Process and intermediates for the preparation of (s) -5-amino-3 - (4 - ((5-fluoro-2-methoxybenzamido) methyl) phenyl) - 1 - (111 - trifluoropropan-2-yl) - 1h - pyrazole-4-carboxamide

Abstract

Provided are methods and key intermediates for the synthesis of (S) -5-amino-3 - (4 - ((5-fluoro-2-methoxybenzamido) methyl) phenyl) - 1 - (111 - trifluoropropan-2-yl) - 1H - pyrazole-4-carboxamide.SOLUTION: For example, it is synthesized starting from N - [[4 - [5-amino-4-cyano-1 - [(1S) - 222 - trifluoro-1-methyl-ethyl] pyrazol-3-yl] phenyl] methyl] - 5-fluoro-2-methoxybenzamide.SELECTED DRAWING: None

Description

[Background technology]

[0001] The present invention relates to the fields of pharmaceutical chemistry and synthetic organic chemistry, and ((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1 Synthesis of (1H-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide We provide methods and key intermediates.

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase related to the src receptor. BTK is a member of the IL-1 c family. It is involved in the development of normal white blood cells known as B cells. It plays a key role in the B cell antigen receptor signaling pathway required for activation and survival. BTK also plays an important role in the growth and survival of various B-cell malignancies. Therefore, BTK is a promising candidate for the treatment of, for example, chronic lymphocytic leukemia, Waldenstrom's hypergammaglobulinemia, and leukemia. Many B-cell leukemias and leukemias, including erythrocytopenia, mantle cell lymphoma, and marginal zone lymphoma It is a useful molecular target for the treatment of cancer and lymphoma.

[0003] The compound, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide (1,1,1-trifluoropropan-2-yl)-1H-methylphenyl -pyrazole-4-carboxamide has the following structure and is referred to herein as having formula (I): It may be referred to as a compound. [ka] Hereinafter, the compound of formula (I) will be referred to as (S)-5-amino-3-(4-((5-fluoro-2 -Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane 5-amino-3-[4- [[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[ (1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide The compounds of formula (I) may also be referred to as thiamids. The compounds of formula (I) are disclosed in US Pat. No. 6,202,020,028,258. The compounds of formula (I) selectively inhibit BTK. Formulations of the compound of formula (I) are disclosed in WO2020 / 028258.

[0004] The above-mentioned documents WO2017 / 103611 and / or WO2020 / 028258 disclose the formula The present disclosure describes a method for synthesizing compounds of formula (I). This new process uses environmentally friendly reagents and provides optimal An efficient and cost-effective method for the preparation of compounds of formula (I) that allows for impurity control and results in the formation of highly pure crystalline material. The pure crystalline material allows for easy purification of the product. Furthermore, this embodiment can be used to prepare compounds of formula (I): To provide a novel intermediate. Summary of the Invention

[0005] The present embodiments describe methods that can be used to prepare compounds of formula (I) and novel This provides a useful intermediate.

[0006] One such embodiment is (S)-5-amino-3-(4-((5-fluoro-2 -Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane A method for preparing (benzo-2-yl)-1H-pyrazole-4-carboxamide (I), comprising the steps of: viii) a compound of formula (III) [ka] , (In the formula, PG 1 are -CH3, -CH2CH3, -C(CH3)3, -CH2CH= CH2, methoxymethyl, tetrahydropyran, benzyl, trimethylsilyl, tert -butyldimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl phenyl[pyren-1-ylmethoxy]silyl, tert-butyldiphenylsilyl, acetyl or benzoyl) and [(1S)-2,2,2-trifluoro-1-methyl- N-[[4-[5-amino-4-thiazolinone] hydrazine (8) No-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-3 -yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (10) or obtaining the salt; ix) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro (S)-5-amino-3-(4-methoxybenzamide (10) or its salt -((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1, 1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide(I) and x) optionally (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzyl) 1-(1,1,1-trifluoropropan-2-yl)-2-benzodibenzofuran-2-yl (S)-5-pyrazole-4-carboxamide (I) was crystallized to give the crystalline form (S)-5-pyrazole-4-carboxamide (I). -amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl )-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxylate providing ruboxamide (I).

[0007] Another embodiment is an intermediate designated as a compound of formula (II), shown below: Compound II) is N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl The compound is methyl-5-fluoro-2-methoxy-benzamide. [ka]

[0008] Thus, in another embodiment, the method comprises using a compound of formula (II) to produce a compound of formula (I In other words, described herein is a method for obtaining a compound of formula (S)-5-a 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of oxamide (I), N-[[4-(2,2-dicyano-1-hydroxy-vinyl (phenyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide (II) This is a method.

[0009] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (III). [ka]

[0010] In formula (III), "PG 1 " refers to a protecting group. 1 Examples of what can constitute -CH3, -CH2CH3, -C(CH3)3, -CH2CH=CH2, methoxymethyl methyl, tetrahydropyranyl, benzyl, silyl, acetyl, or benzoyl, or and pharmaceutically acceptable salts thereof. Silyl groups include trimethylsilyl, tert-butylsilyl, and the like. Dimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl[pyrene but includes tert-butyldiphenylsilyl, tert-butyl-1-ylmethoxysilyl, and tert-butyldiphenylsilyl, Not limited to these.

[0011] A preferred embodiment of the present invention is a PG compound in which the compound of formula (III) is methyl 1 I have This compound is prepared as follows: N-[[4-(2,2-dicyano-1-methoxy-vinyl phenyl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide, IA) below. [ka]

[0012] Thus, in one embodiment, the method of the present invention comprises using a compound of formula (III) In other words, this embodiment involves obtaining a compound of formula (I). 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-( 1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide Some embodiments include the use of a compound of formula (III) in the preparation of compound (I). In one embodiment, this is achieved by reacting a compound of formula (IIIA) to give a compound of formula (I). and

[0013] Compounds of formula (II) can be prepared using the following Scheme I, which is described in more detail herein. It can be prepared using [ka]

[0014] Further embodiments include more efficient and environmentally friendly methods of producing compounds of formula (I). Such embodiments include those using compounds of formula (II) and / or compounds of formula (III). This may include:

[0015] Other embodiments include the reaction / reaction of Scheme II (described in more detail herein). Scheme II may include a method for preparing a compound of formula (I) comprising using a compound of formula (I) Using a compound of formula (II) to convert it to a compound of formula (III), and then The compound is converted to a compound of formula (I). [ka]

[0016] The embodiment shown in Scheme II is represented using a compound of formula (III). Thus, compounds of formula (IIIA) are a subgenus of compounds of formula (III), wherein PG 1 is methyl. Those skilled in the art will recognize that PG of the compound of formula (III) 1 Using other species as It will be appreciated that similar schemes can be used and constructed. For example, different PGs in formula (III) 1 are used) are all as disclosed herein Similar techniques and schemes can be used to prepare compounds of formula (I). can.

[0017] As shown in Schemes I and II, the method includes one or more of the following steps: Available: i) 5-fluoro-2-methoxy-benzoic acid (1) is converted to 5-fluoro-2-methoxybenzoic acid (2). obtaining oxy-benzoyl chloride (2); ii) 5-fluoro-2-methoxy-benzoyl chloride (2) with 4-(aminomethyl ) benzoic acid to give 4-[[(5-fluoro-2-methoxy-benzoyl ) obtaining amino]methyl]benzoic acid (3) or a salt thereof; iii) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The aromatic acid (3) or its salt is reacted with 4-[[(5-fluoro-2-methoxy-benzoyl)amino] methyl]benzoyl chloride (4), iv) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The methyl chloride (4) was reacted with malononitrile to give N-[[4-(2,2-dicyano- 1-Hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzal obtaining the intermediate (II), v) N'-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzohydrin azide (6) or its salts with [(1S)-2,2,2-trifluoro-1-methyl-ethyl hydrazine hydrochloride (7), vi) [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride The salt (7) was reacted with [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine ( 8) Step 2: vii) N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl

[0033] 5-fluoro-2-methoxy-benzamide (II) in the presence of a compound of formula (III) [ka] , (In the formula, PG 1 are -CH3, -CH2CH3, -C(CH3)3, -CH2CH= CH2, methoxymethyl, tetrahydropyran, benzyl, trimethylsilyl, tert -butyldimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl phenyl[pyren-1-ylmethoxy]silyl, tert-butyldiphenylsilyl, acetyl or benzoyl), viii) a compound of formula (III) [ka] , [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) or reacts with its salt to give N-[[4-[5-amino-4-cyano-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl obtaining 5-fluoro-2-methoxy-benzamide (10) or a salt thereof; ix) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro 5-amino-3-[4-[[( 5-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(1S )-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide and x) optionally 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzo[ 1-[(1S)-2,2,2-trifluoro-1-(2-aminomethylphenyl)-2-yl]amino]methyl]phenyl]- ... [methyl-ethyl]pyrazole-4-carboxamide (I) was crystallized to give the crystalline form of 5- Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl] Phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo providing aryl-4-carboxamide (I).

[0018] In a further embodiment, there is provided an intermediate compound selected from: [ka] (In the formula, PG 2 is fluorenylmethoxycarbonyl, tert-butoxycarbonyl, Benzylcarbonyl, trifluoroacetamide, phthalimide, benzyl, triphenyl methyl, benzylideneamine, p-toluenesulfonamide, PG 1 is -CH 3, -CH2CH3, -C(CH3)3, -CH2CH=CH2, methoxymethyl, tetramethyl Hydropyranyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, dihydropyranyl -tert-butylisobutylsilyl, di-tert-butyl[pyren-1-ylmethox silyl, tert-butyldiphenylsilyl, acetyl, or benzoyl). Some of the methods and processes by which the above compounds can be converted into compounds of formula (I) Embodiments are described and illustrated herein.

[0019] Detailed Description of the Invention Here, the compound N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]

[0023] The present invention describes [5-fluoro-2-methoxy-benzamide]. [ka]

[0020] This compound of formula (II) can be made according to the methods outlined herein This compound of formula (II) can be reacted to produce a compound of formula (I). Specifically, after obtaining the compound of formula (II), the compound of formula (II) can be reacted with the compound of formula (II) according to the following procedure: can be converted to a compound of formula (I) using one or more of the following steps: The compound of formula (II) is reacted to form N-[[4-(2,2-dicyano-1-methoxy- Vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide (IIIA) obtaining a step of N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5- Fluoro-2-methoxy-benzamide (IIIA) and [(1S)-2,2,2-trifluoromethyl-2-methoxy-benzamide (IIIA)] and coupling with N-fluoro-1-methyl-ethylhydrazine (8) or a salt thereof to form a -[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro-1 -methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methyl obtaining thoxy-benzamide (10) or a salt thereof; N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro -1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2 -Methoxy-benzamide (10) or its salt to (S)-5-amino-3-(4-(( 5-Fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trimethylphenyl) Synthesis of (trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (I) a step of: Optionally, 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl )amino]methyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl [S-ethyl]pyrazole-4-carboxamide (I) was crystallized to give the crystalline form (S)- 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4- Providing carboxamide (I).

[0021] The step of reacting the compound of formula (II) comprises reacting the compound of formula (II) with a compound of formula (III) In some embodiments, this involves converting a compound of formula (II) This reaction (alkylation reaction) can be carried out by reacting the compound with a protecting group. Other methods of performing the above (which may be the case) may also be used.

[0022] The above N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl] -5-fluoro-2-methoxy-benzamide (IIIA) and [(1S)-2,2,2- Coupling with trifluoro-1-methyl-ethylhydrazine (8) can be carried out under basic conditions, but other conditions, such as direct conversion from the hydrazine salt, can also be used. It is possible.

[0023] Finally, as mentioned above, compounds of formula (I) are obtained from the above synthetic steps. A selective crystallization step can be used to purify this compound. However, other methods and / or reactions and / or conditions may be used to convert compounds of formula (II) to compounds of formula (I ) can also be converted into the compound. Other purification methods besides crystallization can also be used. .

[0024] Compounds of formula (III) which can be converted to compounds of formula (I) by reaction are also described herein. In one embodiment, the compound of formula (III) is a compound of formula (IIIA) and PG 1 is methyl, and N-[[4-(2,2-dicyano-1-methoxy-vinyl phenyl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide. [ka]

[0025] The compound of formula (IIIA) can be converted to a compound of formula (I). In this case, the conversion is done as follows: N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5- Fluoro-2-methoxy-benzamide (IIIA) and [(1S)-2,2,2-trifluoromethyl-2-methoxy-benzamide (IIIA)] and coupling with N-fluoro-1-methyl-ethylhydrazine (8) or a salt thereof to form a -[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro-1 -methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methyl obtaining thoxy-benzamide (10) or a salt thereof; N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro -1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2 -Methoxy-benzamide (10) or its salt to (S)-5-amino-3-(4-(( 5-Fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trimethylphenyl) Synthesis of (trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (I) do, Optionally, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzyl) Amido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)- 1H-pyrazole-4-carboxamide (I) was crystallized to give (S)-5-azathioprine in crystalline form. 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate To provide the oxamide (I).

[0026] As mentioned above, this N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl methyl]-5-fluoro-2-methoxy-benzamide (IIIA) and [(1S)- Coupling with 2,2,2-trifluoro-1-methyl-ethylhydrazine (8) The above steps can be carried out under basic conditions, although other conditions can also be used. The compound of formula (I) can also be obtained from the above synthesis steps. This compound can be purified using a HPLC. Of course, other methods and and / or reactions and / or conditions are used to convert a compound of formula (II) into a compound of formula (I). Other purification methods besides crystallization can also be used.

[0027] (S)-5-amino-3-(4-((5-fluoro-2-methoxy)methyl)-2-methyl ... (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- The preparation of (I)-1H-pyrazole-4-carboxamide (I) comprises the following steps: For convenience, the compound numbers of Schemes I and II are included herein: i) 5-fluoro-2-methoxy-benzoic acid (1) or a salt thereof is converted to 5-fluoro- obtaining 2-methoxy-benzoyl chloride (2); ii) 5-fluoro-2-methoxy-benzoyl chloride ( 2) was coupled with 4-(aminomethyl)benzoic acid to give 4-[[(5-fluoro- Obtaining 2-methoxy-benzoyl)amino]methyl]benzoic acid (3) or a salt thereof , iii) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The aromatic acid (3) or its salt is reacted with 4-[[(5-fluoro-2-methoxy-benzoyl)amino] methyl]benzoyl chloride (4), iv) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The methyl chloride (4) was reacted with malononitrile to give N-[[4-(2,2-dicyano- 1-Hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzal obtaining the intermediate (II), v) N'-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzohydrin Deprotection of azide (6) or its salt to give [(1S)-2,2,2-trifluoro-1-methyl obtaining [tri-ethyl]hydrazine hydrochloride (7); vi) [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride The salt (7) was reacted with [(1S)-2,2,2-trifluoro-1-methyl-ethyl hydrazine (8), vii) N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl 1-fluoro-2-methoxy-benzamide (II) with alkylating agents. , N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5- obtaining fluoro-2-methoxy-benzamide (IIIA), viii) N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl [(1S)-2,2, 2-trifluoro-1-methyl-ethyl]hydrazine (8) under basic conditions. N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl 1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro- obtaining 2-methoxy-benzamide (10) or a salt thereof; ix) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro (S)-5-amino-3-(4-methoxybenzamide (10) or its salt -((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1, 1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide(I) and x) optionally (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzyl) 1-(1,1,1-trifluoropropan-2-yl)-2-benzodibenzofuran-2-yl (S)-5-pyrazole-4-carboxamide (I) was crystallized to give the crystalline form (S)-5-pyrazole-4-carboxamide (I). -amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl )-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxylate Providing ruboxamide (I).

[0028] The above step i) is a step of reacting 5-fluoro-2-methoxy-benzoic acid (1) or a salt thereof with 5- Fluoro-2-methoxy-benzoyl chloride (2) is obtained by converting some In embodiments, the reaction may be a chlorination (e.g., reaction with a chlorinating agent, etc.). Other conditions can also be used to effect the conversion. Fluoro-2-methoxy-benzoic acid (1) or its salts are converted to 5-fluoro-2-methoxy-benzoic acid (2) or its salts. Conversion to the benzoyl chloride (2) can be achieved under a variety of chlorination conditions. For example, , thionyl chloride, oxalyl chloride, phosphorus(V) chloride, phosphorus(III) chloride, or other similar Those skilled in the art can use the following reagents to convert carboxylic acids to anhydrides or activated ester groups. It will be appreciated that other reagents and / or conditions may be used, such as for converting

[0029] The above step ii) is carried out by reacting 5-fluoro-2-methoxy-benzoyl chloride (2) with 4 -(aminomethyl)benzoic acid in combination with 4-[[(5-fluoro-2-methoxy- The method involves obtaining benzoyl)amino]methyl]benzoic acid (3) or its salt. In embodiments, the reaction may be an amide coupling reaction. Other conditions can also be used for the 5-fluoro-2- Methoxy-benzoyl chloride (2) in combination with 4-(aminomethyl)benzoic acid 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid (3) or its salts can be achieved using a variety of non-nucleophilic bases. Diethylamine, diisopropylethylamine, or other similar reagents can be used. Those skilled in the art will appreciate that other reagents and / or conditions may be used.

[0030] The above step iii) is the reaction of 4-[[(5-fluoro-2-methoxy-benzoyl)amine benzoic acid (3) or its salts with 4-[[(5-fluoro-2-methoxybenzoyl) The process involves converting the benzoylaminomethylbenzoyl chloride (4) to In embodiments, the reaction may be a chlorination and may be carried out using a chlorinating agent. Other conditions for performing the conversion may also be used. [(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid (3) or The salt of (5-fluoro-2-methoxy-benzoyl)amine is converted to 4-[[(5-fluoro-2-methoxy-benzoyl)amine using a chlorinating agent. Conversion to benzoyl chloride (4) was achieved under a variety of chlorination conditions. For example, thionyl chloride, oxalyl chloride, phosphorus(V) chloride, phosphorus(III) chloride or other similar reagents can be used. Those skilled in the art can convert carboxylic acids to anhydrides or activated It will be understood that other reagents and / or conditions can be used, such as converting the hydroxyl group to a hydroxyl group or a hydroxyl group to a hydroxyl group. cormorant.

[0031] The above step iv) is 4-[[(5-fluoro-2-methoxy-benzoyl)amino ]methyl]benzoyl chloride (4) in combination with malononitrile to give N-[[4-( 2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5-fluoro-2- In some embodiments, this comprises obtaining methoxy-benzamide (II). The reaction may be an amide coupling reaction and may be accomplished using a non-nucleophilic base. Other conditions may be used to achieve this. (5-Fluoro-2-methoxy-benzoyl)amino]methyl]benzoyl chloride (4 ) in combination with malononitrile to give N-[[4-(2,2-dicyano-1-hydroxy -vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide (II) Obtaining the hydroxyl group can be achieved using a variety of non-nucleophilic bases, such as triethylamine, Diisopropylethylamine, or other similar reagents, can be used. It will be understood that other reagents and / or conditions may be used.

[0032] The above step v) is N'-[(1S)-2,2,2-trifluoro-1-methyl- [(1S)-2,2,2-trimethylbenzohydrazide (6) or its salt to give [(1S)-2,2,2-trimethylbenzohydrazide (6)] ... Several experiments were carried out to obtain [fluoro-1-methyl-ethyl]hydrazine hydrochloride (7). In embodiments, the reaction can be a debenzoylation reaction, which can be carried out under acidic or basic conditions. You can use other types of conditions to perform this transformation. In some embodiments, N'-[(1S)-2,2,2-trifluoromethyl] -1-methyl-ethyl]benzohydrazide (6) or its salts with [(1S)-2,2,2- Conversion of the compound to trifluoro-1-methyl-ethylhydrazine hydrochloride (7) can be carried out using acidic or This can be achieved under basic conditions. For example, acidic conditions can be used, such as HCl or other similar Alternatively, if basic conditions are used, KOH, K2CO3 Reagents such as HCl, HCl, or other similar reagents may be added. Those skilled in the art will appreciate that other reagents and / or conditions may be used. You will understand that you can use it.

[0033] The above step vi) is [(1S)-2,2,2-trifluoro-1-methyl-ethyl ]hydrazine hydrochloride (7) with [(1S)-2,2,2-trifluoro-1-methyl- In some embodiments, the reaction comprises converting the hydroxyl group to a hydroxyl group (8). This can be done under basic conditions, but other conditions can also be used to effect this transformation. In some embodiments, [(1S)-2,2,2-trifluoro-1-methyl -ethyl]hydrazine hydrochloride (7) was reacted with [(1S)-2,2,2-trifluoro-1-methyl Conversion to [tri-ethyl]hydrazine (8) can be achieved under a variety of basic conditions. For example, triethylamine, diisopropylethylamine, aqueous NaOH solution, aqueous LiOH solution solution, aqueous K2CO3, or other similar reagents can be used. Those skilled in the art will appreciate that other It will be understood that any reagent and / or condition can be used.

[0034] Step vii) above is N-[[4-(2,2-dicyano-1-hydroxy-vinyl )phenyl]methyl]-5-fluoro-2-methoxy-benzamide (II) by converting , N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5- Some experiments involve obtaining fluoro-2-methoxy-benzamide (IIIA). In some embodiments, this reaction may be an alkylation. Other conditions may be used to effect this transformation. In some embodiments, N-[[4-(2,2-dicyano-1 -hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzami Benzene(II) to N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl [C]-5-fluoro-2-methoxy-benzamide (IIIA) is useful in various alkylation reactions. This can be achieved under conditions such as trimethyl orthoformate, methyl triflate, tetrafluoroborate, etc. Trimethylammonium fluoroborate, N,N'-diisopropyl-O-methylisourea or other similar reagents may be used. Those skilled in the art will appreciate that other reagents and / or conditions may be used. You will understand that you can use it.

[0035] The above step viii) is N-[[4-(2,2-dicyano-1-methoxy-vinyl )phenyl]methyl]-5-fluoro-2-methoxy-benzamide (IIIA) and [( 1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) or its salt and N-[[4-[5-amino-4-cyano-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl The reaction involves obtaining [5-fluoro-2-methoxy-benzamide (10)]. In this embodiment, the reaction may be a cyclization. Other conditions may be used to effect this transformation. In some embodiments, N-[[4-(2,2-dicyano-1 -Methoxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide (IIIA) and [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine and coupling with N-[[4-[5-amino-4-cyano- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl phenyl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (10) or its Obtaining salts can be achieved using a variety of non-nucleophilic bases. For example, triethylamine A reagent such as ethanol, diisopropylethylamine, or other similar reagents can be used. One will understand that other reagents and / or conditions can be used.

[0036] Step ix) above is N-[[4-[5-amino-4-cyano-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl (S)-5-fluoro-2-methoxy-benzamide (10) or a salt thereof Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In some embodiments, the reaction comprises synthesizing boxamide (I). It can be a decomposition. Other conditions can also be used to perform this transformation. In an embodiment, N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2 -trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5 -fluoro-2-methoxy-benzamide (10) or a salt thereof to (S)-5-amino- 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-( 1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide Synthesis of methyl methyl ether (I) can be achieved under acidic conditions using a variety of acids. Use ethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, polyphosphoric acid, sulfuric acid, or other similar reagents. Hydrolysis can be carried out under basic, oxidative, or metal-catalyzed / stoichiometric conditions. For example, potassium tert-butoxide, sodium hydroxide, Substances, ruthenium hydroxide, manganese dioxide, copper(II) acetate, Perkin's catalyst, MnO2 / S iO2, or other similar reagents can be used. Those skilled in the art will appreciate that enzymatic reactions or amidine It will be understood that other reagents and / or conditions may be used, such as the use of intermediates.

[0037] The process for preparation described herein may be further described, wherein the chlorinating reagent in step i) is thionyl chloride. the non-nucleophilic base in step ii) is triethylamine; and the non-nucleophilic base in step iii) is triethylamine. The chlorinating reagent in step iv) is thionyl chloride and the non-nucleophilic base in step iv) is triethylamine and the acid in step v) is hydrochloric acid, the temperature at which the reaction is carried out is 102°C, and The base in step vi) is triethylamine and the alkylating reagent in step vii) is ortho- The reaction temperature is 92°C, and the oxidizing conditions of step ix) are: The reaction temperature is 85°C, and step x) The solvent in step i) is methanol. The method is preferably the method wherein the non-nucleophilic base in step ii) is triethylamine. A preferred preparation method is one in which the chlorinating agent in step iii) is thionyl chloride. A preferred method is one in which the non-nucleophilic base in step iv) is triethylamine. A preferred method of preparation is where the acid in step v) is hydrochloric acid and the temperature at which the reaction is carried out is 102°C. A preferred method of preparation is where the base in step vi) is triethylamine. ) the alkylating agent is trimethyl orthoformate and the temperature at which the reaction is carried out is 92°C The preferred method of preparation is that the oxidizing conditions in step ix) are an aqueous methanesulfonic acid solution, A preferred method of preparation is one in which the reaction temperature is 85°C. The preferred production method is

[0038] In further embodiments, there is provided a compound selected from: [ka] (In the formula, PG 2 is fluorenylmethoxycarbonyl, tert-butoxycarbonyl , benzyl carbonyl, trifluoroacetamide, phthalimide, benzyl, triphenyl phenylmethyl, benzylideneamine, p-toluenesulfonamide, PG 1 -C H3, -CH2CH3, -C(CH3)3, -CH2CH=CH2, methoxymethyl, tetramethyl tetrahydropyranyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, Di-tert-butylisobutylsilyl, di-tert-butyl[pyren-1-ylmethan silyl, tert-butyldiphenylsilyl, acetyl, or benzoyl) .

[0039] The following schemes (Schemes III-VI) are used in the synthesis of compounds of formula (I): The following routes have not been formally completed, but are intended to lead to the following compounds: It is believed that it can be produced in this way.

[0040] [ka] The hydrazide (11) or its salt is reacted with a trifluoromethyl group in a polar aprotic solvent such as THF. Condensation with propan-2-one can give the hydrazone (12) or its salt. The reduction of hydrazone (12) or its salts can be carried out with NaBH4 or with palladium or This can be accomplished by platinum-catalyzed hydrogenation to give the hydrazide (13) or its salt. The phenylacetate group can be removed by heating under acidic conditions such as HCl in MeOH. to give hydrazine (8), which can optionally be isolated as the HCl salt. Potassium hydrazine (8) or its salts can be obtained by heating them in a pressure vessel. Reaction of ammonium(dicyanoethenylidene)azanide with aminopyrazole (IV) or Those skilled in the art will recognize that cyclization can be carried out directly from hydrazine or its salt. Conversion of the primary amine at C-3 of a pyrazole to a bromide can be achieved in a variety of This can be achieved by using a brominating agent, among which CuBr2 can be used. The nitrile moiety of pyrazole (V) or its salt is converted to carboxamide (VI) or its salt. The conversion can be carried out using a suitable hydride-platinum complex such as the Ghaffar-Parkins catalyst. or in polar solvents such as H2O2, NaOH, and DMSO or EtOH. This can be achieved under basic conditions using a solvent to obtain the precursor of boronic ester (14). Then, the acid chloride (2) was converted under Schotten-Baumann conditions using TEA in DCM. or directly from benzoic acid (1) or its salts using a suitable activating agent to form the amide Those skilled in the art will recognize that activating agents include HATU, PyBOP, C Understand that this includes, but is not limited to, DI, DCC, EDCI and T3P The bromide moiety of amide (VII) can be converted to palladium, rhodium, or can be prepared by heating in a polar aprotic solvent such as DMSO using a suitable catalyst such as zinc. The phosphate ester (14) can be obtained by, for example, Pd(PPh3)4 or Pd2 A palladium(0) source such as (dba)3 is used, and a base such as potassium carbonate or cesium carbonate is used. Suzuki coupling of boronic acid ester (14) with bromide (VI) or its salt using Compounds of formula (I) can be obtained using

[0041] [ka] Benzoic acid (15) or its salts can be converted to the corresponding acid salts using the typical chlorination conditions described above. The TH compound (16) can be obtained by the use of thionyl chloride. The reaction of chloride (16) with malononitrile using NaH in a suitable solvent such as F After acidic workup, the enol alcohol (17) can be obtained. The alkylation of the enol alcohol (17) can be carried out with a mild base such as NaHCO3, as previously described. and a suitable alkylating agent including trimethyl orthoformate or alternatively dimethyl sulfate. It will be appreciated that ring formation to substituted pyrazole (19) or a salt thereof can be carried out by A solution of the hydrazine (8) or its salt is added to the aryl enol ether (18). Those skilled in the art will appreciate that primary amine (VIII) can be prepared by acidic hydrolysis. It has been found that it can be synthesized from acetal (19) or its salt via reductive amination after hydrolysis. Using the hydrolysis conditions described above, the nitrile of the substituted pyrazole (VIII) can be obtained. The aryl group can be converted to give carboxamide (IX) or a salt thereof. and benzoic acid (1) or a salt thereof to obtain a compound of formula (I ) can be obtained.

[0042] [ka] As previously mentioned, amide (VII) can be prepared using an amine base such as TEA or DIEA. from the acid chloride (2) or from a suitable reaction product as described in the description of Scheme III. It can be obtained directly from benzoic acid (1) or its salts using a derivatizing agent. Using an amine base such as A and heating in a protic solvent such as EtOH, malononitrile and hydrazine (8) or its salt by cyclization reaction to obtain pyrazole (X) or its salt. Conversion to boronic acid (XI) or its salt, or alternatively its ester After introducing a suitable protecting group to the primary amine moiety, such as a BOC group, BISP Combine a bisboronate source such as IN, an iridium catalyst, and a pyridine base and heat to reflux. This can be accomplished by driving the reaction to completion using the Suzuki reaction method previously described in Scheme III. Using the aryl coupling between bromide (VII) and boronic acid (XI) The compound of formula (I) can also be obtained by

[0043] [ka] The ester (21) or its salt is prepared by maintaining low temperatures for both the reaction and subsequent workup. While, HCl gas dissolved in MeOH was used to convert carboxylic acid (20) or its salt The chlorine compounds described in Scheme I can be obtained using thionyl chloride or oxalyl chloride. The chloride (22) can be obtained by the addition of the thiol amine (23) under the same conditions as in Scheme IV. The chloride (22) is dissolved in a mixture of malononitrile and NaH in a suitable solvent such as HF. The addition can be used to give the enol alcohol (23) after acidic workup. Alkylation of the alcohol (23) was carried out using dimethyl sulfate in refluxing THF to give the enol (24). The hydrazine (8) or its salt and THF, etc. can be used to obtain the hydrazine (XVII). by cyclization using an amine base such as TEA at reflux in a polar aprotic solvent of Pyrazole (XVIII) or its salt can be obtained by the addition of LiOH in aqueous MeOH. by selective hydrolysis of the ester (XVIII) or a salt thereof using mild conditions of Carboxylic acid (XX) or its salt can be obtained. Carbamate (XXI) or its salt The reaction mixture is a mixture of DPPA, an appropriate alcohol (benzyl alcohol in this case), and TEA. Carbamates can be obtained by refluxing in toluene using carbamate rearrangement conditions. Cleavage of the alkyl moiety was achieved by using TMS-I in acetonitrile to give primary alkyl groups. A combination of polar solvents such as DMSO and EtOH can be used to obtain amine (VIII). The synthesis of substituted pyrazoles (VIII) under basic conditions using NaOH and H2O2 Hydrolysis of the nitrile moiety of (IX) can give carboxamide (IX) or its salt. The amide coupling reaction between amine (IX) or its salt and benzoic acid (1) or its salt can be carried out. can be used to obtain the compound of formula (I).

[0044] (S)-5-amino-3-(4-((5-fluoro-2-methoxy)methyl)-2-methyl ... (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- The preparation of (I)-1H-pyrazole-4-carboxamide (I) comprises the following steps: For convenience, the compound numbers of Scheme III are included herein: i) converting 2-phenylacetohydrazide (11) or a salt thereof to give 2-phenyl-N -[(Z)-(2,2,2-trifluoro-1-methyl-ethylidene)amino]acetate obtaining amide (12) or a salt thereof; ii) 2-phenyl-N-[(Z)-(2,2,2-trifluoro-1-methyl-ethyl] 2-phenyl-N'-[(1S)-(2-phenyl-N' ... [2,2,2-trifluoro-1-methyl-ethyl]acetohydrazide (13) Step iii) 2-phenyl-N'-[(1S)-2,2,2-trifluoro-1-methyl- Ethyl]acetohydrazide (13) or its salts with [(1S)-2,2,2-trifluoromethyl]acetohydrazide (14) -1-methyl-ethyl]hydrazine (8), iv) [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8 ) or a salt thereof with dicyanoethenylidene azanide or a pharmaceutically acceptable salt thereof. 3,5-diamino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl obtaining pyrazole-4-carbonitrile (IV) or a salt thereof; v) 3,5-diamino-1-[(1S)-2,2,2-trifluoro-1-methyl- thyl]pyrazole-4-carbonitrile (IV) or its salt with 5-amino-3-bromo- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxylate converting the benzonitrile (V) or a salt thereof into vi) 5-amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl] 5-amino-3-methyl-ethyl]pyrazole-4-carboxamide (VI) or its salts -Bromo-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo synthesizing benzoyl-4-carbonitrile (V) or a salt thereof; vii) converting 5-fluoro-2-methoxy-benzoic acid (1) or a salt thereof to give 5-fluoro-2-methoxy-benzoic acid (1) obtaining fluoro-2-methoxy-benzoyl chloride (2); viii) 5-fluoro-2-methoxy-benzoyl chloride using a non-nucleophilic base Coupling of 2 with 4-bromo-benzylamine gave N-[(4-bromophenoxy)methyl] Step for obtaining [(5-fluoro-2-methoxy-benzamide (VII)]-[ ... , ix) N-[(4-bromophenyl)methyl]-5-fluoro-2-methoxy-benz Amide (VII) to 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetra ... tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzami synthesizing (14); and x) 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)phenyl]methyl]benzamide (14) -amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl 1, by coupling with pyrazole-4-carboxamide (VI) or a salt thereof (S) -5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) (1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4 - Obtaining carboxamide (I).

[0045] (S)-5-amino-3-(4-((5-fluoro-2-methoxy)methyl)-2-methyl ... (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- The preparation of (I)-1H-pyrazole-4-carboxamide (I) comprises the following steps: For convenience, the compound numbers of Scheme IV are included herein: i) 4-formylbenzoic acid (15) or its salt is converted to 4-formylbenzoic acid chloride. obtaining (16); ii) 4-Formylbenzoyl chloride (16) was reacted with malononitrile under basic conditions. Pulling to obtain 2-[(4-formylphenyl)-hydroxy-methylene]propanediol obtaining nitrile (17); iii) 2-[(4-formylphenyl)-hydroxy-methylene]propanedinitri (17) to 2-[[4-(dimethoxymethyl)phenyl]-methoxy-methylene]propanol synthesizing propanedinitrile (18); iv) 2-[[4-(dimethoxymethyl)phenyl]-methoxy-methylene]propane Dinitrile (18) and [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine 5-amino-3-[4-(dimethoxymethyl)-2-propanol]-4-one )phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyra obtaining azole-4-carbonitrile (19) or a salt thereof; v) 5-amino-3-[4-(dimethoxymethyl)phenyl]-1-[(1S)-2, 2,2-Trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (19) or its salts, 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (VI II) or a salt thereof, vi) 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2,2 ,2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (VIII ) or a salt thereof to obtain 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S) -2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide ( IX), and vii) 5-fluoro-2-methoxy-benzoic acid (1) or its salt with 5-amino-3- [4-(aminomethyl)phenyl]-1-[(1S)-2,2,2-trifluoro-1- methyl-ethyl]pyrazole-4-carboxamide (IX) or its salt, S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole -4-Carboxamide (I)

[0046] (S)-5-amino-3-(4-((5-fluoro-2-methoxy)methyl)-2-methyl ... (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- The preparation of (I)-1H-pyrazole-4-carboxamide (I) comprises the following steps: For convenience, the compound numbers for Scheme V are included herein: i) 5-fluoro-2-methoxy-benzoic acid (1) or a salt thereof is converted to 5-fluoro- obtaining 2-methoxy-benzoyl chloride (2); ii) 5-fluoro-2-methoxy-benzoyl chloride ( 2) was coupled with 4-bromo-benzylamine to give N-[(4-bromophenyl )methyl]-5-fluoro-2-methoxy-benzamide (VII), iii) [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine ( 8) or a salt thereof is reacted with malononitrile to give 5-amino-1-[(1S)-2,2, 2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (X) or obtaining a salt of iv) 5-amino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl ]pyrazole-4-carbonitrile (X) or a salt thereof to give [5-amino-4- Ano-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole- 3-yl]boronic acid (XI) or a salt thereof; v) N-[(4-bromophenyl)methyl]-5-fluoro-2-methoxy-benzal Imido (VII) was treated with [5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl- 1-methyl-ethyl]pyrazol-3-yl]boronic acid (XI) or a salt thereof N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl-N-(2-methyl-N ...

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034] [ obtaining 2-methoxy-benzamide (10) or a salt thereof; and vi) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine] Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro 2-Methoxy-benzamide (10) or a salt thereof to give (S)-5-amino- 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-( 1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide Step to obtain (I).

[0047] (S)-5-amino-3-(4-((5-fluoro-2-methoxy)methyl)-2-methyl ... (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- The preparation of (I)-1H-pyrazole-4-carboxamide (I) comprises the following steps: For convenience, the compound numbers of Scheme VI are included herein: i) 4-(2-methoxy-2-oxo-ethyl)benzoic acid (21) is converted to methyl obtaining 2-(4-chlorocarbonylphenyl)acetate (22); ii) Methyl 2-(4-chlorocarbonylphenyl)acetate (22) to methyl 2 -[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]acetate (23) a step of synthesizing iii) methyl 2-[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl] Alkylation of acetate (23) gave methyl 2-[4-(2,2-dicyano-1-methionyl)- obtaining (Xy-vinyl)phenyl] acetate (XVII), iv) methyl 2-[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]acetate The thate (XVII) was reacted with [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine. hydroxylase (8) or its salt to give methyl 2-[4-[5-amino-4-cyano- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl obtaining phenyl]phenyl]acetate (XVIII) or a salt thereof; v) methyl 2-[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trimethyl Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]acetate (XVI II) or a salt thereof, to give 2-[4-[5-amino-4-cyano-1-[(1S)- 2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]acetic acid obtaining an acid (XX) or a salt thereof; vi) 2-[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl- [O-1-methyl-ethyl]pyrazol-3-yl]phenyl]acetic acid (XX) or its salt From benzyl N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2- Trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]carba synthesizing mate (XXI) or a salt thereof; vii) benzyl N-[[4-[5-amino-4-cyano-1-[(1S)-2,2, 2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]ca Transformation of 5-amino-3-[4-(aminomethyl) Phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo obtaining benzoyl-4 carbonitrile (VIII) or a salt thereof; viii) 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (VI II) or a salt thereof from 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide synthesizing compound (IX) or a salt thereof; and ix) 5-Fluoro-2-methoxy-benzoic acid (1) with 5-amino-3-[4-(amino (1S)-2,2,2-trifluoro-1-methyl-phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl- 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate Obtaining the oxamide (I).

[0048] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (IV). [ka]

[0049] Thus, in one embodiment, the method uses a compound of formula (IV) or a salt thereof In other words, what is described herein is a method for producing a compound of formula (I) by reacting (S )-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)fluoro (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole- In the preparation of 4-carboxamide (I), 3,5-diamino-1-[(1S)-2,2, 2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (IV) or This is a method of using the salt.

[0050] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (V): [ka]

[0051] Thus, in one embodiment, the method comprises using a compound of formula (V) or a salt thereof , to obtain a compound of formula (I). In other words, described herein is a method for preparing a compound of formula (S) -5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) (1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4 In the preparation of -carboxamide (I), 5-amino-3-bromo-1-[(1S)-2, 2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile(V) or is a method for using the salt.

[0052] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (VI): [ka]

[0053] Thus, in one embodiment, the method uses a compound of formula (VI) or a salt thereof In other words, what is described herein is a method for producing a compound of formula (I) by reacting (S )-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)fluoro (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole- In the preparation of 4-carboxamide (I), 5-amino-3-bromo-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide (VI ) or a salt thereof.

[0054] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (VII). [ka]

[0055] Thus, in one embodiment, the method comprises using a compound of formula (VII) to produce a compound of formula (I In other words, described herein is a method for obtaining a compound of formula (S)-5-a 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of oxamide (I), N-[(4-bromophenyl)methyl]-5-fluoro- This method uses 2-methoxy-benzamide (VII).

[0056] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (VIII). [ka]

[0057] Thus, in one embodiment, the method comprises using a compound of formula (VIII) to produce a compound of formula ( In other words, described herein is a method for obtaining a compound of formula I) comprising the steps of: Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of voxamide (I), 5-amino-3-[4-(aminomethyl)phenyl]- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxylate This method uses benzonitrile hydrochloride (VIII).

[0058] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (IX): [ka]

[0059] Thus, in one embodiment, the method uses a compound of formula (IX) or a salt thereof In other words, described herein is a method for preparing a compound of formula (I) by reacting (S) -5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) (1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4 In the preparation of 5-amino-3-[4-(aminomethyl)phenyl]-carboxamide (I), -1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole- This method uses 4-carboxamide (IX) or a salt thereof.

[0060] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (X): [ka]

[0061] Thus, in one embodiment, the method comprises using a compound of formula (X) or a salt thereof In other words, described herein is a method for obtaining a compound of formula (I). 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4- In the preparation of carboxamide (I), 5-amino-1-[(1S)-2,2,2-trifluoromethyl] [fluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (X) or its salts This is how to do it.

[0062] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (XI): [ka]

[0063] Thus, in one embodiment, the method uses a compound of formula (XI) or a salt thereof: In other words, described herein is a method for preparing a compound of formula (I) by reacting (S) -5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) (1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4 In the preparation of -carboxamide (I), [5-amino-4-cyano-1-[(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]boronic acid (XI ) or a salt thereof.

[0064] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XII). [ka]

[0065] Thus, in one embodiment, the method comprises using a compound of formula (XII) to produce a compound of formula (I In other words, described herein is a method for obtaining a compound of formula (S)-5-a 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of tert-butyl N-tert-butoxycarbonyl-N -[4-cyano-2-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pi The method uses benzophenone-3-yl carbamate (XII).

[0066] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XIII). [ka]

[0067] Thus, in one embodiment, the method comprises using a compound of formula (XIII) to produce a compound of formula ( In other words, described herein is a method for obtaining a compound of formula I) comprising the steps of: Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of boxamide (I), tert-butyl N-tert-butoxycarbonyl- N-[4-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborola (1S)-2,2,2-trifluoro-1-methyl-ethyl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] The method uses benzophenone-3-yl carbamate (XIII).

[0068] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XIV). [ka]

[0069] Thus, in one embodiment, the method comprises using a compound of formula (XIV) to produce a compound of formula (I In other words, described herein is a method for obtaining a compound of formula (S)-5-a 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of oxamide (I), N-[[4-(2,2-dicyano-1-hydroxy-vinyl The method uses phenylmethylcarbamate (XIV).

[0070] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XV). [ka]

[0071] Thus, in one embodiment, the method comprises using a compound of formula (XV) to produce a compound of formula (I): In other words, described herein is a method for obtaining a compound of formula (S)-5-aminopropyl. 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1 -(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide In the preparation of tert-butyl N-[[4-(2,2-dicyan-1-methyl- The method uses methyl-(vinyl)phenyl)carbamate (XV).

[0072] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XVI): [ka]

[0073] Thus, in one embodiment, the method comprises using a compound of formula (XVI) or a salt thereof to obtain a compound of formula (I). In other words, described herein is a method for producing a compound of formula (I) )-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)fluoro (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole- In the preparation of 4-carboxamide (I), tert-butyl N-[[4-[5-amino- 4-cyano-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo Methods using phenyl-3-ylphenylmethylcarbamate (XVI) or its salts is.

[0074] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate is a compound of formula (XVII). [ka]

[0075] Thus, in one embodiment, the method comprises using a compound of formula (XVII) to produce a compound of formula ( In other words, described herein is a method for obtaining a compound of formula I) comprising the steps of: Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl) -1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate In the preparation of voxamide (I), methyl 2-[4-(2,2-dicyano-1-methoxy- (vinyl)phenyl]acetate (XVII).

[0076] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be a compound of formula (XVIII): [ka]

[0077] Thus, in one embodiment, the method comprises reacting a compound of formula (XVIII) or a salt thereof In other words, what is described herein includes obtaining a compound of formula (I) by using (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl )phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazoline In the preparation of methyl 2-[4-[5-amino-4-thiol No-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-3

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043] [

[0078] In another embodiment, different intermediates can be used to prepare compounds of formula (I). Specifically, this intermediate can be represented by formula (XIX): [ka]

[0079] Thus, in one embodiment, the method comprises using a compound of formula (XIX) or a salt thereof to obtain a compound of formula (I). In other words, described herein is a method for producing a compound of formula (I) )-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)fluoro (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole- In the preparation of 4-carboxamide (I), 2-[4-[5-amino-4-carbamoyl- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl [phenyl]acetic acid (XIX) or a salt thereof is used.

[0080] The reactions described herein can be carried out in conventional glass by standard techniques known to those skilled in the art. This may be done by using a gas instrument, or by using an autoclave pressure chamber. These reactions may also be carried out in equipment designed for such transformations. These reactions may be carried out on a batch and / or production scale. Each may be carried out by either a batch process or a flow reaction method. The term "batch process" as used in this document refers to a process in which raw materials are combined in a reactor or vessel. The term "continuous" as used herein refers to a method in which the reaction is carried out in a continuous manner and the product is removed at the end of the reaction. "Continuous processing" or "flow reaction" is a process in which there is a continuous inflow of raw materials and an outflow of products. Such continuous processing refers to a completely continuous process starting from an initial starting material. This provides a platform from which the final product can be synthesized through a series of operations.

[0081] Individual isomers, enantiomers, and diastereomers can be separated using selective crystallization techniques or chiral crystallization. at any convenient time in the synthesis of the compounds of Formula I by methods such as column chromatography. In this respect, it may be separated or divided by a person skilled in the art (see, for example, J. Jacques, t al., “Enantiomers, Racemates, and Resolut ions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and SH Wilen, “Stereochemistry o f Organic Compounds”,Wiley-Interscience, 1994). Additionally, tautomers may occur in certain compounds of the present invention. For example, compound (II) may exist in any ratio of the following isomeric forms: [ka] These forms are within the scope of this embodiment.

[0082] Additionally, certain intermediates described in the preparations below contain one or more nitrogen protecting groups. Variable protecting groups may be used in different occurrences depending on the particular reaction conditions and the particular transformation being performed. The protection and deprotection conditions are well known to those skilled in the art and can be found in the literature (e.g. "Greene's Protective Groups in Organic Synthesis”, Fourth Edition, by Peter GM Wuts and Theodora W. Greene,John Wiley an (See, e.g., Firmware Developments, Inc., 2007). The compounds, intermediates, and pharmaceutically acceptable salts thereof are listed by name, formula number, compound, It will be understood by those skilled in the art that the compounds may equally be referred to by number, or by number from the formula alone. For example, the formula (III) or (III):

[0083] Compounds prepared by synthesis as described herein, or pharmaceutically acceptable salts thereof The salts may be prepared by a variety of procedures known in the art, some of which are Some are illustrated in the following schemes, preparations, and examples. If no chemistry is specified, all individual enantiomers and mixtures thereof, as well as The specific synthetic steps of each of the routes described may be synthesized in different ways. The steps in the following schemes may be combined in a formula or from different schemes. The products of each step are extracted, evaporated, precipitated, chromatographed, filtered, triturated, and lysed. It may be recovered by conventional methods well known in the art, including crystallization. The reactants are readily available to one skilled in the art. The reactions are generally carried out using techniques known to those skilled in the art. Observe until completion using techniques such as TLC, HPLC, GC, LC / MS, and RAMAN. Those skilled in the art will appreciate that the techniques used will depend on the scale of the reaction, the size of the vessel in which the reaction is carried out, and the It will be appreciated that this will depend on a variety of factors, including the type and reaction itself.

[0084] As used herein, the term "reacting" refers to the use of any suitable chemical reaction. vinegar.

[0085] The abbreviations used herein are defined as follows: "DMSO" is dimethyl sulfoxide; "EtOAc" refers to ethyl acetate. "EtOH" refers to ethanol or ethyl acetate. "GC" stands for gas chromatography. "HPLC" stands for high performance liquid chromatography. "LC / " refers to the Karl Fischer assay. "MS" refers to liquid chromatography-mass spectrometry. "MeOH" refers to methanol or "MsOH" refers to methanesulfonic acid. "MOM" refers to methoxy "RAMAN" refers to Raman spectroscopy. "RPM" refers to revolutions per minute. "TLC" refers to thin layer chromatography. "Tec" refers to the "THP" refers to tetrahydropyran. "DCM" refers to dihydroxybenzoate. "ACN" refers to acetonitrile. "Ghaffar-Parki The "ns catalyst" is a hydride (dimethylphosphinic acid - kP) [hydrogen bis(dimethylphosphinic acid) NITO-kP) refers to platinum(II), CAS number 173416-05-2. "TEA" refers to triethylamine. "DMA" refers to diisopropylethylamine. "P" refers to 4-dimethylaminopyridine. "TMS-I" refers to trimethylsilyl iodide. "DPPA" refers to diphenylphosphoryl azide. "FA" refers to formic acid. "B "OC" refers to the tert-butyloxycarbonyl group. "BOC2O" refers to Boc anhydride. "rt" refers to tert-butoxycarbonyl tert-butyl carbonate. "BISPIN" refers to (E)-1-pentene-1,2-diboronic acid bis(pi) "T3P" refers to 2,4 ,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4, 6-trioxide. "PE" refers to petroleum ether or diethyl ether. "H ATU" is N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b ]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate "PyBOP" refers to benzophenone N-oxide, CAS number 148893-10-1; (1-isotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate "TFA" refers to trifluoroacetic acid, CAS number 128625-52-5 "CDI" refers to 1,1'-carbonyldiimidazole. "DMF" refers to dimethylformamide. "DCC" refers to N,N'-dicyclohexylcarbodiimide. "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide "dba" refers to the dibenzylideneacetone group. "Fmoc" refers to fluorenylmethacrylate. "Cbz" refers to a carboxybenzyl group. "Bn" refers to a benzoyl group. "Tr" refers to a trityl or triphenylmethyl group. "Ts" refers to a trityl or triphenylmethyl group. It refers to a silyl group or a toluenesulfonyl group.

[0086] The compound of formula (I), (S)-5-amino-3-(4-((5-fluoro-2-methoxy benzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl N-[[[(1H-pyrazole)-1H-pyrazole-4-carboxamide can be prepared as shown in Scheme II. 4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5-fluoro- The compound of formula (II), N, is prepared using 2-methoxy-benzamide (IIIA). -[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5-phenyl Fluoro-2-methoxy-benzamide can be prepared by the procedure shown in Scheme I. It is prepared using oro-2-methoxy-benzoic acid (1) or its salts.

[0087] [ka] The substituted benzoic acid (1) or its salt is dissolved in a suitable polar aprotic solvent, and thionyl chloride is added. , oxalyl chloride, or phosphorus pentachloride to form the unisolated The acyl chloride (2) is obtained as an intermediate. Then, 4-(aminomethyl)benzoic acid is converted to the acyl chloride (3). Coupling with silyl (2) gives the further substituted benzoic acid (3) or its salt. The acyl chloride intermediate (4) can be synthesized under the same conditions as the acyl chloride (2). Malononitrile is dissolved in a suitable solvent and stirred until the mixture becomes homogeneous. The aryl acyl intermediate (4) is then added to the mixture. To a cold solution of a non-nucleophilic base, aryl enol (II) or The reaction mixture is then acidified with 1,000 sucrose and 1,000 sucrose. After the formation of an insoluble solid, the aryl enol (II) or its salt is isolated by filtration. do.

[0088] [ka] Suitable reagents such as trimethyl orthoformate and methyl methyl esters typically used in the synthesis of the enol ether moiety are available. The aryl enol (II) can be converted to the aryl enol ether using equivalent reagents available. The substituted hydrazine salt (7) is alkylated to (III). It is synthesized according to the reaction conditions previously disclosed. It is dissolved in a suitable polar protic solvent and cooled. To a solution of (7), a non-nucleophilic base is added to form monosubstituted hydrazine (8). The cyclization to the hydrazole (10) or a salt thereof can be carried out by adding a solution of the above hydrazine (8) or a salt thereof to the hydrazine (10). Similarly, aryl enol ethers dissolved in polar protic solvents and isolated by filtration (III) is then added to the nitrile of pyrazole (10) or The salt is hydrolyzed under aqueous acidic conditions and heated to form the primary amide (I), followed by the appropriate The reaction mixture is adjusted to pH using aqueous base and then isolated by filtration. It will be appreciated that this transformation may be carried out under basic conditions and / or in the presence of a metal catalyst. Crystallization and purification of I) was carried out according to the conditions previously disclosed in WO2020 / 028258. This is achieved to give the compound of formula (I) as a white crystalline solid.

[0089] As stated above, the above structures and schemes are obtained using formula (IIIA). Thus, formula (IIIA) is a subspecies of the broader formula (III). and in formula (IIIA), PG 1 (wherein PG is methyl). 1 As other species It will be appreciated that similar schemes and examples can be created using the PG 1 and converting the compound into compound (10) or a salt thereof and / or finally compound (I). The transformations used to convert the .alpha.-to- ...

[0090] The following schemes detail synthetic routes that may be used in the synthesis of compounds of formula (I): Although the following route has not been formally completed, the following compound can be prepared as follows: It is thought that this is possible.

[0091] [ka] The hydrazide (11) or its salt is reacted with a trifluoromethyl group in a polar aprotic solvent such as THF. Condensation with propan-2-one can give the hydrazone (12) or its salt. The reduction of hydrazone (12) or its salts can be carried out with NaBH4 or with palladium or This can be accomplished by platinum-catalyzed hydrogenation to give the hydrazide (13) or its salt. The phenylacetate group can be removed by heating under acidic conditions such as HCl in MeOH. to give hydrazine (8), which can optionally be isolated as the HCl salt. Potassium hydrazine (8) or its salts can be obtained by heating them in a pressure vessel. Reaction of ammonium(dicyanoethenylidene)azanide with aminopyrazole (IV) or The conversion of the primary amine at C-3 of the pyrazole to a bromide can be carried out in various ways. This can be achieved by using a variety of brominating agents, among which CuBr2 can be used. The nitrile moiety of pyrazole (V) or its salt is converted to carboxamide (VI) or its salt. The conversion of or under mild conditions such as H2O2, NaOH, and polar solvents such as DMSO or EtOH. This can be achieved under basic conditions using a solvent. To do this, acid chloride (2) was prepared under Schotten-Baumann conditions using TEA in DCM. or directly from benzoic acid (1) or its salts using a suitable activating agent. Those skilled in the art will recognize that activating agents include HATU, PyBOP, It is understood that these include, but are not limited to, CDI, DCC, EDCI and T3P. The bromide moiety of amide (VII) can be catalyzed by palladium, rhodium, or or zinc, and heating in a polar aprotic solvent such as DMSO to form the The hydroxybenzoate (14) can be obtained by, for example, Pd(PPh3)4 or Pd A palladium(0) source such as 2(dba)3 is used, and a salt such as potassium carbonate or cesium carbonate is used. Suzuki coupling of boronic ester (14) with bromide (VI) or its salt using the Compounds of formula (I) can be obtained using the method of

[0092] [ka] Benzoic acid (15) or its salts can be converted to the corresponding acid salts using the typical chlorination conditions described above. The TH compound (16) can be obtained by the use of thionyl chloride. The reaction of chloride (16) with malononitrile using NaH in a suitable solvent such as F After acidic workup, the enol alcohol (17) can be obtained. The alkylation of the enol alcohol (17) can be carried out with a mild base such as NaHCO3, as previously described. and a suitable alkylating agent including trimethyl orthoformate or alternatively dimethyl sulfate. It will be appreciated that ring formation to substituted pyrazole (19) or a salt thereof can be carried out by A solution of the hydrazine (8) or its salt is added to the aryl enol ether (18). Those skilled in the art will appreciate that primary amine (VIII) can be prepared by acidic hydrolysis. It has been found that it can be synthesized from acetal (19) or its salt via reductive amination after hydrolysis. Using the hydrolysis conditions described above, the nitrile of the substituted pyrazole (VIII) can be obtained. The aryl group can be converted to give carboxamide (IX) or a salt thereof. and benzoic acid (1) or a salt thereof to obtain a compound of formula (I ) can be obtained.

[0093] [ka] As previously mentioned, amide (VII) can be prepared using an amine base such as TEA or DIEA. from the acid chloride (2) or by suitable activation as also described in the description of Scheme 3. It can be obtained directly from benzoic acid (1) or its salts using an agent such as DIEA. amine base, and by heating in a protic solvent such as EtOH, Cyclization of hydrazine (8) or its salt to obtain pyrazole (X) or its salt. The conversion of boronic acid (XI) or its salt, or alternatively its ester, can be carried out by: After introducing a suitable protecting group to the primary amine moiety, such as a BOC group, BISPIN A bisboronate source such as methyl methyl ketone, an iridium catalyst, and a pyridine base are combined and heated to reflux. The reaction can be carried to completion by using the Suzuki conditions previously described in Scheme III. Using aryl coupling between bromide (VII) and boronic acid (XI), Compounds of formula (I) can also be obtained.

[0094] [ka] The ester (21) or its salt is prepared by maintaining low temperatures for both the reaction and subsequent workup. While, HCl gas dissolved in MeOH was used to convert carboxylic acid (20) or its salt The chlorine compounds described in Scheme I can be obtained using thionyl chloride or oxalyl chloride. The chloride (22) can be obtained by the addition of the thiol amine (23) under the same conditions as in Scheme IV. Addition of chloride (22) to a mixture of malononitrile and NaH in a suitable solvent such as HF Addition can be used to give the enol alcohol (23) after acidic workup. Alkylation of the alcohol (23) was carried out using dimethyl sulfate in refluxing THF to give the enol The ether (XVII) can be obtained by the reaction of hydrazine (8) or its salt with THF or the like. Cyclization using an amine base such as TEA at reflux in a polar aprotic solvent affords the LiOH in aqueous MeOH solution can be used to obtain benzotriazole (XVIII) or its salt. Selective hydrolysis of the ester (XVIII) or its salt using mild conditions is used to obtain the carboxylate. Carbamate (XXI) or its salt can be obtained by the reaction of carboxylic acid (XX) or its salt. , DPPA, the appropriate alcohol (in this case benzyl alcohol), TEA Curtius Rearrangement conditions can be used to obtain carbamates by refluxing in toluene. Cleavage of the moiety was achieved using TMS-I in acetonitrile to give the primary amine. The compound (VIII) can be obtained by combining polar solvents such as DMSO and EtOH. Substituted pyrazoles (VIII) under basic conditions, both using NaOH and H2O2 Hydrolysis of the nitrile moiety of the compound (IX) can give the carboxamide (IX) or a salt thereof. The amide coupling of amine (IX) or its salt with benzoic acid (1) or its salt is used. The compound of formula (I) can be obtained by

[0095] The following preparations and examples further illustrate this invention.

[0096] Preparation 1 [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride [ka] At room temperature, N'-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzene Zohydrazide (200g, 8.61mol), water (300g, 166.53mol), 3 5% concentrated HCl (360 g, 34.50 mol, 35 w%), and m-xylene (150 m L) are added together. The contents are stirred and heated to 102°C for 24 hours. The reaction is then The mixture was cooled to 85°C, toluene (1200 mL) was added, and the solution was slowly cooled to 25°C. The layers are separated and the organic layer is discarded. The aqueous layer is washed with toluene (300 mL) and stirred at 25°C. The layers were separated and the organic layer was discarded, and the title compound (709 g, 20w%) is obtained.

[0097] Preparation 2 N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5- Fluoro-2-methoxy-benzamide [ka] in ACN (2000 mL) under N2 at 25 °C. 1 containing 250 g of (-benzoyl)aminomethylbenzoic acid (824 mmol) Thionyl chloride (117.7 g, 989 mmol) was added dropwise, and the mixture was stirred at 25° C. for 2 hours. The solution is concentrated to a small volume, ACN (750 mL) is added, and the solution is concentrated to a small volume again. ACN (1000 mL) was added and the solution was stirred at 30°C for 30 minutes, then ACN ( Add 250 mL of TE together with malononitrile (81.7 g, 1.24 mol). A solution of A (191.8 g, 1.90 mol) and ACN (250 mL) was added to empty container 2. Add 100ml of water, cool to -5°C, and stir for 120 minutes to reach a constant temperature. Maintain the temperature at -5°C. While adding the acid chloride / malononitrile solution in vessel 1 to the triethylamine solution in vessel 2, After the addition is complete, the reaction is stirred at -10°C for 15 hours. Aqueous HCl (1073 g, 1.285 HCl equivalents) was added and the temperature was adjusted to 10°C. This was then added to the product solution in vessel 2 while maintaining the temperature at 10°C and stirred for 3 hours. The solids are filtered and the filter cake is washed with water. The solid wet cake (66 The wet cake (9.2 g) was divided into two portions, one of which (535.4 g) was used again in this experiment. The slurry was continued, and the other wet cake portion (133.8 g) was dried and used for research purposes. Evaluate the quality for reslurry. Set aside the first wet cake (535.4 g). The mixture is transferred to a 400 mL container and ACN (700 mL) and water (1400 mL) are added. Heat to 10°C and stir for 15 hours. Reduce the temperature to 10°C and stir for 2 hours. Filter the solid. The solid was dried in vacuo at 60-65°C to give the title compound (193.5g, 55 1 mmol) is obtained. 1H NMR(400MHz,DMSO-d6)δ3.89(s, 3H),4.52(d,2H),7.18(m,1H),7.20(br,1H),7. 34(m,1H),7.36(d,2H),7.51(m,1H),7.57(d,2H ),8.85(m,1H).

[0098] Preparation 3 N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5-phenyl Fluoro-2-methoxy-benzamide [ka] N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5 1-Fluoro-2-methoxy-benzamide (300 g, 849 mmol) was treated with orthoformic acid Add methyl acrylate (3 L, 270.0 mol) to the mixture and heat to 92°C for 18 hours. The solution is cooled to 40°C and then heated under vacuum while maintaining the temperature below 50°C. The solution is concentrated to approximately 1200 g. The mixture is cooled to 20° C. to obtain the title compound (12 00g, 8.54mmol, 26% wt. solution).

[0099] Preparation 3a N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl]-5-phenyl Fluoro-2-methoxy-benzamide N-[[(4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]- 5-Fluoro-2-methoxy-benzamide (20 g, 56.9 mmol) and orthogonal Trimethyl methyl ester (190 g, 200 mL, 1790 mmol) was added and the mixture was cooled to 9°C. Heat to 5° C. for 15 h. Reduce temperature to 40° C. and add MeOH (200 mL). 200 ml of HCl was removed from the reaction mixture using reduced pressure (200 mbar) to maintain a temperature of 40°C. Distill off 200 mL of MeOH. Repeat the distillation process 6 times. A final total solution volume of approximately 200 mL is obtained. Add N-[[4-(2,2-dicyano-1- Methoxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide After seeding, the temperature is cooled to 22°C and the mixture is stirred overnight. If so, the crystals can be produced by a number of known techniques, as will be appreciated by those skilled in the art. The resulting solid is collected by filtration and washed with MeOH (100 mL). The title compound (13.3 g, 36.4 mmol, 64% yield) was obtained by vacuum drying at 20°C. Obtained as a white solid. ES / MS m / z 388 (M+Na), 366 (M+H ), 1 H NMR 400MHz,(DMSO-d6)δ3.89(s,3H),3.9 0(s,3H),4.60(d,2H),7.19(dd,1H),7.35(m,1H ),7.52(dd,1H),7.55(d,2H),7.65(d,2H),8.93 (m,1H).

[0100] Preparation 4 N-[[4-[(1S)-5-amino-4-cyano-1-(2,2,2-trifluoro- 1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2- Methoxy-benzamide [ka] N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]methyl at 15°C ]-5-fluoro-2-methoxy-benzamide (1200 g, 8.5 mol, 26 wt % solution), add 95% EtOH (1.14 L). Another containing (2-chloropropan-2-yl)hydrazine hydrochloride (total solution 709 g, 20 wt%) After adding 95% EtOH (600 mL) to the vessel, the temperature was maintained at 0 to 5°C. TEA (390 g, 38.5 mol) was added dropwise over 1 hour. The solution was recorded as pH = 9. While maintaining the temperature at 15-20°C, (1,1,1-trifluoropropane- 2-yl)hydrazine solution with N-[[4-(2,2-dicyano-1-methoxy-ethyl) Add dropwise over 1 hour to the phenylmethyl-5-fluoro-2-methoxybenzamide solution. The container containing (1,1,1-trifluoropropan-2-yl)hydrazine is At ~20 °C, rinse the reaction mixture with 95% EtOH (510 mL) and add the mixture at 25 °C. Stir for 18 hours, then add water (1200 mL) over 30 minutes at 25°C. 4-[(1S)-5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl (ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy -benzamide (1.5 g, 3.25 mmol) at 25°C and stirred for 1 hour. (3120 mL) is added over 3 hours at 25° C. and stirring is continued for another 3 hours. The solid is filtered. and washed with 28% EtOH in water (2 x 1.4 L) and water (1.5 L). 95% EtOH (3.0 L) was added to the recovered wet cake and the mixture was heated to 65°C. Stir for 1 hour. Cool the reaction to 55°C and add water (3. Add 0.0 L of HCl dropwise over 3 hours. Cool the mixture to 21°C and stir at 21°C for 60 hours. The solid was collected, washed with water (600 mL), and dried in vacuo at 55°C for 24 hours to give the title compound. Product (336g, yield 83%, purity 99.3%, analytical value 97.1%, chiral purity 99.7%) ) as an off-white solid. KF = 0.26 wt %, residual solvent EtOH 0.1 7% by weight, methyl formate, trimethyl orthoformate, toluene, MeOH, and m-xylene were not detected. It is not served. 1 H NMR(DMSO-d6)δ1.65(d,3H),3.89(s, 3H),4.55(d,2H),5.29(m,1H),7.09(s,2H),7.1 7(dd,1H),7.33(m,1H),7.43(d,2H),7.51(dd,1 H), 7.75(d,2H), 8.86(m,1H).

[0101] Example 1 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl phenyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pi 4-carboxamide [ka] N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro -1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2 -Methoxybenzamide (20 g, 43.4 mmol), MsOH (80 mL, 1220 (1.50 g, 83.3 mmol) and water (1.50 g, 83.3 mmol) were added together and the mixture was stirred. The reaction temperature is maintained at 85°C for 6 hours and then cooled to 20°C. In a separate container, add water (100 mL) and NH4OH in water (28 wt%, 200 mL, 100 Add 100 mmol) and cool to 0-10°C. While maintaining the temperature at 0-10°C, add the acid The reaction mixture is slowly poured into the NH4OH solution over 6-7 hours. (20 mL) for 30 minutes at 5-20°C, while maintaining the temperature at 5-20°C during the addition. Add NH4OH to the quench solution over 1-2 hours. The mixture was heated to 25°C, EtOAc (140 mL) was added, and the mixture was stirred at 15-25°C for 30 minutes. Stir and then let stand for 30 minutes. Remove the aqueous layer. Stir for 30 minutes at 20°C with Et Add water (100 mL) to the OAc solution and then let the layers stand for 30 minutes. Separate the aqueous layer. EtOAc (130 mL) was added to the existing EtOAc solution and stirred at 20°C for 30 minutes. The organic layer is then concentrated under vacuum to 140 mL at a temperature below 50° C. Additional Et OAc (120 mL) was added and stirred at 20° C. for 30 minutes, then at a temperature below 50° C. Concentrate under vacuum until the total volume is 140 mL. Add EtOH (120 mL) and Concentrate the mixture at a temperature below 50 °C until the total volume of the solution is 120 mL. Addition of 20 mL of HCl and concentration to a total solution volume of 120 mL were repeated twice. The solution temperature was adjusted to 42°C. Add EtOH (12 mL) and heat to 50-60°C. L) is added over 30 minutes at 50-60°C. (1S)-2,2-(2-methoxy-benzoyl)amino]methyl]phenyl)-1-[(1S)-2,2-(2-methoxy-benzoyl)amino]methyl]phenyl] ,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide seed crystals (0 Add 0.40g, 0.83mmol) and stir the mixture at 50-60°C for 3-4 hours. The first portion of n-heptane (56 mL) was added at a constant rate over 5 hours at 50-60°C. The second portion of n-heptane (93 mL) was added at a constant rate over 5 hours at 55 °C. The mixture is cooled to 15°C over 4 hours and stirred for an additional 4 hours. The solid is collected and placed on a wet cake. The mixture was dried at 50°C for 66 hours to give the title compound (17.5 g, 84% yield) as a white solid. and get it.

[0102] Example 2 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl phenyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pi 4-carboxamide [ka] 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl ethyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] Pyrazole-4-carboxamide (3.5 kg, 7.30 mol) was dissolved in MeOH (17.5 Add the solution to the flask and stir, then heat to 50-60°C. Maintain the temperature at 50-60°C for 1 hour. The solution was polish filtered, rinsed with MeOH (3.5 L), and transferred to combine with the substrate solution. Adjust the temperature to 55-65°C and stir for 0.5-1 hour. Maintain the temperature at 55-65°C. Add water (9450 mL) dropwise over 1-2 hours while stirring at 91 RPM. The temperature was adjusted to 50-60°C, and then 5-amino-3-[4-[[(5-fluoro-2 -methoxy-benzoyl)amino]methyl]phenyl]-1-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide seeds (35 g, Add 73mmol of ethanol. Continue stirring at 50-60℃ for 1-2 hours. While stirring, add water (4.55 L) dropwise over 8 to 10 hours. Cool to 15°C in 5-7 hours and maintain the mixture at 5-15°C for 2-4 hours. The solid is collected and washed with MeOH:water (3:2) solution (2 x 3.5 L). The title compound (3312 g, 95% yield, 100% purity) was obtained as an off-white solid. is obtained as a solid. 1 H NMR(400MHz,DMSO-d6)δ1.62(d,3 H),3.89(s,3H),4.56(d,2H),5.30(m,1H),6.68 (bs,2H),7.18(dd,1H),7.33(m,1H),7.43(d,2H ),7.47(d,2H),7.52(dd,1H),8.83(m,1H)

[0103] Preparation 5 3,5-Diamino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] Pyrazole-4-carbonitrile [ka] [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride (0 0.5g, 3mmol) and potassium (dicyanoethenylidene)azanide (0.4g, 3m mol) is combined with water (2 mL) in a pressure flask and heated to 100°C overnight. The mixture is cooled to room temperature and a precipitate forms. The precipitate is filtered and the aqueous filtrate is concentrated in vacuo. The residue was then dissolved in DCM (1 mL) and purified by silica gel chromatography (gradient elution with Purify using 0-100% EtOAc in hexanes. Combine the product-containing fractions. Concentrate in vacuo to give the title compound (130 mg, 593 μmol, 20% yield). ES / MS m / z=220.1(M+H). 1 H NMR 400MHz, (DMSO -d6)δ1.46(d,J=1.00Hz,3H),4.91-5.09(m,1H) ,5.31(s,2H),6.67(s,2H).

[0104] Preparation 6 5-Amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl- ethyl]pyrazole-4-carbonitrile [ka] 3,5-Diamino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl ]pyrazole-4-carbonitrile (56.6 mg, 258 μmol) and ACN (2 m To the resulting solution, copper(II) bromide (57.7 mg, 12.1 μL, 258 μmol) was added. The mixture is stirred for 20 minutes while cooling in a brine / ice bath. Dissolve ethyl acetate (26.6 mg, 30.8 μL, 258 μmol) in ACN (2 mL) and react. The reaction mixture was stirred at -20°C for 2 hours. The reaction was then diluted with water (6 mL ), extract the organics with EtOAc (3 × 20 mL), and add sodium sulfate. Dry, filter and concentrate in vacuo. The residue is purified by silica gel chromatography (gradient elution Purify using a gradient of 0-100% EtOAc in heptane as the starting material. Empty and concentrate to give the title compound (21 mg, 74 μmol, 29% yield). ES / MS m / z( 79 Br / 81 Br)=283.00 / 285.00(M+); 1 H NMR 400MHz, (DMSO-d6)δ1.58(d, J=1.00Hz, 3H), 5. 17~5.30(m,1H), 7.40(s,2H).

[0105] Preparation 7 5-Amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl- ethyl]pyrazole-4-carboxamide [ka] In a 20 mL reaction vial, 5-amino-3-bromo-1-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile (16.5 mg, 58.3 μmol) and Ghaffar-Parkins catalyst (25.0 mg, 58.3 1 μmol) in EtOH (2 mL) and water (0.5 mL). The mixture is heated to 80°C. After cooling to room temperature, the mixture was passed through a 0.45 μm filter. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (gradient elution). Purify using 0-10% MeOH and 0.1% NH4OH in DCM. The containing fractions were combined and concentrated in vacuo to give the title compound (12.5 mg, 41.5 μmol, yield The compound was obtained as a white solid (71% yield). 79 Br / 81 Br)=301 .0 / 303.0(M+); 1 H NMR 400MHz, (DMSO-d6) δ 1.5 6(d,J=1.00Hz,3H),5.18-5.39(m,1H),6.54(br s, 1H), 6.98 (s, 2H), 7.31 (brs, 1H).

[0106] Preparation 8 5-amino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo 4-aminobenzoylcarbonitrile [ka] [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride (0 0.5g, 3mmol), DIEA (0.8g, 1mL, 6mmol) and EtOH (25 mL) in a round-bottom flask. Stir the reaction mixture for 30 minutes until the hydrazine solid is dissolved. The mixture was stirred for 1 minute. Then, 2-(ethoxymethylene)propanedinitrile (0.4 g, 3 m mol) is added portionwise to the reaction mixture and the reaction vessel is sealed. The reaction is stirred at 60°C overnight. The reaction is concentrated in vacuo and purified by silica chromatography (hexane as gradient eluent). Purify using 0-100% EtOAc in water. Combine product-containing fractions and concentrate in vacuo. Condensation affords the title compound (385 mg, 1.89 mmol, 60% yield). m / z = 204.9 (M+H); 1 H NMR 400MHz, (DMSO-d6)δ 1.58(d,J=1.00Hz,3H),5.13-5.30(m,1H),7.00 (s,2H),7.66(s,1H).

[0107] Preparation 9 tert-Butyl N-tert-butoxycarbonyl-N-[4-cyano-2-[(1S )-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]carbamate Route [ka] (S)-5-amino-1-(1,1,1-trifluoropropan-2-yl)-1H- Pyrazole-4-carbonitrile (290 mg, 1 equiv., 1.42 mmol) was added to a round-bottom flask. Dissolve in THF (5 mL) in a raspberry jar. Then add DMAP (17.4 mg, 0.1 eq.) , 142 μmol), BOC2O (620 mg, 653 μL, 2 equivalents, 2.84 mmol ), and TEA (431 mg, 594 μL, 3 eq, 4.26 mmol) were added to the reaction. The reaction mixture is stirred at ambient temperature overnight. The reaction is diluted with saturated aqueous NH4Cl (15 mL ) and extract through a phase separator frit with DCM (3 x 15 mL). Concentrate in vacuo and the residue is purified by silica chromatography (0-10% hexane as gradient eluent). 0% EtOAc). The product-containing fractions were combined and concentrated in vacuo to give the product shown in Table 1. The title compound (409.8 mg, 1.013 mmol, 71% yield) is obtained. 1 H NMR 400MHz,(DMSO-d6)δ7.82(s,1H),4.58(m,1H),1 .68-1.66(d,3H),1.41(s,9H),1.37(s,9H).

[0108] Preparation 10 tert-Butyl N-tert-butoxycarbonyl-N-[4-cyano-5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S) -2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]carbamate to [ka] BISPIN (47 mg, 1.5 equivalents, 0.19 mmol), tert-butyl Nt ert-Butoxycarbonyl-N-[4-cyano-2-[(1S)-2,2,2-trifluoromethyl [Fluoro-1-methyl-ethyl]pyrazol-3-yl]carbamate (50 mg, 0.1 2mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer ( 1 mg, 2 μmol), and 4-tert-butyl-2- (4-tert-butyl-2- (pyridyl)pyridine (1 mg, 4 μmol) was placed in a microwave vial containing 1,4-dioxa Combine with 0.5 mL of ethanol. Seal the reaction vial and heat to 80°C for 2 hours. The material was cooled to ambient temperature, diluted with DCM (20 mL), and then filtered through a phase separation frit. Extract with DCM (3 x 20 mL). Concentrate the organics in vacuo. Then, add the residue to silica gel. using chromatography (0-100% EtOAc in heptane as gradient eluent) The product-containing fractions are combined, concentrated in vacuo, and then dried under vacuum. The precipitate was suspended in 4 mL of ethanol and sonicated for 4 minutes, and then the precipitate was isolated by filtration to give the title compound. The compound (20 mg, 38 μmol, 30% yield) is obtained. 1 H NMR 400MHz, (DMSO-d6)δ5.71(m,1H),1.60(d,3H),1.39(s,9 H), 1.38(s,9H), 1.32(S,12H).

[0109] Preparation 11 N-[(4-bromophenyl)methyl]-5-fluoro-2-methoxy-benzamide [ka] 5-Fluoro-2-methoxybenzoic acid (10.0 g, 58. 8mmol) and 4-bromobenzylamine (10.9g, 58.8mmol) were mixed with stirring. The mixture was added with DIEA (22.8 g, 176.3 mmol) and T3P (44.9 g, 70. 5 mmol, 50% in EtOAc) is added dropwise at room temperature under N2. The resulting mixture is Stir at 50°C for 1.5 hours. Cool the mixture to room temperature. Add room temperature water (150 mL). The reaction is quenched by the addition of 100 mL of 1,0 ... The combined organic layers were washed with brine (2 x 100 mL) and extracted with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (17 g, 84% yield) as a yellow solid. Obtained as a colored solid. 1 H NMR 300MHz,(CDCl3)δ8.28(s,1H ),7.94(dd,1H),7.51-7.41(m,2H),7.31-7.20( m,2H),7.18-7.11(m,1H),6.93(dd,1H),4.62(d ,2H),3.92(s,3H).

[0110] Preparation 12 tert-Butyl N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl ]methyl]carbamate [ka] 4-[(tert-butoxycarbonylamino)methyl]ammonium chloride in DCM (200 mL) Benzoic acid (10.0 g, 39.8 mmol) and malononitrile (3.39 g, 51.3 mmol) To a stirred mixture of 25.7 g (198.98 mmol) of DIEA was added under N2. To the above mixture, T3P (75.97 g, 119.4 mmol, EtOAc) was added. Add dropwise 50% of the above solution at room temperature over 30 minutes. Stir the resulting mixture for another 2 hours at room temperature. The reaction is quenched with water (200 mL) and extracted with DCM (3 x 200 mL). The organic layer was washed with saturated aqueous NaCl (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (10. 5 g, 88%) as a dark orange oil. 1 H NMR 400MHz, (DMSO-d 6)δ8.17(s,1H),7.52(d,2H),7.21(d,2H),4.14 (d,2H), 1.40(s,9H).

[0111] Preparation 13 tert-Butyl N-[[4-(2,2-dicyano-1-methoxy-vinyl)phenyl] Methyl]carbamate [ka] tert-Butyl N-[[4-(2,2-dicyano-1-hydroxybenzoate]-1,2-dihydro-2,4-dimethyl-2,5-dimethyl-1,2-dihydro ... Hydroxy-vinylphenylmethylcarbamate (10.5g, 35.1mmol) To the stirred solution of 10.7 g (105.2 mmol) was added in small portions at room temperature under N2. To the above mixture, add dimethyl sulfate (26.6 g, 210.5 mL) in THF (2 mL). The resulting mixture is stirred at 50°C for a further 3 hours. Cool to room temperature. Quench the reaction with water (200 mL) and add EtOAc (2 x 200 mL). The combined organic layers are washed with brine (3 x 100 mL) and anhydrous NaSO The mixture was dried at 4°C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 2,4-dimethyl-3,5-dimethyl-2,6-dimethyl-1,7 ... 10.9 g, 99% yield, is obtained as a dark yellow oil.1 H NMR 300MHz, (D MSO-d6)δ7.67-7.59(m,2H),7.46(d,2H),4.24( d, 2H), 3.89 (s, 3H), 1.41 (s, 9H).

[0112] Preparation 14 tert-Butyl N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2 -trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]carbohydrate Bamet [ka] tert-Butyl N-[[4-(2,2-dicyano-1-methanone]] in THF (20 mL) (1.00 g, 3.191 mmol, 1 To a stirred solution of [(1S)-2,2,2-trifluoro-1-methyl-ethyl] [Isopropyl]hydrazine hydrochloride (0.53 g, 3.2 mmol) and TEA (0.65 g, 6.3 8 mmol) is added at room temperature. The resulting mixture is stirred at 50°C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. PE / EtOAc (5: The residue was purified by silica gel column chromatography eluting with a 2:1 to 3:1 dilution of 1:1 HCl. The title compound (1.2 g, 92% yield) is obtained as a yellow solid. 1 H NMR 400MHz ,(DMSO-d6)δ7.72(d,2H),7.33(d,2H),7.09(s, 2H),5.32-5.25(m,1H),4.15(d,2H),1.65(d,3H ),1.40(s,9H).

[0113] Preparation 15 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2,2,2-trimethyl- Trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile hydrochloride [ka] In a 25 mL round-bottom flask, add tert-butyl N-[[4-[5-amino-4-cyano- 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl [phenyl]methyl]carbamate (1.20 g, 2.93 mmol) and HCl (1 4M in 4-dioxane, 7 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture is concentrated in vacuo, then washed with Et2O (3 x 5 mL) and again concentrated in vacuo. The crude product was carried on to the next step without further purification. Use directly. ES / MS m / z=310.1[M+H] + . 1 H NMR 400M Hz,(DMSO-d6)δ8.50(s,2H),7.84-7.71(m,2H), 7.64-7.53(m,2H),7.20(s,2H),5.45-5.38(m,1 H),4.08-4.04(m,2H),1.65(d,3H).

[0114] Preparation 16 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2,2,2-trimethyl- Trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide [ka] 5-amino-3-[4-(aminomethyl)-2-(2-methyl-2-propanol]-2-one in DMSO (1 mL) and EtOH (6 mL) 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] A mixture of benzothiazolinone-4-carbonitrile (120 mg, 0.388 mmol) and NaOH (77 To a stirred mixture of 0.6 mg, 1.94 mmol) was added H2O2 (0.7 ml, 30% in H2O). ) is added dropwise at room temperature. The resulting mixture is then stirred at 50°C for 2 hours. The mixture is then cooled to room temperature. The crude product (100 mg) was purified by Prep-HPLC ( XBridge Prep C18 OBD™ Column, 19 x 150 mm, 5 μm ; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; Gradient: 10% B to 26% B in 6 min, 26% B; Wavelength: 254 / 220 nm) The product-containing fractions were lyophilized to give the title compound (15.2 mg, yield 12%). %) as a white solid. ES / MS m / z=328.2 [M+H] + . 1 HNM R 400MHz,(DMSO-d6)δ7.55-7.31(m,4H),5.21( q,1H),4.19(t,0.5H),3.78(t,1.5H),1.75-1.5 0(m,3H).

[0115] Preparation 17 [5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro-1-methyl- Ethyl]pyrazol-3-yl]boronic acid [ka] tert-Butyl N-tert-butoxycarbonyl-N-[4-cyano-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S )-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]carbamate The acetone (25 mg, 47 μmol) was dissolved in DCM (1 mL) and TFA (0.54 g, 0 Treat with 100 mL of HCl (0.36 mL, 4.7 mmol). Stir the reaction at ambient temperature for 3 hours. The resulting solution was purified by silica chromatography (gradient elution: 0-100% EtOAc in hexane). c) and directly purify without workup. The product-containing fractions were combined and concentrated in vacuo. , to give the title compound (7 mg, 0.03 mmol, 60% yield). 1 H NMR 400 MHz,(DMSO-d6)δ.67(d,J=1.00Hz,3H),5.33-5. 58(m,1H),9.03(brs,2H),11.56(s,1H)12.46(s ,1H).

[0116] Preparation 18 4-(2-Methoxy-2-oxo-ethyl)benzoic acid [ka] To a stirred solution of HCl (gas) in MeOH (1000 mL, 0.3 N) was added 4-(carbohydrate). Add 100 ml of 2,000 sucrose (278 mmol) ... The resulting mixture is concentrated under reduced pressure while maintaining the temperature below 20° C. The residue was recrystallized from PE / EtOAc (120 mL / 40 mL) to give the title compound. The compound (40.0 g, 74% yield) is obtained as an off-white solid. 1 H NMR 4 00MHz,(DMSO-d6)δ12.93(s,1H),7.91(d,2H),7 .40(d,2H),3.79(s,2H),3.63(s,3H).

[0117] Preparation 19 Methyl 2-[4-(2,2-dicyano-1-methoxy-vinyl)phenyl]acetate [ka] 4-(2-Methoxy-2-oxo-ethyl)benzoic acid (40 mL) in DCM (300 mL) To a stirred solution of 1.0 g (206.2 mmol) of methyl 2-bromo-3-chloro-2-methylpropional (2.0 g, 206.2 mmol) was added a few drops of DMF. Xalyl (31.4 g, 247.4 mmol) was added dropwise at 0° C. The resulting mixture was heated to room temperature. The mixture was concentrated under reduced pressure to give crude methyl 2-(4-chlorocarbonyl) In another bottle, add malononitrile in THF (100 mL) to obtain phenyl acetate. A solution of (13.61 g, 206.2 mmol) of NaH(1 Add dropwise to a stirred suspension of 6.5 g, 412.4 mmol, (60%) in oil at 0-10°C under N2 The hydride mixture is then stirred at room temperature for 20 minutes. Then, THF (200 mL) ) to the reaction mixture. Add dropwise at ~10°C. Stir the reaction at room temperature for 1 hour. Add dimethyl sulfate (31.2g, 24 7.4 mmol) is added to the reaction. The mixture is refluxed under N2 at 80°C overnight. Add water (300 mL) and extract the organics with EtOAc (3 x 300 mL). The combined organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc:4 The title compound (42.0 g, 88% yield) was obtained as a yellow solid. do. 1 H NMR 400MHz,(CDCl3)δ7.51-7.40(m,4H), 3.96(s,3H),3.75(s,3H),3.74(s,2H).

[0118] Preparation 20 Methyl 2-[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl 1-methyl-ethyl]pyrazol-3-yl]phenyl]acetate [ka] Methyl 2-[4-(2,2-dicyano-1-methoxy-vinyl) To a stirred solution of [(1S)-2 ,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride (231.2 mg, 1 0.40 mmol) and TEA (236.9 mg, 2.34 mmol) were added at room temperature under N2. The resulting mixture is stirred at 50°C under N2 for 2 hours. The mixture is cooled to room temperature and Concentrate under reduced pressure. Column chromatography on silica gel eluting with PE / EtOAc (4:1 to 1:1) The residue was purified by chromatography to give the title compound (210 mg, 51% yield) as a white solid. ES / MS m / z=353.1[M+H] + .

[0119] Preparation 21 2-[4-[5-amino-4-carbamoyl-1-[(1S)-2,2,2-trifluoromethyl [1-methyl-ethyl]pyrazol-3-yl]phenyl]acetic acid [ka] Methyl 2-[4-[5-amino- 4-cyano-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazo A stirred solution of 1,3-dihydroxybenzoyl-3-ylphenylacetate (100 mg, 0.284 mmol) To the solution, NaOH (34.1 mg, 0.85 mmol) and H2O2 (0.5 mL, in H2O) 30%) is added at room temperature under N. The resulting mixture is stirred at 50° C. under N for 2 hours. The mixture is cooled to room temperature and then acidified to pH 5 with aqueous HCl (1N). The mixture is extracted with EtOAc (3 x 10 mL). The combined organic layers are washed with saturated aqueous NaCl. (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product is purified by Prep-HPLC under the following conditions (column: XSe Elect CSH Prep C18 OBD™ Column, 19 x 150 mm, 5μ m; Mobile phase A: Water (0.05% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 15% B to 44% B in 8 min; wavelength: 254 / 220 nm. Product-containing fractions were collected. Lyophilization affords the title compound (18.4 mg, 18% yield) as a white solid. MS m / z=357.05[M+H] + . 1 H NMR 400MHz, (DMSO- d6)δ7.43(d,2H),7.35(d,2H),6.66(brs,3H),5 .34-5.23(m,2H),3.62(s,2H),1.61(d,3H).

[0120] Preparation 22 2-[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl- Ethyl)pyrazol-3-yl]phenyl]acetic acid [ka] Methyl 2-[4-[5-amino-4-cyano] No-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl] phenyl]acetate (3.20 g, 9.08 mmol) and LiOH (0.65 g, 27 A solution of 0.3 mmol) was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to remove the solvent. Then EtOAc (10 mL) is added. The filter cake is dissolved in water (50 mL). Acidify with aqueous HCl (4 M) to pH 6. The resulting mixture is diluted with EtOAc (3×10 The combined organic layers were washed with saturated aqueous NaCl (2 x 50 mL). Dry over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give crude compound (3 g, 9 7%) as a brown solid. ES / MS m / z=339.2 [M+H] + .

[0121] Preparation 23 Benzyl N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1 -methyl-ethyl)pyrazol-3-yl]phenyl]methyl]carbamate [ka] 2-[4-[5-amino-4-cyano-1-(2,2 ,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]acetic acid (1 0.00g, 2.956mmol, 1.00eq) and benzyl alcohol (383.60 To a stirred solution of TEA (598.2 mg, 5 mg, 3.547 mmol, 1.20 equiv.) 0.91 mmol) and DPPA (1.22 g, 4.43 mmol) were added dropwise at room temperature under N2. The resulting mixture is stirred at 110°C under N2 overnight. The mixture is cooled to room temperature. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel eluting with PE / EtOAc (2:1 to 1:1). The product was purified by gel column chromatography to give the title compound (300 mg, 23% yield). ) as a yellow solid. ES / MS m / z=444.1 [M+H] + . 1 H NMR 400MHz,(DMSO-d6)δ7.90-7.86(m,1H),7.79-7 .69(m,2H),7.38-7.32(m,6H),7.10(s,2H),5.3 5-5.06(m,1H),5.06(s,2H),4.31-4.24(m,2H), 1.66(d,3H).

Claims

1. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo A method for preparing benzoyl-4-carboxamide (I), comprising the steps of: viii) a compound of formula (III) 【Chemistry 1】 、 (In the formula, PG １ is -CH ３ , -CH ２ CH ３ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , methoxymethyl, tetrahydropyran, benzyl, trimethylsilyl, tert-butyl butyldimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl[ pyren-1-ylmethoxy]silyl, tert-butyldiphenylsilyl, acetyl, or is benzoyl), and [(1S)-2,2,2-trifluoro-1-methyl-ethyl ]hydrazine (8) or its salt to give N-[[4-[5-amino-4 -cyano-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole [0010] 1-(2-(2-phenyl-3-yl)phenyl]methyl)-5-fluoro-2-methoxy-benzamide (10 ) or a salt thereof; ix) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine] [Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro (S)-5-amino-3-(4-methoxy-benzamide (10) or its salt -((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1, 1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (I) and x) optionally, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzyl) amido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)- 1H-pyrazole-4-carboxamide (I) was crystallized to give (S)-5-a in crystalline form. 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carbohydrate providing an oxamide (I); A method comprising:

2. The compound of formula (III) 【Chemistry 2】 、 [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) or before the coupling step with the salt of N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5 2-fluoro-2-methoxy-benzamide (II) is reacted with an alkylating agent to form a compound of the formula 10. The method of claim 1, further comprising obtaining the compound of formula (III). 【Transformation 3】

3. The compound of formula (III) and [(1S)-2,2,2-trifluoro-1-methyl- before the coupling step with methyl]hydrazine (8), [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride (7 ) to [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) The method of claim 1 or 2, further comprising a converting step.

4. [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride (7 ) to [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) Before converting, N'-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzohydrazine and reacting (6) or a salt thereof with [(1S)-2,2,2-trifluoro-1-methyl 4. The method of claim 3, further comprising the step of obtaining [-ethyl]hydrazine hydrochloride (7).

5. N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5 before reacting 2-fluoro-2-methoxy-benzamide (II) with an alkylating agent, 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoyl The chloride (4) is reacted with malononitrile to give N-[[4-(2,2-dicyano-1-hydroxybenzoyl)- hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide ( The method of any one of claims 2 to 4, further comprising the step of obtaining II).

6. 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoyl Before reacting the chloride (4) with malononitrile, 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid (3 ) or a salt thereof, ] The method of claim 5, further comprising the step of converting the compound (2) to benzoyl chloride (4).

7. 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid (3 ) or a salt thereof before conversion, 5-Fluoro-2-methoxy-benzoyl chloride (2) with 4-(aminomethyl)benzoyl chloride Coupling with aromatic acid to give 4-[[(5-fluoro-2-methoxy-benzoyl)amine The method of claim 6, further comprising the step of obtaining benzoic acid (3) or a salt thereof. Law.

8. 5-Fluoro-2-methoxy-benzoyl chloride (2) with 4-(aminomethyl)benzoyl chloride Before coupling with aromatic acid, 5-Fluoro-2-methoxy-benzoic acid (1) or a salt thereof is converted to 5-fluoro- The method of claim 7, further comprising obtaining 2-methoxy-benzoyl chloride (2). method.

9. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo A method for preparing benzoyl-4-carboxamide (I), comprising the steps of: i) 5-fluoro-2-methoxy-benzoic acid (1) or a salt thereof is reacted with 5-fluoro-2-methoxy-benzoic acid (2) or a salt thereof is reacted with 5-fluoro-2-methoxy-benzoic acid (3) or a salt thereof is reacted with 5-fluoro-2-methoxy-benzoic acid (4) or a salt thereof is reacted with 5-fluoro-2-methoxy-benzoic acid (5) or a salt thereof is reacted with 5-fluoro-2-methoxy-benzo converting the compound to benzoyl chloride (2); ii) 5-fluoro-2-methoxy-benzoyl chloride (2) with 4-(aminomethyl ) benzoic acid to give 4-[[(5-fluoro-2-methoxy-benzoyl ) obtaining [amino]methyl]benzoic acid (3) or a salt thereof; iii) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The aromatic acid (3) or its salt is reacted with 4-[[(5-fluoro-2-methoxy-benzoyl)amino] methyl]benzoyl chloride (4); iv) 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzo The methyl chloride (4) was reacted with malononitrile to give N-[[4-(2,2-dicyano- 1-hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzal obtaining mide (II); v) N'-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzohydride azide (6) or a salt thereof with [(1S)-2,2,2-trifluoro-1-methyl-ethyl hydrazine hydrochloride (7); vi) [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine hydrochloride The salt (7) was reacted with [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine ( 8) converting vii) N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl [0033] 5-fluoro-2-methoxy-benzamide (II) to form a compound of formula (III) 【Chemistry 4】 、 (In the formula, PG １ is -CH ３ , -CH ２ CH ３ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , methoxymethyl, tetrahydropyran, benzyl, trimethylsilyl, tert-butyl butyldimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl[ pyren-1-ylmethoxy]silyl, tert-butyldiphenylsilyl, acetyl, or is benzoyl; viii) a compound of formula (III) 【Transformation 5】 、 [(1S)-2,2,2-trifluoro-1-methyl-ethyl]hydrazine (8) or N-[[4-[5-amino-4-cyano-1-[(1S) -2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl] methyl]-5-fluoro-2-methoxy-benzamide (10) or a salt thereof Pu and, ix) N-[[4-[5-amino-4-cyano-1-[(1S)-2,2,2-triphenylphosphine] [Fluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro (S)-5-amino-3-(4-methoxy-benzamide (10) or its salt -((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1, 1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (I) and x) optionally (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzaldehyde) (1,1,1-trifluoropropan-2-yl)-1-( ... H-pyrazole-4-carboxamide (I) was crystallized to give (S)-5-amino- No-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1 -(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide providing an amide (I); A method comprising:

10. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo A method for preparing N-[[4-(2,2-dicyano- -1-methoxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benzal S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide) (methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-biphenyl and converting the compound into benzothiazolinone-4-carboxamide (I).

11. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo A method for preparing N-[[4-(2,2-dicyano- -1-hydroxy-vinyl)phenyl]methyl]-5-fluoro-2-methoxy-benz The amide was prepared as S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide )methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H- and converting the compound into pyrazole-4-carboxamide (I).

12. N-[[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]methyl]-5 -fluoro-2-methoxy-benzamide. 【Transformation 6】

13. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 13. Use of the compound according to claim 12 in the preparation of aryl-4-carboxamide (I).

14. compound 【Transformation 7】 、 (In the formula, PG １ is -CH ３ , -CH ２ CH ３ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , methoxymethyl, tetrahydropyran, benzyl, trimethylsilyl, tert-butyl butyldimethylsilyl, di-tert-butylisobutylsilyl, di-tert-butyl[ pyren-1-ylmethoxy]silyl, tert-butyldiphenylsilyl, acetyl, or is benzoyl).

15. PG １ Ga-CH ３ 15. The compound of claim 14, wherein:

16. 15. The compound of claim 14, wherein: 【Transformation 8】

17. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 15. Use of the compound according to claim 14 for preparing aryl-4-carboxamide (I).

18. The compound of any one of claims 1 to 3, wherein the compound of formula (III) is a compound of formula (IIIA):

1. The method according to claim 1. 【Chemistry 9】

19. A compound selected from the group consisting of: 【Chemistry 10】 (In the formula, PG ２ is fluorenylmethoxycarbonyl, tert-butoxycarbonyl, Benzylcarbonyl, trifluoroacetamide, phthalimide, benzyl, triphenyl methyl, benzylideneamine, p-toluenesulfonamide, PG １ is -CH ３ , -CH ２ CH ３ , -C(CH ３ ) ３ , -CH ２ CH=CH ２ , methoxymethyl, tet Hydropyranyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, di -tert-butylisobutylsilyl, di-tert-butyl[pyren-1-ylmethoxy] silyl, tert-butyldiphenylsilyl, acetyl, or benzoyl).

20. 3,5-diamino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl ]pyrazole-4-carbonitrile: 【Chemistry 11】 、 or a salt thereof.

21. 5-amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl- Ethyl]pyrazole-4-carbonitrile: 【Chemistry 12】 、 or a salt thereof.

22. 5-amino-3-bromo-1-[(1S)-2,2,2-trifluoro-1-methyl- Ethyl]pyrazole-4-carboxamide: 【Chemistry 13】 、 or a salt thereof.

23. 5-amino-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyra Zole-4-carbonitrile: 【Chemistry 14】 、 or a salt thereof.

24. tert-Butyl N-tert-butoxycarbonyl-N-[4-cyano-2-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]carba 20. The compound of claim 19, which is a mate. 【Chemistry 15】

25. tert-Butyl N-tert-butoxycarbonyl-N-[4-cyano-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S )-2,2,2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]carbamate 20. The compound of claim 19, which is a carboxylate. 【Chemistry 16】

26. tert-Butyl N-[[4-[5-amino-4-cyano-1-[(1S)-2,2, 2-trifluoro-1-methyl-ethyl]pyrazol-3-yl]phenyl]methyl]ca Lubamate: 【Chemistry 17】 、 or a salt thereof.

27. 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrazole-4-carbonitrile hydrochloride, 20. The compound according to claim 19. [Chemistry 18]

28. 5-amino-3-[4-(aminomethyl)phenyl]-1-[(1S)-2,2,2- Trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide: 【Chemistry 19】 、 or a salt thereof.

29. [5-amino-4-cyano-1-[(1S)-2,2,2-trifluoro-1-methyl -ethyl]pyrazol-3-yl]boronic acid: 【Chemistry 20】 、 or a salt thereof.

30. Methyl 2-[4-[5-amino-4-cyano-1-[(1S)-2,2,2-trifluoromethyl [0042] [1-methyl-ethyl]pyrazol-3-yl]phenyl]acetate: 【Chemistry 21】 、 or a salt thereof.

31. 2-[4-[5-amino-4-carbamoyl-1-[(1S)-2,2,2-trifluoromethyl [O-1-methyl-ethyl]pyrazol-3-yl]phenyl]acetic acid: 【Chemistry 22】 、 or a salt thereof.

32. 2-[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl [0049] [-ethyl]pyrazol-3-yl]phenyl]acetic acid: 【Chemistry 23】 、 or a salt thereof.

33. Benzyl N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro- 1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]carbamate: 【Chemistry 24】 、 or a salt thereof.

34. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 34. The method according to claim 19 for preparing 4-amino-4-carboxamide (I). or any one of claims 20 to 23, claim 26, or claim 28 34. Use of the salt thereof according to any one of claims 1 to 33.

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