropyrimidine-5-carboxylate; or (iii) reacting the compound of formula X with 2,4-dichloropyrimidine-5-carboxylic acid ester in the presence of a base and a solvent, wherein preferably the base is an amine base and the solvent is an alcohol solvent, preferably the amine base is 2,6-lutidine, and preferably the solvent is isopropanol; and / or (iv) the amine protecting group is t-butyloxycarbonyl (Boc); The process.

10. Formula X: 【Chemistry 20】 or a salt thereof, comprising: Formula XI: 【Chemistry 21】 with tert-butyl carbazate and a reducing agent to form a compound of formula X; preferably (i) reacting the compound of formula XI with tert-butyl carbazate in the presence of sodium cyanoborohydride; or (ii) reacting the compound of formula XI with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst; The process.

11. Formula XI: 【Chemistry 22】 1. A process for preparing a compound of formula XII: 【Chemistry 23】 with a reducing agent to form a compound of formula XI; Preferably, the reducing agent is diisobutylaluminum hydride. The process.

12. Formula XII: 【Chemistry 24】 1. A process for preparing a compound of formula (I), comprising: Formula XIII: 【Chemistry 25】 with an alkylating agent to form a compound of formula XII; preferably (i) the alkylating agent is selected from 2-iodopropane, 2-bromopropane, 2-isopropyl mesylate, and 2-isopropyl tosylate; or (ii) the alkylating agent is 2-iodopropane; process.

13. Formula XIV: 【Chemistry 26】 1. A process for preparing a compound of formula (I), comprising: Formula XV: 【Chemistry 27】 or a salt thereof, with a compound of formula XVI: 【Chemistry 28】 with a compound of formula XIV to form a compound of formula XIV; preferably (i) reacting said compound of formula XV with said compound of formula XVI in the presence of a solvent and a base, preferably said solvent is selected from ethanol, isopropanol and tetrahydrofuran, preferably said base is an amine base, more preferably said base is selected from triethylamine and diisopropylethylamine; or (ii) reacting the compound of formula XV with the compound of formula XVI at a temperature of −20° C. to 25° C.; or (iii) said reaction of said compound of formula XV with said compound of formula XVI gives a compound of formula XVII: 【Chemistry 29】 also forms a compound of the formula: Preferably, the compound of formula XVII forms an AUC of less than 5% compared to the area of ​​the compound of formula XIV. Preferably, said compound of Formula XIV is isolated containing an AUC of less than 1%, less than 0.5%, less than 0.25%, or less than 0.15% of said compound of Formula XVII; or (iv) said process converting said compound of formula XIV into a compound of formula XXI: 【Transformation 30】 to form a compound of formula VI: 【Chemistry 31】 and further comprising obtaining a compound of formula (I) Optionally, the compound of formula VI may be mixed with gentisic acid in a solvent to produce a compound of formula XVIII: 【Chemistry 32】 and further comprising forming a compound of The process. (i) A compound of formula XIV: prepared by the process of claim 13, item (i). 【Transformation 33】 or a salt thereof; or (ii) Formula XVII: 【Transformation 34】 or a salt thereof; or (iii) Formula XX: 【Chemistry 35】 or a salt thereof; or (iv) Formula XXVIII: 【Transformation 36】 or a salt thereof; or (v) Formula XXVIV: 【Chemistry 37】 or a salt thereof; or (vi) Formula XXX: 【Transformation 38】 or a salt thereof A compound.

15. Formula XIV: 【Chemistry 39】 1. A process for preparing a compound of formula (I), comprising: Formula X: 【Chemistry 40】 or a salt thereof, with a compound of formula XVI: 【Chemistry 41】 with a compound of formula XIV to form a compound of formula XIV In the formula, R １４ is an amine protecting group.

16. Formula XXX: 【Chemistry 42】 2. A process for preparing a compound of formula XXVII: 【Chemistry 43】 or a salt thereof, with a compound of formula XVI: 【Chemistry 44】 with a compound of formula XXX to form a compound of formula XXX; preferably (i) reacting the compound of formula XXVIV with the compound of formula XVI in the presence of a solvent and a base; Preferably, the solvent is selected from ethanol, isopropanol and THF. Preferably, the base is an amine base, more preferably the base is selected from triethylamine and diisopropylethylamine; or (ii) the reaction is carried out at a temperature of from −20° C. to 25° C.; The process.

17. Formula XXVIV: 【Chemistry 45】 or a salt thereof, comprising: Formula XXVIII: 【Chemistry 46】 with an acid to form a compound of formula XXVII, or a salt thereof; preferably (i) the acid is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; or (ii) the reaction is carried out at a temperature of from 0°C to 75°C; The process.

18. Formula XXVIII: 【Chemistry 47】 or a salt thereof, comprising: Formula XXVII: 【Chemistry 48】 with tert-butyl carbazate and a reducing agent to form a compound of formula XXVIII; Preferably, the compound of formula XXVII is reacted with tert-butyl carbazate in the presence of hydrogen and a transition metal catalyst. The process.

19. The compound of formula XXX may be reacted with a compound of formula XXI: 【Chemistry 49】 to form a compound of formula XXXI: [Transformation 50] further comprising forming a compound of Optionally, said compound of formula XXXI is 【Chemistry 51】 wherein X is a leaving group and R 15 is an alkyl group; to form a compound of formula XXXII: 【Chemistry 52】 or a salt thereof, preferably wherein R 15 is an isopropyl group or a methyl group.

17. The process of claim 16.

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