CN115109048B - (hetero) aryl amide compound - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and relates to (hetero) aryl amide compounds or pharmaceutically acceptable stereoisomers thereof, or crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which can inhibit the activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, in particular Bcr-Abl1, as well as preparation methods of the compounds, pharmaceutical compositions containing the compounds and application of the compounds or the compositions in preparation of medicaments. The compound of the invention has better Bcr-Abl kinase inhibition activity and pharmacodynamic performance, and can be used for treating and/or preventing Bcr-Abl caused diseases in subjects.

Description

A (hetero) aromatic amide compound

Technical Field

The present invention relates to the field of medical technology, and in particular to a (hetero) aromatic amide compound capable of inhibiting the tyrosine kinase activity of Abelson protein (Abl1), Abelson-related protein (Abl2) and related chimeric proteins, in particular Bcr-Abl1, a pharmaceutical composition containing the same, and a preparation method and use thereof.

Background Art

The known (hetero) aromatic amide compounds are a class of Bcr-Abl kinase inhibitory active compounds and are allosteric inhibitors of Bcr-Abl tyrosine kinase. The Bcr-Abl fusion gene is caused by the reciprocal translocation between chromosomes 9 and 22 in human hematopoietic stem cells, and the fusion of Bcr and Abl1 genes on the Philadelphia chromosome (Ph). The tyrosine kinase expressed by it causes a series of signaling pathways that regulate cell growth, differentiation, and death to be abnormally activated, causing changes in cell proliferation, adhesion, and survival properties, and thus leading to the generation of a variety of tumors. Therefore, inhibiting Bcr-Abl tyrosine kinase can effectively inhibit tumor growth.

(Hetero)aromatic amide structural compounds such as ABL001 (also known as Asciminib, chemical name (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl) nicotinamide) are Abl1 kinase allosteric inhibitors developed by Novartis Pharmaceuticals. They target the myristoyl pocket of the allosteric site of Abl1 and inactivate it. Combination with ATP-competitive Bcr-Abl tyrosine kinase inhibitors can effectively prevent the emergence of resistance to the use of ATP-competitive inhibitors and/or allosteric inhibitors. ABL-001 has been shown to have a radical effect on CML in mouse models when combined with the second-generation Bcr-Abl inhibitor nilotinib. Novartis is developing a treatment regimen combining ABL001 with multiple ATP-competitive Bcr-Abl inhibitors, including imatinib, nilotinib, and dasatinib. The drug was launched in the United States in 2021.

TGRX-678 is the first and fastest-developed fourth-generation Bcr-Abl1 allosteric inhibitor developed by Targeted Pharmaceuticals in China, and is also the second Bcr-Abl1 allosteric inhibitor in the world. The results of preclinical in vitro and in vivo studies showed that compared with ABL001, TGRX-678 has higher activity and selectivity for Bcr-AblT315I cells, better oral bioavailability, and better safety in animals than ABL001.

However, there is still a need in the art to develop compounds that have inhibitory activity against Bcr-Abl kinase or better pharmacodynamic properties.

Summary of the invention

The purpose of the present invention is to provide a novel class of (hetero)aryl amide compounds or their pharmaceutically acceptable stereoisomers, or their crystal forms, pharmaceutically acceptable salts, hydrates or solvates having Bcr-Abl kinase inhibitory activity and better pharmacodynamic properties, which can be used to treat and/or prevent diseases caused by Bcr-Abl in subjects.

The present invention also provides a preparation method of the (hetero) aromatic amide compound and its intermediate.

The present invention also provides a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

The present invention also provides use of the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate or hydrate or the pharmaceutical composition of the present invention for preparing a drug.

To this end, the technical solution adopted by the present invention is as follows:

In the first aspect of the present invention, there is provided a compound as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

wherein Y is selected from CH or N;

R ₁ is independently selected from hydrogen, halogen, nitrile, hydroxyl, and may be mono-, di- or poly-substituted; R ₂ is selected from -CF ₂ -Y ₁ ;

_Y is selected from hydrogen, chlorine, fluorine, methyl, difluoromethyl and trifluoromethyl;

Z is selected from a chemical bond, O and S(O) _0-2 ; or -ZR ₂ together represent -SF ₅ ;

Het is pyrrolidinyl; wherein the pyrrolidinyl is substituted with one or more _Ra groups;

_Ra is selected from the group consisting of hydrogen, hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, cyano and amino-carbonyl;

Link is urea, thiourea,

_R3 is wherein X ₁ -X ₉ are independently selected from CR _c or N, and one of X ₆ , X ₇ , X ₈ and X ₉ is a C atom to which the parent core is attached, X ₁₀ is selected from O, S or NR _b , and X ₁₁ is selected from O, S, NR _b or C(R _c ) ₂ ;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3, 4, 5, 6 or 7;

R _b is independently selected from hydrogen, acetyl, C _1-6 alkyl or C _1-6 haloalkyl;

R and R _c are independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 alkylthio, C 1-6 haloalkoxy} , C _3-7 heterocycloalkyl, C _6-10 aryl or C _5-10 heteroaryl _;

Or two R groups on the same atom or adjacent atoms may together form a C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, or C _5-10 heteroaryl;

The halogen is F, Cl, or Br.

In certain preferred embodiments, disclosed is formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

Wherein, R ₁ is independently selected from hydrogen, halogen, nitrile, hydroxyl, and may be mono-, di- or poly-substituted;

R _a is independently selected from hydrogen, hydroxyl, halogen, nitrile, carboxyl, and may be mono-, di- or poly-substituted;

Link is urea, thiourea,

_R3 is

wherein X ₁ -X ₉ are independently selected from CR _c or N, and one of X ₆ , X ₇ , X ₈ and X ₉ is a C atom connected to the parent core, X ₁₀ is selected from O, S or NR _b , and X ₁₁ is selected from O, S, NR _b or C(R _c ) ₂ ;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3, 4, 5, 6 or 7;

R _b is independently selected from hydrogen, acetyl, C _1-6 alkyl or C _1-6 haloalkyl;

R and R _c are independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 alkylthio, C 1-6 haloalkoxy} , C _3-7 heterocycloalkyl, C _6-10 aryl or C _5-10 heteroaryl _;

Two R groups on either the same atom or adjacent atoms may together form a C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, C _6-10 aryl, or C _5-10 heteroaryl;

The halogen is F, Cl, or Br.

Further, the R ₁ is independently selected from hydrogen and halogen; _{Ra is} independently selected from hydrogen and hydroxyl;

Link is urea, thiourea,

R _b is independently selected from hydrogen, acetyl, C _1-3 alkyl or C _1-3 haloalkyl;

R and R _c are independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH ₂ , -NHC _1-3 alkyl, -N(C _1-3 alkyl) ₂ , C _1-3 alkyl, C 1-3 haloalkyl, _{C 1-3} hydroxyalkyl, C _1-3 alkoxy, C _{1-3 alkylthio, C 1-3 haloalkoxy} , C _3-7 heterocycloalkyl, C _6-10 aryl or C _5-10 heteroaryl;

Alternatively, two R groups on the same atom or adjacent atoms may be taken together to form a C _3-7 cycloalkyl group, a C _3-7 heterocycloalkyl group, a C _6-10 aryl group, or a C _5-10 heteroaryl group.

In certain preferred embodiments, disclosed is formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

wherein _{Ra is} independently selected from hydrogen and hydroxyl;

Link is urea, thiourea,

_R3 is selected from the following groups optionally substituted by one, two or three R:

R _b is independently selected from hydrogen, acetyl or C _1-3 alkyl;

R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 haloalkoxy, C3-7 heterocycloalkyl, _{C6-10 aryl} or _C5-10 heteroaryl.

Further, the _Ra is a hydroxyl group;

Link is thiourea,

R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, _-NH2 , _-NHC1-3 alkyl, -N( _C1-3 alkyl) ₂ , _C1-3 alkyl, _C1-3 haloalkyl _{, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 alkylthio , C1-3} haloalkoxy.

In certain more preferred embodiments, the (hetero)arylamide compound of the present invention is any one of the compounds in Table 1 below or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:

Table 1 shows some of the compounds of the present invention.

In another aspect, the present invention provides a method for preparing a compound of formula (XI) and an intermediate thereof, comprising the following steps:

(1) Preparation of intermediate (V): 2-amino-5-methylpyridine (IV) was dissolved in concentrated sulfuric acid, and a mixed acid solution of concentrated sulfuric acid and concentrated nitric acid in a volume ratio of 1:1 was added under ice bath conditions, and the mixture was heated to 55° C. The reaction solution was poured into crushed ice and sodium nitrite was added, and the mixture was stirred under ice bath conditions to obtain intermediate (V);

(2) Preparation of intermediate (VI): Add 2-hydroxy-5-methyl-3-nitropyridine (V) into a reaction flask, add phosphorus oxychloride, and heat under reflux for 8 hours to obtain intermediate (VI);

(3) Preparation of intermediate (VII): 2-chloro-5-methyl-3-nitropyridine (VI) was dissolved in concentrated sulfuric acid, potassium dichromate was added in batches under ice bath conditions, and stirred at room temperature for 16 h to obtain intermediate (VII);

(4) Preparation of intermediate (VIII): 6-chloro-5-nitronicotinic acid (VII) was dissolved in anhydrous DCM, dichlorothionyl (SOCl ₂ ) was added, and the mixture was stirred under heating for 4 hours, dried under vacuum, and dissolved in anhydrous DCM, and then the corresponding substituted aniline was added, and the mixture was stirred at room temperature to obtain intermediate (VIII);

(5) Preparation of intermediate (IX): Dissolve intermediate (VIII) in anhydrous DMSO, add N,N-diisopropylethylamine (DIEA) and correspondingly substituted pyrrolidine, and heat to react to obtain intermediate (IX);

(6) Preparation of intermediate (X): Dissolve intermediate (IX) in anhydrous MeOH, add palladium carbon (Pd/C), and heat under _H2 to obtain intermediate (X);

(7) Preparation of target product (XI):

Condensation reaction, specifically, the steps are: dissolving the intermediate (X) in anhydrous acetonitrile, adding various substituted acid chlorides, and then adding triethylamine (TEA), stirring at room temperature for 1 hour to obtain the target product (XI);

or addition reaction, the specific steps are: dissolving the intermediate (X) in anhydrous methanol, adding various substituted cycloalkyl ketones, heating and stirring to react to obtain the target product (XI);

or reductive amination reaction, specifically, the intermediate (X) is dissolved in anhydrous methanol, various substituted cycloalkyl ketones are added, heated and stirred for reaction for 2 hours, sodium cyanoborohydride (NaBH ₃ CN) is added, and heated for reaction to obtain the target product (XI);

or addition reaction, specifically, the intermediate (X) is dissolved in anhydrous ethanol, various substituted isothiocyanates and TEA are added, and stirred at 80° C. for 4 h to obtain the target product (XI);

Or condensation reaction, the specific steps are: dissolving the intermediate (X) in N,N-dimethylformamide, adding various substituted carboxylic acids, and then adding 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA, stirring at room temperature for 18 hours to obtain the target product (XI).

In another aspect, the present invention provides a pharmaceutical composition, which contains any of the compounds of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate or hydrate, and a pharmaceutically acceptable excipient. The compound can be added with a pharmaceutically acceptable carrier to make a common pharmaceutical preparation, such as tablets, capsules, syrups, suspensions, injections, and can be added with spices, sweeteners, liquid or solid fillers or diluents and other common pharmaceutical excipients. In a specific embodiment, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a preventive effective amount.

The present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate and pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing a disease caused by Bcr-Abl in a subject.

In a specific embodiment of the present invention, the disease caused by Bcr-Abl is a proliferative disease selected from: solid tumors, sarcomas, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other hyperplastic or proliferative diseases. In a specific embodiment of the present invention, the disease caused by Bcr-Abl is metastatic invasive cancer, viral infection or CNS disorder.

Pharmacological experiments show that the compound of the present invention can produce good anti-proliferation effects on human chronic myeloid leukemia cell lines K562 and KBM5, can be used to prepare drugs for treating chronic myeloid leukemia, acute myeloid leukemia and other cancers, and has good application prospects.

DETAILED DESCRIPTION

The following examples are provided so as to provide those skilled in the art with a complete disclosure and description of how to perform, prepare and evaluate the methods and compounds claimed herein and are intended to merely illustrate the invention and not to limit the scope of the invention.

The structures of the compounds of the present invention are determined by mass spectrometry (MS) and/or nuclear magnetic resonance ( ¹ HNMR) equipment.

Synthesis method

The compounds of the present invention can be prepared according to conventional methods in the art, and using suitable reagents, raw materials and purification methods known to those skilled in the art. The preparation method of the compounds of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

Usually, in the preparation, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.

Example 1 Preparation of (R,E)-5-(((5-bromothiophen-2-yl)methylene)amino)-N-(4-(chlorodifluoromethoxy) phenyl)-6-(3- hydroxypyrrolidin-1-yl)nicotinamide (Compound 1)

Step 1: Synthesis of 2-hydroxy-5-methyl-3-nitropyridine (Compound 1b).

Add 300 mL of concentrated sulfuric acid to the reaction bottle, add 2-amino-5-methylpyridine (1a, 60.0 g, 554.8 mmol) and 70 mL of concentrated sulfuric acid and concentrated nitric acid (V:V = 1:1) under ice bath, stir at room temperature for 1 hour, then heat to 55 ° C and stir for 2 hours. Pour the reaction solution into ice water, add 77 g of sodium nitrite in batches under ice bath, keep warm and stir for 4 hours to produce a large amount of yellow solid. Filter by suction, dry the filter cake, and obtain 45.2 g of yellow solid, yield: 52.9%.

Step 2: Synthesis of 2-chloro-5-methyl-3-nitropyridine (Compound 1c).

Add 2-hydroxy-5-methyl-3-nitropyridine (1b, 45.2 g, 272.5 mmol) and 750 mL of phosphorus oxychloride to the reaction flask and heat to reflux for 8 h. After the reaction solution was concentrated under reduced pressure, it was poured into crushed ice. A large amount of yellow solid precipitated. After suction filtration, washing and drying, 42.1 g of the product was obtained, with a yield of 89.5%.

Step 3: Synthesis of 6-chloro-5-nitronicotinic acid (Compound 1d).

Add 2-chloro-5-methyl-3-nitropyridine (1c, 42.1 g, 197.4 mmol) to the reaction bottle, dissolve in 500 mL of concentrated sulfuric acid, stir at room temperature, add potassium dichromate (92.3 g, 313.8 mmol) in batches, and stir at room temperature for 16 h. Pour the reaction solution into crushed ice, stir to cool, extract with ethyl acetate three times, combine the organic phases, concentrate under reduced pressure, and recrystallize to obtain 36.72 g of the product, with a yield of 74.3%.

Step 4: Synthesis of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitronicotinamide (Compound 1e).

6-Chloro-5-nitronicotinic acid (1d, 36.53 g, 180.35 mmol) and thionyl chloride (SOCl ₂ , 550 mL) were added to the reaction bottle, stirred at 80°C for 4 hours, dried in vacuo, added with 500 mL of anhydrous DCM to dissolve, and then added with 4-(chlorodifluoromethoxy)aniline (34.91 g, 180.35 mmol), stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain 52.13 g of the product, with a yield of 76.4%.

Step 5: Synthesis of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-nitronicotinamide (Compound 1f).

Compound 1e (52.06 g, 137.6 mmol) and (R)-3-hydroxypyrrolidine (12.00 g, 137.6 mmol) were added to the reaction bottle, 400 mL of anhydrous DMSO was added, DIEA (35.57 g, 275.3 mmol) was added, and the mixture was heated to 100 °C and stirred for 2 hours. Excess water was added to dilute, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to obtain 45.73 g of the product in a yield of 77.4%.

Step 6: Synthesis of (R)-5-amino-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 1g)

Compound 1f (45.7 g, 106.5 mmol), palladium on carbon (Pd/C, 2 g) and 300 mL of anhydrous MeOH were added to the reaction bottle, replaced _{with H2} , stirred at 40°C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 33.4 g of the product, with a yield of 78.63%.

Step 7: Synthesis of (R,E)-5-(((5-bromothiophen-2-yl)methylene)amino)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidine-1)nicotinamide (Compound 1)

Add compound 1g (200mg, 0.5mmol), 5-bromothiophene-2-carboxaldehyde (190mg, 1mmol), formic acid (2.3mg, 0.05mmol) and 3mL of anhydrous methanol to the reaction flask, heat and stir at 50°C for 2 hours. Purify by silica gel column chromatography and reverse phase column chromatography to obtain 61.6mg of the product, with a yield of 21.4%. LC-MS (ESI): m/z=570.99; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.18 (s, 1H), 8.75 (s, 1H), 8.62 (d, J = 2.1Hz, 1H), 7.90-7.85 (m, 2H), 7.82 (d, J = 2.2Hz, 1H), 7.54 (d, J ＝3.9Hz,1H),7.40(d,J＝3.9Hz,1H),7.38-7.33(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.81-3.78(m,3H),3.68(s,1H),1.98-1.82(m,2H).

Example 2 Preparation of (R,E)-5-(((5-bromofuran-2-yl)methylene)amino)-N-(4-(chlorodifluoromethoxy) Phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 2)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced with 5-bromo-2-furancarboxaldehyde to finally obtain 72.8 mg of the product with a yield of 26.2%. LC-MS(ESI):m/z＝555.02[M+H] ⁺ ； ¹ H-NMR(400MHz,DMSO-d ₆ )δ10.15(s,1H),8.61(d,J＝2.1Hz,1H),8.41(s,1H),7.87(d,J＝9.1Hz,2H),7.75(d,J＝2.2Hz,1H),7.35(d,J＝8.6Hz,2H),7.21(d,J＝3.5Hz,1H),6.89(d,J＝3.5Hz,1H),4.94(d,J＝3.3Hz,1H),4.33(s,1H),3.88-3.75(m,3H),3.66-3.62(m,1H),1.96-1.82(m,2H)。

Example 3 Preparation of (R,E)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(((5-(hydroxymethyl)furan-2-yl) Methyl)amino)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 3)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced with 5-hydroxymethylfurfural to finally obtain 80.0 mg of the product with a yield of 31.6%. LC-MS (ESI): m/z=507.12 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.14(s,1H),8.59(d,J＝2.1Hz,1H),8.41(s,1H),7.91-7.84(m,2H),7.71(d,J＝2.2Hz,1H),7.38-7.31(m,2H),7.12(d,J＝3.4Hz,1H),6.56(d,J＝3. 4Hz,1H),5.48(t,J＝5.8Hz,1H),4.93(d,J＝3.3Hz,1H),4.51(d,J＝5.8Hz,2H),4.32(s,1H),3.79-3.76(m,3H),3.65-3.62(m,1H),1.98-1.80(m,2H).

Example 4 Preparation of (R,E)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5- (((5-methoxypyridin-3-yl)methylene)amino)nicotinamide (Compound 4)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced with 5-methoxy-pyridine-3-carboxaldehyde to finally obtain 49.0 mg of the product with a yield of 18.9%. LC-MS (ESI): m/z=518.14 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.20(s,1H),8.76(s,1H),8.70(d,J＝1.6Hz,1H),8.65(d,J＝2.1Hz,1H),8.46(d,J＝2.9Hz,1H),7.90(s,1H),7.87(s,1H),7.83(d,J＝2.1Hz,2H),7.3 6(d,J＝8.6Hz,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.92(s,3H),3.85-3.81(m,3H),3.70-3.67(m,1H),1.97-1.81(m,2H).

Example 5 Preparation of (R,E)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5- ((Pyridin-4-ylmethylene)amino)nicotinamide (Compound 5)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced by 4-pyridinecarboxaldehyde to finally obtain 39.3 mg of the product with a yield of 16.1%. LC-MS(ESI):m/z＝488.13[M+H] ⁺ ； ¹ H-NMR(300MHz,DMSO-d ₆ )δ10.21(s,1H),8.81-8.77(m,2H),8.75(s,1H),8.67(d,J＝2.2Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1.3Hz,3H),7.85(d,J＝1.7Hz,1H),7.41-7.31(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.86-3.81(m,3H),3.70-3.65(m,1H),1.99-1.84(m,2H)。

Example 6 Preparation of (R,E)-5-(((6-bromopyridin-3-yl)methylene)amino)-N-(4-(chlorodifluoromethoxy) Phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 6)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced with 5-bromopyridine-3-carboxaldehyde to prepare Compound 6. LC-MS (ESI): m/z=566.04 [M+H] ⁺ .

Example 7 Preparation of (R,E)-N-(4-(chlorodifluoromethoxy)phenyl)-5-((2-hydroxy-5-nitrobenzylidene)amino 1-Hydroxypyrrolidin-1-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 7)

Referring to the method of Example 1, 5-bromothiophene-2-carboxaldehyde was replaced with 5-nitrosalicylicylaldehyde to prepare Compound 7. LC-MS (ESI): m/z=548.12 [M+H] ⁺ .

Example 8 Preparation of (R)-5-(((5-bromothiophen-2-yl)methyl)amino)-N-(4-(chlorodifluoromethoxy)benzene 1-Hydroxypyrrolidin-1-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 8)

Compound 1g (200mg, 0.5mmol), 5-bromothiophene-2-carboxaldehyde (190mg, 1mmol), formic acid (2.3mg, 0.05mmol) and 3mL of anhydrous methanol were added to the reaction bottle, heated and stirred at 50°C for 2 hours, sodium cyanoborohydride ( _NaBH3CN , 128mg, 2mmol) was added, stirred and reacted at room temperature for 1 hour, diluted with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated sodium chloride solution, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 113.4mg of the product, with a yield of 39.6%. LC-MS (ESI): m/z = 573.02 [M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ )δ10.13(s,1H),8.21(d,J＝1.9Hz,1H),7.90-7.81(m,2H),7.33-7.29(m,2H),7.21(d,J＝2.0Hz,1H),7.08(d,J＝3.7Hz,1H),6.95(d,J＝3.7Hz,1H),5.64 (t,J＝5.5Hz,1H),4.93(d,J＝3.6Hz,1H),4.47(d,J＝5.4Hz,2H),4.37(d,J＝3.7Hz,1H),3.88-3.68(m,2H),3.47-3.42(m,1H),3.30-3.25(m,1H),2.05-1 .77(m,2H).

Example 9 Preparation of (R)-5-(((5-bromofuran-2-yl)methyl)amino)-N-(4-(chlorodifluoromethoxy)benzene 1-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 9)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced with 5-bromo-2-furancarboxaldehyde to prepare Compound 9. LC-MS (ESI): m/z=557.04 [M+H] ⁺ .

Example 10 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(((5-(hydroxymethyl)furan-2-yl)methyl 6-(3-hydroxypyrrolidin-1-yl)amino)nicotinamide (Compound 10)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced with 5-hydroxymethylfurfural to obtain 35.0 mg of the product with a yield of 13.7%. LC-MS (ESI): m/z=509.16 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.15(s,1H),8.19(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.3Hz,2H),7.27(d,J＝2.0Hz,1H),6.20(s,2H),5.30(t,J＝5.8Hz,1H),5.17(t, J＝5.7Hz,1H),4.91(d,J＝3.7Hz,1H),4.36(s,2H),4.34(s,2H),3.74-3.70(m,2H),3.49-3.39(m,1H),3.31-3.26(m,1H),2.04-1.74(m,2H).

Example 11 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5- (((5-methoxypyridin-3-yl)methyl)amino)nicotinamide (Compound 11)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced with 5-methoxy-pyridine-3-carboxaldehyde to obtain 64.0 mg of the product with a yield of 24.6%. LC-MS (ESI): m/z = 520.15 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.12(s,1H),8.23(d,J＝1.7Hz,1H),8.18-8.13(m,2H),7.88-7.80(m,2H),7.39-7.35(m,1H),7.32-7.26(m,2H),7.10(d,J＝2.0Hz,1H),5.55(t,J =5.7Hz,1H),4.93(d,J＝3.6Hz,1H),4.36(s,3H),3.81(s,5H),3.49-3.45(m,1H),3.33-3.28(m,1H),2.05-1.79(m,2H).

Example 12 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-((pyrrolidone) (4-pyridin-4-ylmethyl)amino)nicotinamide (Compound 12)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced by 4-pyridinecarboxaldehyde to obtain 55.0 mg of the product with a yield of 22.4%. LC-MS (ESI): m/z = 490.16 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.11(s,1H),8.52(d,J＝5.0Hz,2H),8.18(d,J＝1.9Hz,1H),7.82(d,J＝2.1Hz,1H),7.80(d,J＝2.3Hz,1H),7.42-7.37(m,2H),7.31(d,J＝8.7Hz,2H),6.9 5(d,J＝2.0Hz,1H),5.66(t,J＝5.7Hz,1H),4.94(d,J＝3.5Hz,1H),4.40-4.36(m,3H),3.92-3.73(m,2H),3.52-3.48(m,2H),2.06-1.80(m,2H).

Example 13 Preparation of (R)-5-(((6-bromopyridin-3-yl)methyl)amino)-N-(4-(chlorodifluoromethoxy)benzene 1-Hydroxypyrrolidin-1-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Compound 13)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced with 5-bromopyridine-3-carboxaldehyde to finally obtain 127.5 mg of the product with a yield of 44.9%. LC-MS (ESI): m/z=568.06 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.12(s,1H),8.43(d,J＝2.5Hz,1H),8.19(d,J＝2.0Hz,1H),7.88-7.80(m,2H),7.76-7.72(m,1H),7.63-7.58(m,1H),7.32-7.28(m,2H),7.06(d,J ＝2.0Hz,1H),5.58(d,J＝5.7Hz,1H),4.92(d,J＝3.6Hz,1H),4.36(d,J＝5.6Hz,3H),3.84-3.73(m,2H),3.49-3.45(m,1H),3.33-3.29(m,1H),2.07-1.74 (m,2H).

Example 14 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-((2-hydroxy-5-nitrobenzyl)amino)- 6-(3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 14)

Referring to the method of Example 8, 5-bromothiophene-2-carboxaldehyde was replaced with 5-nitrosalicylicylaldehyde to obtain 98.0 mg of the product with a yield of 35.7%. LC-MS (ESI): m/z = 550.13 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ11.44(s,1H),10.14(s,1H),8.18(d,J＝1.9Hz,1H),8.11(d,J＝2.9Hz,1H),8.05(d,J＝8.9Hz,1H),7.81(d,J＝9.1Hz,2H),7.31(d,J＝8.6Hz,2H),7.08-6 .94(m,2H),5.61(s,1H),4.97(s,1H),4.36(d,J＝19.7Hz,3H),3.84-3.80(m,2H),3.52-3.49(m,1H),3.33-3.28(m,1H),2.09-1.77(m,2H).

Example 15 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(2- Nitrobenzoylamino)nicotinamide (Compound 15)

To the reaction flask, o-nitrobenzoic acid (84 mg, 0.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 228 mg, 0.6 mmol), N,N-diisopropylethylamine (DIEA, 129 mg, 1 mmol) and 3 mL of DMF were added, and the mixture was stirred at room temperature for 1 hour. Compound 1 g (200 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, extracted with ethyl acetate for 3 times, the organic phases were combined, washed with saturated sodium chloride solution, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 36.0 mg of the product, with a yield of 13.16%. LC-MS (ESI): m/z=548.12[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.36 (s, 1H), 10.30 (d, J = 1.8 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.15-8.11 (m, 1H), 7.99 (d, J = 2. 2Hz,1H),7.92-7.87(m,3H),7.82-7.76(m,2H),7.39-7.32(m,2H),5.01-4 .97(m,1H),4.37(s,1H),3.82-3.71(m,3H),3.55-3.48(m,1H),2.00-1.83 (m,2H).

Example 16 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(thiophene) Phthalene-2-carboxamido)nicotinamide (Compound 16)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with thiophene-2-carboxylic acid to finally obtain 37.0 mg of the product with a yield of 14.5%. LC-MS (ESI): m/z=509.11[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.18 (s, 1H), 10.17 (s, 1H), 8.72 (d, J = 2.3Hz, 1H), 8.06-7.94 (m, 2H), 7.94-7.81 (m, 3H), 7. 46-7.33(m,2H),7.25-7.21(m,1H),4.99(d,J＝3.3Hz,1H),4.32-4.28(m,1H),3.70-3.67(m,3H),3.55-3.43(m,1H),1.98-1.74(m,2H).

Example 17 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(furan-2-carboxamido)-6-(3-hydroxy 1-Pyrrolidin-1-yl)nicotinamide (Compound 17)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with furoic acid to finally obtain 69.0 mg of product with a yield of 28.0%. LC-MS (ESI): m/z=493.12[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 10.10 (s, 1H), 8.71 (d, J = 2.3Hz, 1H), 7.95 (m, 2H), 7.90-7.87 (m, 2H), 7.39-7. 28(m,3H),6.71(dd,J＝3.5,1.8Hz,1H),4.99(d,J＝3.3Hz,1H),4.32-4.29(m,1H),3.76-3.62(m,3H),3.47-3.42(m,1H),1.97-1.77(m,2H).

Example 18 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)pyridineamide (Compound 18)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-pyridinecarboxylic acid to finally obtain 59.0 mg of the product with a yield of 23.4%. LC-MS (ESI): m/z=504.14 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.55(s,1H),10.20(s,1H),8.80-8.67(m,2H),8.15-8.11(m,1H),8.08-8.06(m,1H),8.05-8.00(m,1H),7.94-7.84(m,2H),7.69-7.64(m,1H),7 .34-7.31(m,2H),4.95(d,J＝3.4Hz,1H),4.29-4.25(m,1H),3.79-3.62(m,3H),3.47-3.42(m,1H),1.96-1.72(m,2H).

Example 19 Preparation of N-{4-[(chlorodifluoromethyl)oxy]phenyl}-4-[(3R)-3-hydroxytetrahydro-1H-pyrrole- 1-yl]-3-[(pyridin-4-ylcarbonyl)amino]benzamide (Compound 19)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced by isonicotinic acid to prepare Compound 19. LC-MS (ESI): m/z=504.15 [M+H] ⁺ .

Example 20 Preparation of (R)-5-(5-bromonicotinamide)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrole Alk-1-yl) nicotinamide (Compound 20)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-bromonicotinic acid to prepare Compound 20. LC-MS (ESI): m/z=582.03 [M+H] ⁺ .

Example 21 Preparation of (R)-5-(2-bromonicotinamide)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrole (Compound 21)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-bromonicotinic acid to prepare Compound 21. LC-MS (ESI): m/z=582.03 [M+H] ⁺ .

Example 22 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(4- Nitrobenzoylamino)nicotinamide (Compound 22)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-bromonicotinic acid to finally obtain 23.0 mg of the product with a yield of 8.4%. LC-MS (ESI): m/z=548.13[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 10.22 (s, 1H), 8.74 (d, J = 2.2Hz, 1H), 8.44-8.38 (m, 2H), 8.27-8.21 (m, 2H), 7. 99(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.39-7.30(m,2H),4.98(d,J＝3.3Hz,1H),4.30(d,J＝4.9Hz,1H),3.78-3.61(m,3H),3.53-3.44(m,1H),1.95-1. 76(m,2H).

Example 23 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- (4-Nitrophenyl)thiourea)nicotinamide (Compound 23)

Add 4-nitrophenyl isothiocyanate (108 mg, 0.6 mmol), triethylamine (TEA, 101 mg, 1 mmol), compound 1 g (200 mg, 0.5 mmol) and 2 mL of anhydrous ethanol to the reaction flask, stir at 80°C for 4 hours, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 162.3 mg of the product, with a yield of 56.1%. LC-MS (ESI): m/z=579.23[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.62 (s, 1H), 10.16 (s, 1H), 9.75 (s, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.30-8.16 (m, 2H), 7.95 (d, J＝5.5Hz,2H),7.91-7.70(m,3H),7.41-7.28(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.76-3.72(m,3H),3.55-3.51(m,1H),1.96-1.84(m,2H).

Example 24 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- (Pyridin-3-yl)thiourea)nicotinamide (Compound 24)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 3-pyridyl isothiocyanate to finally obtain 92.9 mg of the product with a yield of 34.7%. LC-MS (ESI): m/z=535.22[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.15 (s, 1H), 9.63 (s, 2H), 8.72 (d, J = 2.2Hz, 1H), 8.60 (s, 1H), 8.36-8.32 (m, 1H), 7.97 (s, 2 H),7.94-7.86(m,2H),7.37-3.34(m,3H),4.38(s,1H),3.75-3.71(m,4H),3.57-3.52(m,1H),2.03-1.83(m,3H).

Example 25 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- (p-Tolyl)thiourea)nicotinamide (Compound 25)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with p-toluene isothiocyanate to finally obtain 215.6 mg of the product with a yield of 78.8%. LC-MS (ESI): m/z=548.12 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.14(s,1H),9.68(s,1H),9.28(s,1H),8.68(d,J＝2.2Hz,1H),7.91(d,J＝3.5Hz,2H),7.87(d,J＝2.2Hz,1H),7.36(d,J＝1.2Hz,1H),7.35-7.29(m,3H ),7.16(d,J＝8.1Hz,2H),5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.68(m,3H),3.55-3.51(m,1H),2.29(s,3H),1.99-1.80(m,2H).

Example 26 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- Phenylthiourea) nicotinamide (Compound 26)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with phenylthioisocyanate to finally obtain 48.8 mg of the product with a yield of 18.3%. LC-MS (ESI): m/z=534.14 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.15(s,1H),9.79(s,1H),9.37(s,1H),8.69(d,J＝2.3Hz,1H),7.93(s,1H),7.91-7.85(m,2H),7.47(d,J＝7.9Hz,2H),7.38(s,1H),7.37-7.34(m, 2H),7.33-7.28(m,1H),7.21-7.13(m,1H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.76-3.72(m,3H),3.56-3.51(m,1H),2.00-1.80(m,2H).

Example 27 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(3-(4-cyanophenyl)thioureido)-6- (3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 27)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 4-cyanophenyl isothiocyanate to finally obtain 59.9 mg of the product with a yield of 21.5%. LC-MS (ESI): m/z＝559.11[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.23 (s, 1H), 10.16 (s, 1H), 9.68 (s, 1H), 8.80-8.65 (m, 1H), 7.94 (s, 1H), 7.89 (d, J＝2.2Hz, 1H),7.89-7.83(m,2H),7.79-7.74(m,3H),7.39-7.30(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.96-1.82( m,2H).

Example 28 Preparation of (R)-5-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N-(4-(chlorodifluoromethoxy) 6-(3-hydroxypyrrolidin-1-yl)-1-nitro-2-nitro-1-yl)-2-nitro-1-nitro-2-nitro ...2-nitro-1-yl)-1-nitro-2-nitro-

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 3,5-bis(trifluoromethyl)phenyl isothiocyanate to obtain 196.3 mg of the product with a yield of 58.7%. LC-MS (ESI): m/z=670.08 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.61(s,1H),10.15(s,1H),9.74(s,1H),8.74(d,J＝2.2Hz,1H),8.29(d,J＝19.2Hz,2H),7.99(s,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝2.1Hz,1H),7 .84(s,1H),7.41-7.30(m,2H),5.02(d,J＝3.2Hz,1H),4.37(s,1H),3.76-3.71(m,3H),3.56-3.51(m,1H),2.00-1.84(m,2H).

Example 29 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(3-(4-fluorophenyl)thioureido)-6-(3- Hydroxypyrrolidin-1-yl) nicotinamide (Compound 29)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 4-fluorophenyl isothiocyanate to finally obtain 81.9 mg of the product with a yield of 29.7%. LC-MS(ESI):m/z＝552.10[M+H] ⁺ ； ¹ H-NMR(300MHz,DMSO-d ₆ )δ10.14(s,1H),9.67(s,1H),9.40(s,1H),8.69(d,J＝2.2Hz,1H),7.93(s,1H),7.92-7.85(m,2H),7.44(s,2H),7.35-7.31(m,2H),7.18-7.14(m,2H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.98-1.82(m,2H)。

Example 30 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- (4-(Trifluoromethyl)phenyl)thioureido)nicotinamide (Compound 30)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 4-(trifluoromethyl)phenyl isothiocyanate to finally obtain 162.5 mg of the product with a yield of 54.0%. LC-MS (ESI): m/z＝602.10[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.37 (s, 1H), 10.23 (s, 1H), 10.16 (s, 1H), 9.62 (s, 1H), 8.71 (d, J＝2.2Hz, 1H), 7.95 (s, 1H), 7.92-7.85(m,2H),7.78(s,1H),7.70(d,J＝8.5Hz,2H),7.44-7.24(m,2H), 5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.70(m,3H),3.56-3.51(m,1H),2 .00-1.79(m,2H).

Example 31 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(3-(3,5-dichlorophenyl)thioureido)- 6-(3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 31)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 3,5-dichlorophenyl isothiocyanate to obtain Compound 31. LC-MS (ESI): m/z=602.03 [M+H] ⁺ .

Example 32 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3- (4-Methoxyphenyl)thiourea)nicotinamide (Compound 32)

Referring to the method of Example 23, 4-nitrophenyl isothiocyanate was replaced with 4-methoxyphenyl isothiocyanate to obtain Compound 32. LC-MS (ESI): m/z=548.15 [M+H] ⁺ .

Example 33 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-6-fluoropicolinamide (Compound 33)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-fluoropyridine-6-carboxylic acid to finally obtain 40.0 mg of the product with a yield of 15.3%. LC-MS (ESI): m/z=522.11 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.48(s,1H),10.19(s,1H),8.70(d,J＝2.3Hz,1H),8.25(t,J＝7.9Hz,1H),8.09(d,J＝2.1Hz,1H),7.98(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.58-7.4 9(m,1H),7.42-7.30(m,2H),4.95(d,J=3.3Hz,1H),4.29(s,1H),3.67-3.61(m,3H),3.46-3.42(m,1H),1.93-1.75(m,2H).

Example 34 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-5-fluoropicolinamide (Compound 34)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-fluoro-2-pyridinecarboxylic acid to finally obtain 53.0 mg of the product with a yield of 20.3%. LC-MS (ESI): m/z=522.12[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.52 (s, 1H), 10.19 (s, 1H), 8.76 (d, J = 2.8Hz, 1H), 8.70 (d, J = 2.4Hz, 1H), 8.22-8.16 (m, 1H), 7.99-7.94(m,2H),7.94-7.84(m,2H),7.34(d,J＝8.5Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.64(m,3H),3.46-3.42(m,1H),1.98-1.68(m, 2H).

Example 35 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-3-fluoropicolinamide (Compound 35)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 3-fluoropyridine-2-carboxylic acid to finally obtain 128.0 mg of the product with a yield of 49.12%. LC-MS (ESI): m/z=522.11 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.46(s,1H),10.22(s,1H),8.71(d,J＝2.3Hz,1H),8.59-8.57(m,1H),7.99-7.96(m,1H),7.97-7.92(m,1H),7.91-7.85(m,2H),7.77-7.73(m,1H) ),7.38-7.32(m,2H),4.97(d,J=3.3Hz,1H),4.31(s,1H),3.73-3.65(m,3H),3.50-3.45(m,1H),1.95-1.79(m,2H).

Example 36 Preparation of (R)-5-(2-bromoisonicotinamide)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidone Pyrrolidin-1-yl)nicotinamide (Compound 36)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-bromo-4-pyridinecarboxylic acid to finally prepare Compound 36. LC-MS (ESI): m/z=582.03 [M+H] ⁺ .

Example 37 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(6- (Trifluoromethyl)nicotinamido)nicotinamide (Compound 37)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 6-trifluoromethylnicotinic acid to finally prepare Compound 37. LC-MS (ESI): m/z=572.11 [M+H] ⁺ .

Example 38 Preparation of (R)-2,6-dichloro-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2- (3-Hydroxypyrrolidin-1-yl)pyridin-3-yl)nicotinamide (Compound 38)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2,6-dichloronicotinic acid to finally prepare Compound 38. LC-MS (ESI): m/z=572.05 [M+H] ⁺ .

Example 39 Preparation of (R)-3,5-dichloro-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2- (3-Hydroxypyrrolidin-1-yl)pyridin-3-yl)pyridineamide (Compound 39)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 1H-benzimidazole-2-carboxylic acid to finally obtain 78.0 mg of the product with a yield of 27.3%. LC-MS (ESI): m/z=572.03[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.45 (s, 1H), 10.27 (s, 1H), 8.77 (d, J = 2.0Hz, 1H), 8.73 (d, J = 2.3Hz, 1H), 8.46 (d, J = 2.0Hz, 1H ),7.96(d,J＝2.4Hz,1H),7.92-7.86(m,2H),7.38-7.31(m,2H),4.98(d,J＝3.3Hz,1H),4.34(s,1H),3.79-3.71(m,3H),3.52-3.47(m,1H),1.95-1.83(m ,2H).

Example 40 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (40)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 6-hydroxypyridine-2-carboxylic acid to finally prepare Compound 40. LC-MS (ESI): m/z=520.12 [M+H] ⁺ .

Example 41 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (41)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with pyrimidine-2-carboxylic acid to finally prepare Compound 41. LC-MS (ESI): m/z=505.12 [M+H] ⁺ .

Example 42 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)pyrazine-2-carboxamide (Compound 42)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-pyrazinecarboxylate to finally prepare Compound 42. LC-MS (ESI): m/z=505.13 [M+H] ⁺ .

Example 43 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (4-(2 ...

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 4-pyrimidinecarboxylic acid to finally prepare compound 43. LC-MS (ESI): m/z=505.12 [M+H] ⁺ .

Example 44 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(nicotinic acid Nicotinamide (Compound 44)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with nicotinic acid to finally prepare Compound 44. LC-MS (ESI): m/z=504.12 [M+H] ⁺ .

Example 45 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(iso Nicotinamide) Nicotinamide (Compound 45)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with isonicotinic acid to finally prepare Compound 45. LC-MS (ESI): m/z=504.13 [M+H] ⁺ .

Example 46 Preparation of (R)-5-bromo-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxy 1-(2-(4-(2 ...

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-bromo-2-(methylmercapto)-4-pyrimidinecarboxylic acid to finally obtain 96.0 mg of the product with a yield of 30.5%. LC-MS (ESI): m/z=629.02[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 10.29 (s, 1H), 9.02 (s, 1H), 8.74 (d, J = 2.2Hz, 1H), 7.94 (d, J = 2.3Hz, 1H), 7.91- 7.86(m,2H),7.35(d,J＝8.7Hz,2H),5.00(d,J＝3.3Hz,1H),4.35(s,1H),3.78-3.74(m,3H),3.57-3.52(m,1H),2.60(s,3H),1.99-1.83(m,2H).

Example 47 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-5-methylpyrazine-2-carboxamide (Compound 47)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-methylpyrimidine-2-carboxylic acid to finally obtain 89.0 mg of the product with a yield of 34.3%. LC-MS (ESI): m/z＝519.13[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.61 (s, 1H), 10.20 (s, 1H), 9.15 (d, J = 1.4Hz, 1H), 8.73 (d, J = 1.4Hz, 1H), 8.71 (d, J = 2.3Hz, 1H ),7.99(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.37-7.32(m,2H),4.95(s,1H),4.27(s,1H),3.73-3.64(m,3H),3.46-3.41(m,1H),2.65(s,3H),1.94-1 .75(m,2H).

Example 48 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(cyclopropanecarboxamido)-6-(3-hydroxy Pyrrolidin-1-yl)nicotinamide (Compound 48)

Add compound 1g (200mg, 0.5mmol), triethylamine (TEA, 50.7mg, 0.75mmol), cyclopropylcarbonyl chloride (104.9mg, 1mmol) and 3mL anhydrous acetonitrile to the reaction bottle, stir at room temperature for 2 hours, and purify by silica gel column chromatography to obtain 23.3mg of the product, yield: 9.9%. LC-MS (ESI): m/z＝467.12[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.17 (s, 1H), 9.40 (s, 1H), 8.64 (d, J = 2.3Hz, 1H), 7.91-7.85 (m, 2H), 7.83 (d, J = 2.3Hz, 1H), 7 .34-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.32(s,1H),3.73-3.56(m,3H),3.41(m,1H),3.24-3.17(m,1H),2.31-2.08(m,4H),2.05-1.69(m,2H).

Example 49 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(cyclobutanecarboxamido)-6-(3-hydroxy Pyrrolidin-1-yl)nicotinamide (Compound 49)

Referring to the method of Example 48, cyclopropylcarbonyl chloride was replaced with cyclobutylcarbonyl chloride to finally obtain 53.0 mg of the product with a yield of 22.0%. LC-MS (ESI): m/z＝481.15[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.82 (s, 1H), 8.64 (s, 1H), 7.87 (d, J = 9.9Hz, 3H), 7.34 (d, J = 8.5Hz, 2H), 5.00 (d ,J＝2.9Hz,1H),4.35(s,1H),3.70-3.65(m,3H),3.45(d,J＝11.8Hz,1H),3.24-3.18(m,1H),2.31-2.08(m,4H),2.05-1.76(m,4H).

Example 50 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(cyclopentanecarboxamido)-6-(3-hydroxy Pyrrolidin-1-yl)nicotinamide (Compound 50)

Referring to the method of Example 48, cyclopropylcarbonyl chloride was replaced by cyclopentylcarbonyl chloride to finally obtain 130.0 mg of the product with a yield of 52.6%. LC-MS (ESI): m/z = 495.16 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.19(d,J＝4.1Hz,1H),9.52(d,J＝3.6Hz,1H),8.64(dt,J＝3.9,2.3Hz,1H),7.89-7.85(m,3H),7.35(d,J＝9.2Hz,2H),5.00-4.97(m,1H),4.34(s,1H) ,3.69(d,J＝9.0Hz,3H),3.44(d,J＝11.6Hz,1H),2.79-2.72(m,1H),1.97-1.80(m,4H),1.79-1.62(m,4H),1.61-1.50(m,2H).

Example 51 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(cyclohexanecarboxamido)-6-(3-hydroxy Pyrrolidin-1-yl)nicotinamide (Compound 51)

Referring to the method of Example 48, cyclopropylcarbonyl chloride was replaced by cyclohexylcarbonyl chloride to finally obtain 18.0 mg of the product with a yield of 7.3%. LC-MS (ESI): m/z＝509.18[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.20 (d, J＝4.2Hz, 1H), 9.44 (d, J＝4.1Hz, 1H), 8.69-8.60 (m, 1H), 7.86-7.83 (m, 2H), 7.77 (q, J＝2.4Hz,1H),7.38-7.30(m,2H),4.97(s,1H),4.33(s,1H),3.67(d,J＝13.2 Hz,3H),3.43(d,J＝11.7Hz,1H),2.34(s,1H),1.94-1.58(m,8H),1.47-1.12( m,4H).

Example 52 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(cycloheptanecarboxamido)-6-(3-hydroxy Pyrrolidin-1-yl)nicotinamide (Compound 52)

Referring to the method of Example 48, cyclopropylcarbonyl chloride was replaced with cycloheptylcarbonyl chloride to finally prepare Compound 52. LC-MS (ESI): m/z=523.17 [M+H] ⁺ .

Example 53 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(tetrafluoroethylene)-1-yl Hydrogen-2H-pyran-4-carboxamido)nicotinamide (Compound 53)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with tetrahydropyran-4-carboxylic acid to finally obtain 92.0 mg of the product with a yield of 36.0%. LC-MS (ESI): m/z=511.16 [M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d6) δ10.20(s,1H),9.53(s,1H),8.65(d,J＝2.3Hz,1H),7.90-7.84(m,2H),7.79(d,J＝2.2Hz,1H),7.34(d,J＝8.8Hz,2H),4.98(d,J＝3.2Hz ,1H),4.34(s,1H),3.97-3.88(m,2H),3.65-3.61(m,3H),3.47-3.38(m,1H),3.32-3.27(m,2H),2.66-2.54(m,1H),1.90-1.64(m,6H).

Example 54 Preparation of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(tetrafluoroethylene)-1-yl (2-Hydrofuran-2-carboxamido)nicotinamide (Compound 54)

Referring to the method of Example 48, cyclopropylcarbonyl chloride was replaced with tetrahydrofuran-2-carbonyl chloride to obtain 55.0 mg of the product with a yield of 22.17%. LC-MS (ESI): m/z=497.13 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.19 (s, 1H), 9.55 (d, J=2.7 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 7.91-7.86 (m, 2H), 7.83 (t, J=2.9 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 4.99 (t, J=3.0 Hz, 1H), 4.41-4.37 (m,1H),4.33(s,1H),4.06-3.94(m,1H),3.84-3.80(m,1H),3.72-3.61(m,3H),3.45(t,J＝11.2Hz,1H),2.23-2.18(m,1H),2.01-1.93(m,1H),1.89- 1.75(m,4H).

Example 55 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-6-methylpicolinamide (Compound 55)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 6-methyl-2-pyridinecarboxylic acid to finally obtain 128.0 mg of the product with a yield of 49.5%. LC-MS (ESI): m/z=518.14 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.42(s,1H),10.21(s,1H),8.69(d,J＝2.3Hz,1H),8.12(d,J＝2.2Hz,1H),7.95(d,J＝1.9Hz,1H),7.94(s,1H),7.92-7.87(m,2H),7.56-7.52(m,1H) ,7.34(d,J＝10.8Hz,2H),4.96(d,J＝3.4Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.47-3.43(m,1H),2.62(s,3H),1.98-1.76(m,2H).

Example 56 Preparation of N-{4-[(chlorodifluoromethyl)oxy]phenyl}-4-[(3R)-3-hydroxytetrahydro-1H-pyrrole- 1-yl]-3-[(1H-pyrrol-2-ylcarbonyl)amino]benzamide (Compound 56)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with pyrrole-2-carboxylic acid to finally prepare Compound 56. LC-MS (ESI): m/z=492.13 [M+H] ⁺ .

Example 57 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-hydroxyfuran-2-carboxamido)-6- (3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 57)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-hydroxyfuran-2-carboxylic acid to finally prepare Compound 57. LC-MS (ESI): m/z=509.11 [M+H] ⁺ .

Example 58 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-chlorofuran-2-carboxamide)-6-(3- Hydroxypyrrolidin-1-yl) nicotinamide (Compound 58)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-chloro-2-furoic acid to finally obtain 72.0 mg of the product with a yield of 27.3%. LC-MS (ESI): m/z=527.06[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.18 (d, J=3.0Hz, 2H), 8.71 (d, J=2.3Hz, 1H), 7.94 (d, J=2.3Hz, 1H), 7.90-7.85 (m, 2H), 7.41 ( d,J＝3.6Hz,1H),7.35(d,J＝8.8Hz,2H),6.78(d,J＝3.6Hz,1H),4.98(d,J＝3.2Hz,1H),4.32(s,1H),3.67-3.62(m,3H),3.45-3.40(m,1H),1.96-1.79(m,2 H).

Example 59 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(furan-3-carboxamido)-6-(3-hydroxy 1-(2-(2-pyrrolidin-1-yl)nicotinamide (Compound 59)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 3-furoic acid to finally prepare Compound 59. LC-MS (ESI): m/z=493.11 [M+H] ⁺ .

Example 60 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(thiophene) Phthalene-3-carboxamido)nicotinamide (Compound 60)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 3-thiophenecarboxylic acid to finally prepare Compound 60. LC-MS (ESI): m/z=509.09 [M+H] ⁺ .

Example 61 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(5- Methylthiophene-2-carboxamide)nicotinamide (Compound 61)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-methyl-2-thiophenecarboxylic acid to finally obtain 67.0 mg of the product with a yield of 25.6%. LC-MS (ESI): m/z=523.08 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.19(s,1H),10.05(s,1H),8.70(d,J＝2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.77(d,J＝3.7Hz,1H),7.34-7.31(m,2H),6.94-6.92( m,1H),4.98(d,J=3.2Hz,1H),4.31(s,1H),3.68-3.63(m,3H),3.47-3.41(m,1H),2.51(s,3H),1.93-1.79(m,2H).

Example 62 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-chlorothiophene-2-carboxamide)-6-(3- Hydroxypyrrolidin-1-yl) nicotinamide (Compound 62)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-chlorothiophene-5-carboxylic acid to finally obtain 79.0 mg of the product with a yield of 29.1%. LC-MS (ESI): m/z=543.04[M+H] ⁺ ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.29 (s, 1H), 10.19 (s, 1H), 8.71 (d, J = 2.2Hz, 1H), 7.98 (d, J = 2.3Hz, 1H), 7.89-7.86 (m, 2H), 7.85(d,J＝4.2Hz,1H),7.35(d,J＝8.7Hz,2H),7.31(d,J＝4.1Hz,1H),4.99(d,J＝3.2Hz,1H),4.32(s,1H),3.76-3.60(m,3H),3.48-3.41(m,1H),1.92-1.8 1(m,2H).

Example 63 Preparation of (R)-5-(4-bromothiophene-2-carboxamido)-N-(4-(chlorodifluoromethoxy)phenyl)-6- (3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 63)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 4-bromothiophene-2-carboxylic acid to finally prepare Compound 63. LC-MS (ESI): m/z=586.98 [M+H] ⁺ .

Example 64 Preparation of (R)-5-(5-bromothiophene-2-carboxamido)-N-(4-(chlorodifluoromethoxy)phenyl)-6- (3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 64)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-bromo-2-carboxythiophene to finally obtain 54.0 mg of the product with a yield of 18.4%. LC-MS(ESI):m/z＝586.99[M+H] ⁺ ； ¹ H-NMR(400MHz,DMSO-d ₆ )δ10.27(s,1H),10.19(s,1H),8.71(d,J＝2.3Hz,1H),7.98(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.80(d,J＝4.0Hz,1H),7.40(d,J＝4.0Hz,1H),7.37-7.32(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.73-3.62(m,3H),3.46-3.42(m,1H),1.92-1.80(m,2H)。

Example 65 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)thiazole-2-carboxamide (Compound 65)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with thiazole-2-carboxylic acid to finally obtain 79.0 mg of the product with a yield of 31.0%. LC-MS (ESI): m/z＝510.08[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.64 (s, 1H), 10.19 (s, 1H), 8.72 (d, J = 2.3Hz, 1H), 8.15 (q, J = 3.1Hz, 2H), 7.99 (d, J = 2.3Hz, 1H ),7.92-7.84(m,2H),7.39-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.66(m,3H),3.49-3.42(m,1H),1.95-1.78(m,2H).

Example 66 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (alkyl-1-yl)pyridin-3-yl)-2-methylthiazole-5-carboxamide (Compound 66)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-methylthiazole-5-carboxylic acid to finally prepare Compound 66. LC-MS (ESI): m/z=524.09 [M+H] ⁺ .

Example 67 Preparation of (R)-2-bromo-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxy 1-(2-(2-pyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (Compound 67)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-bromo-4-thiazolecarboxylic acid to finally obtain 74.0 mg of the product with a yield of 25.2%. LC-MS (ESI): m/z=587.98[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.31 (s, 1H), 10.18 (s, 1H), 8.70 (d, J = 2.3Hz, 1H), 8.46 (s, 1H), 7.93 (d, J = 2.2Hz, 1H), 7.91- 7.86(m,2H),7.39-7.29(m,2H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.73-3.60(m,3H),3.45-3.41(m,1H),1.95-1.77(m,2H).

Example 68 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrolidin- 1-yl)pyridin -3-yl)isoxazole-5-carboxamide (Compound 68)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with isoxazole-5-carboxylic acid to finally obtain 53.0 mg of the product with a yield of 21.5%. LC-MS (ESI): m/z＝494.11[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.70 (s, 1H), 10.20 (s, 1H), 8.86 (d, J = 1.9Hz, 1H), 8.73 (d, J = 2.3Hz, 1H), 8.00 (d, J = 2.2Hz, 1H ),7.93-7.83(m,2H),7.35-7.31(m,1.0Hz,2H),7.27(d,J＝2.0Hz,1H),4.99 (d,J＝3.3Hz,1H),4.32(s,1H),3.66-3.61(m,3H),3.46-3.41(m,1H),1.97-1 .79(m,2H).

Example 69 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H- Pyrazole-4-carboxamide) nicotinamide (Compound 69)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 1H-pyrazole-4-carboxylic acid to finally prepare Compound 69. LC-MS (ESI): m/z=493.12 [M+H] ⁺ .

Example 70 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H- Pyrazole-3-carboxamide) nicotinamide (Compound 70)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with pyrazole-3-carboxylic acid to finally prepare Compound 70. LC-MS (ESI): m/z=493.12 [M+H] ⁺ .

Example 71 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1- Methyl-1H-pyrazole-4-carboxamido)nicotinamide (Compound 71)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 1-methylpyrazole-4-carboxylic acid to finally prepare Compound 71. LC-MS (ESI): m/z=507.14 [M+H] ⁺ .

Example 72 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1- Methyl-1H-imidazole-4-carboxamido)nicotinamide (Compound 72)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 1-methyl-4-imidazolecarboxylic acid to finally prepare Compound 72. LC-MS (ESI): m/z=507.13 [M+H] ⁺ .

Example 73 Preparation of (R)-5-(Benzo[b]thiophene-2-carboxamido)-N-(4-(chlorodifluoromethoxy)phenyl)- 6-(3-Hydroxypyrrolidin-1-yl)nicotinamide (Compound 73)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with benzothiophene-2-carboxylic acid to finally obtain 67.0 mg of the product with a yield of 24.0%. LC-MS (ESI): m/z=559.09 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.48(s,1H),10.22(s,1H),8.74(d,J＝2.3Hz,1H),8.30(s,1H),8.12-8.06(m,1H),8.04(s,1H),8.02(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.55-7 .45(m,2H),7.39-7.28(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.78-3.65(m,J＝4.1Hz,3H),3.51-3.45(m,1H),2.00-1.74(m,2H).

Example 74 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (4-(2 ...

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-indolecarboxylic acid to finally obtain 78.0 mg of the product with a yield of 28.8%. LC-MS (ESI): m/z=542.12 [M+H] ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ )δ11.77(s,1H),10.22(s,1H),10.17(s,1H),8.73(d,J＝2.3Hz,1H),8.03(d,J＝2.2Hz,1H),7.94-7.85(m,2H),7.68(d,J＝8.0Hz,1H),7.47-7.42(m,1H ),7.37-7.34(m,3H),7.23-7.19(m,1H),7.08-7.05(m,1H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.50-3.45(m,1H),1.90-1.80( m,2H).

Example 75 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (4-(2 ...

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with indazole-3-carboxylic acid to finally obtain 46.0 mg of the product with a yield of 16.9%. LC-MS (ESI): m/z=543.13 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ13.79(s,1H),10.20(d,J＝5.5Hz,2H),8.71(d,J＝2.3Hz,1H),8.19(m,1H),8.03(d,J＝2.3Hz,1H),7.92-7.88(m,2H),7.68-7.62(m,1H),7.46-7.42( m,1H),7.37-7.32(m,2H),7.29-7.26(m,1H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.74-3.71(m,3H),3.58-3.48(m,1H),1.94-1.77(m,2H).

Example 76 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole alkyl-1-yl)pyridin-3-yl)-1H-benzo[d]imidazole-2-carboxamide (Compound 76)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 1H-benzimidazole-2-carboxylic acid to finally obtain 37.0 mg of the product with a yield of 13.6%. LC-MS (ESI): m/z=543.13 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ13.46(s,1H),10.78(s,1H),10.21(s,1H),8.73(d,J＝2.2Hz,1H),8.01(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.82(d,J＝7.8Hz,1H),7.59(d,J＝7.8Hz, 1H),7.38-7.32(m,4H),4.95(d,J＝3.4Hz,1H),4.29(s,1H),3.75-3.69(m,3H),3.51-3.46(m,1H),1.92-1.78(m,2H).

Example 77 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-hydroxynicotinamide)-6-(3-hydroxypyrrolidone (1-Pyridin-1-yl)nicotinamide (Compound 77)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-hydroxynicotinic acid to finally prepare Compound 77. LC-MS (ESI): m/z=520.12 [M+H] ⁺ .

Example 78 Preparation of (R)-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxypyrrole (4-(2-((4-( ...

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 5-fluoro-2-pyridinecarboxylic acid to finally obtain 57.0 mg of the product with a yield of 21.8%. LC-MS (ESI): m/z=522.11[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ10.53 (s, 1H), 10.19 (s, 1H), 8.76 (d, J = 2.8Hz, 1H), 8.70 (d, J = 2.2Hz, 1H), 8.22-8.20 (m, 1H), 8.01-8.98(m,2H),7.91-7.86(m,2H),7.34(d,J＝8.8Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.65(m,3H),3.46-3.42(m,1H),1.96-1.74(m, 2H).

Example 79 Preparation of (R)-4-chloro-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxy (4-(2-(2-pyrrolidin-1-yl)pyridin-3-yl)pyridinecarboxamide (Compound 79)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 4-chloro-2-pyridinecarboxylic acid to finally obtain 88.0 mg of the product with a yield of 32.7%. LC-MS (ESI): m/z=538.08 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.65(s,1H),10.20(s,1H),8.75-8.71(m,1H),8.71(d,J＝2.3Hz,1H),8.14-8.11(m,1H),8.00(d,J＝2.3Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1 .3Hz,2H),7.34-7.31(m,2H),4.94(d,J=3.3Hz,1H),4.28(s,1H),3.68-3.62(m,3H),3.47(s,1H),1.93-1.77(m,2H).

Example 80 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-chloroisonicotinamide)-6-(3-hydroxypyrrolidone (1-Pyridin-1-yl)nicotinamide (Compound 80)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 2-chloroisonicotinic acid to finally obtain 93.0 mg of the product with a yield of 34.6%. LC-MS (ESI): m/z=538.07 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.56(s,1H),10.22(s,1H),8.74(d,J＝2.2Hz,1H),8.67-8.65(m,1H),8.02-8.00(m,1H),7.99(d,J＝2.3Hz,1H),7.92-7.90(m,1H),7.90-7.86(m, 2H),7.39-7.28(m,3H),4.97(d,J＝3.2Hz,1H),4.31(s,1H),3.65-3.62(m,3H),3.44-3.41(m,1H),1.92-1.80(m,2H).

Example 81 Preparation of (R)-3-chloro-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxy (4-(2-(2-pyrrolidin-1-yl)pyridin-3-yl)pyridineamide (Compound 81)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 3-chloro-2-pyridinecarboxylic acid to finally obtain 48.0 mg of the product with a yield of 17.8%. LC-MS (ESI): m/z=538.08 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ )δ10.41(s,1H),10.27(s,1H),8.72(d,J＝2.3Hz,1H),8.66-8.63(m,1H),8.13-8.11(m,1H),7.96(d,J＝2.2Hz,1H),7.89(d,J＝9.1Hz,2H),7.64-7.61(m ,1H),7.35-7.32(m,2H),4.99(d,J＝3.3Hz,1H),4.34(s,1H),3.77-3.72(m,,3H),3.54-3.50(m,1H),1.97-1.82(m,2H).

Example 82 Preparation of (R)-6-bromo-N-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-hydroxy (4-(2-(2-pyrrolidin-1-yl)pyridin-3-yl)pyridinecarboxamide (Compound 82)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 6-bromo-2-pyridinecarboxylic acid to finally obtain 65.0 mg of the product with a yield of 22.4%. LC-MS (ESI): m/z=582.03[M+H] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 10.19 (s, 1H), 8.70 (d, J = 2.3Hz, 1H), 8.14-8.11 (m, 1H), 8.03-8.00 (m, 2H), 8. 00-7.93(m,1H),7.91-7.85(m,2H),7.34(m,2H),4.96(d,J=3.3Hz,1H),4.30(s,1H),3.74-3.64(m,3H),3.45-3.41(m,1H),1.95-1.79(m,2H).

Example 83 Preparation of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(6- Nicotinamide (Methylnicotinamide) Nicotinamide (Compound 83)

Referring to the method of Example 15, o-nitrobenzoic acid was replaced with 6-methylnicotinic acid to finally prepare Compound 83. LC-MS (ESI): m/z=518.13 [M+H] ⁺ .

Biological activity test

Example 84 In vitro tumor cell (K562, KBM5) antiproliferative activity experiment

1. The experiment was conducted using K562 and KBM5 human chronic myeloid leukemia cell lines, which were cultured in suspension in 1640+10% FBS (Gibco) complete medium at 37°C, 5% CO ₂ , and 95% humidity.

2. The following is the general experimental method: Take logarithmically growing K562 and KBM5 cells, centrifuge, obtain cell pellets, add fresh culture medium to resuspend, count with plate blue staining, dilute cells to appropriate concentration, take 50uL cells and plant them in 96-well plates, 3000 cells/well, and place the cell plates in a carbon dioxide incubator for overnight culture; prepare the mother solution of the compound to be tested, the DMSO mother solution of all compounds is 10mM, store at -80℃, and use in aliquots. According to the required working concentration, dilute the compound mother solution with culture medium to the appropriate concentration, take 50uL of the compound solution to be tested and add it to the cell wells, and set up three replicate wells for each compound to be tested; place the cell plate in a carbon dioxide incubator and continue to culture for 3 days.

3. End point plate reading: Add 10uL Cell Counting Kit-8 reagent to each well, incubate at room temperature for 2-4 hours, read the absorbance at 450nm using an ELISA reader, and calculate the cell growth inhibition efficiency.

4. Data processing

Data were analyzed using GraphPad Prism 9.0 software, and the dose-effect curve was obtained by nonlinear S-curve regression fitting, and the IC ₅₀ value was calculated from it. Cell viability (%) = {(OD test drug - OD culture solution control) / (OD cell control - OD culture solution control)} × 100%.

The results of the preliminary screening of the in vitro antiproliferative activity of cells in the examples are summarized in Table 2 below.

Table 2 Cytotoxicity of the compounds screened in the examples

As shown in Table 2, the experimental results show that the compounds of the present invention all have certain anti-tumor cell (K562/KBM5) proliferation activity. Among them, compounds 16, 33, 35 and 67 show significant anti-proliferation activity against K562 and KBM5. From the above examples, it can be seen that some compounds of the (hetero)arylamide class of the present invention can produce good anti-proliferation effects on human chronic myeloid leukemia cell lines K562 and KBM5, and can be used to prepare drugs for treating cancers such as chronic myeloid leukemia and acute myeloid leukemia.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

1. A compound represented by formula I: Or its pharmaceutically acceptable salts or stereoisomers, wherein: Y is selected from CH or N; R ₁ is independently selected from hydrogen, halogen, nitrile group, and hydroxyl group, and can be single, double or polysubstituted; R ₂ is selected from -CF ₂ -Y ₁ ; Y ₁ is selected from hydrogen, chlorine, fluorine, methyl, difluoromethyl and trifluoromethyl; Z is selected from chemical bonds, O and S(O) _0-2 ; Or -ZR ₂ together means -SF ₅ ; Het is pyrrolidinyl; wherein said pyrrolidinyl is substituted by 1 or more R _a groups; R _a is selected from hydrogen, hydroxyl, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, cyano and amino-carbonyl; Link is thiourea, R ₃ is selected from the following groups optionally substituted by one, two or three R: R _b is independently selected from hydrogen, acetyl, C _1-6 alkyl or C _1-6 haloalkyl; R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH ₂ , -NHC _1-3 alkyl, -N(C _{1 -3} alkyl) ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 Haloalkoxy; The halogen is F, Cl, or Br. 2. The compound according to claim 1, having formula (II): Or its pharmaceutically acceptable salts or stereoisomers, wherein: R ₁ is independently selected from hydrogen, halogen, nitrile group, and hydroxyl group, and can be single, double or polysubstituted; R _a is independently selected from hydrogen, hydroxyl, halogen, nitrile group, and carboxyl group, and can be single, double, or polysubstituted; Link is thiourea, _R3 is as claimed in claim 1. 3. The compound of claim 2, wherein: The R ₁ is independently selected from hydrogen and halogen; R _a is independently selected from hydrogen and hydroxyl; Link is thiourea, R _b is independently selected from hydrogen, acetyl, C _1-3 alkyl or C _1-3 haloalkyl. 4. The compound according to claim 1, having formula (III): Or its pharmaceutically acceptable salts or stereoisomers, wherein: R _a is independently selected from hydrogen and hydroxyl; Link is thiourea, R ₃ is selected from the following groups optionally substituted by one, two or three R: R _b is independently selected from hydrogen, acetyl or C _1-3 alkyl; R as claimed in claim 1. 5. The compound according to claim 4, characterized in that, The R _a is hydroxyl; Link is thiourea, R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH ₂ , -NHC _1-3 alkyl, -N(C _{1 -3} alkyl) ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 Haloalkoxy. 6. The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, said compound being selected from: 7. A pharmaceutical composition containing the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer thereof, and a pharmaceutically acceptable excipient. 8. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer thereof or the pharmaceutical composition of claim 7 for use in the treatment of a subject and/ Or application in drugs to prevent diseases caused by Bcr-Abl. 9. Application according to claim 8, wherein the disease caused by Bcr-Abl is a proliferative disease, which is selected from: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia, Myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases. 10. The use according to claim 8, wherein the disease caused by Bcr-Abl is metastatic invasive cancer, viral infection or CNS disorder.